Page 1 of 66 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460

OFFICE OF PREVENTION, PESTICIDES
AND TOXIC SUBSTANCES

Date: 11/21/07

MEMORANDUM

SUBJECT: 2,6-Dichlorobenzamide (BAM ) as a Metabolite/Degradate of Fluopicolide and

Dichlobenil. Human Health Risk Asse ssment for Proposed Uses of Fluopicolide on Tuberous and Corm Vegetabl es, Leafy Vegetables (except Brassica ), Fruiting Vegetables, Cucurbit Vegetables, Grapes, Tu rf, and Ornamentals, and for Indirect

or Inadvertent Residues on the Rota tional Crop Wheat. PC Codes: 027402 (BAM) and 027412 (Fluopicolide), Pe tition No: 5F7016, DP Number: 345918.

Regulatory Action: Se ction 3 Registration Action Risk Assessment Type: Multiple Chemicals/Aggregate

FROM: Nancy Dodd, Risk Assessor Amelia Acierto, Chemist Kelly O’Rourke, Biologist Myron Ottley, Toxicologist Registration Action Branch 3 Health Effects Division (7509P)

AND Robert Mitkus, Toxicologist Registration Action Branch 1 Health Effects Division (7509P)

THROUGH: Christine Olinger, Chemist Mary Elissa Reaves, Ph.D., Toxicologist

Risk Assessment Review Committee Health Effects Division (7509P)

AND Paula Deschamp, Branch Chief Registration Action Branch 3 Health Effects Division (7509P)

TO: Janet Whitehurst/Tony Kish, RM Team #22 Fungicide Branch Registration Division (7505P)Page 2 of 66 This human health risk asse ssment is for 2,6-dichlorobenzam ide (BAM) which is the common metabolite/degradate of dichlobenil and fluopicolide. This assessment summarizes the human health risks from exposure to BAM resulting from the use of dichl obenil and fluopicolide on agricultural commodities, turf, and ornamentals. The residue chemistry assessment was provided by Amelia Acierto (RAB3), the occupational and residential exposure assessment by Kelly O’Rourke (RAB3), the hazard characterization by Myron Ottley (RAB3) and Robert Mitkus (RAB1), and the dietary exposure assessment a nd risk assessment by Nancy Dodd (RAB3).Page 3 of 66 Table of Contents

1.0 Executive Summary

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

2.0 Ingredient Profile

............................................................................................................ 11 2.1 Summary of Registered/Proposed Uses................................................................ 11

2.2 Structure and Nomenclature ................................................................................. 12 2.3 Physical and Chemical Properties......................................................................... 12

3.0 Hazard Characterization/Assessment

........................................................................... 13 3.1 Hazard and Dose-Response Characterization....................................................... 13

3.1.1 Studies Considered in the Toxi city and Dose-Response Evaluation........ 13 3.1.2 Sufficiency of Studies/Data ...................................................................... 13 3.1.3 Mammalian Toxicology............................................................................... 13 3.2 Absorption, Distribution, Metabolism, Excretion................................................. 14 3.3 FQPA Considerations ........................................................................................... 15 3.3.1 Adequacy of the Toxicity Data Base ........................................................ 15 3.3.2 Developmental Toxicity Study (Rabbit)................................................... 15 3.3.3 Evidence of Neurotoxicity ........................................................................ 16

3.3.4 Additional Information from Literature Sources ...................................... 16 3.3.5 FQPA Safety Factor (SF) for Infants and Children .................................. 17 3.4 Hazard Identification and Toxicity Endpoint Selection........................................ 17 3.5 Classification of Carcinogenic Potential............................................................... 21 3.6 Endocrine disruption............................................................................................. 22

4.0 Public Health and Pesticide Epidemiology Data

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

5.0 Dietary Exposure/Risk Characterization

..................................................................... 22 5.1 Pesticide Metabolism and Environmental Degradation........................................ 22 5.1.1 Metabolism in Primary Crops................................................................... 23 5.1.2 Metabolism in Rotational Crops ............................................................... 24

5.1.3 Metabolism in Livestock........................................................................... 24 5.1.4 Analytical Methodology ........................................................................... 25 5.1.5 Environmental Degradation...................................................................... 26 5.1.6 Comparative Metabolic Profile................................................................. 26 5.1.7 Toxicity Profile of BAM........................................................................... 27

5.1.8 Pesticide Metabolites and Degradates of Concern.................................... 28 5.1.9 Drinking Water Residue Profile................................................................ 28

5.1.10 Food Residue Profile............................................................................... 32

5.1.11 International Residue Limits................................................................... 40 5.2. Dietary Exposure and Risk ................................................................................... 40 5.2.1 Acute Dietary Exposure/Risk ................................................................... 41 5.2.2 Chronic Dietary Exposure/Risk ................................................................ 41 5.2.3 Cancer Dietary Risk.................................................................................. 41 5.3. Anticipated Residue and Percent Crop Treated (%CT) Information.................... 42

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

............................ 43 6.1. Residential Handler Exposure............................................................................... 43 6.2. Residential Postapplication Exposure................................................................... 43 6.3. Other (Recreational Exposure; Spray Drift) ......................................................... 46

7.0 Aggregate Risk Assessments and Risk Characterization

............................................ 47Page 4 of 66 7.1 Acute Aggregate Risk........................................................................................... 47 7.2 Short-Term Aggregate Risk.................................................................................. 47 7.3 Intermediate-Term Aggregate Risk ...................................................................... 49 7.4 Long-Term Aggregate Risk .................................................................................. 49

8.0 Aggregate Risk Assessments and Risk Characterization

............................................ 49

9.0 Occupational Exposure/Risk Pathway

.......................................................................... 50 9.1 Short-/Intermediate-/Long-Term/C ancer (if needed) Handler Risk ..................... 50 9.2 Short-/Intermediate-/Long-Term/Cancer (if needed) Postapplication Risk ......... 50

10.0 Data Needs and Label Recommendations

.................................................................... 53 10.1 Toxicology ............................................................................................................ 53 10.2 Residue Chemistry................................................................................................ 53 10.3 Occupational and Residential Exposure ............................................................... 53

References:

............................................................................................................................... .... 53 Appendix A: Toxicity Profile Table a nd Executive Summaries/Published Abstracts

........ 54 Appendix B: Metabolism Assessment

...................................................................................... 64

B.1 Metabolism Guidance and Considerations ........................................................... 64

B.2 Chemical Names and Structures ........................................................................... 65 Appendix C: Tolerance Rea ssessment Summary and Table

................................................. 66 Appendix D: Review of Human Research

............................................................................... 66Page 5 of 66 1.0 Executive Summary

2,6-Dichlorobenzamide (BAM) is a metabolite a nd/or environmental degradate of both the fungicide fluopicolide and the herbicide dichlobenil. This human health risk assessment includes

residues of BAM from uses of both fluopicolide and dichlobenil; i.e

. , this human health risk assessment assesses BAM as a metabolite/degradate resulting from established/proposed uses of fluopicolide on tuberous and corm vegetables (ex cept potato), leafy vegetables (except

Brassica ), fruiting vegetables, cucurbit vegetabl es, grapes, turf, and ornamentals and from established/pending uses of dichlobenil . This assessment includes only BAM because there is no common toxicological effect fo r BAM and other fluopicolide residu es of concern. A separate human health risk assessment is being conducted concurrently for other fluopicolide residues of concern (DP #325091, N. Dodd, 11/21/07).

This memo does not address the proposed use of fluopicolide on potato or the proposed tolerances for the rotational crop wheat since the potato use will not be registered at this time and some label restrictions will be applie d to rotational crops at this time. Since tolerances on crops with associated livestock feed items (potato and wheat) will not be established at this time, livestock commodity tolerances are not needed at this time and

livestock issues are not discussed in this do cument. This risk assessment focused on the residues of BAM from both fluopicolide and di chlobenil. General information from the concurrent risk assessment for fluopicolide and th e latest risk assessment for dichlobenil is mentioned below; however, for more detail s refer to the specific risk assessment.

Use Profile: 2,6-Dichlorobenzamide (BAM; AE C653711) is a metabolite and/or environmental degradate of both fluopicolide and di chlobenil. As discussed in th e concurrent Fluopicolide Risk Assessment Document (DP #325091, N. Dodd, 11/21/ 07), BAM is a residue of concern for the risk assessment for drinking water and all plant and livestock matrices. Sources of BAM are

tabulated below:

Table 1.0 Sources of BAM Pesticide Food Water Residential OccupationalFluopicolide Ag Crop Uses Ag Crop/NonCrop Uses Postapplication

Adult Dermal

Postapplication

Child Dermal +

Incidental Oral Postapplication

Dermal

Dichlobenil Ag Crop Uses +

Tolerances with

no Domestic Registrations Ag Crop/Non Crop Uses No Significant Exposure Not assessed

because no significant

exposure was expected.

Fluopicolide:

Fluopicolide is a fungicide to be used on tubero us and corm vegetables (except potato), leafyPage 6 of 66 vegetables (except Brassica ), fruiting vegetables, cucurbit vegetables, grapes, turf, and

ornamentals. A maximum of four foliar applications are to be made to agricultural crops with a maximum seasonal application rate of 0.375 lb active ingredient/acr e (ai/A). The fungicide can be sprayed on turf (residential, commercial , golf course, and sod farms) with a maximum seasonal application rate of 0.54 lb ai/A. The maximum seasonal application rates on ornamental plants (landscapes, commercial greenhouses and nur series) are 0.54 lb ai/A for overhead sprays

and 27 lb ai/A for drench treatments.

HED is presently recommending for the followi ng tolerances for fluopicolide (parent):

Tolerances to be established for residues of the fungicide fluopicolide [2,6-dichloroN

-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]m ethyl] benzamide] as an indicator of combined residues of fluopicolide and its metabolite 2,6-dichlorobenamide, under “(a) General ”:

Grape*................................................................................................2.0 ppm Grape, raisin*................................................................................... 6.0 ppm Vegetable, cucurbit, group 9.......................................................... 0.50 ppm Vegetable, fruiting, group 8............................................................. 1.6 ppm Vegetable, leafy, except Brassica , group 4....................................... 25 ppm Vegetable, tuberous and corm, except potato, subgroup 1D ......... 0.02 ppm

* These tolerances have been established for imported grapes (40 CFR §180.627).

Tolerances have been established (40 CFR §180 .627) for residues of fluopicolide, 2,6-dichloroN

-[[3-chloro-5-(trifluoromethyl)-2 -pyridinyl]methyl] benzamide, on grape at 2.0 ppm and grape,
raisin at 6.0 ppm for use on imported crops. No livest ock tolerances have been established. No Codex, Canadian, or Mexican Ma ximum Residue Limits (MRLs) or tolerances have been established for fluopicolide.

Dichlobenil:

Dichlobenil is registered as a granular (G) formulation (C asoron® 4G; EPA Reg. No. 400-168; date of issuance: 5/18/05) for us e on apple, blueberry, cherry, filb ert, grape, and pear at 6 lb ai/A/season and on blackberry, cranbe rry, and raspberry at 4 lb ai/A /season. Dichlobenil is also used on roses and woody ornamentals (surrounding soil/mulch at rates up to 8 lb ai/A and on nutsedge at 10 lb ai/A. A registration for Casor on® 4G for use on rhubarb at 2 lb ai/A/season is pending (DP Number 315266, W. Cutchin, 2/22/06).

Tolerances are established (40 CFR § 180.231) for the herbicide dichlobenil (2,6- dichlorobenzonitrile) and its metabolite 2,6-dichlorobenzamide as follows. A tolerance for rhubarb is pending.Page 7 of 66 Tolerances established (40 CFR §180.231) for the combined residues of the herbicide dichlobenil (2,6-dichloro benzonitrile) and its metabolite 2,6-

dichlorobenzamide

Apple........................................................................ 0.5 ppm Blackberry................................................................ 0.1 ppm Blueberry................................................................ 0.15 ppm Cranberry ................................................................. 0.1 ppm Filbert....................................................................... 0.1 ppm Fruit, stone, group 12............................................. 0.15 ppm Grape...................................................................... 0.15 ppm Pear .......................................................................... 0.5 ppm Raspberry ................................................................. 0.1 ppm

Tolerance pending for the combined residues of the herbicide dichlobenil (2,6-dichlorobenzonitrile) and its metabolite 2,6-dichlorobenzamide

Rhubarb.................................................................. 0.06 ppm

The revised RED (7/31/96) recommended deletion of a stone fruit crop group tolerance which was not being supported by the petiti oner and establishment of a separate tolerance on cherries. However, as stated in the previous RED, the stone fruit crop group was in cluded in this dietary exposure assessment since as long as the tolerance exists commodities containing BAM residues could be imported (Kathryn Boyle, 07/31/96, DP Number D000000: Dich lobenil: The Revised HED Chapter of the Reregistration Eligibility Decision Document (RED), Case 0263, Chemical 027401, 027402 (BAM).

Human Health Risk Assessment for BAM:

Toxicity/Hazard: Appropriate endpoints were iden tified for acute dietary, chronic dietary, incidental oral, derm al, and inhalation exposures:

The acute dietary (females 13-49) NOA EL is 30 mg/kg/day. The LOAEL is 90 mg/kg/day based on a developmen tal toxicity (rabbit) study.

The acute dietary (general population, including infants and children) LOAEL is 100 mg/kg/day from a single oral dose in the in vivo mouse erythrocyte micronucleus assay.

A NOAEL was not established.

The chronic dietary NOAEL is 4.5 mg/kg/day, based on a chroni c toxicity (dog) study.

The inhalation (short-, intermediate-, and long-term) NOAEL is 3.1 mg/kg/day based on a 28-day inhalation study using dichlobenil.

The estimated dermal short-/intermediate-t erm exposures were compared to the NOAEL of 25 mg/kg/day from a dermal toxicity study in the mouse (using dichlobenil) in whichPage 8 of 66 olfactory epithelial damage was observed at the LOAEL of 50 mg/kg/day. Because this endpoint is from a dermal study, the estimated dermal exposures did not need to be adjusted for dermal absorption.

Short-/intermediate-term incide ntal oral exposures (for todd lers) were compared to the NOAEL of 14 mg/kg/day from a 90-day or al toxicity study in the rat.

The 10X FQPA Safety Factor has been retained for acute dietary, chronic dietary, and incidental oral exposures. This is due to the incompleteness of the database with regard to the systemic neurotoxic potential of BAM, including olfactory toxicity. Th e 10X FQPA Safety Factor is reduced to 1X for dermal and inhalation exposur es because higher doses of BAM are needed to induce levels of olfactory toxic ity that are similar to those ca used by dichlobenil and olfactory toxicity was the endpoint chosen for these exposur e scenarios. Since olfa ctory toxicity was the most sensitive endpoint, further protecti on under FQPA is not deemed necessary.

Relating to the carcinogenic poten tial of BAM, to be conservative, EPA has assumed that BAM’s potential for carcinogenicity is similar to the parent having the greatest carcinogenic potential, i.e., dichlobenil. (The parent fungicide fluopicolide is “not likely to be carcinogenic to humans.”) Dichlobenil is classified as “G roup C, possible human carcinogen” with the RfD approach utilized for quantification of human risk.

Dietary Exposure (Food and Drinking Water): The dietary analyses were performed on BAM to support Section 3 requests for use of parent fluopicolide on tuberous and corm vegetables (except potato), leafy vegetables (except Brassica ), fruiting vegetables, cucurbit vegetables, grapes, turf, and ornamentals. Th e dietary exposure assessment was conducted for residues of BAM in food and drinking water from uses of fluopicolide and dichlobenil since BAM is a metabolite/degradate of both pesticides. Considering uses of fluopicolide, dichlobenil, and both pesticides (on grapes and rhubarb, the only crops on which both pesticides will be registered), the highest drinking water residue estimate (56.2 ppb) was from SciGrow modeling

of BAM residues from dichlobeni l use on nutsedge at 10 lb ai/A.

The acute dietary (food and drinki ng water) exposure to BAM from fluopicolide and dichlobenil

uses is below HED’s level of concern for the general U.S. popul ation and all population subgroups. The acute dietary exposure estimates at the 99.9 th percentile of the exposure

distribution are 11% of the acu te Population Adjusted Dose (aPAD) for the general U.S. population and 28% aPAD for all infants (<1 ye ar old), the most highly exposed group.

The chronic dietary (food and drinking wate r) exposure to BAM from fluopicolide and

dichlobenil uses is below HED’ s level of concern for the ge neral U.S. population and all population subgroups. The chronic dietary expos ure estimates are 29% chronic Population Adjusted Dose (cPAD) for the general U.S. population and 93% cPAD for all infants (<1 year old), the most highly exposed group which is of concern to HED.

As noted above, EPA has assumed that BAM’s potentia l for carcinogenicity is similar to that of dichlobenil, which is classified as “Group C, possible human carcinogen” with the RfD approach utilized for quantification of human risk. The quantification of cancer risk using the RfDPage 9 of 66 approach is identical to the assessment for ch ronic effects; no sepa rate carcinogenic risk assessment is necessary.

Residential Exposure: As mentioned previously, BAM is known to be a metabolite of fluopicolide and dichlobenil. While it is necessa ry to evaluate residential exposure from all sources of BAM, the use pattern for dichlobenil is not expected to result in scenarios with significant residential/non-occupa tional exposure. Therefore, BAM exposure estimates are based on fluopicolide use only.

Residential handler exposure is not anticipated because th e metabolite BAM is believed to form slowly in plants and soil after the product cont aining the parent (fluopicolide) has been applied.

Residential postapplication exposure via the dermal route is likely for adults and children entering treated lawns. Toddlers may also e xperience exposure via in cidental non-dietary ingestion [i.e., hand-to-mouth, object-to-mouth (turfgrass), and soil ingestion] during postapplication activities on treated turf.

Exposure and risk estimates for residential expos ure scenarios are typically assessed for the day of application (“Day 0”) because it is assumed that adults and toddlers could contact the lawn immediately after application. However, BAM is a metabolite/degradate which forms slowly; therefore, the scenarios were assessed assuming th at BAM is present at le vels which reflect highend measurements observed in the longer-term metabolism studies in order to provide a protective assessment. The short-/intermediate-te rm dermal MOEs for adults and children are 10,000 and 6,000, respectively , and the combined incidental oral MOE for toddlers is 62,000. These MOEs are greater than the LOC of 100 for dermal exposure and 1,000 for incidental oral exposure, on the day of application, and therefore, are not of concern.

Aggregate Risk: In examining acute aggregate risk , HED has assumed that the only pathway of exposure relevant to the acute time frame is dietary exposure ( i.e ., any non-dietary exposures are short- and/or intermediate-term in dur ation). Therefore, the acute aggregate risk is composed of exposures to BAM residues in food and drinking water from uses of fluopicolide and dichlobenil and is equivalent to the acute di etary risk. The acute dietary exposure estimates

at the 99.9 th percentile of the exposure distribution are 11% of the acute Population Adjusted Dose (aPAD) for the general U.S. population and 28% of the aPAD for all infants (<1 year old), the most highly exposed group. The acute risk es timates are well below HED’s level of concern for the general U.S. population and all population subgroups.

The short-term aggregate risk combines dietary (food and dri nking water) exposures of BAM from both fluopicolide and dichlobenil uses a nd incidental oral e xposures of BAM from fluopicolide. (Based on the dichlobenil use pa ttern, no significant residential exposure is expected to occur from dichl obenil.) Short-term exposures (1 to 30 days of continuous exposure) may occur as a result of activities on treated turf. Dermal exposures were not aggregated with oral exposures be cause of different toxicity. Inci dental oral exposures related to turf activities (Table 6.2.5) have been combined with chronic di etary exposure estimates (as an estimate of background dietary exposure; Table 5.2.2) to assess short-term aggregate exposure. Since aggregate MOEs are greater than 1000, they represent risk estimates that are below HED’s

level of concern.Page 10 of 66 The intermediate-term aggregate risk is the same as described above for the short-term aggregate risk; the intermediate-term aggregate risk is below HED’s level of concern for the U.S. population and all popula tion subgroups.

In examining long-term aggregate risk , HED has assumed that the only pathway of exposure

relevant to that time fr ame is dietary exposure ( i.e ., any non-dietary exposures are short- and/or intermediate-term in duration). Therefore, th e long-term aggregate ri sk is composed of exposures to BAM residues in f ood and drinking water from uses of fluopicolide and dichlobenil and is equivalent to the chroni c dietary risk. The chronic risk estimates are below HED’s level of concern for the general U.S. population and all population subgroups.

With respect to cancer risk , the quantification of cancer risk for BAM using the RfD approach is identical to the assessment for chronic effects; no separate carcinoge nic risk assessment is

necessary.

Occupational Exposure/Risk: Occupational handler exposure was not evaluated

because the metabolite BAM is be lieved to form slowly in pl ants and soil after the product containing the parent (fluopi colide) has been applied.

Occupational postapplication exposure to BAM may occur after application of fluopicolide to agricultural crops as well as tu rf and ornamentals. (BAM whic h may occur after application of dichlobenil is not included since no significan t exposure to BAM from dichlobenil was expected.) Postapplication inha lation exposure after applicati on of fluopicolide and dichlobenil is expected to be negligible; however, dermal exposure to the metabolite BAM after application of fluopicolide is possible for workers enteri ng treated areas to tend or harvest crops, mow/maintain turfgrass, or tend orna mentals in nurseries and greenhouses.

The results of the occupational postapplication 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 on the day of application, and therefore, are not of concern.

The parent fluopicolide technical material has been classified in Toxicity Category IV for acute dermal and primary skin irritati on, and in Category III for primar y eye irritation. Per the Worker Protection Standard (WPS), a 12-hr restricted entry interval (R EI) is required for chemicals classified under Toxicity Category III/IV. The proposed fluopicolide labels indicate an REI of 12 hrs, which is in compliance with the WPS fo r uses that reach an MOE of 100 on the day of application. Fluopicolide is also intended for non-agricultural use sites (e.g., golf course) to which the WPS does not apply; the labels approp riately contain language cautioning unprotected persons to keep out of treated areas until sprays have dried.Page 11 of 66 Environmental Justice Considerations:

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance wi th U.S. Executive Order 12898, "Federal Actions

to Address Environmental Jus tice in Minority Populations an d Low-Income Populations," http://www.eh.doe.gov/oepa/ guidance/justice/eo12898.pdf ).

As a part of every pesticide risk assessment , OPP considers a large variety of consumer subgroups according to well-establis hed procedures. In line with O PP policy (as it relates to an imported crop), HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food consum ption. Extensive data on food consumption patterns are compiled by the USDA under the Conti nuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all proposed/registered food uses/tolerances of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, special ized subgroups and exposure assessments are performed when conditions or ci rcumstances warrant. Further c onsiderations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure fr om traditional dietary patterns among specific subgroups.

Review of Human Research :

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies (listed in Appendix D) have been determined to require a revi ew of their ethical conduct. They are also subject to review by

the Human Studies Review Board. The listed st udies have received the appropriate review.

2.0 Ingredient Profile

2.1 Summary of Registered/Proposed Uses

Fluopicolide is a fungicide to be used on tubero us and corm vegetables (except potato), leafy vegetables (except Brassica ), fruiting vegetables, cucurbit vegetables, grapes, turf, and ornamentals. Four foliar applications are to be made to cucurbit vegeta bles (except potato), fruiting vegetables, grapes, and leafy vegetables at the maximum seasona l application rate of 0.34-0.375 lb active ingredient/acre (ai/A). Fo r agricultural plants, minimum retreatment intervals of 7-14 days and a preharvest interval of 2-21 days are to be observed. The proposed application rates on turf (residen tial, commercial, golf course, and sod farms) range from 0.21 to 0.27 lb ai/A, at 14-day intervals. The propos ed application rates on ornamental plants (landscapes, commercial greenhouses and nurseries ) range from 0.21 to 0.54 lb ai/A for overhead sprays and from 5.3 to 27 lb ai/A for drench tr eatments, at 14-day interv als. (Refer to the concurrent Fluopicolide Risk Assessment Document (DP #325091, N. Dodd, 11/21/07) for detailed used directions for fluopicolide).

Dichlobenil is registered as a granular (G) formulation (C asoron® 4G; EPA Reg. No. 400-168; date of issuance: 5/18/05) for us e on apple, blueberry, cherry, filb ert, grape, and pear at 6 lbPage 12 of 66 ai/A/season and on blackberry, cranbe rry, and raspberry at 4 lb a i/A/season. A registration for

Casoron® 4G for use on rhubarb at 2 lb ai/A/season is pending (DP Number 315266, W. Cutchin, 2/22/06).

There are no registered uses for BAM itself.

2.2 Structure and Nomenclature

Table 2.2. BAM Nomenclature

Chemical Structure Cl

Cl N H

2

O

Empirical Formula C 7 H 5 Cl 2 N 1 O 1 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

2.3 Physical and Chemical Properties

Table 2.3. Physiochemical Properties

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 3.26 x 10 -5 mm Hg Product Chemistry (HSDB, 2002)

Dissociation constant, pKa Not available
Octanol/water partition coefficient, logP OW (25°C) K

ow = 30 mL/g** HSDB, 2002

UV/visible absorption spectrum Not available

* DP #340773, J. Angier, Ph.D., 8/29/07 and DP #325804, J. Lin, 5/3/07 ** The octanol/water partition coefficient (K

ow ) is defined as the ratio of the molar concentrations of a chemical in n-octanol and water, in dilute solution.Page 13 of 66 3.0 Hazard Characterization/Assessment

3.1 Hazard and Dose-Response Characterization

3.1.1 Studies Considered in the Toxici ty and Dose-Response Evaluation

Data from the following studies were used to evaluate the haza rd potential of BAM:

• Acute (for olfactory toxicity): one intraperitoneal (single do se) olfactory toxicity study (mouse)

• Subchronic: One oral (rat) toxicity study

• Chronic: One oral toxicity (dog) study and one combined oral toxicity/carcinogenicity (rat) study

• Reproduction/developmental: One developmental (ra bbit) toxicity study

• Other: Three genotoxicity screens ( in vivo/in vitro )

3.1.2 Sufficiency of Studies/Data

The available submitted acute and chronic studies were sufficient to evaluate human hazard potential, and data qualit y is acceptable.

3.1.3 Mammalian Toxicology

The major dichlobenil soil metabolite a nd minor fluopicolide foliar metabolite, 2,6- dichlorobenzamide (BAM), demonstrated moderate acute toxicity (Category III) via the oral route of exposure (Table 3.1a). Because the subchronic and chronic toxicity of BAM is considered less than or equal to that of dich lobenil (parent herbicide) based on submitted and published toxicity studies

, the acute toxicity of BAM via th e inhalation and dermal routes is expected to be less than or equa l to that of dichlobenil. Th e acute toxicity of BAM via the inhalation and dermal routes is expected to be mo re than or equal to the toxicity of fluopicolide.

A summary of the subchronic and chronic toxicity and genotoxici ty databases for BAM is found

in Table 3.1b. In the subchronic and chronic oral toxicity studies in the rat and dog, respectively, body weight change was the toxico logical effect most often obser ved at the LOAEL. In the combined chronic toxicity/carcinog enicity study in the rat, toxico logically significant changes in body weight were also observed at the LOAEL, as we re eosinophilic foci in the liver. In general,

adverse liver effects were observed in the subm itted studies at doses of BAM that were higher than those of dichlobenil (parent).

While BAM is formally unclassified with respect to human cancer risk, the available data do not suggest a cancer concern higher than that for dich lobenil. BAM is not mu tagenic or clastogenic in submitted genotoxicity studies and there is no evidence of carcinogenicity in the 2-year combined chronic toxicity/carcinogenicity study of BAM in rats. Alt hough an increase in incidence of liver heptatocellu lar adenomas in female rats was reported at the highest dose tested, the statistical signif icance was considered marginal (p = 0.049) and there was no progression to liver hepato cellular carcinomas. BAM is not yet classified for cancer risk becausePage 14 of 66 it was tested in only one species. Since the carc inogenic potential of BAM has been evaluated in only one species, BAM is assumed to have the eq uivalent carcinogenic potential as the parent compound dichlobenil, which is classified as a possible human carcinogen. An RfD approach was used to quantify the potential human cancer risk. The point of departure chosen for

derivation of the RfD for dichlobe nil is also assumed to be prot ective of both liver toxicity and the potential tumorigenicity for BAM, especially considering that BAM is not genotoxic and the

adverse liver effects observed in the submitted to xicity studies for BAM were at higher doses than those reported for dichlobenil.

There was no evidence of increased susceptibility to offspring following pre-natal exposure to rabbits in a developmental toxicity study with BAM.

BAM-mediated olfactory toxicity was observed in one study collected from the open literature (Brittebo et al. 1991). Alt hough olfactory epithelial necros is was observed after i.p. administration of BAM, the dose (100 mg/kg) was eight times higher than that which caused the same effect using dichlobenil in two other studies, i.e., 12 mg /kg i.p. (Brandt et al. 1990; Eriksson and Brittebo 1995). Based on this study a nd in the absence of studies via other routes of exposure, BAM-mediated olfactory toxicity is considered by HED to be less than that of dichlobenil (parent herbicide).

In addition to toxicity to the olfactory sensor y neurons that was obser ved following a single i.p. exposure of mice to BAM (Brittebo et al. 1991), clinical signs of neurotoxic ity were observed in several submitted studies. In the 90-day oral to xicity study in rats, reduced muscle tone was observed with increasing dose. Lethargy and ataxia were observed in mice tested orally in a pilot (dose-range finding) study for the in vivo erythrocyte micronucleus assay. The effects were

resolved after 24 hours. In addition, in a two-week dietary study recently submitted, but not fully reviewed by the Agency (MRID 46892401), clinic al signs of toxicity (slightly decreased muscle tone, slight loss of pinnae reflexes) we re observed in mice at 2500 ppm (approximately equal to 375 mg/kg/day).

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)

In a series of disposition studies (MRIDs 46708633, 46708634, and 46708635), radiolabeled BAM suspended in aqueous 0.75% methyl cellulose was administered by oral gavage to three groups of Sprague Dawley rats/sex. Two groups of four rats/sex were given a single dose of [ 14 C]-AE C653711 at nominal dose levels of 10 or 150 mg/kg. A third group of five rats/sex was given 14 daily doses of [ 14 C]-AE C653711 at a nominal dose level of 10 mg/kg. The recovery of radioactivity over six days (sev en days for the single high dose group) was determined, and the

concentrations of radi oactivity in tissues and excreta were determined. Metabolites were identified and quantified in the urine and feces.

The majority of the radioactivity was recovered in the urine. Abso rption and excretion of the test compound was relatively rapid. The minimum levels of absorption were estimated from the total recovery of radioactivity in urine, cage washes, and tissues to be at least 77.7-85.9% of the administered dose, indicating high oral bioavailability. Excretion of radioactivity in the urine and feces was mostly complete by 48 (single low dose study) to 72 (single high dose and repeat low dose studies) hours post-dosing. The tissues (including the re sidual carcass) accounted forPage 15 of 66 <2.3% of the administered dose 144 or 168 h post-dos ing. In general, the highest concentrations of radioactivity were detected in the kidneys, liver, Harderian gla nd, skin (and fur), and adrenals. Measurement of radioactivity in th e nasal tissues was not performed.

The test compound was extensively metabolized to at least 14 compounds. The majority of radioactivity in urine and fecal extract sample s was present as parent and a mercapturic acid conjugate of hydroxyl-chlorobenzamide. Metabo lic profiles were qualitatively similar across dose levels, multiple doses had no appreciable effect on metabolism, and generally no

differences were noted between sexes. In ex creta, parent and identified compounds accounted

for 50.3-78.6% of the administered dose. Unid entified metabolites accounted for 8.2-14.6% of the administered dose, but each compound represente d <5% of the administered dose. The total administered dose accounted for in the analyzed excreta was 64.4-90.2%.

Parent compound accounted for 13.0-24.6% of the to tal radioactivity elim inated, and was found in both urine and fecal extracts. The majority of the radioactivity was associated with a mercapturic acid conjugate of hydroxyl-chlorobenzamide (15-5-26.2 %) that was present in the urine. Other metabolites presen t at >5% of the administered do se were identified and included the cysteine and O -glucuronide conjugates of chlor obenzamide (3.4-6.6%), the cysteine conjugate of hydroxyl-chlorobenzamide (1.9-12.4%), the O -sulfate conjugate of dichlorobenzamide/thiomethyl-chlorobenzamid e (5.4-13.8%), and 3-hydroxy-chlorobenzamide (2.7-7.3%; detected in the high dose study only).

3.3 FQPA Considerations

3.3.1 Adequacy of the Toxicity Data Base

The toxicology database used to assess pre- and/or post-natal e xposure to the soil metabolite, BAM, is incomplete; however, since BAM is a soil metabolite of dichlobenil and a plant metabolite of fluopicolide, additional studies ar e not required at this time. The following acceptable study is available:

• One developmental toxicity study in rabbits

3.3.2 Developmental Toxicity Study (Rabbit)

In an Acceptable/Guideline, prenatal developmental toxicity study (MRID 43003601, 43265201), 2,6-dichlorobenzamide (dichloben il soil metabolite) ( 99.4% a.i.; batch# FUX001000) was administered by gavage in 1% gum tragacanth to 16 pregnant New Zealand white rabbits/sex/dose from gest ation day (GD) 7-19 inclusive at daily dose levels of 0, 10, 30, or 90 mg/kg/day. Five (of 16) females tr eated at 90 mg/kg/day were sacrificed in extremis

. Three of the 5 sacrificed high-dose dams had late abortions (GD 19, 21, and 22, respectively). The incidence of abortion followed by sacrifi ce at 0, 10, and 30 mg/kg/day was 1/16, 1/16, and 0/16, respectively. The other 2/5 high-dose animals were sacrificed moribund. Moribund condition followed by sacrifice was observed in 1/16, 0/16, and 2/16 animals at 0, 10, and 30 mg/kg/day, respectively. The incidence of thin appearance was increased at 90 mg/kg/dayPage 16 of 66 (10/16), whereas the incidences at 0, 10, and 30 mg/kg/day were 1/16, 0/16, and 2/16, respectively.

A decrease (129%) in mean body weight gain, re lative to controls, wa s observed during the dosing period (GD 7-19) in does treated at 90 mg/kg/day. Similarly, food consumption at 90 mg/kg/day was decreased during the dosing period by 49%, relative to controls. Body weight gain and food consumption in high-dose animal s rebounded above control levels during the postdosing period (GD 20-28). No treatmen t-related gross pathology was observed. The maternal LOAEL is 90 mg/kg bw/day, based on increased in cidences of clinical si gns (late abortion, thin appearance) and decreased (sev ere) body weight gain and food consumption during dosing. The maternal NOAEL is 30 mg/kg bw/day.

No treatment-related effects were observed on se veral developmental endpoints, including the number of resorptions, post-implantation loss, litt er size, and sex ratio. Mean fetal body weight at 90 mg/kg bw/day (33.9 g) was decr eased by 6%, relative to controls; however, the change was not statistically si gnificant and the mean value fell with in the historical control range (27.7 g39.4 g). No treatment-related cha nges were observed on the incidences of external defects.

An increase in the incidence of bipartite interparietal bone wa s observed at 90 mg/kg bw/day. Litter incidences were 1/14, 1/15, 2/14, and 3/11 l itters at 0, 10, 30, and 90 mg/kg/day. (Bipartite interparietal bone is considered a malformation in rats. 1 ) Historical control data were not provided for the litter incidences of bipartite interparietal bone, and fetal incidences only were reported for the current study. However, the fetal incidences were not st atistically significant different from concurrent controls, and the conc urrent control fetal incidence (0.8%) exceeded

that of the historical controls (0.3%). An increase in the in cidence of postcaval lung lobe agenesis was also observed at 90 mg/kg bw/day . Litter incidences were 0/14, 0/15, 1/14, and 3/11 at 0, 10, 30, and 90 mg/kg/day. The fetal inci dence of postcaval lung lobe agenesis at 90 mg/kg bw/day (3.2%) exceeded that of the histori cal controls (1.2%), whereas that at 30 mg/kg bw/day (0.9%) did not. The developmental LOAEL is 90 mg/kg bw/day, based on increased

incidences of late abortion and skeletal (bipartite inte rparietal bone) and vis ceral (postcaval lung lobe agenesis) anomalies. The developmental NOAEL is 30 mg/kg bw/day.

3.3.3 Evidence of Neurotoxicity

As mentioned in section 3.1.3, toxicity to the olfactory sensory neurons was observed following single i.p. exposures of mice to BAM (Brittebo et al. 1991), as were clinical signs of neurotoxicity following oral exposur e in several short-term assays.

3.3.4 Additional Information from Literature Sources

Dichlobenil and its soil metabolite, BAM, have bot h been shown to be olfactory toxicants in adult animals following intraperitoneal (i.p.) expo sure (Brandt et al. 1990 ; Brittebo et al. 1991; Eriksson and Brittebo 1995). Dichlobenil alone also causes olfactory toxicity in neonatal

1 Solecki R

, Burgin H

, Buschmann J et al. 2001. Harmonisation of rat fetal skeletal terminology and classification. Report of the Third Workshop on the Terminology in Developmental Toxicology. Berlin, 14-16 September 2000. Reprod Toxicol 15(6):713-21.Page 17 of 66 animals following subcutaneous (s.c.) exposure (E riksson and Brittebo 1995) . Olfactory toxicity has also been demonstrated after dermal exposur e of dichlobenil (Deamer at al. 1994) to adult

animals.

Experimental evidence suggests th at dichlobenil and BAM are activ ated to the ultimate olfactory toxicant (currently unknown) by cy tochrome P (CYP) 450 enzymes located in Bowman’s glands of the nasal mucosa (Brandt et al. 1990; Brittebo 1997). It is suggested that damage to the olfactory epithelium is a secondary effect of damage to the Bowm an’s glands (primary lesion),

which are located in the lamina propria of the olfactory mucosa (Brandt et al. 1990; Brittebo et al. 1991). Since CYP 450s are abundant in both the olfactory epithelium and Bowman’s glands, both areas may be sites of bioactivation of dich lobenil and BAM (Harkema et al. 2006). Further, it has been hypothesized that damage to the olf actory epithelium, as well as the liver, may be mediated by hydroxylated metabolites of dichlobenil or BAM, the metabolites of which have

been shown in vitro to be uncouplers of oxidative phosphoryl ation in rat liver mitochondria (Brittebo et al. 1991).

3.3.5 FQPA Safety Factor (SF) for Infants and Children

There was no evidence of increased prenatal susc eptibility in the developm ental toxicity study in the rabbit. In this study, an increase in the inci dences of late abortion, as well as visceral and skeletal anomalies, were observed at the high dose. However, seve re maternal toxicity (severely decreased body weight gain and food consumption and late abortion) was also observed at the

same dose.

The risk assessment team recommends that the 10X FQPA SF be retain ed for those exposure scenarios that do not rely on dichlo benil toxicity data. This is due to the incompleteness of the database with regard to the systemic neurotoxic potential of BAM, incl uding olfactory toxicity. [A subchronic neurotoxicity screening battery, modified to assess olfactory toxicity, could fill this data gap.] For those exposure scenarios that do rely on dichlobenil to xicity data, the risk assessment team recommends that the FQPA SF for BAM toxicity be reduced to 1X. The reasons for this are that, as stat ed previously, higher doses of BA M are needed to induce levels of olfactory toxicity th at are similar to those caused by dich lobenil (Brandt et al. 1990; Brittebo et al. 1991; Eriksson and Brittebo 1995) and olfactory toxicity wa s the endpoint chosen for these exposure scenarios. Since olfactory toxicity wa s the most sensitive endpoint, further protection under FQPA is not deemed necessary.

3.4 Hazard Identification and Toxicity Endpoint Selection

3.4.1 aRfD - Females age 13-49

The aRfD for females 13-49 years of age wa s established based on the LOAEL from the developmental toxicity study in rabbits. The NOAEL is 30 mg/kg/day. The LOAEL of 90 mg/kg/day is based on increased incidences of la te abortion and skeletal (bipartite interparietal bone) and visceral (postcaval lung lobe agenesis) anomalies. Wh ile the increased incidence of late abortion is not considered a single dose e ffect, the increased incidence of skeletal and

visceral effects can be considered single-dose effects, enabling the use of this study in this riskPage 18 of 66 assessment. This study and endpoint are the mo st appropriate for the population of concern, namely, women of childbearing age. The 10X FQ PA SF has been retained in the form of a database uncertainty factor (UF DB ) for this exposure scenario to account for the lack of guideline neurotoxicity data, including olfactory toxicity data, follo wing oral exposure to BAM.

3.4.2 aRfD - General Population

The aRfD for the general populat ion, including infants and chil dren, was established based on the LOAEL from the dose-range finding assay for the in vivo mouse erythrocyte micronucleus assay. The LOAEL of 100 mg/kg/day is based on lethargy following a single oral dose of BAM.

A NOAEL was not identified in this study. Since a LOAEL was used to estimate a point of departure for this exposure scenario and to accoun t for the lack of guideline neurotoxicity data, including olfactory toxicity data, following oral exposure to BAM, the 10X FQPA SF has been

retained in the form of a UF DB and an uncertainty factor for us e of a LOAEL to extrapolate to a NOAEL (UF L ).

3.4.3 cRfD

The cRfD was established based on the NOAEL (4.5 mg/kg/day) from the chronic toxicity study in the dog. The LOAEL of 12.5 mg/kg/day is ba sed on decreased body weight and body weight gain. The NOAEL of 4.5 mg/kg is the lowest in the BAM database. In addition, the study duration is appropriate for the dur ation of exposure. The 10X FQPA SF has been retained in the

form of a UF DB for this exposure scenario to account for the lack of guideline neurotoxicity data, including olfactory toxicity data, following oral exposure to BAM.

3.4.4 Incidental Oral Exposure (Short- and Intermediate-Term)

The effects of concern that are relevant to the selection of the short- and intermediate-term

incidental oral doses are decr eased body weight gain observed in males and reduced skeletal muscle tone (observed on day 4 only in male s and on days 91 and 92 only in females) at 49 mg/kg/day in the 90-day oral toxi city study in rats. The study le ngth and effects are appropriate for the durations of exposure, namely, 1-30 da ys (short-term) and 1-6 months (intermediateterm). The NOAEL of 14 mg/kg/day is protectiv e of the population of concern, namely, infants and children. The 10X FQPA SF has been retained in the form of a UF DB for this exposure scenario to account for the lack of guideline neur otoxicity data, including olfactory toxicity data, following oral exposure to BAM.

3.4.5 Dermal Absorption

No dermal absorption study is ava ilable in the database. Since a route-specific toxicity study (5- day dermal in mouse using the parent herbicide dichlobenil) is being used for dermal risk assessment, calculation of dermal absorption is not necessary.Page 19 of 66 3.4.6 Dermal Exposure (Short-, Intermediate-, and Long-Term)

The effects of concern that are relevant to the selection of the short-, intermediate-, and longterm dermal doses are olfactory epithelial damage observed in a published 5-day dermal toxicity study in rats (Deamer et al. 1994) using the parent herbicide dichlobenil. The route of exposure of this study is ideal for these dermal exposure scenarios. While this study is of very short duration compared with interm ediate- and long-term exposure scenarios, it does nevertheless provide endpoints that will be more protective than those provided by any other study available for this risk assessment. The FQPA SF has been reduced to 1X for these exposure scenarios for the following reasons: 1) based on the submitted data and published literature studies, BAM is considered less toxic than dichlobenil; 2) the most sensitive endpoint, olfactory toxicity, was measured and observed in the study.

3.4.7 Inhalation Exposure (Short-, Intermediate-, and Long-Term)

The 28-day inhalation toxicity study using the parent herbicide dich lobenil in the rat was chosen for the short-, intermediate-, and long-term inhala tion exposure scenarios. The effect of concern

that is relevant to th e selection of short-, intermediate-, and long-term inhalation endpoints is nasal degeneration observed at 5.5 mg/kg/day (NOAEL = 3.1 mg/kg/da y) in this study using the parent herbicide dichlobenil. The route of e xposure of this study is ideal for these exposure scenarios. The FQPA SF has been reduced to 1X for these exposure scenarios for the following reasons: 1) based on the submitted data and publishe d literature studies, BAM is considered less toxic than dichlobenil; 2) the most toxic endpoint , olfactory toxicity, was measured and observed in the study.

A summary of the toxicological endpoints and doses chosen for the relevant exposure scenarios

for human risk assessment is found in Table 3.4.Page 20 of 66 Table 3.4. Summary of Toxicological Doses and Endpoints for 2,6-Dichlorobenzamide (BAM) for Use in Dietary, Residential, and Occupati onal 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 LOAEL = 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

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-, Intermediate-, 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: Formally unclassified; 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 popu lation (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 a dverse 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 C57Bl mouse. Neurotoxicology 15(2):287-93Page 21 of 66 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 toxicity 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 scenarios 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].

3.4.8 Level of Concern for Margin of Exposure

The MOEs for occupational and residential exposure risk assessments are as follows:

Table 3.4.8. Summary of Levels of Concern for Risk Assessment

Duration

Route Short-Term (1-30 days) Intermediate-Term (1-6 Months) Long-Term (> 6 Months)

Occupational (Worker) Exposure

Dermal 100 100 100

Inhalation 100 100 100

Residential (Non-Dietary) Exposure

Oral 1000 1000 1000

Dermal 100 100 100

Inhalation 100 100 100

3.4.9 Recommendation for Aggregate Exposure Risk Assessments

For occupational exposure, dermal and inhalation exposures can be aggregated because the endpoint (adverse effects on the nose) is the same even though the studies and routes are different. However, for residential exposure, expo sures from the three different routes cannot be aggregated because the endpoint for incidental oral (decreased body weight gain and reduced skeletal muscle tone) are not the same as the en dpoint for dermal and inhalation (adverse nasal effects).

3.5 Classificati on of Carcinogenic Potential

BAM was determined to be non-mutagenic in bacteria and non-clastogenic in an in vivo mouse erythrocyte micronucleus assay. BAM did not induce unscheduled DNA synthesis inPage 22 of 66 mammalian cells. There was no evidence of carcinogenicity in the combined chronic toxicity/carcinogenicity study of BAM in the rat. As stated previ ously, an increased incidence of hepatocellular adenomas was observed at the high dose in females only in the study. However, the statistical significance of the effect was ma rginal (P=0.049), dosing was considered adequate in the study, and the tumors were non-cancer ous. A mouse cancer study was not available.

BAM is a metabolite of di chlobenil (Group C, possibl e human carcinogen with the recommendation of an RfD approach to quantificati on of cancer risk). BA M is also a metabolite of fluopicolide (“not likely to be carcinogenic in humans”).

Since the carcinogenic potential of BAM was ev aluated in only one species, HED considers the carcinogenic potential of BAM to be similar to that of the parent herbicide dichlobenil (Group C, possible human carcinogen). As for dichlobenil, and RfD approach to qu antification of cancer risk is considered appropriate for BAM.

3.6 Endocrine disruption

EPA is required under the Federal Food, Drug, a nd Cosmetic Act (FFDCA), as amended by FQPA, to develop a screening program to determ ine whether certain substances (including all pesticide active and other ingredient s) “may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” Following recommendations of its Endocrine Disruptor and Testing Advisory Committee (EDSTAC), EPA determined that there was a scientific basis for including, as part of the program, the androgen and thyroid hormone sy stems, in addition to the estrogen hormone system. EPA also adopted EDSTAC’s recommenda tion that the Program include evaluations of potential effects in wildlife. For pesticide ch emicals, EPA will use the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and, to th e extent that effects in wildlife may help determine whether a substance may have an eff ect in humans, FFDCA authority to require the

wildlife evaluations. As the sc ience develops and resources a llow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Pr ogram (EDSP). When additional appropriate screening and/or testing protocols being considered under the Agency’s EDSP have been developed, BAM may be subjected to further screening a nd/or testing to better

characterize effects related to endocrine disruption. No evidence of endocrine modulation was observed in any study with BAM.

4.0 Public Health and Pesticide Epidemiology Data

Because BAM is a metabolite and there are no registered uses for BAM itself, HED does not expect any incident reporti ng data to be available.

5.0 Dietary Exposure/Risk Characterization

5.1 Pesticide Metabolism and Environmental Degradation

Refer to the concurrent Huma n Health Risk Assessment for fluopicolide (DP #325091, N. Dodd, 11/21/07) for details regarding fluopicolide metabolism. Refer to Appendix B for names andPage 23 of 66 structures of dichlobenil, fluopicolide, and meta bolites/degradates. Re fer to the Dichlobenil Reregistration Eligibility Decision (RED) (E PA-738-R-98-003, October 1998) for dichlobenil

metabolism data.

5.1.1 Metabolism in Primary Crops

BAM is a metabolite and/or environmental degradate of both fluopicolide and dichlobenil.

BAM is included in the tolerance expressi on for dichlobenil because it is a major metabolite/degradate of dichlobenil in primary crops as shown in grape and apple metabolism studies (Dichlobenil Reregist ration Eligibility Decision (R ED), EPA-738-R-98-003, October 1998): “In the grape metabolism study, mature gr ape vines were treate d with a single soil application of uniformly benzene-ring labeled [ 14 C]dichlobenil at a rate equivalent to 1x. HPLC analyses of the organosoluble a nd acid-hydrolyzed aqueous extracts indicated that BAM was the major residue, amounting to 82.1% of the tota l radioactive residues (TRR). 4-Hydroxy-BAM

was also identified as a residue at 1.9% of the TRR. In the apple metabolism study, an apple tree was treated with a single soil applicat ion of uniformly benzene-ring labeled [ 14 C]dichlobenil at a rate equivalent to 1x. HPLC analyses of the or ganosoluble extracts of th e apples indicated that BAM was the major residue, amounting to 57% of the TRR. The remaining TRR were insoluble or unidentified soluble fractions, individually accounting for <0.01 ppm.”

BAM is a minor metabolite of fluopicolide. Th e tolerance expression fo r plants will include fluopicolide (parent) as an indi cator of combined residues of fluopicolide and BAM. BAM is included in the risk assessment for the propos ed uses of fluopicolide on the primary domestic plants (cucurbit vegetables, frui ting vegetables, grapes, leafy vege tables, and tuberous and corm vegetables). Metabolism of fluopicolide in grapes , lettuce, and potato was found to be similar. Fluopicolide was the primary residue identified in grape fruit, lettuce leaves, and potato tubers, accounting for ~51-98% TRR. The metabo lites 2,6-dichlorobenzamide (BAM;AE C653711) and 3-chloro-5-trifluoromethylpyridine-2-carbox ylic acid (PCA; AE C657188) were found in foliarly-treated grape fruit and lettuce leaves at <4% TRR each. In lettuce which had received soil drench application, BAM was found (17-20 % TRR), and both BAM and PCA were found in potato tubers (12-26% TRR each). One a dditional metabolite (AE C643890; 2,6-dichloro- N -[(3- chloro-5-trifluoromethylpyridin-2-yl)methyl]- 3-hydroxybenzamide) was identified in grape, lettuce, and potato commodities at <3% TRR.

Fluopicolide is metabolized slowly to 2,6- dichlorobenzamide (BAM; AE C653711) and 3- chloro-5-trifluoromethylpyridine-2-carboxylic acid (PCA; AE C657188), via cleavage of the

bond between the carbon attached to the pyridine ring and the am ide nitrogen of the parent compound, and to AE C643890 (2,6-dichloro- N -[(3-chloro-5-trifluoromethylpyridin-2- yl)methyl]-3-hydroxybenzamide) via hydroxylation of the phenyl ring in the parent compound. Based on the results of the soil drench applications in lettuce, fluopicolide is metabolized in soil to BAM, which is then taken up by the lettuce plan t. (HED notes that because of the radiolabel

of the test substance used for the soil drench applications, the metabolite PCA would not have been observed.)Page 24 of 66 5.1.2 Metabolism in Rotational Crops

Metabolism of dichlobenil in rotational crops is not pertinen t since dichlobenil is registered on orchard crops, grapes, and cane and bush berrie s, and proposed for use on rhubarb; these crops

are not considered to be rotated (OPPTS 860.1850).

Based on confined rotational crop studies for fluopicolide on lettuce, radish, and wheat, the metabolism of fluopicolide in rotati onal crops appears to be more extensive than that observed in primary crops (grapes, lettuce, and potato). In addition to fluopicolide , BAM, and PCA, four other metabolites [2,6-dichloro-3-hyd roxybenzamide (AE C657378; 3-OH-BAM), 3- methylsulfinyl-5-trifluorome thylpyridine-2-carboxylic acid ( AE 1344122; P1X), 3-chloro-5- (trifluoromethyl)-2-pyridine carboxamide (AE C653598), and 3-chloro-5-(trifluoromethyl)-2- pyridinol (AE B102859)] were observed in the conf ined rotational crop studies that were not observed in the primary crop metabolism studies. The confined rotational crop data indicate the potential for quantifiable fluopicolide and metabolites in rotated crop commodities.

The tolerance expression for rotati onal crops will include fluopicoli de (parent) as an indicator of combined residues of fluopicolide and BAM. The residues of concern for the risk assessment are fluopicolide (parent) and BAM for a ll rotational crops except the grai n of cereal grains used as

human food. The residues of concern for the risk assessment for the grain portion of cereal grain rotational crops used as human food are fluopicolide (p arent), BAM, PCA, and 3-methylsulfinyl5-fluoromethylpyridine-2-carboxy lic acid (P1X; AE 1344122).

5.1.3 Metabolism in Livestock

Because dichlobenil is not a significant plant residue, metabolism studies were conducted in which ruminants and poultry were dosed with 14 C- BAM (Dichlobenil Reregistration Eligibility Decision (RED), EPA-738-R-98-003, October 1998) : Lactating goats were dosed with [Uphenyl] 14 C-BAM at a dose level of 10 ppm for five days. The primary residue found in milk, kidney, fat, and muscle of goats was unchanged BAM. The major residue found in goat liver was the glutathione conjugate 6-chloro-3-hydroxy-2-mercaptobenzamide. Laying hens were dosed with [U-phenyl] 14 C-BAM at a dose level of 10 ppm for five days. The primary residue found in all poultry matrices co llected was unchanged BAM.

The residues of concern from fluopicolide in liv estock commodities are tentative since additional information is needed to support the rumina nt and poultry metabolism studies. Pending submission of the required additional data, HED ha s tentatively determined that the residue of

concern in livestock commodities for a tolerance e xpression is BAM. The residues of concern in livestock commodities for the risk assessment have been tentatively determined to be parent fluopicolide and BAM. BAM as a metabolite of fluopicolide is found in the ruminant metabolism study in milk (3.9%) and in th e poultry metabolism study in liver (37%).Page 25 of 66 5.1.4 Analytical Methodology

Plant Methods for BAM

Data Collection Methods: Acceptable data collection methods, LC/MS/MS Methods 00782, 00782/M001, 00782/M002, and 00782/M003, or modified ve rsions of these methods, were used in the storage stability, crop fiel d trial, processing, and field ro tational crop studies associated with this petition. Method 00782/ M002 determines residues of fluopicolide (parent), BAM, PCA, and P1X. Method 00782/M003 determines 3-OH-BAM. Radiovalidation data have been

submitted which indicate that the extracti on procedures of Methods 00782/M002 and 00782/M003 adequately extract aged residues of fluopicolide, BAM, PCA, P1X, and 3-OHBAM from grape and wheat straw samples. Adequate method validation data were submitted. An independent laboratory validation was conducted on Method 00782/M002. All methods were validated with an LOQ of 0.01 ppm for each analyte in each commodity.

HED notes that for the storage stability, crop fi eld trial, processing, and field rotational crop submissions associated with this petition, residues of each analyte were reported in terms of the analyte (i.e., residues of metabolites were not converted to parent equivalents).

Livestock Methods for BAM

Data Collection Method: Valent U.S.A. Corporation’s LC /MS/MS method, Method AR 303-02 (MRID 46708516), which determines residues of fluopicolide and its metabolites AE C653711 (BAM) and AE C657188 (PCA) in/on milk, meat, fat, liver, and kidney of cattle, is adequate for data collection. Adequate method validation data (recovery data) have been submitted. Radiovalidation data are not required because th e extraction solvents used in the method are

similar to those used in the cattle metabolism study. The validated limits of quantitation (LOQs) for each analyte are 0.01 ppm for milk, 0.02 pp m for meat, and 0.05 ppm for fat, liver, and kidney.

Multiresidue Methods for Fluopicolide and BAM

Adequate multiresidue method testing data (MRID 46708525) have been submitted for fluopicolide and BAM. These data indicate that the multiresidue methods are not appropriate for determining residues of fluopico lide and BAM using some matri ces. Protocol C testing of fluopicolide and BAM indicated that these co mpounds were found to chromatograph with sufficient response on all tested modules except DG18. Fluopicolide and BAM were tested under Protocol D, using tomato as the representa tive nonfatty matrix, and F, using potato chips as the representative fatty ma trix. Fluopicolide and BAM were found to be unrecoverable when

tested under Protocol D due to matrix interferen ce. Therefore, further testing under Protocol E

was not conducted. BAM was found to be unrec overable when tested under Protocol F. Fluopicolide had small recoveries (29-42%) from a representative fatty matrix, potato chips,

under Protocol F. The data have been forwarded to FDA.

The FDA PESTDATA database dated 1/94 (PAM, Volume I, Appendix I) indicates that BAM is completely recovered (>80%) us ing Section 302, and not recove red using Sections 303 and 304.Page 26 of 66 5.1.5 Environmental Degradation

Based on two aerobic soil metabolism studies, fluopico lide (parent) and BAM are the residues of concern in drinking water. BAM was a major me tabolite of fluopicolide in these aerobic soil metabolism studies, present at levels up to 40%.

“The major routes of degradation for fluopicoli de and its degradates in laboratory studies are photodegradation in water and on soil and aerobi c microbial degradati on. Laboratory studies predict that fluopicolide should pe rsist in soil and aquatic envir onments. Degradation in soil was

slow with a mean half-life of 413 days. In an aerobic aquatic system, fluopicolide slowly partitioned into the sediment and degraded from the water-sediment system with half-lives of 699 to 866 days. In an anaerobic aquatic system, fl uopicolide partitions from water into sediment (water dissipation half-lives of 21.6 to 24.7 days), then slowly degrad es with system half-lives of 967 to 1553 days. A mean K OC value of 340 suggests that fluopico lide could leach in soil but this leaching potential should abate due to a time dependent increase in K OC . Field studies support the conclusion that fluopicolide will not leach. In the soil environment, fluopicolide degradation was faster with half-lives of 72 to 315 days (mean 181 days) in terrestrial field studies with no significant leaching of parent, AE C653711.”

As stated in the Dichlobenil Registration Eligibility Decision (E PA-738-R-98-003, October 1998): “Dichlobenil dissipates in the environment (on soil and in surface water) principally by volatilization. However, it is persistent under field conditions that reduce the potential for volatilization (i.e., cooler climates). When degradation proceeds through aerobic soil metabolism, 2,6-dichlorobenzamide (BAM) is gene rated (13.1% at 50 weeks). Under conditions

where dichlobenil does not volatilize, there is potential for both dichlobenil and BAM to move to ground water in coarse-textured soils low in organic matter.”

5.1.6 Comparative Metabolic Profile

In the rat, fluopicolide was readily absorbed and rapidly excreted. The major metabolites identified appeared to be oxidative N-deal kylation cleavage products, including BAM at 0.09%

of the total administered dose in rats. The ra dioactivity concentrations in any given tissue consistently represented consider ably less than 1% of the admini stered dose within 24 hours of

administration.

Because crops with associated livestock feed items (potato and the rotational crop wheat) will not be registered at this time, residues are not expected to occur in livestock commodities (ruminants and poultry) as a result of use of fl uopicolide. In the livestock metabolism studies, the major residues (> 10% TRR) in ruminants were fluopi colide (parent) and the dihydroxy glucuronide of fluopicolide; the major residues in poultry were fluopicolide (parent), BAM, AE 0712556 (2,6-dichloro- N -[(3-chloro-5-trifluoromethyl-2- pyridyl)methyl]-4-hydroxybenzamide), Metabolite 1 (2,6-dichloro- N -{[3-chloro-5-(trifluoromet hyl)pyridin-2-yl]methyl}-3- (methylsulfonyl)benzamide), and the dihydroxy sulfate of fluopicolide.Page 27 of 66 With the possible exception of potatoes, residues are expected to occur in primary (treated) plants. In the plant metabolism studies, fluopicoli de (parent) is the major residue in primary plants after foliar application. In the potato metabolism study, BAM and PCA also occurred at levels > 10% TRR. Fluopicolide is metaboli zed slowly to BAM, PCA, and AE C643890 (2,6-

dichloro- N -[(3-chloro-5-trifluoromethylpyridin-2 -yl)methyl]-3-hydroxybenzamide). The majority of the residue after foliar application and short preharvest inte rvals is on the surface of the plant.

More extensive metabolism was observed in rotati onal crops than in primary crops. In addition to residues found in primary crops, four additional metabolites were found in the confined rotational crop study. The confined rotational crop studi es indicate the pote ntial for occurrence of quantifiable residues of fluopico lide and metabolites in rotati onal crops. The major residues (> 10% TRR) found in the confined rotational crop study were fluopicolide (parent), BAM, PCA, AE C643840 (in wheat), 3-OH-BAM, and P1X.

5.1.7 Toxicity Profile of BAM

BAM (2,6-dichlorobenzamide; AE C653711) is a metabolite and/or environmental degradate of both fluopicolide and dichlobenil. The acute and chronic studies were sufficient to evaluate human hazard potential. BAM demonstrated modera te acute toxicity (Cat egory III) via the oral route of exposure. Because the subchronic and ch ronic toxicity of BAM is considered less than or equal to that of dichlobenil (parent herb icide) based on submitted and published toxicity studies, the acute toxicity of BA M via the inhalation and dermal r outes is expected to be less than or equal to that of di chlobenil. The cPAD (0.0045 mg/kg/ day) is based on decreased body weight and decreased body weight gain in the chronic oral toxi city study (dog). There was no evidence that BAM was either mutagenic or clastoge nic in submitted genotoxicity studies. In the absence of carcinogenicity study data for a second species, HED has assumed, to be conservative, that BAM’s carcinogenic potential is similar to that of di chlobenil, the parent compound having the greatest carcinoge nicity potential. Dichlobenil is classified as “Group C, possible human carcinogen” with the RfD approach used for quantification of human cancer risk.

BAM is considered to be neurotox ic. No evidence of endocrine mediated toxicity was observed. An FQPA SF of 10X for database uncertainty is applied to acute a nd chronic dietary and incidental oral exposure scenarios for incompletene ss of the database with regard to the systemic neurotoxic potential of BAM, in cluding olfactory toxicity) and als o, in the case of acute dietary exposure, use of a LOAEL to extrapolate to a NOAEL.

The soil metabolite BAM has a differe nt toxicity profile than parent fluopicolide. The parent has no acute dietary endpoint and a cPAD of 0.32 mg /kg/day. BAM has aPADs of 0.1 mg/kg/day for the general population and 0.03 mg/kg/day for females 13-49 years old, and a cPAD of 0.0045 mg/kg/day for the general population.Page 28 of 66 5.1.8 Pesticide Metabolites and Degradates of Concern

For dichlobenil , the residues which are regulated in plant commodities are dichlobenil (parent) and BAM (40 CFR §180.231). No livestock tolera nces have been established. In drinking water, residues of concern from use of dichlobenil are dichlo benil and BAM.

For fluopicolide , the residues of concern are shown in the table below. HED notes that tolerances on rotational crops and livestock will not be establ ished at this time.

Table 5.1.8. Summary of Metabolites and De gradates to be included in the Risk Assessment and Tolerance Expression for Fluopicolide

Matrix Residues included in Risk

Assessment 1 Residues included in Tolerance Expression

Primary Crops

All primary crops except Tuberous and Corm Vegetables fluopicolide (parent) and BAM

Tuberous and Corm Vegetables fluopicolide (parent), BAM,

and PCA fluopicolide (parent) as

an indicator of

combined residues of fluopicolide and BAM

Rotational Crops

All rotational crops except cereal grains fluopicolide (parent) and BAM

Cereal grains: grain for

human food fluopicolide (parent), BAM, PCA, and P1X Plants
(Tuberous and Corm Vegetables, Leafy Vegetables (except

Brassica ), Fruiting Vegetables, Cucurbit Vegetables, and
Grapes)

Cereal grains: forage/hay/straw and grain for livestock feed fluopicolide (parent) and BAM fluopicolide (parent) as

an indicator of

combined residues of fluopicolide and BAM

Ruminant Livestock

Poultry fluopicolide (parent) and BAM BAM

Drinking Water fluopicolide (parent) an d BAM Not applicable

1 The residues of concern for primary and rotational crops were determined in a RARC1 meeting on 7/19/07 and in subsequent HED Chemical Team Meetings. The residues of concern in livestock are tentative since additional information is needed to support the ruminant and poultry metabolism studies.

5.1.9 Drinking Water Residue Profile

Drinking Water Assessment for the BAM (2,6-Dichlorobenzamide) Degradate of Dichlobenil, DP #340773, J. Angier, Ph.D., 8/29/07

Drinking Water Exposure Assessment for Fluopicolide Uses on Grapes, Vegetables, Potatoes, Sugar Beet, Onion, and Turf – Exposure of 2,6-Dichlorobenzamide (BAM), DP #325804, J. Lin, 5/3/07.Page 29 of 66 Considering residues of BAM in dr inking water from uses of fluopi colide, uses of dichlobenil, and uses of both pesticides as described below, the highest drinking water residue estimate (56.2 ppb) was from SciGrow modeling of BAM residues from dichlobe nil use on nutsedge at 10 lb ai/A. Therefore, 56.2 ppb was used as the value of BAM residues in drinking water in the dietary assessment for both th e acute and chronic assessments.

BAM in Drinking Water from Dichlobenil Uses

No monitoring data were available for BAM. Drinking water residues of BAM were modeled for exposures resulting from currently approved uses of the parent herbicide, dichlobenil. The toxic degradate of concern, BAM, is formed as a result of accepted usage of the parent

dichlobenil. This assessment utilizes know n physical/chemical characteristics of BAM,

combined with estimated rates of formation of the degradate following dichlobenil application.

The OPP/EFED Tier 2 surface water model PRZM-EXAMS was used in this assessment. Percent Cropped Area (PCA) correcti ons were applied for appropriate crops as well. Dichlobenil use is currently registered for: control of weeds in fruit and nu t orchards (6 lbs a.i./acre), noncrop areas (12 lbs a.i./acre), and, control of nut sedge (10 lbs a.i./acre). Note that this memorandum replaces an earlier version where nuts edge usage was evaluated at 20 lbs a.i./acre;

current label restricts this use to a maximum a pplication rate of 10 lbs a.i./acre. New use on rhubarb (2 lbs a.i./acre) is also pending. A screening assessment for the impact of BAM on potential groundwater drinki ng water sources, using the Tier 1 groundwater model SciGrow, has

also been conducted. Results and co nclusions are contained herein.

Below are the model results for predicted su rface water concentrations (using the PRZMEXAMS model) and gro undwater concentrations (using SciGrow). There were no specific PRZM scenarios for some uses (e.g., nutsedge contro l, rhubarb), so the cl osest surrogates were used instead. For rhubarb, the nearest surrogates for which scenarios were available (in terms of crop type, agricultural practices, an d setting) were: lettuce, cabbage, and sugar beet, in the states of California, Florida, and Minnesota. The most protective surrogate, lettuce grown in California, was used in this assessment. For other cases, the Oregon Apple PRZM scenario was used for orchard crops, Florida Turf was used as a proxy for nutsedge co ntrol in non-crop areas,

and Florida Turf used for weed control in non-crop areas. Howeve r, since the weed control in non-crop areas is typically applied beneath a semi-p rotective layer such as concrete, vinyl liner, etc., it is not expected to contribute substantia lly to runoff or infiltration (as the covering will restrict contact with water).

Each run was performed using fate and mobility parameters for BAM only. To determine the equivalent amount of BAM degradate applied as a result of dichlobenil usage, the ‘applied’ BAM amounts were calculated by multiplying th e maximum amount of BAM expected to form as a result of registered dichlobenil use (13.1% ) by the (maximum allowed for each scenario) amounts of dichlobenil applied. However, since BAM has a di fferent molecular weight (190.3 g/mol) than parent dichlobenil (172 g/L), a furt her correction was applied. Thus, in terms of total mass, BAM represents 14.5% of parent dichl obenil. Results are lis ted below; rhubarb and orchard values have had Percent Cropped Area (PCA) adjustments of 87% applied, while the nutsedge control and other non-cr op uses have no PCA applied.Page 30 of 66 SURFACE WATER DRINKING WATER CONCENTRATIONS (ppb ) FOR THE DEGRADATE BAM (RESULTING FROM DI CHLOBENIL USE), MODELED USING

PRZM-EXAMS

Scenario Peak ( acute ) 1 in 10 Year Annual Mean 30 Year Overall Mean FL turf (Nutsedge control):

20.9 8.61 3.97

CA lettuce (surrogate for Rhubarb):

12.9 6.59 3.69

OR apple (Orchards):

6.13 3.63 0.896

Results for estimated (high-end) groundwater BA M concentrations from SciGrow were obtained using the maximum proposed application rates (adj usted to reflect 14.5% of applied dichlobenil) and the available fate parameters for BAM.

GROUND WATER DRINKING WATER CONCENTRATIONS FOR BAM, RESULTING

FROM PARENT DICHLOBENIL US E – MODELED USING SCIGROW

SciGrow output for Nutsedge control use = 56.2 ppb SciGrow output for Orchard use = 33.7 ppb SciGrow output for Rhubarb use = 11.2 ppb

Based on modeling resu lts, the estimated ground water drinking water concentration for BAM

from use of dichlobenil is 56.2 ppb (based on SciGrow modeling of dichlobenil use on nutsedge). (The use for non-crop weed control is not expected to exceed the use for nutsedge control on an actual per acre basis. ) This BAM residue level is hi gher than estimated residues in

surface water.Page 31 of 66 Table 5.1.9a Summary of Estimated Surface Water and Groundwater Concentrations

for BAM from Dichlobenil Uses.

BAM

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

Acute 20.9 56.2

Chronic (non-cancer) 8.61 56.2

a From the Tier II PRZM-EXAMS - Index Reservoir model. Input parameters are based on FL turf (nutsedge control with an application rate of 10 lbs fluopicolide ai/acre.

b From the SCI-GROW model assuming a maximum seasonal ap plication rate of 0.054 lb BAM/acre (based on a maximum seasonal application rate for nutsedge of 10 lb ai/A, a K

oc of 30 mL/g, and an aerobic soil metabolism half-life of 365 days.

BAM in Drinking Water from Fluopicolide Uses

No monitoring data were available for BAM. Drinking water residues of BAM were modeled for exposures through ingestion of drinking water fr om uses of the parent fungicide, fluopicolide, on grapes, vegetables, sugar beet, onion, and turf. Surface water concentrations were estimated using the Tier II model PRZM versi on 3.12 and EXAMS version 2.98. Ground water

concentrations were estimated us ing the Tier I SCI-GROW model.

Based on modeling results, the es timated surface wate r drinking water concentrations for 2,6- dichlorobenzamide (BAM) – a major de gradate of fluopicolide are:

4.26 ug /L for the 1 in 10 year annua l peak concentration (acute)

1.53 ug /L for the 1 in 10 year annual mean concentration (non-cancer chronic) and

The 1 in 10 year annual peak (acute) was derive d from modeling on Florida peppers. The 1 in 10 year annual mean (non-cancer chronic) was derive d from modeling on California lettuce. These values were highest among all modeling scenarios examined.

The SCI-GROW estimated ground water drinking water concentrations for BAM are not expected to exceed 4.19 μ g/L , which was based on 2 applications of 0.054 lb ai/acre per application.Page 32 of 66 Table 5.1.9b Summary of Estimated Surface Water and Groundwater Concentrations for BAM from Fluopicolide Uses.

BAM

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

Acute 4.26 4.19

Chronic (non-cancer) 1.53 4.19

a From the Tier II PRZM-EXAMS - Index Reservoir model. Input parameters are based on ...

b From the SCI-GROW model assuming a maximum seasonal application rate of 0.054 lb BAM/acre, a K

oc of 30 mL/g, and an aerobic soil metabolism half-life of 365 days.

BAM in Drinking Water from bot h Dichlobenil and Fluopicolide Uses

Grapes and rhubarb (a leafy vegetable) are the only crops on which both dichlobenil and fluopicolide are to be used. The rates on grapes are 2 lb ai/A for dich lobenil and 0.375 lb ai/A for fluopicolide. The rates on rhubarb are also 2 lb ai/A for dichlobenil and 0.375 lb ai/A for fluopicolide. The rate for dichlobenil on nutsedge is much higher (10 lb ai/A); the use of dichlobenil on nutsedge will result in th e highest residues in drinking water.

Considering residues of BAM in dr inking water from uses of fluopi colide, uses of dichlobenil, and uses of both pesticides (on grapes and rhuba rb, the only crops on which both pesticides will be registered), the highest drinking water residue estimate (56.2 ppb) was from SciGrow modeling of BAM residues from dichlobenil use on nutsedge at 10 lb ai/A. Therefore , this assessment will use the highes t estimate of 56.2 ppb (from SciGrow modeling of BAM residues from dichlobenil use on nutsedge) fo r the drinking water estimate for both the acute and chronic exposures:

56.2 ppb for the 1 in 10 year annual p eak concentration (acute)

56.2 ppb for the 1 in 10 year annual mean concentration (non-cancer chronic).

5.1.10 Food Residue Profile

Fluopicolide. PP#5F7016. Petition for Establishment of Tolerances for Use on Tuberous and Corm Vegetables, Leafy Vegetables (except Bras sica), Fruiting Vegetables, Cucurbit Vegeta bles, Grapes and on the Rotational Crop
Wheat. Summary of Analytical Chemistry and Residue Data,, DP Number326080, Amelia Acierto, 11/19/07

.

2,6-Dichlorobenzamide (BAM) as a Metabolite of Fluopicolide and Dichlobenil. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Actions for Fluopicolide on Tuberous and Corm Vegetables, Leafy Vegetables (excep t Brassica), Fruiting Vegetables, Cucurbit Vegetables, and Grapes, and for Indirect or Inadvertent Residues on the Rotational Crop Wheat, DP Number 340366, N. Dodd, 11/21/07.

BAM as a Metabolite/Degradate from Established/Proposed Uses of Fluopicolide on Tuberous and Corm Vegetables, Leafy Vegetables (except Brassica ), Fruiting Vegetables, Cucurbit Vegetables, and Grapes and from Established/Pending Uses of Dichlobenil :

BAM is a metabolite and/or environmental degradat e of both fluopicolide and dichlobenil. This

risk assessment includes residues of BAM in fo od and drinking water from uses of bothPage 33 of 66 fluopicolide and dichlobenil. A separate risk assessment is being conducted concurrently for fluopicolide (parent).

Fluopicolide:

HED is presently recommending for the following tolerances for fluopicoli de (parent) based on

the submitted residue data:

Tolerances to be established for residues of of the fungicid e fluopicolide [ 2,6-dichloroN -[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]meth yl] benzamide] as an indicator of combined residues of fluopicolide and its met abolite, 2,6-dichlorobenzamide, under “(a) General ”:

Grape*.........................................................................................2.0 ppm Grape, raisin*..............................................................................6.0 ppm Vegetable, cucurbit, group 9 .....................................................0.50 ppm Vegetable, fruiting, group 8 ........................................................1.6 ppm Vegetable, leafy, except Brassica , group 4..................................25 ppm Vegetable, tuberous and corm, except potato, subgroup 1D.....0.02 ppm

* These tolerances have been establis hed for imported grapes (40 CFR §180.627).

Tolerances have been established (40 CFR §180 .627) for residues of fluopicolide, 2,6-dichloroN

-[[3-chloro-5-(trifluoromethyl)-2 -pyridinyl]methyl] benzamide, on grape at 2.0 ppm and grape,
raisin at 6.0 ppm for use on imported crops. No livest ock tolerances have been established. No Codex, Canadian, or Mexican Ma ximum Residue Limits (MRLs) or tolerances have been established for fluopicolide.

Dichlobenil:

Dichlobenil is registered as a granular (G) formulation (C asoron® 4G; EPA Reg. No. 400-168; date of issuance: 5/18/05) for us e on apple, blueberry, cherry, filb ert, grape, and pear at 6 lb ai/A/season and on blackberry, cranbe rry, and raspberry at 4 lb a i/A/season. A registration for

Casoron® 4G for use on rhubarb at 2 lb ai/A/season is pending (DP Number 315266, W. Cutchin, 2/22/06).

Tolerances are established (40 CFR § 180.231) for the herbicide dichlobenil (2,6- dichlorobenzonitrile) and its metabolite 2,6-dichlorobenzamide as follows. A tolerance for rhubarb is pending.

Tolerances established (40 CFR §180.231) for the comb ined residues of the herbicide dichlobenil (2,6-dichlorobenzonitrile) an d its metabolite 2,6-dichlorobenzamide

Apple...........................................................................................0.5 ppm Blackberry...................................................................................0.1 ppm Blueberry...................................................................................0.15 ppm Cranberry ....................................................................................0.1 ppm Filbert..........................................................................................0.1 ppm Fruit, stone, gr oup 12 ................................................................0.15 ppm Grape.........................................................................................0.15 ppm Pear .............................................................................................0.5 ppmPage 34 of 66 Raspberry ....................................................................................0.1 ppm

Tolerance pending for the combined residues of the herbicide dichlobenil (2,6- dichlorobenzonitrile) and its metabolite 2,6-dichlorobenzamide

Rhubarb.....................................................................................0.06 ppm

The revised RED (7/31/96) recommended deletion of stone fruit crop group tolerance which was not being supported by the petitioner and establis hment of a separate tolerance on cherries. However, as stated in the previous RED, the stone fruit crop group was in cluded in this dietary exposure assessment since as long as the tolerance exists commodities containing BAM residues could be imported (Kathryn Boyle, 07/31/96, DP Number D000000: Dich lobenil: The Revised HED Chapter of the Reregistration Eligibility Decision Document (RED), Case 0263, Chemical 027401, 027402 (BAM).

Residue Data used for Acute and Chronic Assessments:

Maximum residues of BAM from fluopicolide field trials on tuberous and corm vegetables (except potato), leaf y vegetables (except Brassica ), fruiting vegetables, cucurbit vegetables, and grapes (domestic and imported) and from dichlobenil field trials on food commodities with established/pending dichlobenil tolerances (40 CFR §180.231) were included in the assessment. The assessments assumed 100% crop treated fo r fluopicolide and dichlo benil, except for the following dichlobenil-treated crops: 1) for the acute assessment: apples (2.5%), blueberries (2.5%), cherries (2.5%), peaches (2.5%), pears (2.5%), and raspberries (5%); and 2) for the

chronic assessment: apples (1%), blueberries (1%), cherries (1%), cranberries (45%), peaches (1%), pears (1%), and raspberries (5%).

No livestock tolerances are esta blished or proposed for either fl uopicolide or dichl obenil. Since the potato use will not be registered at this time and some restrictions will be applied to rotational crops, no livesto ck feed items are associated with this fluopicolide petition. DEEM default processing factors were used in the calculation.

Magnitude of BAM Residues in Pl ants from Use of Fluopicolide

Table 5.1.10.1. BAM Residues in Tuberous and Co rm Vegetables (except Potato), Leafy Vegetables (except Brassica ), Fruiting Vegetables, Cucurbit Vegetabl es, and Grapes from Field Trials with Fluopicolide. Residue Levels (ppm) Commodity (MRID) (Formulation) Total Applic.

Rate (lb ai/A) PHI (days) n Min. Max. HAFT* Median (STMdR) Mean (STMR) Std.

Dev

Celery (46708539) 0.354-

0.365 2 12 <0.041 0.041 0.039 NA** NA NA

Cantaloupe (46708531) 0.352-

0.362 2 18 <0.01 <0.01 NA NA NA NA

Cucumber (46708532) 0.349-

0.361 2 12 <0.01 <0.01 NA NA NA NA

Grape (46708541) 0.346-

0.401 20-21 32 <0.01 <0.01 NA NA NA NAPage 35 of 66 Table 5.1.10.1. BAM Residues in Tuberous and Co rm Vegetables (except Potato), Leafy Vegetables (except Brassica ), Fruiting Vegetables, Cucurbit Vegetabl es, and Grapes from Field Trials with Fluopicolide. Residue Levels (ppm) Commodity (MRID) (Formulation) Total Applic.

Rate (lb ai/A) PHI (days) n Min. Max. HAFT* Median (STMdR) Mean (STMR) Std.

Dev

Lettuce, head (46708533) 0.350-

0.368 2 14 <0.01 0.0132 0.012 <0.01 <0.01 NA

Lettuce, leaf (46708534) 0.349-

0.364 2 14 <0.01 0.038 0.031 <0.01 0.012 0.010

Pepper, bell (46708530) 0.349-

0.358 2 14 <0.01 <0.01 NA NA NA NA

Pepper, chile (46708535) 0.355-

0.363 2 6 <0.01 <0.01 NA NA NA NA

Spinach (46708540) 0.357-

0.365 2 14 0.022 0.188 0.170 0.065 0.072 0.047

Squash,

summer (46708538) 0.354-

0.367 2 12 <0.01 <0.01 NA NA NA NA

Tomato (46708536) 0.356-

0.368 2 24 <0.01 <0.01 NA NA NA NA

* HAFT = Highest Average Field Trial. ** NA = Not Applicable.

HED’s memo entitled “Guidance for Translatio n of Field Trial Data from Representative Commodities in the Crop Group Regulati on to Other Commodities in Each Crop Group/Subgroup, HED Standard Oper ating Procedure 2000.1 (9/12/200 0) was used to translate residue data from celery, head lettuce, leaf lettuce, or spinach to other Group 4 commodities.

Magnitude of BAM Residues in Pl ants from Use of Dichlobenil

Residues of BAM in crops from dichlobenil field tr ials are reported in the tables below. (The maximum residues are bolded.)

Table 5.1.10.2a. BAM Residues in Apples and Grapes from Field Trials with Dichlobenil

. Residue Levels (ppm) Commodity (MRID) Formulation Total Applic.

Rate (lb ai/A) PHI (days) n Min. Max.

85 3 0.064 0.271 Apples 1,2
(42177102) 4%G 6 (1x)

154-167 12 0.011 0.048 Grapes 1
(42117101) 4%G 6 (1x) 119-158 12 0.027 0.064

1 DP #174526, CBRS 9390, D. McNeilly, 7/2/92.

2 Data for apples in MRID 42177102 will translate to pears.Page 36 of 66 Table 5.1.10.2b. BAM Residues in Apples, Blackberries, Cranb erries, and Plums from Field Trials

with Dichlobenil Commodity (MRID) Formulation Total Applic

Rate (lb ai/A) PHI (days) n Residue Levels (ppm)

Apples 1
(42452802) 4%G 6 (1x) 80-

179 15 <0.01

Blueberries 2
(42304201) 4%G 6 (1x) 94 3 0.04- 0.06

Blackberries 1
(42452803) 4%G 4 (1x) 94 3 <0.01

Cherries No BAM data on cherries. Use plum data

until data are available.

Cranberries 1
(42452801) 4%G 4 (1x) 158,

166 6 0.02- 0.03

Filberts 3
(42476101) 4%G 6 (1x) 160 3 <0.01 (Use 0.02 ppm because of approx. 50% degradation in storage.) Grapes 3
(42476103) 4%G 6 (1x) 124-

173 12 0.01- 0.09 *

Peaches 3
(42476102) 4%G 6 (1x) 63-68 6 0.02- 0.04

Plums 1
(42452804)

Or (42452801) 4%G 6 (1x) 154

Or

158-

166 2 0.43, 0.46

Pear No BAM data have been submitted on pear. Use apple data. Raspberries No BAM data were submitted on raspberries. Use blackberry data.

Rhubarb 4
(45572201) 4%G 2 (1x) 64-83 3 <0.01**

1 DP #182600, C. Olinger, 3/5/93.

2 DP #179079, C. Olinger, 2/9/93.

3 DP #183209, C. Olinger, 3/24/94.

4 DP #315266, C. Olinger, 2/22/06. * The value 0.09 ppm is the highest BAM residue in/on grapes from use of dichlobenil. The value of 0.10 ppm for grapes (the sum of 0.09 for BAM from dichlobenil + 0.01 for BAM from fluopicolide) was used in the DEEM. ** The value <0.01 ppm is the highest BAM residue in/on rhubarb from use of dichlobenil. The value of 0.05 ppm (sum of <0.01 ppm for BAM from dichlobenil + 0.041 ppm (translated from celery) for BAM from fluopicolide)

was used in the DEEM.

For the stone fruit crop group, residue data on th e representative crops peach and plum were

translated to the individual cr ops in the crop group without data (HED SOP 200.1: Guidance for Translation of Field Trial Data from Repres entative Commodities in the Crop Group Regulation to Other Commodities in Each Crop Group/S ubgroup, HED Standard Operating Procedure (9/12/2000). The peach residue of 0.04 ppm was tr anslated to apricot and nectarine; the plum residue of 0.46 ppm was translated to various plums and plumcot.

For filberts, the highest reported residue wa s doubled to 0.02 because of approximately 50% degradation on storage.Page 37 of 66 Magnitude of BAM Residues in Plants fr om Use of both Fluopicolide and Dichlobenil

Considering the registered and proposed crops, grapes and rhubarb (a member of the Leafy Vegetables, except Brassica , Crop Group, Crop Group 4) are the only commodities which may be treated with both dichlobenil and fluopicolide.

The maximum residue of BAM from use of fluopicolide on imported grapes is 0.047 ppm (DP Number 321209, A. Acierto, 11/29/06). The maxi mum residue level of BAM from use of fluopicolide on domestic grapes is <0.01 ppm (Table 5.1.10.1 above). The maximum residue of

BAM from use of dichlobenil on domestic grapes is 0.09 ppm (Table 5.1.10.2b above). A total of 0.10 ppm for BAM in grapes was used in this assessment, the result of summing the highest

residues from domestic uses of fluopicolide and dichlobenil.

A total of 0.05 ppm was used for residues of BAM in rhubarb in this assessment. The value of 0.05 ppm for rhubarb is the sum of residues of 0.041 ppm from use of fluopicolide (translated from celery field trial data as directed by SOP 2000.1) and <0.01 ppm from use of dichlobenil.

BAM Processing Studies

Dichlobenil

Although an adequate processing study is not availa ble for apples, the availa ble data indicate that residues of BAM do not significantl y concentrate in apple juice and wet pomace processed from apples individually spiked with BAM at appr ox 0.1 ppm (DP Number 203324, Paula Deschamp, 7/1/94.) Residues concentrate in dry a pple pomace (DP Number 203324, Paula Deschamp, 7/1/94). Adequate processing studies are not available for dichlobenil on grapes (D182033, C. Olinger, 3/8/93) and plum s ((MRID 42679001; DP Number 188926, C. Olinger, 3/16/04).

Fluopicolide

Processing studies were conducte d for BAM on grape and tomato.

Table 5.1.10.3. Summary of Processing Factors for BAM

Average Processing Factor 1 RAC Processed Commodity BAM

Juice 1x Grape (DP#321209) Raisin 4x 2

Paste NC Tomato

Puree NC

1 NC = Not calculated; a processing factor could not be calculated for this matrix as residues were below the LOQ in both the RAC and the processed commodity. Estimated (~) processing factors were calculated when residues were reported below the LOQ in the RAC and/or the processed matrix.

2 The dietary assessment uses the tolerance of 6.0 ppm for raisin, instead of the grape tolerance (2.0 ppm) and a processing factor.

In this assessment, DEEM default processing factors were used. The following processing

factors were used:Page 38 of 66 BAM Processing Factors Used (D EEM Default Processing Factors

Table 5.1.10.4. Summary of Processing Factors for BAM

RAC Processed Commodity Processing Factor Used

dried apple 8.0x Apple

Juice 1.3x

Apricot dried apricot 6.0x

Beef dried meat 1.92x

Cherry Juice 1.5x

Cranberry Juice 1.1x

juice 1.2x

Raisin 4.3x Grape

wine & sherry 1.2x (based on grape juice)

dried peach 7.0x Peach

Juice 1.5x

Pear dried pear 6.25x

dried prune 5.0x Plum

prune juice 1.4x

dried tomato 14.3x

Juice 1.5x

Paste 5.4x Tomato

Puree 3.3x

Percent Crop Treated

Percent crop treated data (below) were used for apples, blueberries, cherries, cranberries, peaches, pears, and raspberries as provided by the Biological and Econo mic Analysis Division (DP #342741, Jihad Alsadek, 8/22/07). “Percent of Crop Treated” values were used for the chronic assessment; “Maximum Percent of Crop Treated” values were used for the acute

assessment.

Table 5.1.10.5. Scree ning Level Estimates of Agricultural Uses of Dichlobenil Crop Pounds of Active Ingredient Percent of Crop Treated Maximum Percent of Crop Treated Apples 6,000 <1 <2.5

Blueberries <500 <1 <2.5 Cherries 2,000 <1 <2.5 Cranberries 30,000 45 -- Grapes 3,000 <1 <2.5 Peaches 1,000 <1 <2.5

Pears <500 <1 <2.5 Raspberries 1,000 5 5

Strawberries* <500 <1 <2.5 *No tolerance is established on strawberries. Percent crop treated data on grapes we re not used because BAM on grapes comes from two sources (dichlobenil and fluopicolide).Page 39 of 66 Meat, Milk, Poultry, Eggs

Wet apple pomace is the only livestock feed associated with crops with established/pending

dichlobenil tolerances. Wet apple pomace is fed to beef and dairy cattle. There are no poultry or

swine feedstuffs associated with the established/pending uses of dichlobenil.

Feed items from potatoes (potato culls and pro cessed potato waste) and wheat (grain, forage, hay, straw, aspirated grain fractions, milled byproducts) are the only livestock feeds from fluopicolide uses on tuberous and corm vegetables, leaf y vegetables, fruiting vegetables, cucurbit vegetables, grapes, and the rotational crop wheat.

The dietary burdens of BAM residu es in livestock from dichlobe nil and fluopicolide uses, based on reasonably balanced diets, are presented in th e table below. The dietary burdens of BAM are 0.13 ppm for beef cattle, 0.12 ppm for dairy cattle, and 0.009 ppm for swine and poultry.

Table 6. Calculation of Dietary Burdens of BA M Residues in Livestock from Fluopicolide and

Dichlobenil Uses.*

Feedstuff Type 1 % Dry

Matter 2 % Diet 2 BAM

Maximum Residues (ppm) Dietary Contribution (ppm) 3

Beef Cattle R: 15%; CC: 75 %; PC: 10%

Wheat, hay R 88 15 0.102 0.017

Potato, processed waste CC 15 30 0.05 4 0.10

Wheat, milled byproducts CC 88 40 0.018 5 0.0082

CC (untreated) CC N/A 5 N/A 6

-- PC (untreated) PC N/A 10 N/A
--
TOTAL BURDEN -- -- 100 0.13

Dairy Cattle R: 45%; CC: 45 %; PC: 10%

Wheat, hay R 88 40 0.102 0.046

R (untreated) R N/A 5 N/A --

Wet apple pomace CC 40 10 0.27 1 0.068

Wheat, milled byproducts CC 88 35 0.018 5 0.0072

PC (untreated) PC N/A 10 N/A
--
TOTAL BURDEN -- -- 100 0.12

Poultry CC: 75 %; PC: 25%

Wheat, milled byproducts CC 88 50 0.018 5 0.009

CC (untreated) CC N/A 25 N/A --

PC (untreated) PC N/A 25 N/A
--
TOTAL BURDEN -- -- 100 0.009

Swine CC: 85 %; PC: 15%

Wheat, milled byproducts CC 88 50 0.018 5 0.009

CC (untreated) CC N/A 35 N/A --

PC (untreated) PC N/A 15 N/A
--
TOTAL BURDEN -- -- 100 0.009Page 40 of 66 1 R: Roughage; CC: Carbohydrate concentrate; PC: Protein concentrate.

2 OPPTS 860.1000 Table 1 Feedstuffs (October 2006).

3 Contribution = ([tolerance /% DM] X % diet) for beef and dairy cattle; contribution = ([tolerance] X % diet) for poultry and swine.

4 The value of 0.05 ppm for processed potato waste is based on a concentration factor for wet peel of 4.9x and the LOQ (0.01 ppm) as the BAM residue in the RAC samples.

5 Residues of BAM in wheat grain (field accumulation in rotational wheat study: MRID 46708547) were below the calculated LOD of 0.0029-0.0077 ppm; the LOQ is 0.01 ppm. BAM concentration factor s are 1.7x for wheat bran, 0.7x for flour, 1.1x for middlings, 1.2x for shorts, and 1.8x for germ. The value of 0.018 ppm for wheat milled byproducts and aspirated grain fractions is based on the highest concentration factor of 1.8x for BAM and a grain (RAC) residue of 0.01 ppm (LOQ) for BAM.

6 N/A: Not applicable.

No livestock tolerances are established for dich lobenil and no livestock tolerances have been proposed for fluopicolide. Since the potato use w ill not be registered at this time and some restrictions will be applied to rotational crops so that tolerances on the rotational crop wheat will not be established at this time, no livestock f eed items are associated with this fluopicolide petition.

5.1.11 International Residue Limits

.

This topic is not applicable since th ere is no registration for BAM itself.

5.2 Dietary Exposure and Risk

Fluopicolide. PP#5F7016. Petition for Establishment of Tolerances for Use on Tuberous and Corm Vegetables, Leafy Vegetables (except Bras sica), Fruiting Vegetables, Cucurbit Vegeta bles, and Grapes and for Indirect or Inadvertent Residues on the Rotational Crop Wheat. Sum mary of Analytical Chemistry and Residue Data, DP

Number326080, Amelia Acierto,11/19/07.

.

2,6-Dichlorobenzamide (BAM) as a Metabolite of Fluopicolide and Dichlobenil. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Actions for Fluopicolide on Tuberous and Corm Vegetables, Leafy Vegetables (excep t Brassica), Fruiting Vegetables, Cucurbit Vegetables, and Grapes, and for Indirect or Inadvertent Residues on the Rotational Crop Wheat, DP #340366, N.
Dodd, 11/21/07.

Acute and chronic dietary (food and drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluati on Model DEEM-FCIDTM, Version 2.03, which use food consumption data from the U.S. Depart ment of Agriculture’s Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994- 1996 and 1998. The analyses were performed on BAM to support Section 3 requests for use of parent fluopicolide on tuberous and corm vegetables (except potato), leafy vegetables (except Brassica ), fruiting vegetables, cucurbit vegetables, and grapes..

BAM is formally unclassified with respect to cancer; the parent herb icide dichlobenil is classified as “Group C, possible human carci nogen” with the RfD approach utilized for quantification of human ris k. The parent fungicide fluopicolide is classified as not likely to be carcinogenic to humans.Page 41 of 66 This risk assessments includes only BAM because there is no common toxicological effect for BAM and other fluopicolide residues of concern. A separate human health risk assessment is being conducted concurrently for other fluopicolide residues of concern [i.e., fluopicolide (parent); also including P1X and/ or PCA in some crops]. This assessment

includes residues of BAM from uses of both fluopicolide and dichlobenil since BAM is a metabolite and/or environmental degradate of both fluopicolide and dichlobenil.

5.2.1 Acute Dietary Exposure/Risk

A conservative acute exposure assessment wa s conducted. Maximum residues of BAM from fluopicolide field trials on tuberous and corm vege tables (except potato), leafy vegetables (except Brassica ), fruiting vegetables, cucurbit vegetabl es, and grapes (domestic and imported)

and from dichlobenil field trials on food commodities with established/pending tolerances (40 CFR 180.231) were included in the assessments. The assessments assumed 100% crop treated for fluopicolide and dichlobenil, except for the following dichlobenil-treated crops: 1) for the

acute assessment: apples (2.5%), blueberries (2.5%), cherries (2.5%), peaches (2.5%), pears (2.5%), and raspberries (5%); and 2) for the chronic assessment: apples (1%), blueberries (1%), cherries (1%), cranberries (45%), peaches (1%), pears (1%), and raspberries (5%). No livestock

tolerances are established or proposed for either fluopicolide or dichlobenil. DEEM default processing factors were used.

The acute dietary (food and drinki ng water) exposure to BAM from fluopicolide and dichlobenil

uses is below HED’s level of concern for the general U.S. popul ation and all population subgroups. The acute dietary exposure estimates at the 99.9 th percentile of the exposure

distribution are 11% of the acu te Population Adjusted Dose (aPAD) for the general U.S. population and 28% of the aPAD for all infants (<1 year old), the most highly exposed group.

5.2.2 Chronic Dietary Exposure/Risk

A conservative chronic exposure assessm ent was conducted as described above.

The chronic dietary (food and drinking wate r) exposure to BAM from fluopicolide and

dichlobenil uses is below HED’ s level of concern for the ge neral U.S. population and all population subgroups. The chronic dietary exposure estimates are 29% of the chronic Population Adjusted Dose (cPAD) for the general U.S. popul ation and 93% of the cPAD for all infants (<1 year old), the most highly exposed group which is of concern to HED. Residues in drinking water contribute the most to exposure.

5.2.3 Cancer Dietary Risk

As noted above, EPA has assumed that BAM’s potentia l for carcinogenicity is similar to that of dichlobenil, which is classified as “Group C, possible human carcinogen” with the RfD approach utilized for quantification of human risk. The quantification of cancer risk using the RfD approach is identical to the assessment for ch ronic effects; no sepa rate carcinogenic risk assessment is necessary.Page 42 of 66 Table 5.2. Results of Acute and Chronic Di etary (Food + Water) Exposure and Risk

Estimates for BAM

.

DEEM-FCID Population Subgroup PAD, mg/kg/day Exposure, mg/kg/day % PAD

Acute Dietary Estimates (99.9 th ) Percentile of Exposure)

U.S. Population 0.1 0.011430 11

All infants (< 1 yr) 0.1 0.028239 28

Children 1-2 yrs 0.1 0.016758 17

Children 3-5 yrs 0.1 0.012291 12

Children 6-12 yrs 0.1 0.007340 7

Youth 13-19 yrs 0.1 0.007223 7

Adults 20-49 yrs 0.1 0.008377 8

Adults 50+ yrs 0.1 0.006619 7

Females 13-49 yrs 0.03 0.008426 28

Chronic Dietary Estimates

U.S. Population 0.0045 0.001312 29

All infants (< 1 yr) 0.0045 0.004167 93

Children 1-2 yrs 0.0045 0.002276 51

Children 3-5 yrs 0.0045 0.001979 44

Children 6-12 yrs 0.0045 0.001292 29

Youth 13-19 yrs 0.0045 0.000926 21

Adults 20-49 yrs 0.0045 0.001191 26

Adults 50+ yrs 0.0045 0.001283 28

Females 13-49 yrs 0.0045 0.001191 26

Cancer Dietary Estimate

U.S. Population * * *

* Classification: BAM is formally unclassified; the parent herbicide dichlobenil is classified as “Group C, possible human carcinogen,” with the RfD approach utilized for quantification of human risk. Since the carcinogenic potential of BAM was evaluated in only one species, HE D considers the carcinogenic potential of BAM to be similar to that of dichlobenil, the parent having the greates t carcinogenic potential. Theref ore, as for dichlobenil, an RfD approach to quantification of cancer risk is considered appropriate for BAM. The quantification of cancer risk using the RfD approach is identical to the assessment for chronic effects; no se parate carcinogenic risk assessment is

necessary.

5.3 Anticipated Residue and Percent Crop Treated (%CT) Information

Maximum residues of BAM from fluopicolide field trials on tuberous and corm vegetables (except potato), leaf y vegetables (except Brassica ), fruiting vegetables, cucurbit vegetables, and grapes (domestic and imported), and from dichlobenil field trials on food commodities with established/pending tolerances (40 CFR 180.231) were included in the assessments.

As discussed in Section 5.1.10, the assessments used 100% crop treated except for apples, blueberries, cherries, cranberries, peaches, pears, and raspberries.Page 43 of 66 6.0 Residential (Non-Occupational) Exposure/Risk Characterization )

O ccupational and Residential Risk Assessment of Metabolite BAM (to Support Request for Registration of Fluopicolide on a Variety of Crops, Residential Turf and Ornamentals), DP #345920, K. O’Rourke, 10/9/07

As mentioned previously, BAM is known to be a metabolite of both fluopicolide and dichlobenil. While it is necessary to evaluate residential e xposure from all sources of BAM, the use pattern for dichlobenil is not expected to result in scenarios with sign ificant residential exposure. Dichlobenil products are not intended for use by re sidential handlers. They may be applied by professional pest control operators (PCOs) to soil/mulch around roses and other woody

ornamentals in established residential plantings, but not to residential lawns or turf. Dermal and incidental oral exposures are expected to be ne gligible from these sources. Therefore, BAM exposure estimates are base d on fluopicolide use only.

Two products containing fluopicolide (i .e., V-10161 VPP Fungi cide and V-10162 VPP Fungicide) are proposed for application to reside ntial turfgrass and recr eational sites. Although the label does not prohibit homeowners using th ese products, residentia l handler exposure was

not evaluated because the metabolite BAM is believed to form slowly in pl ants and soil after the product containing the parent fluopic olide or dichlobenil) has been applied. However, residential postapplication exposure via the dermal route is likely for adults and children entering treated lawns. Toddlers may also experience exposure via incidental non-dietary ingestion (i.e., handto-mouth, object-to-mouth (turfgrass), and soil ingestion) during postapplication activities on

treated turf.

6.1 Residential Handler Exposure

Residential handler exposure was not evaluated b ecause the metabolite BAM is believed to form slowly in plants and soil after the product cont aining the parent (fluopicolide) has been applied.

6.2 Residential Postapplication Exposure

The following postapplication expos ure scenarios resulting from lawn treatment were assessed: (1) adult and toddler postapplication dermal expos ure, (2) toddlers’ inci dental ingestion of pesticide residues on lawns from hand-to-mouth tr ansfer, (3) toddlers’ object-to-mouth transfer from mouthing of pesticide-treated turfgrass, and (4) t oddlers’ incidental i ngestion of soil from pesticide-treated residential areas.

Turf transferable residue (TTR) data were not available. The assessment was based on generic assumptions for TTR and transfer coefficients, as specified by the Recommended Revisions to the Residential SOPs and recommended approa ches by HED’s Science Advisory Council for Exposure (ExpoSAC).

In order to adjust the TTR es timates to reflect BAM residues , data from plant metabolism studies were considered. Grape, lettuce, and potato meta bolism data indicate that the majority of total radioactive residue (TRR) was located on the surface of foliage and fruit samples (DP #327026, A. Acierto, 8/20/07). The parent fluopicolide was the primary resi due identified in grape fruit,Page 44 of 66 lettuce leaves, and potato foliage and tubers, accounting for 51- 98% TRR. The metabolite BAM was found in foliarly-treated grapes (fruit), lett uce leaves and potato foliage at <4% TRR. Although BAM was found at higher percentages in lettuce which had received soil drench application (17-20% TRR) and pot ato tubers (12-26% TRR), the ac tual concentration was lower than BAM occurring on grapes (fru it), lettuce leaves, and potato folia ge. For the purposes of this postapplication exposure assessment, it was conser vatively assumed that the surface residues of BAM are transferable, and that they are pres ent at 4% of the initial amount of parent fluopicolide. In addition, the drinking water assessment (D34 0773, J. Angier, 8/29/07) indicates that, based on aerobic soil metabolism data, BAM may be present at up to 40% of application rate; this value was used to estimate residues for the incidental soil ingestion scenario.

Exposure and risk estimates for residential expos ure scenarios are typically assessed for the day of application (“Day “0”) because it is assumed that adults and toddlers could contact the lawn immediately after application. However, BAM is a metabolite/degradate which forms slowly; therefore, these scenarios were assessed with the assumption that BAM is present at the percentages described above (which were actually measured on days 21 and 369 after application, for plants and soil, respectively) for “Day 0” in order to provide a protective assessment. The equations used for the exposur e calculations and the re sults are presented in Tables 6.2.1 through 6.2.4.

The exposure estimates are based on some uppe r-percentile (i.e., maximum application rate,

initial amount of transferable residue and duration of exposure) and some central tendency (i.e., surface area and body weight) assumptions and are c onsidered to be representative of high-end exposures. The uncertainties associated with this assessment stem from the use of an assumed amount of pesticide available from turf, and assu mptions regarding transfer of chemical residues and hand-to mouth activity. The estimated expos ures are believed to be reasonable high-end estimates based on observations from chemical-sp ecific field studies and professional judgment.

The short-/intermediate-term dermal MOEs ar e above the LOC of 100, and the MOEs for each

incidental oral scenario are a bove the LOC of 1,000; they are not of concern. Although dermal and incidental oral exposure may co-occur for toddl ers, the toxic effects from these two routes are different. Therefore, only th e incidental oral exposures were combined. As shown in Table 6.2.5, the Total incidental oral MOE for childre n is 62,000, which is greater than the LOC of 1,000 on the day of applica tion, and not of concern.Page 45 of 66Table 6.2.1. Postapplication DermalExposure and Risk from Treated LawnsDermal MOE3SubgroupExposedApplicationRate(lb ai/A)Postapplicationday (t)Fraction of aiTransferablefrom theFoliageTurfTransferableResidue1(μg/cm2)DermalTransferCoefficient(cm2/hr)BodyWeight(kg)Daily DermalDose2(mg/kg/day)Short-/Intermediate-termAdults 14,50070 0.0025 10,000Children0.27 0 0.05 0.00605,200150.0042 6,0001Turf Transferable ResiduePostapplication day(μg/cm2)= Application rate of fluopicolide(lb ai/A) x Fraction of ai Transferable from the Foliage x (1- Fraction of ResidueThat Dissipates Daily, 0.1)Postapplication dayx 4.54E+8 μg/lb x 2.47E-8 A/cm2x 0.04 (to adjust for amount of BAM, based on plantmetabolism data)2Daily Dermal Dose = (Turf transferable Residue (μg/cm2) x Absorption Factor (1) x Dermal Transfer Coefficient (cm2/hr) x Exposure Time (2 hrs/day) x 0.001mg/μg] / [Body Weight (kg)]3Dermal MOE = Dermal NOAEL / DailyDermal Dose; where Short-/Intermediate-term NOAEL = 25 mg/kg/day.Table 6.2.2. Postapplication Oral Hand-to-MouthExposure and Risk for Children from Treated LawnsOral MOE3ApplicationRate(lb ai/A)Postapplicationday (t)Fraction of aiTransferablefrom theFoliageTurfTransferableResidue1(μg/cm2)HandSurfaceArea(cm2/event)SalivaExtractionFactorFrequency(events/ hr)BodyWeight(kg)Daily Dose2(mg/kg/day)Short-/Int-term0.2700.050.00602050%20150.00016 87,0001Turf Transferable ResiduePostapplication day(μg/cm2)= Application rate of fluopicolide(lb ai/A) x Fraction of ai Transferable from the Foliage x (1- Fraction of ResidueThat Dissipates Daily, 0.1)Postapplication dayx 4.54E+8 μg/lb x 2.47E-8 A/cm2x 0.04 (to adjust for amount of BAM, based on plantmetabolism data)2Daily Dose = (Turf Transferable Residue (μg/cm2) x Hand Surface Area (cm2/event) x Saliva Extraction factor x Frequency(events/hr) x 0.001 mg/ μg x Exposuretime (2 hrs/day)] / [Body Weight (kg)]3Oral MOE = Oral NOAEL/Daily Dose; where Short-/Intermediate-term NOAEL = 14 mg/kg/day.Table 6.2.3. Postapplication Oral Object-to-Mouth (Turfgrass) Exposure and Risk forChildren from Treated LawnsOral MOE3Application Rate(lb ai/A)Postapplication day(t)Fraction of aiTransferablefrom the FoliageGrass/ObjectResidue1(μg/cm2)Ingestion Rate(cm2/day)BodyWeight(kg)Daily Dose2(mg/kg/day)Short-/Int-term0.2700.290.0352515 0.000058 240,0001Grass/Object residuePostapplication day(μg/cm2) = Application rate of fluopicolide(lb ai/A) x Fraction of ai Transferable from the Foliage (from MRID#: 46708641) x (1-Fraction of Residue That Dissipates Daily)Postapplication dayx 4.54E+8 μg/lb x 2.47E-8 A/cm2x 0.04 (to adjust for amount of BAM, based on plantmetabolism data)2Daily Dose = [Grass reside (μg/cm2) x Ingestion rate (cm2/day) x 0.001 mg/μg] / [Body Weight (kg)]]3Oral MOE = Oral NOAEL / Daily Dose; where Short-/Intermediate-term NOAEL = 14 mg/kg/day.Page 46 of 66 Table 6.2.4. Postapplication Incidental Soil Ingestion Exposure and Risk for Children from

Treated Lawns

Oral MOE 3 Application

Rate (lb ai/A) Fraction of

ai Retained

in the Soil Soil

Residue 1

(μg/g) Ingestion

Rate (mg/day) Body Weight

(kg) Daily Dose 2

(mg/kg/day) Short-/

Intermediate-term

0.27 1 0.81 100 15 0.0000054 2,600,000

1 Soil residue Postapplication day zero (μg/cm 2 ) = Application rate of fluopicolide (lb ai/A) x Fraction of ai Retained on the Soil x (4.54E+8 μg/lb x 2.47E-8 A/cm 2 x 0.67 cm 3 /g soil x 0.4 (to adjust for amount of BAM , based on soil metabolism data)

2 Daily Dose = [Soil reside (μg/g) x Ingestion ra te (mg/day) x 0.000001 g/μg] / [Body Weight (kg)]]

3 Oral MOE = Oral NOAEL/Daily Dose; where S hort-/Intermediate-term NOAEL = 14 mg/kg/day.

Table 6.2.5. Aggregate Exposure and Ri sk Estimates from Residential Lawns

Total MOE 4 Scenario

and

Pathway TTR/GR/SR 0 (μg/cm 2 or g) 1 PDR 0-norm (mg/kg/day) 2 Short-/ IntTerm

MOE 3 Short-/

Int-Term

Adult’s Scenarios

(1) Dermal Postapplication 0.0060 0.0025 10,000 N/A

Children’s Scenarios – All Postapplication

(1) Dermal 0.0060 0.0042 6,000 N/A

(2) Hand-to-Mouth 0.0060 0.00016 87,000

(3) Mouthing Grass/Object 0.035 0.000058 240,000

(4) Soil Ingestion 0.81 0.0000054 2,600,000 62,000

1 TTR=turf transferable residue on day “0"; GR=grass/object residue on day “0"; SR 0 =soil residue on day “0".

2 PDR 0norm =potential dose rate on day “0”.

3 MOE = NOAEL/PDR;

where Short-/Intermediate-term De rmal NOAEL = 25 mg/kg/day, and In cidental Oral NOAEL = 14 mg/kg/day.

4 Total Incidental Oral MOE = 1/ [(1/MOE Hand-to-Mouth ) + (1/MOE Grass ) + (1/MOE Soil )] N/A = not applicable.

6.3 Other (Recreational Exposure; Spray Drift)

Recreational exposures to turf (including from playing golf) are expected to be similar to, or in many cases less than, those evaluated in Section 5.2 Residential Postapplication Exposure and Risk; therefore, a separate recreatio nal exposure assessment was not included.

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial appl ication, but, to a lesser ex tent, could also be a potential source of exposure from the ground ap plication method employed for fluopicolide. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and ot her parties to develop the best spray drift management practices. The Agency is now re quiring interim mitigation measures for aerial applications that must be placed on product la bels/labeling. The Agency has completed itsPage 47 of 66 evaluation of the new data base submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is de veloping a policy on how to appr opriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift and risks associated with aerial as well as other applic ation types where appropriate.

Please note that as indicated in th is assessment, fluopicolide is dire ctly applied to residential turf and does not result in exposures of concern for BAM. It is unlikely that the potential for risk of exposure to spray drift from the agricultural uses would be higher than that estimated for contact

with treated turf.

7.0 Aggregate Risk Assessment s and Risk Characterization

Two products containing fluopicolide (i .e., V-10161 VPP Fungi cide and V-10162 VPP Fungicide) are proposed for applicat ion to residential turfgrass a nd recreational sites. The use pattern for dichlobenil is not expe cted to result in significant reside ntial exposure. Therefore, the non-dietary BAM exposure estimates ar e based on fluopicolide use only.

There is a potential for shor t-/intermediate-term non-occupati onal exposure to BAM during postapplication activities. Chr onic exposure is not expected for the proposed use patterns associated with fluopicolide.

7.1 Acute Aggregate Risk

In examining acute aggregate risk, HED has assu med that the only pathway of exposure relevant to the acute time frame is dietary exposure ( i.e ., any non-dietary exposures are short- and/or intermediate-term in duration). Th erefore, the acute aggregate risk is composed of exposures to BAM residues in food and drinking water and is equivalent to the acute dietary risk discussed in

Section 5.2. As noted in that s ection, the acute risk estimates are well below HED’s level of concern for the general U.S. population and all population subgroups.

7.2 Short-Term Aggregate Risk

Short-term exposures (1 to 30 days of continuous exposure) may occur as a result of activities on

treated turf. Incidental oral e xposures related to turf activities (Table 6.2.5) have been combined with chronic dietary exposure estimates (as an estimated of background dietary exposure; Table 5.2.2) to assess short-term aggregate exposure. Since aggregate MOEs in Table 7.2 are greater than 1000, they represent risk estimates that are below HED’s level of concern.Page 48 of 66 Table 7.2. Short-Term and Intermediate-T erm Aggregate Risk Calculations (1/MOE Approach – All LOCs Identical)

Short- or Intermediate -Term Scenario Population

NOAEL mg/kg/day LOC 1 Max

Allowable Exposure 2
mg/kg/day Average

Food & Water Exposure mg/kg/day Residential Exposure 3
mg/kg/day Aggregate

MOE (food and residential) 4

General U.S. Population 14 1000 0.014 0.001351 NA NA

All Infants (<1 year old) 14 1000 0.014 0.004193 0.0002234 3200

Children 1-2 years old 14 1000 0.014 0.002379 0.0002234 5400

Children 3-5 years old 14 1000 0.014 0.002075 0.0002234 6100

Children 6-12 years old 14 1000 0.014 0.001356 0.0002234 8900

Youth 13-19 years old 14 1000 0.014 0.000965 NA NA

Adults 20-49 years old 14 1000 0.014 0.001221 NA NA

Adults 50+ years old 14 1000 0.014 0.001309 NA NA

Females 13- 49 years old 14 1000 0.014 0.001220 NA NA

1 UF A = 10x (extrapolation from animal to human (interspecies); UF H = 10x potential variation in sensitivity among members of the human population (intraspecies); FQPA SF = 10x. 10 x 10 x 10 = 1000.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC = 14 mg/kg/day ÷ 1000 = 0.014 mg/kg/day.

3 Residential Exposure = Incidental oral exposure, calculated by adding PDR values (for hand-to-mouth, mouthing grass/object, and soil ingestion) as shown in Table 6.2.5 above. Residential exposures were calculated for children only (15 mg bw).

4 Aggregate MOE = [NOAEL/ (Avg Food & Water Exposure + Residential Exposure)]Page 49 of 66 7.3 Intermediate-Term Aggregate Risk

The intermediate-term aggregate risk is the same as described above for the short-term aggregate risk; the intermediate-term aggregate risk is below HED’s level of concern for the U.S. population and all popula tion subgroups.

7.4 Long-Term Aggregate Risk

In examining long-term aggregate risk, HED ha s assumed that the only pathway of exposure

relevant to that time fr ame is dietary exposure ( i.e ., any non-dietary exposures are short- and/or intermediate-term in duration). Therefore, th e long-term aggregate ri sk is composed of exposures to BAM residues in food and drinking water and is equivalent to the chronic dietary

risk discussed in Section 5.2. As shown in Table 5.2, the chronic risk estimates are below HED’s level of concern for the general U.S. population and all population subgroups.

As noted above, EPA has assumed that BAM’s potentia l for carcinogenicity is similar to that of dichlobenil, which is classified as “Group C, possible human carcinogen” with the RfD approach utilized for quantification of human risk. The quantification of cancer risk using the RfD approach is identical to the assessment for ch ronic effects; no sepa rate carcinogenic risk assessment is necessary.

8.0 Cumulative Risk Assessment s and Risk Characterization

Unlike pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a co mmon mechanism of toxicity finding as to BAM and any other substances and BAM does not appe ar to produce a toxic metabolite produced by other substances. For the purposes of this tolerance act ion, therefore, EPA has not assumed that BAM has a common mechanism of toxicity with other substances. For information regarding

EPA’s efforts to determine which chemicals ha ve a common mechanism of toxicity and to

evaluate the cumulative effects of such chemical s, see the policy statements released by EPA’s Office of Pesticide Programs concerning common m echanism 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/.

Fluopicolide and dichlobenil can form the common metabolite BAM. To establish new tolerances for fluopicolide, EPA conducted this hu man health risk assess ment for exposure to BAM resulting from the use of current and propo sed uses of fluopicolide and the herbicide

dichlobenil. The risk assessment is conservati ve in terms of potential dietary and non-dietary exposures. In addition, the Agency retained th e additional 10X FQPA safety factor for the protection of infants and children. The assessmen t includes evaluations of risks for various subgroups, including those composed of infants and children.Page 50 of 66 9.0 Occupational Exposure/Risk Pathway

O ccupational and Residential Risk Assessment of Metabolite BAM (to Support Request for Registration of Fluopicolide on a Variety of Cr ops, Residential Turf and Ornamentals), DP
#345920, K. O’Rourke, 10/9/07

9.1 Short-/Intermediate-/Long-Term/Cancer (if needed) Handler Risk

Occupational handler exposure was not evaluated because the metabolite BAM is believed to form slowly in plants and soil after the product containing the parent (f luopicolide) has been applied.

9.2 Short-/Intermediate-/Long-Term/Can cer (if needed) Postapplication Risk

The registration action for fluopicoli de involves applicati on to agricultural crops as well as turf and ornamentals. Postapplicati on inhalation exposure is expected to be negligible, however, dermal exposure to the metabolite BAM is possible for workers: entering treated areas to tend or harvest crops, mow/maintain tu rfgrass, or tend ornamentals in nurseries and greenhouses. A dislodgeable foliar residue (DFR) study on fluopi colide was submitted by the registrant (MRID#: 46708641) for use in assessing postapplication activ ities. As discusse d in the fluopicolide assessment (K. O’Rourke, DP #326082, 10/9/07), this study is considered to be acceptable, and

the results indicate thatthe initial dislodgeable residue of fluopicolide is 29% of the application rate. The data were considered applicable to residue estimation for agricultural crops and

ornamentals. A turf transferable residue (TTR) study was not availabl e. Therefore, turf scenario

calculations were based on the stan dard turf residue assumption of 5% of the application rate for

the initial transferable residue for fluopicolide

.

In order to adjust these estimates to reflect BAM residues , which were not measured in the DFR study, data from plant metabolism studies were considered. Grape, lettuce, and potato metabolism data indicate that the majority of total radioactive residue (TRR) was located on the surface of foliage and fruit samples (DP #327026, A. Acierto, 8/20/07). The parent fluopicolide was the primary residue identified in grape fru it, lettuce leaves, and potato foliage and tubers, accounting for 51-98% TRR. The metabolite BAM wa s found in foliarly-treate d grapes (fruit), lettuce leaves, and potato folia ge at <4% TRR. Although BAM was found at higher percentages in lettuce which had received soil drench applic ation (17-20% TRR) and potato tubers (12-26% TRR), the actual concentration was lower than BAM occurring on grapes (fruit), lettuce leaves, and potato foliage. For the purposes of this postapplication exposure assessment, it was conservatively assumed that the surface residues of BAM are dislodgeable/tr ansferable, and that they are present at 4% of the initi al amount of parent fluopicolide.

In addition to DFR and TTR, transfer coefficients (Tc) are used to relate the residue values to activity patterns, which take place after application, to estimate potential human exposure. The

transfer coefficients used in this assessment ar e from an interim transfer coefficient guidance document developed by HED’s Science Advisory Council for Exposure using proprietary data from the Agricultural Re-entry Task Force (ARTF) database (SOP# 3.1).Page 51 of 66 Postapplication MOEs are typically estimated for “Day 0" exposure (i.e., the day of application). As shown in Table 9.2, the short-/intermediate-te rm MOEs for BAM are greater than the LOC of 100 on the day of application for a ll agricultural, turf and orname ntal uses of fluopicolide, and

are not of concern.

The fluopicolide technical material has been classified in Toxici ty Categories III-IV for acute dermal and primary skin irritation, and Category III for primary eye irrita tion. Per the Worker Protection Standard (WPS), a 12-hr restricted entry interval (R EI) is required for chemicals classified under Toxicity Category III/IV. The proposed fluopicolide labels indicate an REI of 12 hrs, which is in compliance with the WPS fo r uses that reach an MOE of 100 on the day of application. Fluopicolide is also intended for non-agricultural use sites (e.g., golf course) to which the WPS does not apply; the labels approp riately contain language cautioning unprotected persons to keep out of treated areas until sprays have dried.Page 52 of 66Table 9.2. Summary of Estimated Post-application MOEs for Agricultural CropsCropApplicationRate(lb ai/A)1DAT2DFR orTTR3(μg/cm2)TC4(cm2/hr)Activity4Short-/IntTerm MOE5Agricultural Crops500 Irrigation, scouting, thinning, weeding immature plants 26,000700 Irrigation and scouting mature plants 18,000FruitingVegetables0 0.0171,000 Hand harvesting, pruning, staking, tying 13,000500 Irrigation, scouting, thinning, weeding immature plants 26,0001,500 Irrigation, scouting, weeding mature plants 8,600Cucurbit &LeafyVegetables0 0.0172,500 Hand harvesting, pulling, pruning, and thinning mature plants 5,200500 Hedging, irrigation, scouting, hand weeding 26,0001,000 Scouting 13,0005,000 Hand harvest, leaf pulling, thinning, pruning, training/tying 2,600Grapes 0 0.01710,000 Girdling and cane turning 1,300300 Irrigation, scouting, thinning, weeding immature plants 43,0001,500 Irrigation and scouting mature plants 8,600SweetPotatoes0.130 0.0172,500 Hand harvesting 5,200Turf3,400 Mowing and other maintenance activities 11,000Turf 0.27 0 0.00606,800 Sod harvesting and transplanting 5,300Ornamentals – Nursery Stock100 Hand pruning containerized ornamentals 31,000NurseryStock0.54 0 0.070400 Harvesting, ball/burlap containerized ornamentals 7,800Ornamentals – Cut Flowers500 Pinching 6,200Cut Flowers 0.54 0 0.0705,100 Hand harvesting, pruning, thinning, pinching 6101Maximum application rate from proposed fluopicolide labels.2DAT = Days after treatment needed to reachthe LOC of 100; DAT 0 = The day of treatment, after sprays have dried; assumed to be approximately 12 hours.3DFR or TTR (μg/cm2) = dislodgeable foliar residues (for agricultural crops andornamentals) corresponding to DAT, based on results from a fluopicolide-specific DFRstudy (MRID 46708641) or turf transferable residue based on the standard assumption for turf. Plant metabolism data were usedto adjust residues for amount of BAM.4TC (cm2/hr) = transfer coefficients and associated activities from ExpoSAC Policy Memo #003.1“Agricultural Transfer Coefficients”, 8/17/2000.5MOE = MOE on the corresponding DAT. MOE = NOAEL / Daily Dose.Daily Dose = [(TTR or DFR x TC x 100% Dermal absorptionx 8-hr Exposure Time)] / [(CF: 1000 μg/mg) x (70-kg Body Weight)]Short-/intermediate-term NOAEL= 25 mg/kg/day. The LOC is 100.Page 53 of 66 10.0 Data Needs and Label Recommendations

10.1 Toxicology

• None.

10.2 Residue Chemistry

• Refer to the Fluopicolide Risk Assessme nt Document, DP #325091 (N. Dodd, 11/21/07).

10.3 Occupational and Residential Exposure

• None.

References:

Fluopicolide. PP#5F7016. Petition for Establishment of Tolerances for Use on Tuberous and Corm Vegetables, Leafy Vegetables (except Bras sica), Fruiting Vegetables, Cucurbit Vegeta bles, Grapes and on the Rotational Crop
Wheat. Summary of Analytical Chemistry and Residu e Data, DP Number326080, Amelia Acierto, 11/19/07

.

2,6-Dichlorobenzamide (BAM) as a Metabolite of Fluopicolide and Dichlobenil. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Actions for Fluopicolide on Tuberous and Corm Vegetables, Leafy Vegetables (excep t Brassica), Fruiting Vegetables, Cucurbit Vegetables, and Grapes, and for Indirect or Inadvertent Residues on the Rotational Crop Wheat, DP Number 340366, N. Dodd, 11/21/07.

O ccupational and Residential Risk Assessment of Metabolite BAM (to Support Request for Registration of Fluopicolide on a Variety of Crops, Residential Turf and Ornamentals), DP #345920, K. O’Rourke, 10/9/07.

Drinking Water Assessment for the BAM (2,6-Dichlorobenzamide) Degradate of Dichlobenil, DP #340773, J. Angier, Ph.D., 8/29/07.

Drinking Water Exposure Assessment for Fluopicolide Uses on Grapes, Vegetables, Potatoes, Sugar Beet, Onion, and Turf – Exposure of 2,6-Dichlorobenzamide (BAM), DP #325804, J. Lin, 5/3/07.Page 54 of 66 Appendix A: Toxicity Profile Table a nd Executive Summaries/Published Abstracts

Table 3.1a. Acute toxicity profile for soil metabolite 2,6-dich lorobenzamide (BAM) a

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

a According to Reregistration Eligibility Decision (1998)

Table 3.1b. SUBCHRONIC, CHRONIC, AND GE NO- TOXICITY PROFILE FOR METABOLITE, 2,6- DICHLOROBENZAMIDE (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/Guideline 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/Guideline 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 phosphatas e concentrations (F) and clinical signs (thin appearan ce, 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

Chronic Toxicity/ Carcinogenicity oral (rat; dietary) 42940202 (1971), 44043601 (1996), 44052901 (1996)

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

Borderline statistically signi ficant (P=0.049) increased incidence of hepatocellular adenomas at 25 mg/kg/day (FPage 55 of 66 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)

Unacceptable/Guideline due

to lack of individual animal

data 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 (P AS) 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 glands observed at 100 mg/kg/day (sustained)

870.5100

In vitro

bacterial

reverse mutation (Ames test) 43003603 (1992)

At concentrations up to 5000

μ 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

Unscheduled DNA synthesis (rat hepatocytes) 43003604 (1993)

At concentrations up to 1000

μ g/ml

Acceptable/Guideline Negative.Page 56 of 66 BAM

90-day rat

In a 13-week oral toxicity study (MRI D 00067654), 2,6-dichlorobenzamide technical (dichlobenil soil metabolite) (bat ch # 133/2/4/104; purity not repor ted) was administered to 10

Wistar rats/sex/dose in the diet at dose levels of 0, 50, 180, 600, or 2300 ppm (equal to 0, 4, 14, 49, or 172 mg/kg bw/day).

There were no treatment-related effects on surv ival. Increased relaxation scores (muscle hypotonus; P<0.05) were observed at 600 ppm on day 4 only in males and on days 91 and 92 only in females (Table 1). At 2300 ppm, increas es in relaxation scores (P<0.05) were observed

at each measurement in both sexes. Mean term inal body weights were decreased in both males (18%) and females (11%) at 2300 ppm, relative to controls. Mean body weight gain in males treated at 2300 ppm was decreased by 30% (P=0 .01) during weeks 2-11, while food consumption in the same group was decreased by 16% (P=0.01) . In females, mean body weight gain was decreased by 18% (P=0.01) afte r 11 weeks at 600 ppm and by 30% (P=0.01) at 2300 ppm. Food consumption was decreased by 17% (P=0.01) at 2300 ppm only.

No treatment-related changes were observed in he matological or urinalysis parameters. A 19% (P=0.02) decrease in mean blood coagulation tim e in males at 2300 ppm was not considered clinically significant and was also not dose-depe ndent. Mean serum urea concentration in males was increased by 55% (P<0.001) after 6 weeks at 2300 ppm. After 12 weeks in males, mean serum urea concentration was increased by 53% (P=0.04) at 600 ppm and by 69% (P=0.04) at 2300 ppm. In the absence of hist opathological correlates in the kidney or live r, increased urea concentrations were not considered toxicological ly significant. No bi ologically significant changes in clinical chemistry were observed in females. There was also no difference in bromosulphthalein serum retention (measure of liver function) between control and high-dose

animals.

Mean absolute thymus, heart, and brain weight s were decreased in males by 28% (P=0.01), 21% (P=0.01), and 7% (P=0.01), resp., while mean abso lute spleen, thymus, and heart weights were decreased in females by 13% (P=0.05), 23% (P= 0.01), and 9% (P=0.01), resp. However, there was no difference in mean relative weights for th ese organs in either sex, and the differences from control are likely related to the observed decreases in body weight. For these reasons and because histopathological correlates were lackin g in these organs, the changes in organ weights were not considered toxicologically significant.

The LOAEL for males is 600 ppm (49 mg/kg/day), based on redu ced skeletal muscle tone (males and females) and decreased body weight gain (females). The NOAEL is 180 ppm (14 mg/kg/day).

This 90-day oral toxic ity study in the rat is Acceptable/Guideline and does satisfy the guideline requirement for a 90-day or al toxicity study in rode nts (OPPTS 870.3100; OECD 408).Page 57 of 66 Chronic Toxicity/Carcinogenicity (Rat)

In a combined chronic toxicity/carcinogenicity study (MRID 42940202, 44052901), 2,6- dichlorobenzamide (dichlobenil soil metabolite) (99.5%; batch# 195) was administered in the diet for 106 weeks to Crl:CD®BR rats (35/sex/ dose) at daily dose leve ls of 0, 60, 100, 180, or 500 ppm (equal to 0, 2.2, 3.6, 6.5, or 19 mg/kg/da y in males and 0, 2.8, 4.7, 8.5, or 25 mg/kg/day in females). No treatment-related mortality or clinical signs of toxicity were observed.

Body weight, relative to cont rols, at 500 ppm was decreased by 13% (P<0.05) in males at termination and by 10-21% in females from week 13 until the end of the study. At 180 ppm, body weight in females was decreased by 13% at termination only. At 500 ppm, mean body weight gain was decreased by 10-16% in males a nd by 16-26% in females from on or after week 26. Body weight gain in females treated at 180 ppm was also decreased by 10-17% during the second half of the study. No treatment-related differences in food consumption or food efficiency were observed during the study. Opht halmological findings were similar between the control and high-dose groups.

Mean hematocrit levels were decreased in males at 500 ppm by 4% (week 39) and 11% (week 103). Decreases were also observed in females at 180 ppm (9%, week 26) and at 500 ppm (7%, week 52). Mean hemoglobin concentration (H b) was decreased by 3% (week 26), 8% (week 39), 7% (week 52), and 9% (week 103) at 500 ppm. A decrease (6 %) in females was observed at 180 ppm during week 26 only. Mean erythrocyte counts were decreased in males at 180 ppm (6%, week 40) and at 500 ppm (9%, week 26; 7%, week 39). In females, the same parameter was decreased at 500 ppm by 5% (week 26). Last , mean corpuscular hemoglobin concentration was also decreased by 3% at 500 ppm in females at week 103. Although st atistically significant, the magnitude of change in the hematological pa rameters was not biologically significant. No treatment-related changes were observed in clinical chemistry or urinalysis measurements.

A 25% increases in mean relative liver weight was observed at 500 ppm in females, as was a 48% increase in mean relative adrenal weight. The increase in liver weight was considered toxicologically significant due to the presence of liver histopat hology at 500 ppm. No treatmentrelated changes were observed at necropsy.

Non-neoplastic histopathological obs ervations in the liver are su mmarized in Tables 1 and 2. Dose-dependence was lacking for several paramete rs measured in the liver (Table 1). An increase in “moderate” fat deposition was observed at 500 ppm in females (14/35 vs. 6/26); however, the incidence of “marked” fat depositi on (more severe) was higher at 60 ppm than at 500 ppm. In addition, the reported incidences of fat deposition are unreliable, because the sum

of the number of animals with and without fat de position at each dose is le ss than the number of animals examined per dose. Upon reanalysis of non-neoplastic liver findings (MRID 44043601),

increases in the incidences of eosinophilic (focal) hepatocytes (21/34 vs. 5/26; P<0.01) and centrilobular hepatocytic vacuol ation (16/34 vs. 5/26; P<0.05) we re observed in males at 500 ppm (Table 2). The increase in eosinophilic (focal) staining hepatocytes at 100 ppm (P<0.01) was not considered toxicologically significant, since the incidence at the next highest dose (180 ppm) was not statistically significant. In fema les, an increase in the incidence of eosinophilicPage 58 of 66 hepatocytes (focal) was obser ved at 180 ppm (16/32 vs. 5/25 ; P<0.05) and 500 ppm (23/35 vs. 5/25; P<0.01). Increases were also observed at 500 ppm in the incidences of focal basophilic hepatocytes (23/35 vs. 9/25; P< 0.05) and eosinophilic (diffuse) hepatocytes (18/35 vs. 2/25; P<0.01). No treatment-related hi stopathological effects were obs erved in any other examined

organ.

The LOAEL is 500 ppm (19 mg/kg/day) in ma les, based on decreased body weight and body weight gain and an increased incidence of hepatocellular alteration (eosinophilic foci); and 180 ppm (8.5 mg/kg/day) in females, based on decreased body weight and body weight gain and an increased incidence of hepatocellu lar alteration (eosinophilic foci). The NOAEL is 180 ppm (6.5 mg/kg/day) in males and 100 ppm (4.7 mg/kg/day) in females.

Upon re-analysis of the tumor data (MRID 44043601), a marginally significant increase (P=0.049) in the incidence of hepatocellular adenomas was observed in females at 500 ppm (Table 3). No hepatocellular ca rcinomas were observed in female rats, and neither adenomas nor carcinomas were observed in males. Dosing wa s considered adequate at 500 ppm, based on decreased body weight and body wei ght gain and increased inciden ce of hepatocellular alteration

in both sexes.

This combined chronic toxicity/c arcinogenicity study in the rat is Acceptable/Guideline and does satisfy the guideline requirement for a comb ined chronic toxicity/carcinogenicity study in mammals [OPPTS 870.4300; OECD 453].

2-year dog

In a 2-year toxicity study (MRID 42940203), 2, 6-dichlorobenzamid e (dichlobenil soil metabolite) (97% a.i.; batch # 133-2-4-104) was ad ministered in the diet to Beagle dogs (4/sex/dose) at daily dose levels of 0, 60, 100, 180, or 500 ppm (equal to 0, 1.5, 2.5, 4.5, or 12.5 mg/kg/day). No animals died during the study, an d it was reported that there were no treatmentrelated clinical signs of toxicity. Mean body weight in male s treated at 500 ppm was decreased (non-stat. sig.) at weeks 54 (14%) and 103 (12% ), while in females mean body weight was decreased (P<0.01) at weeks 14 (12%), 54 (21% ), and 103 (23%) at 500 ppm, relative to controls. Mean cumulative body weight gains (w eek 0-103) in males were 19% and 38% lower than control values at 180 and 500 ppm, resp. However, neither was stat istically significantly different from controls (Table 1). Similarly, in females, mean cumulative body weight gains at 100, 180, and 500 ppm were 27%, 32%, and 69% lo wer than control values, respectively, without statistical significance. Changes in body weight or body weight gain at ≤ 180 ppm were not considered toxicologically significant based on the wide variation in these measured parameters (Tables 1 and 2). No adverse eff ects were observed on hematological or clinical chemistry parameters, at necropsy, or on orga n weights. Microscopic pathology was not

observed as a function of dose.

The LOAEL is 500 ppm (12.5 mg/kg/day), base d on decreased body weight and body weight gain. The NOAEL is 180 ppm (4.5 mg/kg/day).Page 59 of 66 This chronic toxicity study in the dog is Acceptable/Guideline and does satisfy the guideline requirement for a chronic toxicity stu dy in non-rodents (OPPTS 870.4100; OECD 452).

3-gen. repro. (rat)

The following executive summary provides an overview of the submitted results of a 3- generation reproduction study (MRI D 42940204), but for which individual animal data were not submitted. BAM (2,6-dichlorobenzamide; 99.5% a.i.; batch # 195) was administered in the diet to Long-Evans rats (10 males/dose and 20 females/dose in the P, F 1 , and F 2 generations) at daily dose levels of 0, 60, 100, or 180 ppm (e quivalent to 0, 4.5, 7.5, or 13.5 mg/kg/day 2 ) for 3 consecutive generations. Two litters were produc ed in each generation. The number of pups per litter was counted on postnatal days (PNDs) 1, 5, a nd 21 (also weighed). Litters were culled to ten animals each on PND 5. P, F 1 , and F 2 generation parental animals were weighed and examined for gross pathology on the day of term ination (unspecified). Organ weights were measured, and histopathology wa s performed on select F 3b weanlings only.

No treatment-related mortality was observed in the P, F 1b , or F 2b parental generations. A 6% (P<0.05) decrease in mean parental terminal body weight was observed at 180 ppm in the F 2b generation; however, the decrease was not biologically signific ant and not observed in P or F 1b parental animals. No treatment-relate d gross pathology was observed in P, F 1b , or F 2b parental animals. Fertility and gestation indices we re similar across treatment groups in P, F 1 , and F 2 generation dams.

The parental systemic LOAEL was not observ ed. The parental systemic NOAEL is 180 ppm (13.5 mg/kg bw/day).

The reproductive LOAEL was not observed. The reproductive NOAEL is 180 ppm (13.5 mg/kg bw/day).

No treatment-related differences we re observed in the mean number of pups per litter on PNDs 1, 5 (pre-cull), or 21 in the F 1 , F 2 or F 3 generations. Viability and lactation indices were similar across the treatment groups in F 1 , F 2 , and F 3 generation pups. Mean survival from birth to PND 5 (viability index) was slightly reduced (86.2%, P<0.01; vs. 95.7% in controls) at 180 ppm in the

F 3b generation; however this decrease was not obs erved in any other generation. In addition, mean survival from birth to weaning was similar across dose for each of th e three generations of offspring. Hyperexcitability was observed in pups (number not reported) from four litters in the

F 1b generation only.

Mean weanling weights (calculated as entire litter weight divided by number of pups per litter) at 180 ppm were decreased by 15% (P<0.05), 12% (P<0.05), and 14% (P<0.01) in the F 1b , F 3a , and

F 3b generations, respectivel y (Table 1); however, the decrease s were not dose-dependent, not

observed in the F 2 generation, and not calculated from individual pup body weights. No

treatment-related differences were observed in mean absolute brain weights or mean brain-tobody weight ratios in F 3b generation weanling rats of either sex. A 12% increase in mean

2 Calculated as follows: Dose (mg/kg bw/day) = (Concentrat ion of a.i. in ppm) x (1 ppm ÷ 0.075 mg/kg bw/day)Page 60 of 66 absolute kidney weights and mean kidney-to- body weight ratios (P< 0.01) was observed in F 3b generation female weanlings at 180 ppm. A 10% increase in mean absolute liver weights and mean liver-to-body weight ratios (P< 0.05) in males at 180 ppm and at ≥ 100 ppm in females was observed in this same generation. Changes in F 3b generation weanling mean organ weights were not considered toxicologically si gnificant, however, due to a lack of histopathological correlates in the liver and kidney.

The offspring LOAEL was not observed. The offspring NOAEL is 180 ppm (13.5 mg/kg bw/day).

This study in the rat is Unacceptable/Guideline and does not satisfy the guideline requirement for a 2-generation reproduction study in mammals (OPPTS 870.3800; OECD 416). Individual animal data necessary to veri fy summary results were not

submitted.

Developmental tox (rabbit)

In a prenatal developmental toxicity study (MRID 43003601, 43265201), 2,6-dichlorobenzamide (dichlobenil soil metabolite) (99.4% a.i.; batch# FUX001000) was admi nistered by gavage in 1% gum tragacanth to 16 pregnant New Zealand whit e rabbits/sex/dose from gestation day (GD) 7- 19 inclusive at daily dose levels of 0, 10, 30, or 90 mg/kg/day. Five (of 16) females treated at 90 mg/kg/day were sacrificed in extremis . Three of the 5 sacrificed high-dose dams had late abortions (GD 19, 21, and 22, resp.). The inciden ce of abortion followed by sacrifice at 0, 10, and 30 mg/kg/day was 1/16, 1/16, and 0/16, respectiv ely. The other 2/5 high-dose animals were sacrificed moribund. Moribund condition followed by sacrifice was observed in 1/16, 0/16, and 2/16 animals at 0, 10, and 30 mg/kg/day, resp. Th e incidence of thin appearance was increased at 90 mg/kg/day (10/16), whereas the incidences at 0, 10, and 30 mg/kg/da y were 1/16, 0/16, and 2/16, respectively.

A decrease (129%) in mean body weight gain, re lative to controls, wa s observed during the dosing period (GD 7-19) in does treated at 90 mg/kg/day. Similarly, food consumption at 90 mg/kg/day was decreased during the dosing period by 49%, relative to controls. Body weight gain and food consumption in high-dose animal s rebounded above control levels during the postdosing period (GD 20-28). No treatmen t-related gross pathology was observed.

The maternal LOAEL is 90 mg/kg bw/day, based on increased incidences of clinical signs (late abortion, thin appearance) and decrea sed (severe) body weight gain and food consumption during dosing. The maternal NOAEL is 30 mg/kg bw/day.

No treatment-related effects were observed on se veral developmental endpoints, including the number of resorptions, post-implantation loss, litt er size, and sex ratio. Mean fetal body weight at 90 mg/kg bw/day (33.9 g) was decr eased by 6%, relative to controls; however, the change was not statistically si gnificant and the mean value fell with in the historical control range (27.7 g39.4 g). No treatment-related cha nges were observed on the incidences of external defects.Page 61 of 66 An increase in the incidence of bipartite interparietal bone wa s observed at 90 mg/kg bw/day. Litter incidences were 1/14, 1/15, 2/14, and 3/11 l itters at 0, 10, 30, and 90 mg/kg/day. Bipartite interparietal bone is considered a malformation in rats. 3 Historical cont rol data were not provided for the litter incidences of bipartite interparietal bone, and fetal incidences only were reported for the current study. However, the fetal incidences were not st atistically significant different from concurrent controls, and the conc urrent control fetal incidence (0.8%) exceeded

that of the historical controls (0.3%). An increase in the in cidence of postcaval lung lobe agenesis was also observed at 90 mg/kg bw/day . Litter incidences were 0/14, 0/15, 1/14, and 3/11 at 0, 10, 30, and 90 mg/kg/day. The fetal inci dence of postcaval lung lobe agenesis at 90 mg/kg bw/day (3.2%) exceeded that of the histori cal controls (1.2%), whereas that at 30 mg/kg bw/day (0.9%) did not.

The developmental LOAEL is 90 mg/kg bw/day, based on increased incidences of late abortion and skeletal (bipar tite interparietal bone) and visceral (postcaval lung lobe agenesis) anomalies. The develo pmental NOAEL is 30 mg/kg bw/day.

This study in the rabbit is Acceptable/Guideline and does satisfy the guideline requirement for a prenatal developmental toxicity stud y in non-rodents (OPPTS 870.3700; OECD 414).

Acute (i.p.) (mouse)

The toxic effects of the herbic ide chlorthiamid (2,6-dichloro thiobenzamide) and its major environmental metabolite 2,6-dichlorobenzamide (DCBA) were examined in the nasal passages of C57Bl mice following single ip injections. Chlorthiamid (12.25, and 50 mg/kg) induced an

extensive destruction of the ol factory region, similar to that previously observed with the analogue dichlobenil (2,6-dichlorobe nzonitrile). Necrosis of Bowman's glands was evident first, whereas degeneration and necrosis of the olfact ory neuroepithelium deve loped less rapidly. The

lesions were most severe in th e dorsomedial region of the nasal cavity. At longer post-treatment intervals, the olfactory epithe lium was replaced by a respiratory-like epithelium, and there was fibrosis of the lamina propria. DCBA was al so toxic to the olfact ory region (100 mg/kg), inducing necrosis of the Bowman's glands and the neuroepitheliu m in the dorsomedial region of the nasal cavity. No lesions were observed in othe r parts of the nasal cavity or in the liver after

administration of chlorthiamid or DCBA. Ch lorthiamid (IC50 = 51 microM), but not DCBA, inhibited the covalent binding of 14C-labeled dichlobenil in the ol factory mucosa in vitro. It is proposed that the toxic effects of chlorthiamid and dichlobenil in the olfactory mucosa are mediated by common or closely related metabolites. 4

Genotoxicity

870.5100

In vitro

bacterial 43003603 (1992)

At concentrations up to 5000 Negative with or without activation.

3 Solecki R

, Burgin H

, Buschmann J et al. 2001. Harmonisation of rat fetal skeletal terminology and classification. Report of the Third Workshop on the Terminology in Developmental Toxicology. Berlin, 14-16 September 2000. Reprod Toxicol 15(6):713-21.

4 Brittebo EB, Eriksson C, Fe il 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 62 of 66 reverse mutation (Ames test) μ g/plate (-/+ activation) in S. typhimurium

Acceptable/Guideline

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)

870.5550

In vitro

Unscheduled DNA synthesis (rat hepatocytes) 43003604 (1993)

At concentrations up to 1000

μ g/ml

Acceptable/Guideline Negative.

Dichlobenil

5-day dermal (mouse)

2,6-Dichlorobenzonitrile (dichloben il) is an herbicide which has previously been reported by other investigators to be toxic to the olfactory mucosa followi ng intraperitoneal administration. The objective of this study was to determine whether a more occupationally-relevant route of pesticide exposure, namely dermal exposure to di chlobenil, also resulted in olfactory system damage. Male C57Bl mice were clipped and admini stered 0-200 mg/kg dich lobenil dermally in acetone either as a single dose or for five cons ecutive days. In addition, olfactory bulb glial fibrillary acidic protein (GFA P) analysis was performed in order to determine whether the damage in the olfactory mucosa translated into da mage which could be measured as an astroglial

increase in GFAP concentration in the olfact ory bulb, a marker of central nervous system neuronal loss. Olfactory mucosal histology reveal ed that single or multiple exposures to 50, 100, 150 and 200 mg/kg dichlobenil dermally caused olf actory epithelial damage (primarily sensory cell loss) in the epithelium lining the dorsal me dial meatus of the nasal cavity. While the olfactory epithelial lesions were much less severe than those caused by i.p. administration of dichlobenil, GFAP was signifi cantly elevated in both the 150 and 200 mg/kg treatment groups, demonstrating that relatively minor damage to a portion of the olfactory mucosa in the nasal cavity can be detected in the central nervous system. 5

7/28-day inhalation (rat)

In a subchronic inhalation toxicity study (MRID 46398701), Sprague-Dawley rats (10/sex/concentration) were exposed by nose-only inhalation to Dichlobenil technical (98.1% a.i., Lot/Batch #: BFI-4138) as a dust aeros ol at concentrations of 0, 2.3, 5.1, or 12 mg/m 3

5 Deamer NJ

, O'Callaghan JP

, Genter MB . (1994). Olfactory toxicity resulting from dermal application of 2,6- dichlorobenzonitrile (dichlobenil) in the C57Bl mouse. Neurotoxicology 15(2):287-93.Page 63 of 66 (equivalent to 0, 0.0023, 0.0051, and 0.012 mg/L, respec tively) for 6 hours/day, 5 days/week for

4 weeks.

There were no treatment-related effects on surviv al, clinical observations, FOB, motor activity, body weights, body weight gains, food cons umption, ophthalmoscopy, hematology, clinical chemistry, organ weights, gross pathology, or hist opathology in either sex at any concentration.

The LOAEL was not observed in this study, and the investigators did not test to the limit concentration (2 mg/L). However, the 7- day range-finding study (MRID 46653001) indicated that toxicity occurred at 21 mg/m 3 based on trace to mild nasal degeneration in males and

females. The nasal effects are considered advers e rather than adaptive since the nasal tissue has been determined to be a target by rout es of exposure othe r than inhalation.

The LOAEL is 21 mg/m 3 (equivalent to 5.5 mg/kg/day) based on increased incidence of nasal degeneration (from the 7 day study). The NOAEL is 12 mg/m 3 (equivalent to 3.1 mg/kg/day), the highest concentration tested.

At the request of the Agency, this study was c onducted for a duration of 28 days, instead of the 90 days required by Guideline OPPTS 870.3465. As ide from the different study duration, this study was conducted in accordance with Guideline OPPTS 870.3465.

This 28-day study is classified as Acceptable/Guideline and does satisfy the guideline requirement (OPPTS 870.3465; OECD 413) for a subchronic inhalation study in the rat.Page 64 of 66 Appendix B: Metabolism Assessment

B.1 Metabolism Guidance and Considerations

BAM is a metabolite and/or environmental degradate of both fluopicolide and dichlobenil.

BAM is included in the tolerance expressi on for dichlobenil because it is a major metabolite/degradate of dichlobenil.

BAM is a minor metabolite of fluopicolide. Th e tolerance expression fo r plants will include fluopicolide (parent) as an indi cator of combined residues of fluopicolide and BAM. HED

determined that BAM should be included as a resi due of concern for the risk assessment for the proposed uses of fluopicolide on the primary dom estic plants [cucurbit vegetables, fruiting vegetables, grapes, leafy vegeta bles, and tuberous and corm ve getables (except potato)].

Based on two aerobic soil metabolism studies, fluopico lide (parent) and BAM are the residues of concern in drinking water. BAM was a major me tabolite of fluopicolide in these aerobic soil metabolism studies, present at levels up to 40%.Page 65 of 66 B.2 Chemical Names and Structures

Appendix I. Chemical Names and Structures

Common name/code Chemical name Chemical structure

Dichlobenil 2,6-dichlorobenzonitrile

Cl Cl CN

Fluopicolide

AE C638206 2,6-dichloro- N -[[3-chloro-5- (trifluoromethyl-2- pyridinyl]methyl]benzamide Cl

Cl N H

N

O Cl F 3 C

AE C653711

BAM 2,6-dichlorobenzamide Cl

Cl N H

2

O

AE C657188

PCA 3-chloro-5-trifluoromethylpyridine2-carboxylic acid

N Cl F 3 C

OH O

AE 1344122

P1X 3-methylsulfinyl-5- trifluoromethylpyridine-2-carboxylic

acid

N F 3 C

OH O SOCH 3Page 66 of 66 Appendix C: Tolerance Reassessment Summary and Table

Not applicable

Appendix D: Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. Thes e studies, listed below, have been determined to require a review of their ethical conduct. They are also subject to review by the

Human Studies Review Board. The listed studies have recei ved the appropriate review.

The PHED Task Force, 1995. The Pesticide Hand lers Exposure Database, Version 1.1. Task Force members Health Canada, U.S. Envir onmental Protection Agency, and the National Agricultural Chemicals Associat ion, released February, 1995.