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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 Assessment for Proposed Uses of Fluopicolide 

on Tuberous and Corm Vegetables, Leafy Vegetables (except Brassica), Fruiting 

Vegetables, Cucurbit Vegetables, Grapes, Turf, and Ornamentals, and for Indirect 

or Inadvertent Residues on the Rotational Crop Wheat. PC Codes: 027402 

(BAM) and 027412 (Fluopicolide), Petition No: 5F7016, DP Number: 345918. 

 

 Regulatory Action: Section 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) 
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This human health risk assessment is for 2,6-dichlorobenzamide (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 dichlobenil 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 and risk assessment by Nancy Dodd (RAB3). 
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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 Toxicity 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............................................ 47 
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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/Cancer (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 and 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 Reassessment Summary and Table ................................................. 66 

Appendix D: Review of Human Research ............................................................................... 66 
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1.0 Executive Summary

2,6-Dichlorobenzamide (BAM) is a metabolite and/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 (except potato), leafy vegetables (except 

Brassica), fruiting vegetables, cucurbit vegetables, grapes, turf, and ornamentals and from 

established/pending uses of dichlobenil. This assessment 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 (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 applied 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 document. This risk assessment focused on the 

residues of BAM from both fluopicolide and dichlobenil. General information from the 

concurrent risk assessment for fluopicolide and the latest risk assessment for dichlobenil is 

mentioned below; however, for more details 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 dichlobenil. As discussed in the 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 Occupational 

Fluopicolide 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 tuberous and corm vegetables (except potato), leafy 
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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/acre (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 nurseries) are 0.54 lb ai/A for overhead sprays 

and 27 lb ai/A for drench treatments. 

 

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

Tolerances to be established for residues of the fungicide fluopicolide [2,6-dichloroN-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl] 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 livestock tolerances have been established. No 

Codex, Canadian, or Mexican Maximum Residue Limits (MRLs) or tolerances have been 

established for fluopicolide. 

Dichlobenil: 

Dichlobenil is registered as a granular (G) formulation (Casoron® 4G; EPA Reg. No. 400-168; 

date of issuance: 5/18/05) for use on apple, blueberry, cherry, filbert, grape, and pear at 6 lb 

ai/A/season and on blackberry, cranberry, 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 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. 
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Tolerances established (40 CFR §180.231) for the combined residues of the 

herbicide dichlobenil (2,6-dichlorobenzonitrile) 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 petitioner and establishment of a separate tolerance on cherries. 

However, as stated in the previous RED, the stone fruit crop group was included 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: Dichlobenil: 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 identified for acute dietary, chronic 

dietary, incidental oral, dermal, and inhalation exposures: 

The acute dietary (females 13-49) NOAEL is 30 mg/kg/day. The LOAEL is 90 

mg/kg/day based on a developmental 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 chronic 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-term exposures were compared to the NOAEL 

of 25 mg/kg/day from a dermal toxicity study in the mouse (using dichlobenil) in which 
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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 incidental oral exposures (for toddlers) were compared to the 

NOAEL of 14 mg/kg/day from a 90-day oral 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. The 10X FQPA Safety Factor is 

reduced to 1X for dermal and inhalation exposures because higher doses of BAM are needed to 

induce levels of olfactory toxicity that are similar to those caused by dichlobenil and olfactory 

toxicity was the endpoint chosen for these exposure scenarios. Since olfactory toxicity was the 

most sensitive endpoint, further protection under FQPA is not deemed necessary. 

Relating to the carcinogenic potential 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 “Group 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. The 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 dichlobenil use on nutsedge at 10 lb ai/A. 

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

uses is below HED’s level of concern for the general U.S. population and all population 

subgroups. The acute dietary exposure estimates at the 99.9th percentile of the exposure 

distribution are 11% of the acute Population Adjusted Dose (aPAD) for the general U.S. 

population and 28% aPAD for all infants (<1 year old), the most highly exposed group. 

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

dichlobenil uses is below HED’s level of concern for the general U.S. population and all 

population subgroups. The chronic dietary exposure 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 potential 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 
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approach is identical to the assessment for chronic effects; no separate carcinogenic risk 

assessment is necessary. 

Residential Exposure: As mentioned previously, BAM is known to be a metabolite of 

fluopicolide and dichlobenil. While it is necessary 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-occupational exposure. Therefore, BAM exposure estimates are 

based on fluopicolide use only. 

Residential handler exposure is not anticipated because the metabolite BAM is believed to form 

slowly in plants and soil after the product containing 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 experience exposure via incidental 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 exposure 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 that BAM is present at levels which reflect highend measurements observed in the longer-term metabolism studies in order to provide a 

protective assessment. The short-/intermediate-term 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 duration). 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 dietary risk. The acute dietary exposure estimates 

at the 99.9th 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 estimates 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 drinking water) exposures of BAM 

from both fluopicolide and dichlobenil uses and incidental oral exposures of BAM from 

fluopicolide. (Based on the dichlobenil use pattern, no significant residential exposure is 

expected to occur from dichlobenil.) 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 because of different toxicity. Incidental oral exposures related to 

turf activities (Table 6.2.5) have been combined with chronic dietary 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.
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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 population subgroups. 

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

relevant to that time frame is dietary exposure (i.e., any non-dietary exposures are short- and/or 

intermediate-term in duration). Therefore, the long-term 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 chronic 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 carcinogenic risk assessment is 

necessary.

Occupational Exposure/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 (fluopicolide) has been applied. 

Occupational postapplication exposure to BAM may occur after application of fluopicolide to 

agricultural crops as well as turf and ornamentals. (BAM which may occur after application of 

dichlobenil is not included since no significant exposure to BAM from dichlobenil was 

expected.) Postapplication inhalation exposure after application of fluopicolide and dichlobenil 

is expected to be negligible; however, dermal exposure to the metabolite BAM after application 

of fluopicolide is possible for workers entering treated areas to tend or harvest crops, 

mow/maintain turfgrass, or tend ornamentals 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 irritation, and in Category III for primary eye irritation. Per the Worker 

Protection Standard (WPS), a 12-hr restricted entry interval (REI) 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 for 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 appropriately contain language cautioning unprotected 

persons to keep out of treated areas until sprays have dried. 
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Environmental Justice Considerations: 

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

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-established procedures. In line with OPP 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 consumption. Extensive data on food consumption 

patterns are compiled by the USDA under the Continuing 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, specialized subgroups and exposure assessments are 

performed when conditions or circumstances warrant. Further considerations are currently in 

development as OPP has committed resources and expertise to the development of specialized 

software and models that consider exposure from 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 review of their ethical conduct. They are also subject to review by 

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

2.0 Ingredient Profile

2.1 Summary of Registered/Proposed Uses 

Fluopicolide is a fungicide to be used on tuberous 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 vegetables (except potato), 

fruiting vegetables, grapes, and leafy vegetables at the maximum seasonal application rate of 

0.34-0.375 lb active ingredient/acre (ai/A). For 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 (residential, commercial, golf course, and sod farms) range from 0.21 to 

0.27 lb ai/A, at 14-day intervals. The proposed 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 treatments, at 14-day intervals. (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 (Casoron® 4G; EPA Reg. No. 400-168; 

date of issuance: 5/18/05) for use on apple, blueberry, cherry, filbert, grape, and pear at 6 lb 
Page 12 of 66 

ai/A/season and on blackberry, cranberry, and raspberry at 4 lb ai/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

H2N

O

Empirical Formula C7H5Cl2N1O1

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, logPOW

(25°C) Kow = 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 (Kow) 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 Toxicity and Dose-Response Evaluation

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

• Acute (for olfactory toxicity): one intraperitoneal (single dose) 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 (rabbit) 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 quality is acceptable. 

3.1.3 Mammalian Toxicology 

The major dichlobenil soil metabolite and 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 dichlobenil (parent herbicide) based on submitted and 

published toxicity studies, the acute toxicity of BAM via the inhalation and dermal routes is 

expected to be less than or equal to that of dichlobenil. The acute toxicity of BAM via the 

inhalation and dermal routes is expected to be more than or equal to the toxicity of fluopicolide. 

A summary of the subchronic and chronic toxicity and genotoxicity 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 toxicological effect most often observed at the LOAEL. In the 

combined chronic toxicity/carcinogenicity study in the rat, toxicologically significant changes in 

body weight were also observed at the LOAEL, as were eosinophilic foci in the liver. In general, 

adverse liver effects were observed in the submitted 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 dichlobenil. BAM is not mutagenic 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. Although an increase in 

incidence of liver heptatocellular adenomas in female rats was reported at the highest dose 

tested, the statistical significance was considered marginal (p = 0.049) and there was no 

progression to liver hepatocellular carcinomas. BAM is not yet classified for cancer risk because 
Page 14 of 66 

it was tested in only one species. Since the carcinogenic potential of BAM has been evaluated in 

only one species, BAM is assumed to have the equivalent 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 dichlobenil is also assumed to be protective 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 toxicity 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). Although olfactory epithelial necrosis 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 and 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 sensory neurons that was observed following a single i.p. 

exposure of mice to BAM (Brittebo et al. 1991), clinical signs of neurotoxicity were observed in 

several submitted studies. In the 90-day oral toxicity 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), clinical signs of toxicity (slightly decreased 

muscle tone, slight loss of pinnae reflexes) were 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 

[

14C]-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 [14C]-AE C653711 at a nominal dose level of 10 mg/kg. The recovery of 

radioactivity over six days (seven days for the single high dose group) was determined, and the 

concentrations of radioactivity 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. Absorption 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 residual carcass) accounted for 
Page 15 of 66 

<2.3% of the administered dose 144 or 168 h post-dosing. In general, the highest concentrations 

of radioactivity were detected in the kidneys, liver, Harderian gland, skin (and fur), and adrenals. 

Measurement of radioactivity in the 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 samples was present as parent and a mercapturic acid 

conjugate of hydroxyl-chlorobenzamide. Metabolic profiles were qualitatively similar across 

dose levels, multiple doses had no appreciable effect on metabolism, and generally no 

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

for 50.3-78.6% of the administered dose. Unidentified metabolites accounted for 8.2-14.6% of 

the administered dose, but each compound represented <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 total radioactivity eliminated, 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 present at >5% of the administered dose were identified and included 

the cysteine and O-glucuronide conjugates of chlorobenzamide (3.4-6.6%), the cysteine 

conjugate of hydroxyl-chlorobenzamide (1.9-12.4%), the O-sulfate conjugate of 

dichlorobenzamide/thiomethyl-chlorobenzamide (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 exposure to the soil metabolite, 

BAM, is incomplete; however, since BAM is a soil metabolite of dichlobenil and a plant 

metabolite of fluopicolide, additional studies are 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 (dichlobenil 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 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, respectively). 

The incidence of abortion followed by sacrifice 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/day 
Page 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, relative to controls, was 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 animals rebounded above control levels during the postdosing period (GD 20-28). No treatment-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 decreased (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 several developmental endpoints, including the 

number of resorptions, post-implantation loss, litter size, and sex ratio. Mean fetal body weight 

at 90 mg/kg bw/day (33.9 g) was decreased by 6%, relative to controls; however, the change was 

not statistically significant and the mean value fell within the historical control range (27.7 g39.4 g). No treatment-related changes were observed on the incidences of external defects. 

An increase in the incidence of bipartite interparietal bone was observed at 90 mg/kg bw/day. 

Litter incidences were 1/14, 1/15, 2/14, and 3/11 litters 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 statistically significant 

different from concurrent controls, and the concurrent control fetal incidence (0.8%) exceeded 

that of the historical controls (0.3%). An increase in the incidence 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 incidence of postcaval lung lobe agenesis at 90 

mg/kg bw/day (3.2%) exceeded that of the historical 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 interparietal bone) and visceral (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 exposure in several short-term assays. 

3.3.4 Additional Information from Literature Sources 

Dichlobenil and its soil metabolite, BAM, have both been shown to be olfactory toxicants in 

adult animals following intraperitoneal (i.p.) exposure (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 (Eriksson and Brittebo 1995). Olfactory toxicity 

has also been demonstrated after dermal exposure of dichlobenil (Deamer at al. 1994) to adult 

animals. 

Experimental evidence suggests that dichlobenil and BAM are activated to the ultimate olfactory 

toxicant (currently unknown) by cytochrome 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 Bowman’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 dichlobenil and BAM (Harkema et al. 2006). Further, 

it has been hypothesized that damage to the olfactory 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 phosphorylation 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 susceptibility in the developmental toxicity study in 

the rabbit. In this study, an increase in the incidences of late abortion, as well as visceral and 

skeletal anomalies, were observed at the high dose. However, severe 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 retained for those exposure 

scenarios that do not rely on dichlobenil toxicity data. This is due to the incompleteness of the 

database with regard to the systemic neurotoxic potential of BAM, including 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 toxicity data, the risk 

assessment team recommends that the FQPA SF for BAM toxicity be reduced to 1X. The 

reasons for this are that, as stated previously, higher doses of BAM are needed to induce levels 

of olfactory toxicity that are similar to those caused by dichlobenil (Brandt et al. 1990; Brittebo 

et al. 1991; Eriksson and Brittebo 1995) and olfactory toxicity was the endpoint chosen for these 

exposure scenarios. Since olfactory toxicity was 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 was 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 late abortion and skeletal (bipartite interparietal 

bone) and visceral (postcaval lung lobe agenesis) anomalies. While the increased incidence of 

late abortion is not considered a single dose effect, the increased incidence of skeletal and 

visceral effects can be considered single-dose effects, enabling the use of this study in this risk 
Page 18 of 66 

assessment. This study and endpoint are the most appropriate for the population of concern, 

namely, women of childbearing age. The 10X FQPA SF has been retained in the form of a 

database uncertainty factor (UFDB) for this exposure scenario to account for the lack of guideline 

neurotoxicity data, including olfactory toxicity data, following oral exposure to BAM. 

3.4.2 aRfD - General Population 

The aRfD for the general population, including infants and children, 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 account 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 UFDB and an uncertainty factor for use of a LOAEL to extrapolate to a 

NOAEL (UFL). 

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 based 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 duration of exposure. The 10X FQPA SF has been retained in the 

form of a UFDB 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 decreased body weight gain observed in males and reduced skeletal 

muscle tone (observed on day 4 only in males and on days 91 and 92 only in females) at 49 

mg/kg/day in the 90-day oral toxicity study in rats. The study length and effects are appropriate 

for the durations of exposure, namely, 1-30 days (short-term) and 1-6 months (intermediateterm). The NOAEL of 14 mg/kg/day is protective of the population of concern, namely, infants 

and children. The 10X FQPA SF has been retained in the form of a UFDB for this exposure 

scenario to account for the lack of guideline neurotoxicity data, including olfactory toxicity data, 

following oral exposure to BAM. 

3.4.5 Dermal Absorption 

No dermal absorption study is available 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 intermediate- 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 dichlobenil in the rat was chosen 

for the short-, intermediate-, and long-term inhalation exposure scenarios. The effect of concern 

that is relevant to the selection of short-, intermediate-, and long-term inhalation endpoints is 

nasal degeneration observed at 5.5 mg/kg/day (NOAEL = 3.1 mg/kg/day) in this study using the 

parent herbicide dichlobenil. The route of exposure 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 published 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 Occupational Human Health Risk Assessments

Exposure Scenario Point of 

Departure 

Uncertainty/ 

FQPA Safety 

Factors 

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment 

Study and Toxicological 

Effects 

Acute Dietary 

(General population, 

including infants 

and children) 

LOAEL = 100 

mg/kg/day 

UFA = 10X 

UFH = 10X 

FQPA SF4,5 = 10X 

(includes UFL and 

UFDB) 

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 

UFA = 10X 

UFH = 10X 

FQPA SF4

 = 10X 

(includes UFDB) 

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 

UFA = 10X 

UFH = 10X 

FQPA SF4

 = 10X 

(includes UFDB) 

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 

UFA = 10X 

UFH = 10X 

FQPA SF4

 = 10X 

(includes UFDB) 

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 

UFA = 10X 

UFH = 10X 

FQPA SF = 1X 

(residential uses 

only) 

Residential and 

Occupational 

LOC for MOE 

= 100 

5-day dermal using dichlobenil6

(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

UFA = 10X 

UFH = 10X 

FQPA SF = 1X 

(residential uses 

only) 

Residential and 

Occupational 

LOC for MOE 

= 100 

28-day inhalation using 

dichlobenil6 (rat) LOAEL = 5.5 

mg/kg/day3

 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, UFA = extrapolation from animal to human (interspecies), UFH = potential 

variation in sensitivity among members of the human population (intraspecies), FQPA SF = FQPA Safety Factor, 

UFL = use of a LOAEL to extrapolate a NOAEL, UFDB = to account for the absence of key data, NOAEL = no 

observed adverse effect level, LOAEL = lowest observed adverse effect level, RfD = reference dose (a = acute, c = 

chronic), PAD = population adjusted dose, MOE = margin of exposure, LOC = level of concern, N/A = Not 

Applicable 

1 Deamer NJ, O'Callaghan JP, Genter MB. (1994). Olfactory toxicity resulting from dermal application of 2,6-

dichlorobenzonitrile (dichlobenil) in the C57Bl mouse. Neurotoxicology 15(2):287-93 
Page 21 of 66 

2

 Calculated as follows: [(NOAEL) x (m3 / 1000 L) x (10.26 L / hr) x 6 hr/day x (1 / 0.236 kg)], where NOAEL= 12 

mg/m3

 from 28-day inhalation toxicity study (Sprague Dawley rat) 3

 Calculated as follows: [(LOAEL) x (m3 / 1000 L) x (10.26 L / hr) x 6 hr/day x (1 / 0.236 kg)], where LOAEL= 21 

mg/m3

 from 28-day inhalation toxicity study (Sprague Dawley rat) 4

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

toxicity data. 

5

 The FQPA SF has been retained in the form of a UFL and UFDB 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, exposures 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 endpoint for dermal and inhalation (adverse nasal 

effects). 

3.5 Classification 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 in 
Page 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 previously, 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 marginal (P=0.049), dosing was considered adequate 

in the study, and the tumors were non-cancerous. A mouse cancer study was not available. 

BAM is a metabolite of dichlobenil (Group C, possible human carcinogen with the 

recommendation of an RfD approach to quantification of cancer risk). BAM is also a metabolite 

of fluopicolide (“not likely to be carcinogenic in humans”). 

Since the carcinogenic potential of BAM was evaluated 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 quantification of cancer 

risk is considered appropriate for BAM. 

3.6 Endocrine disruption 

EPA is required under the Federal Food, Drug, and Cosmetic Act (FFDCA), as amended by 

FQPA, to develop a screening program to determine whether certain substances (including all 

pesticide active and other ingredients) “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 systems, in addition to the estrogen hormone 

system. EPA also adopted EDSTAC’s recommendation that the Program include evaluations of 

potential effects in wildlife. For pesticide chemicals, EPA will use the Federal Insecticide, 

Fungicide, and Rodenticide Act (FIFRA) and, to the extent that effects in wildlife may help 

determine whether a substance may have an effect in humans, FFDCA authority to require the 

wildlife evaluations. As the science develops and resources allow, screening of additional 

hormone systems may be added to the Endocrine Disruptor Screening Program (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 and/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 reporting data to be available. 

5.0 Dietary Exposure/Risk Characterization 

5.1 Pesticide Metabolism and Environmental Degradation 

Refer to the concurrent Human Health Risk Assessment for fluopicolide (DP #325091, N. Dodd, 

11/21/07) for details regarding fluopicolide metabolism. Refer to Appendix B for names and 
Page 23 of 66 

structures of dichlobenil, fluopicolide, and metabolites/degradates. Refer to the Dichlobenil 

Reregistration Eligibility Decision (RED) (EPA-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 expression for dichlobenil because it is a major 

metabolite/degradate of dichlobenil in primary crops as shown in grape and apple metabolism 

studies (Dichlobenil Reregistration Eligibility Decision (RED), EPA-738-R-98-003, October 

1998): “In the grape metabolism study, mature grape vines were treated with a single soil 

application of uniformly benzene-ring labeled [14C]dichlobenil at a rate equivalent to 1x. HPLC 

analyses of the organosoluble and acid-hydrolyzed aqueous extracts indicated that BAM was the 

major residue, amounting to 82.1% of the total 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 application of uniformly benzene-ring labeled [14C]dichlobenil at a 

rate equivalent to 1x. HPLC analyses of the organosoluble extracts of the 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. The tolerance expression for plants will include 

fluopicolide (parent) as an indicator of combined residues of fluopicolide and BAM. BAM is 

included in the risk assessment for the proposed uses of fluopicolide on the primary domestic 

plants (cucurbit vegetables, fruiting vegetables, grapes, leafy vegetables, 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 metabolites 2,6-dichlorobenzamide (BAM;AE C653711) 

and 3-chloro-5-trifluoromethylpyridine-2-carboxylic 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 additional 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 amide 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 plant. (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 pertinent since dichlobenil is registered on 

orchard crops, grapes, and cane and bush berries, 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 rotational 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-hydroxybenzamide (AE C657378; 3-OH-BAM), 3-

methylsulfinyl-5-trifluoromethylpyridine-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 confined 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 rotational crops will include fluopicolide (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 all rotational crops except the grain 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 (parent), BAM, PCA, and 3-methylsulfinyl5-fluoromethylpyridine-2-carboxylic 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 14C- BAM (Dichlobenil Reregistration Eligibility 

Decision (RED), EPA-738-R-98-003, October 1998): Lactating goats were dosed with [Uphenyl]14C-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]14C-BAM at a dose level of 10 ppm for five days. The primary residue 

found in all poultry matrices collected was unchanged BAM. 

The residues of concern from fluopicolide in livestock commodities are tentative since additional 

information is needed to support the ruminant and poultry metabolism studies. Pending 

submission of the required additional data, HED has tentatively determined that the residue of 

concern in livestock commodities for a tolerance expression 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 the 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 versions of these methods, were used 

in the storage stability, crop field trial, processing, and field rotational 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 extraction 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 field 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 the 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 ppm 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 fluopicolide and BAM using some matrices. Protocol C testing of 

fluopicolide and BAM indicated that these compounds 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 representative nonfatty matrix, and F, using potato chips 

as the representative fatty matrix. Fluopicolide and BAM were found to be unrecoverable when 

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

was not conducted. BAM was found to be unrecoverable 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%) using Section 302, and not recovered using Sections 303 and 304. 
Page 26 of 66 

5.1.5 Environmental Degradation 

Based on two aerobic soil metabolism studies, fluopicolide (parent) and BAM are the residues of 

concern in drinking water. BAM was a major metabolite of fluopicolide in these aerobic soil 

metabolism studies, present at levels up to 40%. 

 “The major routes of degradation for fluopicolide and its degradates in laboratory studies are 

photodegradation in water and on soil and aerobic microbial degradation. Laboratory studies 

predict that fluopicolide should persist in soil and aquatic environments. 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, fluopicolide partitions from water into sediment 

(water dissipation half-lives of 21.6 to 24.7 days), then slowly degrades with system half-lives of 

967 to 1553 days. A mean KOC value of 340 suggests that fluopicolide could leach in soil but this 

leaching potential should abate due to a time dependent increase in KOC. 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 (EPA-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 generated (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-dealkylation cleavage products, including BAM at 0.09% 

of the total administered dose in rats. The radioactivity concentrations in any given tissue 

consistently represented considerably less than 1% of the administered 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 fluopicolide. In the livestock metabolism studies, 

the major residues (> 10% TRR) in ruminants were fluopicolide (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-(trifluoromethyl)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, fluopicolide (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 metabolized 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 intervals is on the surface of 

the plant. 

More extensive metabolism was observed in rotational 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 studies indicate the potential for occurrence 

of quantifiable residues of fluopicolide and metabolites in rotational 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 moderate acute toxicity (Category III) via the oral 

route of exposure. Because the subchronic and chronic toxicity of BAM is considered less than 

or equal to that of dichlobenil (parent herbicide) based on submitted and published toxicity 

studies, the acute toxicity of BAM via the inhalation and dermal routes is expected to be less 

than or equal to that of dichlobenil. The cPAD (0.0045 mg/kg/day) is based on decreased body 

weight and decreased body weight gain in the chronic oral toxicity study (dog). There was no 

evidence that BAM was either mutagenic or clastogenic 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 dichlobenil, the parent 

compound having the greatest carcinogenicity 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 neurotoxic. No evidence of endocrine mediated toxicity was observed. 

An FQPA SF of 10X for database uncertainty is applied to acute and chronic dietary and 

incidental oral exposure scenarios for incompleteness of the database with regard to the systemic 

neurotoxic potential of BAM, including olfactory toxicity) and also, in the case of acute dietary 

exposure, use of a LOAEL to extrapolate to a NOAEL. 

The soil metabolite BAM has a different 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 tolerances have been established. In drinking 

water, residues of concern from use of dichlobenil are dichlobenil 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 established at this time.

Table 5.1.8. Summary of Metabolites and Degradates to be included in the Risk 

Assessment and Tolerance Expression for Fluopicolide

Matrix Residues included in Risk 

Assessment1 

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) and 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 drinking water from uses of fluopicolide, 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 dichlobenil 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 the 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 known 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) corrections were applied for appropriate crops as well. Dichlobenil 

use is currently registered for: control of weeds in fruit and nut orchards (6 lbs a.i./acre), noncrop areas (12 lbs a.i./acre), and, control of nutsedge (10 lbs a.i./acre). Note that this 

memorandum replaces an earlier version where nutsedge usage was evaluated at 20 lbs a.i./acre; 

current label restricts this use to a maximum application 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 drinking water sources, using the Tier 1 groundwater model SciGrow, has 

also been conducted. Results and conclusions are contained herein. 

Below are the model results for predicted surface water concentrations (using the PRZMEXAMS model) and groundwater concentrations (using SciGrow). There were no specific 

PRZM scenarios for some uses (e.g., nutsedge control, rhubarb), so the closest surrogates were 

used instead. For rhubarb, the nearest surrogates for which scenarios were available (in terms of 

crop type, agricultural practices, and 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 control in non-crop areas, 

and Florida Turf used for weed control in non-crop areas. However, since the weed control in 

non-crop areas is typically applied beneath a semi-protective layer such as concrete, vinyl liner, 

etc., it is not expected to contribute substantially 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 the 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 different molecular weight (190.3 

g/mol) than parent dichlobenil (172 g/L), a further correction was applied. Thus, in terms of 

total mass, BAM represents 14.5% of parent dichlobenil. Results are listed below; rhubarb and 

orchard values have had Percent Cropped Area (PCA) adjustments of 87% applied, while the 

nutsedge control and other non-crop uses have no PCA applied. 
Page 30 of 66 

SURFACE WATER DRINKING WATER CONCENTRATIONS (ppb) FOR THE 

DEGRADATE BAM (RESULTING FROM DICHLOBENIL 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 BAM concentrations from SciGrow were obtained 

using the maximum proposed application rates (adjusted 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 USE – 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 results, 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 higher 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 application rate of 0.054 lb BAM/acre (based on a 

maximum seasonal application rate for nutsedge of 10 lb ai/A, a Koc 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 from 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 version 3.12 and EXAMS version 2.98. Ground water 

concentrations were estimated using the Tier I SCI-GROW model. 

Based on modeling results, the estimated surface water drinking water concentrations for 2,6-

dichlorobenzamide (BAM) – a major degradate of fluopicolide are: 

4.26 ug /L for the 1 in 10 year annual 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 derived from modeling on Florida peppers. The 1 in 10 

year annual mean (non-cancer chronic) was derived 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 μg/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 Koc of 30 

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

BAM in Drinking Water from both 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 dichlobenil 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 the highest residues in drinking water. 

Considering residues of BAM in drinking water from uses of fluopicolide, uses of dichlobenil, 

and uses of 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 dichlobenil use on nutsedge at 10 lb ai/A. Therefore, this 

assessment will use the highest estimate of 56.2 ppb (from SciGrow modeling of BAM 

residues from dichlobenil use on nutsedge) for the drinking water estimate for both the 

acute and chronic exposures: 

56.2 ppb for the 1 in 10 year annual peak 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 Brassica), Fruiting Vegetables, Cucurbit Vegetables, 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 (except 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 degradate of both fluopicolide and dichlobenil. This 

risk assessment includes residues of BAM in food and drinking water from uses of both 
Page 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 fluopicolide (parent) based on 

the submitted residue data: 

Tolerances to be established for residues of of the fungicide fluopicolide [ 2,6-dichloroN-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl] benzamide] as an indicator of combined 

residues of fluopicolide and its metabolite, 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 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 livestock tolerances have been established. No 

Codex, Canadian, or Mexican Maximum Residue Limits (MRLs) or tolerances have been 

established for fluopicolide. 

Dichlobenil: 

Dichlobenil is registered as a granular (G) formulation (Casoron® 4G; EPA Reg. No. 400-168; 

date of issuance: 5/18/05) for use on apple, blueberry, cherry, filbert, grape, and pear at 6 lb 

ai/A/season and on blackberry, cranberry, and raspberry at 4 lb ai/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 combined residues of the herbicide 

dichlobenil (2,6-dichlorobenzonitrile) 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 
Page 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 establishment of a separate tolerance on cherries. 

However, as stated in the previous RED, the stone fruit crop group was included 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: Dichlobenil: 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), leafy 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 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. Since 

the potato use will not be registered at this time and some restrictions will be applied to 

rotational crops, no livestock feed items are associated with this fluopicolide petition. DEEM 

default processing factors were used in the calculation. 

Magnitude of BAM Residues in Plants from Use of Fluopicolide 

Table 5.1.10.1. BAM Residues in Tuberous and Corm Vegetables (except Potato), Leafy Vegetables 

(except Brassica), Fruiting Vegetables, Cucurbit Vegetables, and Grapes from Field Trials with 

Fluopicolide.

Commodity Residue Levels (ppm) 

(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 NA 
Page 35 of 66 

Table 5.1.10.1. BAM Residues in Tuberous and Corm Vegetables (except Potato), Leafy Vegetables 

(except Brassica), Fruiting Vegetables, Cucurbit Vegetables, and Grapes from Field Trials with 

Fluopicolide.

Commodity Residue Levels (ppm) 

(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 Translation of Field Trial Data from Representative 

Commodities in the Crop Group Regulation to Other Commodities in Each Crop 

Group/Subgroup, HED Standard Operating Procedure 2000.1 (9/12/2000) was used to translate 

residue data from celery, head lettuce, leaf lettuce, or spinach to other Group 4 commodities. 

Magnitude of BAM Residues in Plants from Use of Dichlobenil 

Residues of BAM in crops from dichlobenil field trials 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. 

Commodity Residue Levels (ppm) 

(MRID) 

Formulation Total 

Applic. 

Rate 

(lb ai/A) 

PHI 

(days) n Min. Max. 

Apples 85 3 0.064 0.271 1,2 

(42177102) 

4%G 6 (1x) 

154-167 12 0.011 0.048 

Grapes1 

(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, Cranberries, 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 

Blueberries2 

(42304201) 

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

Blackberries1 

(42452803) 

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

Cherries No BAM data on cherries. Use plum data 

until data are available. 

Cranberries1 

(42452801) 

4%G 4 (1x) 158, 

166 

6 0.02-0.03

Filberts3 

(42476101) 

4%G 6 (1x) 160 3 <0.01 (Use 0.02 ppm because of approx. 50% 

degradation in storage.) 

Grapes3 

(42476103) 

4%G 6 (1x) 124-

173 

12 0.01-0.09* 

Peaches3 

(42476102) 

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

Plums1 

(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. 

Rhubarb4 

(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 the representative crops peach and plum were 

translated to the individual crops in the crop group without data (HED SOP 200.1: Guidance for 

Translation of Field Trial Data from Representative Commodities in the Crop Group Regulation 

to Other Commodities in Each Crop Group/Subgroup, HED Standard Operating Procedure 

(9/12/2000). The peach residue of 0.04 ppm was translated to apricot and nectarine; the plum 

residue of 0.46 ppm was translated to various plums and plumcot. 

For filberts, the highest reported residue was doubled to 0.02 because of approximately 50% 

degradation on storage. 
Page 37 of 66 

Magnitude of BAM Residues in Plants from 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 maximum 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 available for apples, the available data indicate that 

residues of BAM do not significantly concentrate in apple juice and wet pomace processed from 

apples individually spiked with BAM at approx 0.1 ppm (DP Number 203324, Paula Deschamp, 

7/1/94.) Residues concentrate in dry apple 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 plums ((MRID 42679001; DP Number 188926, C. Olinger, 3/16/04). 

Fluopicolide

Processing studies were conducted 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 

Grape Juice 1x 

(DP#321209) Raisin 4x2 

Tomato Paste NC 

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 (DEEM Default Processing Factors

Table 5.1.10.4. Summary of Processing Factors for BAM 

RAC Processed Commodity Processing Factor Used

Apple dried apple 8.0x 

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) 

Peach dried peach 7.0x 

Juice 1.5x 

Pear dried pear 6.25x 

Plum dried prune 5.0x 

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 Economic 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. Screening 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 were 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 processed 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, leafy vegetables, fruiting vegetables, cucurbit 

vegetables, grapes, and the rotational crop wheat. 

The dietary burdens of BAM residues in livestock from dichlobenil and fluopicolide uses, based 

on reasonably balanced diets, are presented in the 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 BAM Residues in Livestock from Fluopicolide and 

Dichlobenil Uses.*

Feedstuff Type1 % Dry 

Matter2 % Diet2

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 0.054 0.10 

Wheat, milled byproducts CC 88 40 0.0185 0.0082 

CC (untreated) CC N/A 5 N/A6 -- 

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 0.271 0.068 

Wheat, milled byproducts CC 88 35 0.0185 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 0.0185 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 0.0185 0.009 

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

PC (untreated) PC N/A 15 N/A -- 

TOTAL BURDEN -- -- 100 0.009 
Page 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 factors 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 dichlobenil and no livestock tolerances have been 

proposed for fluopicolide. Since the potato use will 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 feed items are associated with this fluopicolide 

petition. 

5.1.11 International Residue Limits.

This topic is not applicable since there 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 Brassica), Fruiting Vegetables, Cucurbit Vegetables, and Grapes and for Indirect or 

Inadvertent Residues 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 (except 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 Evaluation Model DEEM-FCIDTM, Version 2.03, which 

use food consumption data from the U.S. Department 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 herbicide dichlobenil is 

classified as “Group C, possible human carcinogen” with the RfD approach utilized for 

quantification of human risk. 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 was conducted. Maximum residues of BAM from 

fluopicolide field trials on tuberous and corm vegetables (except potato), leafy 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. 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 drinking water) exposure to BAM from fluopicolide and dichlobenil 

uses is below HED’s level of concern for the general U.S. population and all population 

subgroups. The acute dietary exposure estimates at the 99.9th 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. 

5.2.2 Chronic Dietary Exposure/Risk 

A conservative chronic exposure assessment was conducted as described above.

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

dichlobenil uses is below HED’s level of concern for the general 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. population 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 potential 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 chronic effects; no separate carcinogenic risk 

assessment is necessary. 
Page 42 of 66 

Table 5.2. Results of Acute and Chronic Dietary (Food + Water) Exposure and Risk 

Estimates for BAM.

DEEM-FCID 

Population Subgroup PAD, mg/kg/day Exposure, mg/kg/day % PAD 

Acute Dietary Estimates (99.9th) 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, HED considers the carcinogenic potential of BAM to be 

similar to that of dichlobenil, the parent having the greatest carcinogenic potential. Therefore, 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 separate 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), leafy 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)

Occupational 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 exposure from all sources of BAM, the use pattern 

for dichlobenil is not expected to result in scenarios with significant residential exposure. 

Dichlobenil products are not intended for use by residential 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 negligible from these sources. Therefore, BAM 

exposure estimates are based on fluopicolide use only. 

Two products containing fluopicolide (i.e., V-10161 VPP Fungicide and V-10162 VPP 

Fungicide) are proposed for application to residential turfgrass and recreational sites. Although 

the label does not prohibit homeowners using these products, residential handler exposure was 

not evaluated because the metabolite BAM is believed to form slowly in plants and soil after the 

product containing the parent fluopicolide 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 because the metabolite BAM is believed to form 

slowly in plants and soil after the product containing the parent (fluopicolide) has been applied. 

6.2 Residential Postapplication Exposure

The following postapplication exposure scenarios resulting from lawn treatment were assessed: 

(1) adult and toddler postapplication dermal exposure, (2) toddlers’ incidental ingestion of 

pesticide residues on lawns from hand-to-mouth transfer, (3) toddlers’ object-to-mouth transfer 

from mouthing of pesticide-treated turfgrass, and (4) toddlers’ incidental ingestion 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 approaches by HED’s Science Advisory Council for 

Exposure (ExpoSAC). 

In order to adjust the TTR estimates to reflect BAM residues, 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 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), lettuce 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 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 transferable, and that they are present at 4% of the initial amount of parent 

fluopicolide. In addition, the drinking water assessment (D340773, 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 exposure 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 exposure calculations and the results are presented in 

Tables 6.2.1 through 6.2.4. 

The exposure estimates are based on some upper-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 considered 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 assumptions regarding transfer of chemical residues 

and hand-to mouth activity. The estimated exposures are believed to be reasonable high-end 

estimates based on observations from chemical-specific field studies and professional judgment. 

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

incidental oral scenario are above the LOC of 1,000; they are not of concern. Although dermal 

and incidental oral exposure may co-occur for toddlers, the toxic effects from these two routes 

are different. Therefore, only the incidental oral exposures were combined. As shown in Table 

6.2.5, the Total incidental oral MOE for children is 62,000, which is greater than the LOC of 

1,000 on the day of application, and not of concern. 
Page 45 of 66 

Table 6.2.1. Postapplication Dermal Exposure and Risk from Treated Lawns

Dermal 

Subgroup 

Exposed 

Application 

Rate 

 (lb ai/A) 

Postapplication 

day (t) 

Fraction of ai 

Transferable 

from the 

Foliage 

Turf 

Transferable 

Residue 1

(μg/cm2) 

Dermal 

Transfer 

Coefficient 

(cm2/hr) 

 Body 

Weight 

(kg) 

 Daily Dermal 

Dose 2

(mg/kg/day) Shor

Intermedi

Adults 14,500 70 0.0025 10,0

Children 

0.27 0 0.05 0.0060 

5,200 15 0.0042 6,00

1 Turf Transferable Residue Postapplication day (μg/cm2)= Application rate of fluopicolide (lb ai/A) x Fraction of ai Transferable from the Foliage x (1- Frac That Dissipates Daily, 0.1) Postapplication day x 4.54E+8 μg/lb x 2.47E-8 A/cm2 x 0.04 (to adjust for amount of BAM, based on plant metabolism data) 2 Daily Dermal Dose = (Turf transferable Residue (μg/cm2) x Absorption Factor (1) x Dermal Transfer Coefficient (cm2/hr) x Exposure Time (2 hrs/damg/μg] / [Body Weight (kg)] 3 Dermal MOE = Dermal NOAEL / Daily Dermal Dose; where Short-/Intermediate-term NOAEL = 25 mg/kg/day. 

Table 6.2.2. Postapplication Oral Hand-to-Mouth Exposure and Risk for Children from Treated Lawn

Application 

Rate 

 (lb ai/A) 

Postapplication 

day (t) 

Fraction of ai 

Transferable 

from the 

Foliage 

Turf 

Transferable 

Residue 1

(μg/cm2) 

Hand 

Surface 

Area 

(cm2/event) 

Saliva 

Extraction 

Factor 

 Frequency 

(events/ hr) 

Body 

Weight 

(kg) 

 Daily Dose2(mg/kg/day) 

0.27 0 0.05 0.0060 20 50% 20 15 0.00016 

1 Turf Transferable Residue Postapplication day (μg/cm2)= Application rate of fluopicolide (lb ai/A) x Fraction of ai Transferable from the Foliage x (1- FracThat Dissipates Daily, 0.1) Postapplication day x 4.54E+8 μg/lb x 2.47E-8 A/cm2 x 0.04 (to adjust for amount of BAM, based on plant metabolism data) 2 Daily Dose = (Turf Transferable Residue (μg/cm2) x Hand Surface Area (cm2/event) x Saliva Extraction factor x Frequency (events/hr) x 0.001 mg/ time (2 hrs/day)] / [Body Weight (kg)] 3 Oral 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 for Children from Treated 

Application Rate 

 (lb ai/A) 

Postapplication day 

(t) 

Fraction of ai 

Transferable 

from the Foliage 

Grass/Object 

Residue 1

(μg/cm2) 

Ingestion Rate 

(cm2/day) 

Body 

Weight 

(kg) 

 Daily Dose2(mg/kg/day) 

0.27 0 0.29 0.035 25 15 0.000058 

1Grass/Object residue Postapplication day (μg/cm2) = Application rate of fluopicolide (lb ai/A) x Fraction of ai Transferable from the Foliage (from MRID#: 

Fraction of Residue That Dissipates Daily) Postapplication day x 4.54E+8 μg/lb x 2.47E-8 A/cm2 x 0.04 (to adjust for amount of BAM, based on plant met

2 Daily 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 MOE3

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 Dose2

(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/cm2) = 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/cm2

 x 0.67 cm3/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 rate (mg/day) x 0.000001 g/μg] / [Body Weight (kg)]] 3

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

Table 6.2.5. Aggregate Exposure and Risk Estimates from Residential Lawns

Total MOE 4 Scenario 

and 

Pathway 

TTR/GR/SR0

(μg/cm2 or g) 1

PDR0-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"; SR0=soil residue on day “0". 2

 PDR0norm=potential dose rate on day “0”. 3 MOE = NOAEL/PDR; 

 where Short-/Intermediate-term Dermal NOAEL = 25 mg/kg/day, and Incidental Oral NOAEL = 14 mg/kg/day. 4

 Total Incidental Oral MOE = 1/ [(1/MOEHand-to-Mouth) + (1/MOEGrass) + (1/MOESoil)] 

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 recreational 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 application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application 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 other parties to develop the best spray drift 

management practices. The Agency is now requiring interim mitigation measures for aerial 

applications that must be placed on product labels/labeling. The Agency has completed its 
Page 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 developing a policy on how to appropriately apply the data and the 

AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast 

and ground hydraulic methods. After the policy is in place, the Agency may impose further 

refinements in spray drift management practices to reduce off-target drift and risks associated 

with aerial as well as other application types where appropriate. 

Please note that as indicated in this assessment, fluopicolide is directly 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 Assessments and Risk Characterization

Two products containing fluopicolide (i.e., V-10161 VPP Fungicide and V-10162 VPP 

Fungicide) are proposed for application to residential turfgrass and recreational sites. The use 

pattern for dichlobenil is not expected to result in significant residential exposure. Therefore, the 

non-dietary BAM exposure estimates are based on fluopicolide use only. 

There is a potential for short-/intermediate-term non-occupational exposure to BAM during 

postapplication activities. Chronic exposure is not expected for the proposed use patterns 

associated with fluopicolide. 

7.1 Acute 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 duration). Therefore, 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 section, 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 exposures 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-Term Aggregate Risk Calculations 

(1/MOE Approach – All LOCs Identical)

Short- or Intermediate-Term Scenario 

Population 

NOAEL 

mg/kg/day 

LOC1 

Max 

Allowable 

Exposure2

mg/kg/day 

Average 

Food & Water 

Exposure 

mg/kg/day 

Residential 

Exposure3

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

 UFA = 10x (extrapolation from animal to human (interspecies); UFH = 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 population subgroups. 

 

7.4 Long-Term Aggregate Risk 

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

relevant to that time frame is dietary exposure (i.e., any non-dietary exposures are short- and/or 

intermediate-term in duration). Therefore, the long-term aggregate risk 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 potential 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 chronic effects; no separate carcinogenic risk 

assessment is necessary. 

8.0 Cumulative Risk Assessments 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 common mechanism of toxicity finding as to BAM 

and any other substances and BAM does not appear to produce a toxic metabolite produced by 

other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that 

BAM has a common mechanism of toxicity with other substances. For information regarding 

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

evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s 

Office of Pesticide Programs concerning common mechanism determinations and procedures for 

cumulating effects from substances found to have a common mechanism on EPA’s website at 

http://www.epa.gov/pesticides/cumulative/.

Fluopicolide and dichlobenil can form the common metabolite BAM. To establish new 

tolerances for fluopicolide, EPA conducted this human health risk assessment for exposure to 

BAM resulting from the use of current and proposed uses of fluopicolide and the herbicide 

dichlobenil. The risk assessment is conservative in terms of potential dietary and non-dietary 

exposures. In addition, the Agency retained the additional 10X FQPA safety factor for the 

protection of infants and children. The assessment includes evaluations of risks for various 

subgroups, including those composed of infants and children. 
Page 50 of 66 

9.0 Occupational Exposure/Risk Pathway

Occupational 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

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 (fluopicolide) has been 

applied. 

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

The registration action for fluopicolide involves application to agricultural crops as well as turf 

and ornamentals. Postapplication 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 turfgrass, or tend ornamentals in nurseries and greenhouses. A 

dislodgeable foliar residue (DFR) study on fluopicolide was submitted by the registrant (MRID#: 

46708641) for use in assessing postapplication activities. As discussed in the fluopicolide 

assessment (K. O’Rourke, DP #326082, 10/9/07), this study is considered to be acceptable, and 

the results indicate that the 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 available. Therefore, turf scenario 

calculations were based on the standard 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 fruit, lettuce leaves, and potato foliage and tubers, 

accounting for 51-98% TRR. The metabolite BAM was found in foliarly-treated grapes (fruit), 

lettuce 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 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/transferable, and that 

they are present at 4% of the initial 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 are 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-term MOEs for BAM are greater than the LOC of 

100 on the day of application for all agricultural, turf and ornamental uses of fluopicolide, and 

are not of concern. 

The fluopicolide technical material has been classified in Toxicity Categories III-IV for acute 

dermal and primary skin irritation, and Category III for primary eye irritation. Per the Worker 

Protection Standard (WPS), a 12-hr restricted entry interval (REI) 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 for 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 appropriately contain language cautioning unprotected 

persons to keep out of treated areas until sprays have dried. 
Page 52 of 66 

Table 9.2. Summary of Estimated Post-application MOEs for Agricultural Crops 

Crop 

Application 

Rate 

(lb ai/A) 1 DAT 2

DFR or 

TTR 3

(μg/cm2) 

TC 4

(cm2/hr) Activity 4

Agricultural Crops 

500 Irrigation, scouting, thinning, weeding immature plants 700 Irrigation and scouting mature plants 

Fruiting Vegetables 0 0.017 1,000 Hand harvesting, pruning, staking, tying 

500 Irrigation, scouting, thinning, weeding immature plants 

1,500 Irrigation, scouting, weeding mature plants 

Cucurbit & 

Leafy 

Vegetables 

0 0.017 

2,500 Hand harvesting, pulling, pruning, and thinning mature plan

500 Hedging, irrigation, scouting, hand weeding 

1,000 Scouting 5,000 Hand harvest, leaf pulling, thinning, pruning, training/tying 

Grapes 0 0.017 

10,000 Girdling and cane turning 

300 Irrigation, scouting, thinning, weeding immature plants 

1,500 Irrigation and scouting mature plants 

Sweet Potatoes 

0.13 

0 0.017 

2,500 Hand harvesting 

Turf

3,400 Mowing and other maintenance activities 

Turf 0.27 0 0.0060 

6,800 Sod harvesting and transplanting 

Ornamentals – Nursery Stock

Nursery 100 Hand pruning containerized ornamentals 

Stock 0.54 0 0.070 400 Harvesting, ball/burlap containerized ornamentals 

Ornamentals – Cut Flowers

500 Pinching 

Cut Flowers 0.54 0 0.070 

5,100 Hand harvesting, pruning, thinning, pinching 

1 Maximum application rate from proposed fluopicolide labels.2 DAT = Days after treatment needed to reach the LOC of 100; DAT 0 = The day of treatment, after sprays have dried; assumed to be approxim3 DFR or TTR (μg/cm2) = dislodgeable foliar residues (for agricultural crops and ornamentals) corresponding to DAT, based on results from a 

study (MRID 46708641) or turf transferable residue based on the standard assumption for turf. Plant metabolism data were used to adjust resid

4 TC (cm2/hr) = transfer coefficients and associated activities from ExpoSAC Policy Memo #003.1 “Agricultural Transfer Coefficients”, 8/17/25 MOE = MOE on the corresponding DAT. MOE = NOAEL / Daily Dose. 

 Daily Dose = [(TTR or DFR x TC x 100% Dermal absorption x 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 Assessment 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 Brassica), Fruiting Vegetables, Cucurbit Vegetables, 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 (except 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. 

Occupational 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 and Executive Summaries/Published Abstracts 

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

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

870.1100/Acute oral toxicity (mouse) 42940201 LD50 ≥ 1538/1144 mg/kg (M/F) III 

870.1100/Acute oral toxicity (rat) 46708602 LD50 ≥ 2000 mg/kg (M) and 

LD50 ≥ 300 mg/kg (F) 

II 

a According to Reregistration Eligibility Decision (1998) 

Table 3.1b. SUBCHRONIC, CHRONIC, AND GENO- 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 phosphatase concentrations (F) and 

clinical signs (thin appearance, dull coat, hair loss) (M) 

870.4700 

Chronic 

toxicity oral 

(dogs; dietary) 

42940203 (1971) 

0, 60, 100, 180, or 500 ppm 

(equal to 0, 1.5, 2.5, 4.5, or 

12.5 mg/kg/day) 

Acceptable/Guideline

NOAEL = 4.5 mg/kg/day 

LOAEL = 12.5 mg/kg/day based on decreased body weight 

and body weight gain 

870.4300 

Combined 

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 significant (P=0.049) increased 

incidence of hepatocellular adenomas at 25 mg/kg/day (F 
Page 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 (PAS) staining of contents of 

Bowman’s glands (measure of mucus production) observed at 

≥25 mg/kg/day (reversible); degeneration of olfactory 

epithelium and necrosis of Bowman’s glands observed at 100 

mg/kg/day (sustained) 

870.5100 

In vitro

bacterial 

reverse 

mutation 

(Ames test) 

43003603 (1992) 

At concentrations up to 5000 

μg/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 

μg/ml 

Acceptable/Guideline

Negative. 
Page 56 of 66 

BAM 

90-day rat

In a 13-week oral toxicity study (MRID 00067654), 2,6-dichlorobenzamide technical 

(dichlobenil soil metabolite) (batch # 133/2/4/104; purity not reported) 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 survival. 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, increases in relaxation scores (P<0.05) were observed 

at each measurement in both sexes. Mean terminal 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) after 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 hematological or urinalysis parameters. A 19% 

(P=0.02) decrease in mean blood coagulation time in males at 2300 ppm was not considered 

clinically significant and was also not dose-dependent. 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 histopathological correlates in the kidney or liver, increased urea 

concentrations were not considered toxicologically significant. No biologically 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 weights were decreased in males by 28% (P=0.01), 21% 

(P=0.01), and 7% (P=0.01), resp., while mean absolute 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 these 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 lacking 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 reduced 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 toxicity study in the rat is Acceptable/Guideline and does satisfy the guideline 

requirement for a 90-day oral toxicity study in rodents (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 levels of 0, 60, 100, 180, or 

500 ppm (equal to 0, 2.2, 3.6, 6.5, or 19 mg/kg/day 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 controls, 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 and 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. Ophthalmological 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 (Hb) 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 statistically significant, 

the magnitude of change in the hematological parameters 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 histopathology at 500 ppm. No treatmentrelated changes were observed at necropsy. 

Non-neoplastic histopathological observations in the liver are summarized in Tables 1 and 2. 

Dose-dependence was lacking for several parameters 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 deposition (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 deposition at each dose is less 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 vacuolation (16/34 vs. 5/26; P<0.05) were 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 females, an increase in the incidence of eosinophilic 
Page 58 of 66 

hepatocytes (focal) was observed 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 histopathological effects were observed in any other examined 

organ. 

The LOAEL is 500 ppm (19 mg/kg/day) in males, 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 hepatocellular 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 carcinomas were observed in female rats, and neither adenomas nor 

carcinomas were observed in males. Dosing was considered adequate at 500 ppm, based on 

decreased body weight and body weight gain and increased incidence of hepatocellular alteration 

in both sexes. 

This combined chronic toxicity/carcinogenicity study in the rat is Acceptable/Guideline and 

does satisfy the guideline requirement for a combined chronic toxicity/carcinogenicity study in 

mammals [OPPTS 870.4300; OECD 453]. 

2-year dog

In a 2-year toxicity study (MRID 42940203), 2, 6-dichlorobenzamide (dichlobenil soil 

metabolite) (97% a.i.; batch # 133-2-4-104) was administered 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, and it was reported that there were no treatmentrelated clinical signs of toxicity. Mean body weight in males 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 (week 0-103) in males were 19% and 38% lower 

than control values at 180 and 500 ppm, resp. However, neither was statistically 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% lower 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 effects were observed on hematological or clinical 

chemistry parameters, at necropsy, or on organ weights. Microscopic pathology was not 

observed as a function of dose. 

The LOAEL is 500 ppm (12.5 mg/kg/day), based 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 study 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 (MRID 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, F1, and F2 generations) at daily 

dose levels of 0, 60, 100, or 180 ppm (equivalent to 0, 4.5, 7.5, or 13.5 mg/kg/day2) for 3 

consecutive generations. Two litters were produced in each generation. The number of pups per 

litter was counted on postnatal days (PNDs) 1, 5, and 21 (also weighed). Litters were culled to 

ten animals each on PND 5. P, F1, and F2 generation parental animals were weighed and 

examined for gross pathology on the day of termination (unspecified). Organ weights were 

measured, and histopathology was performed on select F3b weanlings only. 

No treatment-related mortality was observed in the P, F1b, or F2b parental generations. A 6% 

(P<0.05) decrease in mean parental terminal body weight was observed at 180 ppm in the F2b 

generation; however, the decrease was not biologically significant and not observed in P or F1b 

parental animals. No treatment-related gross pathology was observed in P, F1b, or F2b parental 

animals. Fertility and gestation indices were similar across treatment groups in P, F1, and F2

generation dams.

The parental systemic LOAEL was not observed. 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 were observed in the mean number of pups per litter on PNDs 

1, 5 (pre-cull), or 21 in the F1, F2 or F3 generations. Viability and lactation indices were similar 

across the treatment groups in F1, F2, and F3 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 

F3b generation; however this decrease was not observed in any other generation. In addition, 

mean survival from birth to weaning was similar across dose for each of the three generations of 

offspring. Hyperexcitability was observed in pups (number not reported) from four litters in the 

F1b 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 F1b, F3a, and 

F3b generations, respectively (Table 1); however, the decreases were not dose-dependent, not 

observed in the F2 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 F3b generation weanling rats of either sex. A 12% increase in mean 

 

2 Calculated as follows: Dose (mg/kg bw/day) = (Concentration 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 F3b 

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 F3b generation weanling mean organ weights were 

not considered toxicologically significant, 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 verify 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 administered by gavage in 1% 

gum tragacanth to 16 pregnant New Zealand white 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 incidence of abortion followed by sacrifice 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, resp. The incidence of thin appearance was increased 

at 90 mg/kg/day (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, relative to controls, was 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 animals rebounded above control levels during the postdosing period (GD 20-28). No treatment-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 decreased (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 several developmental endpoints, including the 

number of resorptions, post-implantation loss, litter size, and sex ratio. Mean fetal body weight 

at 90 mg/kg bw/day (33.9 g) was decreased by 6%, relative to controls; however, the change was 

not statistically significant and the mean value fell within the historical control range (27.7 g39.4 g). No treatment-related changes were observed on the incidences of external defects. 
Page 61 of 66 

An increase in the incidence of bipartite interparietal bone was observed at 90 mg/kg bw/day. 

Litter incidences were 1/14, 1/15, 2/14, and 3/11 litters at 0, 10, 30, and 90 mg/kg/day. Bipartite 

interparietal bone is considered a malformation in rats.3

 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 statistically significant 

different from concurrent controls, and the concurrent control fetal incidence (0.8%) exceeded 

that of the historical controls (0.3%). An increase in the incidence 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 incidence of postcaval lung lobe agenesis at 90 

mg/kg bw/day (3.2%) exceeded that of the historical 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 interparietal bone) and visceral (postcaval lung lobe 

agenesis) anomalies. The developmental 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 study in non-rodents (OPPTS 870.3700; OECD 414). 

Acute (i.p.) (mouse)

The toxic effects of the herbicide chlorthiamid (2,6-dichlorothiobenzamide) 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 olfactory region, similar to that previously observed with the 

analogue dichlobenil (2,6-dichlorobenzonitrile). Necrosis of Bowman's glands was evident first, 

whereas degeneration and necrosis of the olfactory neuroepithelium developed less rapidly. The 

lesions were most severe in the dorsomedial region of the nasal cavity. At longer post-treatment 

intervals, the olfactory epithelium was replaced by a respiratory-like epithelium, and there was 

fibrosis of the lamina propria. DCBA was also toxic to the olfactory region (100 mg/kg), 

inducing necrosis of the Bowman's glands and the neuroepithelium in the dorsomedial region of 

the nasal cavity. No lesions were observed in other parts of the nasal cavity or in the liver after 

administration of chlorthiamid or DCBA. Chlorthiamid (IC50 = 51 microM), but not DCBA, 

inhibited the covalent binding of 14C-labeled dichlobenil in the olfactory 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, Feil V, Bakke J, Brandt I. (1991). Toxicity of 2,6-dichlorothiobenzamide (chlorthiamid) 

and 2,6-dichlorobenzamide in the olfactory nasal mucosa of mice. Fundam Appl Toxicol 17(1):92-102. 
Page 62 of 66 

reverse 

mutation 

(Ames test) 

μg/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 

μg/ml 

Acceptable/Guideline

Negative. 

Dichlobenil 

5-day dermal (mouse)

2,6-Dichlorobenzonitrile (dichlobenil) is an herbicide which has previously been reported by 

other investigators to be toxic to the olfactory mucosa following intraperitoneal administration. 

The objective of this study was to determine whether a more occupationally-relevant route of 

pesticide exposure, namely dermal exposure to dichlobenil, also resulted in olfactory system 

damage. Male C57Bl mice were clipped and administered 0-200 mg/kg dichlobenil dermally in 

acetone either as a single dose or for five consecutive days. In addition, olfactory bulb glial 

fibrillary acidic protein (GFAP) analysis was performed in order to determine whether the 

damage in the olfactory mucosa translated into damage which could be measured as an astroglial 

increase in GFAP concentration in the olfactory bulb, a marker of central nervous system 

neuronal loss. Olfactory mucosal histology revealed that single or multiple exposures to 50, 100, 

150 and 200 mg/kg dichlobenil dermally caused olfactory epithelial damage (primarily sensory 

cell loss) in the epithelium lining the dorsal medial 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 significantly 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 aerosol at concentrations of 0, 2.3, 5.1, or 12 mg/m3

 

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, respectively) for 6 hours/day, 5 days/week for 

4 weeks. 

There were no treatment-related effects on survival, clinical observations, FOB, motor activity, 

body weights, body weight gains, food consumption, ophthalmoscopy, hematology, clinical 

chemistry, organ weights, gross pathology, or histopathology 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/m3

 based on trace to mild nasal degeneration in males and 

females. The nasal effects are considered adverse rather than adaptive since the nasal tissue has 

been determined to be a target by routes of exposure other than inhalation. 

 

The LOAEL is 21 mg/m3

 (equivalent to 5.5 mg/kg/day) based on increased incidence of 

nasal degeneration (from the 7 day study). The NOAEL is 12 mg/m3

 (equivalent to 3.1 

mg/kg/day), the highest concentration tested.

At the request of the Agency, this study was conducted for a duration of 28 days, instead of the 

90 days required by Guideline OPPTS 870.3465. Aside 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 expression for dichlobenil because it is a major 

metabolite/degradate of dichlobenil. 

BAM is a minor metabolite of fluopicolide. The tolerance expression for plants will include 

fluopicolide (parent) as an indicator of combined residues of fluopicolide and BAM. HED 

determined that BAM should be included as a residue of concern for the risk assessment for the 

proposed uses of fluopicolide on the primary domestic plants [cucurbit vegetables, fruiting 

vegetables, grapes, leafy vegetables, and tuberous and corm vegetables (except potato)]. 

Based on two aerobic soil metabolism studies, fluopicolide (parent) and BAM are the residues of 

concern in drinking water. BAM was a major metabolite 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

F Cl 3C

AE C653711 

BAM 

2,6-dichlorobenzamide Cl

Cl

H2N

O

AE C657188 

PCA 

3-chloro-5-trifluoromethylpyridine2-carboxylic acid 

N

F Cl 3C

OH

O

AE 1344122 

P1X 

3-methylsulfinyl-5-

trifluoromethylpyridine-2-carboxylic 

acid 

N

F3C

OH

O

SOCH3

 
Page 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. These 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 received the appropriate review. 

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task 

Force members Health Canada, U.S. Environmental Protection Agency, and the National 

Agricultural Chemicals Association, released February, 1995.