UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

                                        WASHINGTON, D.C.  20460

     OFFICE OF	

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: 03/05/08 

MEMORANDUM

SUBJECT:	2,6-Dichlorobenzamide (BAM ) as a Metabolite/Degradate of
Fluopicolide and Dichlobenil.  Human Health Risk Assessment for Proposed
Uses of Fluopicolide on Root Vegetables (Subgroup 1A), Leaves of Root
and Tuber Vegetables (Group 2), Bulb Vegetables (Group 3), and Head and
Stem Brassica (Subgroup 5A)  PC Codes: 027402 (BAM) and 027412
(Fluopicolide), Petition No: 5F7016, DP Number: 349864.

		

		Regulatory Action:  Section 3 Registration Action

Risk Assessment Type: Multiple Chemicals/Aggregate

FROM:	Felecia Fort, Risk Assessor 

		Reregistration Branch I

			AND

		Amelia Acierto, Chemist

		Kelly O’Rourke, Biologist

		Myron Ottley, Toxicologist

		Registration Action Branch III

		Health Effects Division (7509P)

THROUGH:	Paula Deschamp, Branch Chief 

Registration Action Branch III

Health Effects Division (7509P)

 

TO:		Janet Whitehurst/Tony Kish, RM Team #22

		Fungicide Branch

		Registration Division (7505P)



In connection with a request for new uses of the active ingredient,
fluopicolide, the Health Effects Division (HED) of EPA's Office of
Pesticide Programs has evaluated the toxicity and exposure databases for
2,6-dichlorobenzamide (BAM) which is a common metabolite/degradate of
dichlobenil and fluopicolide.  This assessment summarizes the human
health risks from exposure to BAM resulting from the existing uses of
dichlobenil and existing and newly proposed uses of fluopicolide on
agricultural commodities, turf, and ornamentals.   A separate human
health risk assessment has been completed for the other fluopicolide
residues of concern (DP #325091, F. Fort, 03/05/08).

HED recently completed a Section 3 Human Health risk assessment for BAM
as a result of new uses of fluopicolide on tuberous and corm vegetables
(except potato), leafy vegetables (except Brassica), fruiting
vegetables, cucurbit vegetables, grapes, turf, and ornamentals.  Details
of that assessment are contained in the document entitled
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. (D345918, N. Dodd).  This document contains only those
aspects of the BAM risk assessment which are affected by the addition of
the new uses of fluopicolide on root vegetables (Subgroup 1A), leaves of
root and tuber vegetables (Group 2), bulb vegetables (Group 3), and head
and stem Brassica (Subgroup 5A).  

Summary of Registered/Proposed Uses  TC \l2 "2.1	Summary of
Registered/Proposed Uses 

In connection with Petition No. 7E7172, fluopicolide is being proposed
for use on Brassica head and stem vegetables, bulb vegetables, and
leaves of root and tuber vegetables excluding potato and sweet potato. 
The proposed use pattern is for four foliar applications at up to 0.125
lb ai/A/application at a 7 to 14-day retreatment interval (RTI) for all
crops with a maximum seasonal rate of 0.375 lb ai/A and a 2-day
preharvest interval (PHI).  The 4 lb ai/gal SC formulation is to be
applied in a tank mix with fungicides from different target site of
action groups that are registered for the same use and that are
effective against the pathogens of concern.  

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).

BAM is a common metabolite/degradate of both fluopicolide and
dichlobenil.  There are no registered uses for BAM itself. 

Hazard Characterization and Endpoint Selection

The hazard assessment for BAM has not changed since the previous
assessment; therefore only a brief summary is included in this document.
 

The submitted acute and chronic studies on BAM were sufficient to
evaluate human hazard potential.  BAM demonstrated moderate acute
toxicity (Category III) via the oral route of exposure.  In subchronic
and chronic toxicity studies, the primary oral effects seen in the rat
and dog were body weight changes.  Adverse liver effects were also
observed but at doses of BAM that were higher than those of dichlobenil.
 There is no evidence that BAM is either mutagenic or clastogenic nor is
there evidence of endocrine mediated toxicity.  BAM is considered to be
neurotoxic.  In the absence of carcinogenicity study data for a second
species, HED has assumed 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.  Quantification of cancer risk is based on
the reference dose (RfD) approach which requires comparison of the
chronic exposure to the RfD. Using this methodology will adequately
account for all chronic toxic effects, including carcinogenicity, likely
to result from exposure to dichlobenil and therefore to BAM.  An FQPA SF
of 10X for database uncertainty has been retained for the 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. For
the dermal and inhalation routes of exposure, the FQPA SF for BAM
toxicity has been reduced to 1X because the effect of concern, olfactory
toxicity, was chosen for these exposure scenarios. 

A summary of the toxicological endpoints and doses chosen for the
relevant exposure scenarios for human risk assessment is found in Table
1.1.

Table 1.1.  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   HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Deamer+NJ%22%5BAuthor%5D"  Deamer NJ ,  
HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22O%27Callaghan+JP%22%5BAuthor%5D"  O'Callaghan
JP ,   HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Genter+MB%22%5BAuthor%5D"  Genter MB . (1994).
Olfactory toxicity resulting from dermal application of
2,6-dichlorobenzonitrile (dichlobenil) in the C57Bl mouse.
Neurotoxicology 15(2):287-93

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 [  HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Brittebo+EB%22%5BAuthor%5D"  Brittebo EB ,  
HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Eriksson+C%22%5BAuthor%5D"  Eriksson C ,  
HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Feil+V%22%5BAuthor%5D"  Feil V ,   HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Bakke+J%22%5BAuthor%5D"  Bakke J ,   HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Brandt+I%22%5BAuthor%5D"  Brandt I . (1991).
Toxicity of 2,6-dichlorothiobenzamide (chlorthiamid) and
2,6-dichlorobenzamide in the olfactory nasal mucosa of mice.   HYPERLINK
"javascript:AL_get(this,%20'jour',%20'Fundam%20Appl%20Toxicol.');" 
Fundam Appl Toxicol  17(1):92-102].

Dietary Exposure Assessment

Fluopicolide.  PP#7E7172.  Petition for Establishment of Tolerances for
Use on Root Vegetables (Subgroup 1A), Leaves of Root and Tuber
Vegetables (Group 2), Bulb Vegetables (Group 3), and Head and Stem
Brassica (Subgroup 5A).  Summary of Analytical Chemistry and Residue
Data, A. Acierto, 3/10/08.  

	Food Residue

Maximum residues of BAM from fluopicolide field trials on root
vegetables, leaves of root and tuber vegetables, bulb vegetables, and
head and stem Brassica, and from dichlobenil field trials on food
commodities with established/pending tolerances (40 CFR 180.231) were
included in the  dietary assessments.  BAM residues found in the
submitted field trial studies are shown in Table 2.1  

Magnitude of BAM Residues in Plants from Use of Fluopicolide 

Table 2.1  Proposed Uses: BAM Residues in/on Bulb Vegetable, Brassica
Leafy Vegetables, and Root and Tuber Vegetable (except Potato) from
Field Trials with Fluopicolide.

Commodity	Total Applic. Rate

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



	n	Min.	Max.	HAFT1	Median

(STMdR)	Mean

(STMR)	Std. Dev.

Bulb Onion	0.355-0.366	2	14	<0.01	<0.01	<0.01	NA	NA	NA

Green Onion	0.355-0.361	2	6	<0.01	0.014	0.014	0.011	0.012	0.002

Broccoli head & stem	0.353-0.364	2	12	<0.01	<0.01	<0.01	NA	NA	NA

Cabbage w/ wrapper leaves	0.352-0.359	2	14	<0.01	0.017	0.016	0.010	0.011
0.002

Cabbage w/o wrapper leaves	0.352-0.359	2	14	<0.01	0.011	0.011	0.010
0.010	0.000

Carrot	0.353-0.362	7	14	<0.01	<0.01	<0.01	NA	NA	NA

Radish, root	0.353-0.363	7	12	<0.01	<0.01	<0.01	NA	NA	NA

Radish, top	0.353-0.363	7	12	0.012	0.163	0.156	0.045	0.063	0.051

Sugar beet, root	0.355 - 0.367	7	20	<0.01	0.0162	0.0131	0.010	0.0105
0.001

Sugar beet, tops	0.355 - 0.367	7	20	0.014	0.121	0.107	0.021	0.033	0.029

Registered Uses: BAM Residues in Tuberous and Corm Vegetables (except
Potato), Leafy Vegetables (except Brassica), Fruiting Vegetables,
Cucurbit Vegetables, and Grapes from Field Trials with Fluopicolide.

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

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.

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 2.3.   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)

Apples1,2

(42177102)	4%G	6 (1x)	85	3	0.064

Apples 3

(42452802)	4%G	6 (1x)	80-179	15	<0.01

Blueberries4

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

Blackberries3

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

Cherries



	No BAM data on cherries.  Use plum data until data are available. 

Cranberries3

(42452801)	4%G	4 (1x)	158, 166	6	0.02-0.03

Filberts5

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

Grapes5

(42476103)	4%G	6 (1x)	124-173	12	0.01-0.09*

Peaches5

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

Plums3

(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.

Rhubarb6

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

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

2 Data for apples in MRID 42177102 will translate to pears.

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

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

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

6  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. 

	Drinking Water Estimates

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

Since all of the proposed new uses are either equal to or less than all
the application rates used in the previous drinking water assessments
for fluopicolide and BAM, a new drinking water assessment was not
conducted and remain unchanged from the previous assessment.  The
estimated environmental concentrations used in the dietary exposure was
56.2 ppb from SciGrow modeling of BAM residues from dichlobenil use on
nutsedge at 10 lb ai/A.  This BAM residue level is higher than estimated
residues in surface water.

	Dietary Exposure (Food and Drinking Water)

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 Root Vegetables (Subgroup 1A), Leaves of
Root and Tuber Vegetables (Group 2), Bulb Vegetables (Group 3), and Head
and Stem Brassica (Subgroup 5A) and Section 3 Registration Actions for
Dichlobenil on Rhubarb, Caneberries (Subgroup 13A), Bushberries
(Subgroup 13B) and Associated Berry Commodities, DP Number 439722, S.
Piper and D. Rate, 03/10/08.

Conservative acute and chronic (food and drinking water) exposure
assessments were conducted.  Maximum residues of BAM from fluopicolide
and dichlobenil field trials on food commodities with
established/pending tolerances were included in the assessment.  The
assessments used 100% crop treated except for apples, blueberries,
cherries, cranberries, peaches, pears, and raspberries.  No livestock
tolerances are established or proposed for either fluopicolide or
dichlobenil.  The acute dietary (food and drinking water) exposure to
BAM from fluopicolide and dichlobenil established and proposed 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 established and proposed 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.  See Table 3.1. 

Table 3.1.  Summary of Dietary (Food and Drinking Water) Exposure and
Risk for BAM

Population Subgroup	Acute Dietary

(99.9th Percentile)	Chronic Dietary	Cancer

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

(mg/kg/day)	% cPAD	Dietary Exposure

(mg/kg/day)	Risk

General U.S. Population	0.011461   	11	0.001317	29	*	*

All Infants (< 1 year old)	0.028251	28	0.004168	93	N/A	N/A

Children 1-2 years old	0.016639	17	0.002284	51



Children 3-5 years old	0.012326	12	0.001985	44



Children 6-12 years old	0.007359	7	0.001296	29



Youth 13-19 years old	0.007246	7	0.000930	21



Adults 20-49 years old	0.008379	8	0.001196	27



Adults 50+ years old	0.006599	7	0.001288	29



Females 13-49 years old	0.008447	28	0.001196	27





Residential Exposure

Occupational and Residential Risk Assessment of Metabolite BAM (to
Support Request for Registration of Fluopicolide on Brassica, Bulb
Vegetables, and Root and Tuber Vegetables), , DP #347230, K. O’Rourke,
12/13/08.

BAM exposure estimates are based on fluopicolide use only since the use
pattern for dichlobenil is not expected to result in scenarios with
significant residential/non-occupational exposure.  Exposure to BAM from
fluopicolide uses on residential turfgrass and recreational sites, such
as golf courses, has been evaluated in an earlier assessment (D345920,
K. O’Rourke, 10/09/07); a summary of the findings are presented in
this document.

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.

Residential postapplication exposure via the inhalation route is
expected to be negligible; however, dermal exposure 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.  The postapplication risk assessment is
based on generic assumptions as specified by the Recommended Revisions
to the Residential SOPs and recommended approaches by HED’s Science
Advisory Council for Exposure (ExpoSAC).  Because turf transferable
residue (TTR) data were not available, turf residues were estimated
using standard assumptions (in addition to BAM surface residue data from
the metabolism studies).  

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 assuming that BAM is
present at levels which reflect high-end measurements observed in the
metabolism studies (in which sampling occurred up to 41 and 369 days
after application, for plants and soil, respectively) for “Day 0” 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.

Table 4.1.  Aggregate Exposure and Risk Estimates from Residential Lawns



Scenario 

and 

Pathway	

TTR/GR/SR0 (µg/cm2 or g) 1	

PDR0-norm

(mg/kg/day) 2	

Short-/ Int-Term

 MOE 3	

Total MOE 4





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	62,000



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

	

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

	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.

Aggregate Exposure

	Acute Aggregate Risk TC \l2 "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 shown in Table 3. 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.

	

	Short- and Intermediate-Term Aggregate Risk TC \l2 "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 have been combined with chronic dietary
exposure estimates to assess short-term aggregate exposure.  Since
aggregate MOEs in Table 5.1 are greater than 1000, they represent risk
estimates that are below HED’s level of concern.

Table 5.1.  Short-Term and Intermediate-Term Aggregate Risk Calculations


(1/MOE Approach – All LOCs Identical)



Population	Short- or Intermediate-Term Scenario

	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	0.001317	NA	NA

All Infants (<1 year old)	14	1000	0.014	0.004168	0.0002234	3200

Children 1-2 years old	14	1000	0.014	0.002284	0.0002234	5400

Females 13-49 years old	14	1000	0.014	0.001196	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 SFDB = 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 Aggregate MOE = [NOAEL/ (Avg Food & Water Exposure + Residential
Exposure)] 

 	

	Long-Term Aggregate Risk   TC \l2 "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 shown in Table 3.  As shown in Table 3, 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”.  HED is regulating at a
level that would also be protective of potential carcinogenic effects,
therefore additional quantification of cancer risk is not needed.

Cumulative Risk Assessments and Risk Characterization  TC \l1 "8.0
Aggregate 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. 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   HYPERLINK
http://www.epa.gov/pesticides/cumulative/.
http://www.epa.gov/pesticides/cumulative/. 

Occupational Exposure

							

	Handler Exposure and 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.  

	Postapplication Exposure and Risk

The registration action for fluopicolide involves application to
agricultural crops.  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.  

In assessing postapplication activities, a dislodgeable foliar residue
(DFR) study on fluopicolide was used. 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.  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.  Based on these studies, it was
conservatively assumed that the surface residues of BAM are present at
4% of the initial amount of parent fluopicolide.  In addition to DFR,
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).  

Postapplication MOEs are typically estimated for “Day 0" exposure
(i.e., the day of application).  However, BAM is a metabolite/degradate
which forms slowly; therefore, the MOEs were estimated assuming that BAM
is present at the percentage described above (which was actually
measured on day 21 after application) for “Day 0” in order to
provide a protective assessment.  As shown in Table 4, the
short-/intermediate-term MOEs for BAM are greater than the LOC of 100 on
the day of application for all agricultural uses of fluopicolide, and
therefore, 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 label indicates an REI of 12 hrs, which is in compliance
with the WPS.  

Table 4.  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	Short-/Int-

Term MOE 5

Agricultural Crops

Brassica Vegetables	0.13	0	0.017	2,000	Irrigation, scouting, thinning,
weeding immature plants	6,500





4,000	Scouting mature plants	3,200





5,000	Hand harvesting, irrigation, pruning, topping, tying mature plants
2,600

Bulb Vegetables,

Root & Tuber Vegetables

0	0.017	300	Irrigation, scouting, thinning, weeding immature plants
43,000





1,500	Irrigation and scouting mature plants	8,600





2,500	Hand harvesting	5,200

1 Maximum application rate from proposed fluopicolide label: V-10161 4
SC (Reg No. 59639-RUN).

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 approximately
12 hours.

3 DFR (µg/cm2) = dislodgeable foliar residues corresponding to DAT,
based on results from a fluopicolide-specific DFR study (MRID 46708641).
 Plant metabolism data were used to adjust residues for amount of BAM.

4 TC (cm2/hr) = transfer coefficients and associated activities from
ExpoSAC Policy Memo #003.1 “Agricultural Transfer Coefficients”,
8/17/2000.

5 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.



Data Needs and Label Recommendations  TC \l1 "10.0	Data Needs and Label
Recommendations 

	Toxicology  TC \l2 "10.1	Toxicology 

None.

	Residue Chemistry  TC \l2 "10.2	Residue Chemistry 

None

	Occupational and Residential Exposure   TC \l2 "10.3	Occupational and
Residential Exposure 

None.

References:  TC \l1 "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 Number
326080, Amelia Acierto, 11/19/07.

Fluopicolide.  PP#7E7172.  Petition for Establishment of Tolerances for
Use on Root Vegetables (Subgroup 1A), Leaves of Root and Tuber
Vegetables (Group 2), Bulb Vegetables (Group 3), and Head and Stem
Brassica (Subgroup 5A).  Summary of Analytical Chemistry and Residue
Data, A. Acierto, 3/10/08.  

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 Root Vegetables (Subgroup 1A), Leaves of
Root and Tuber Vegetables (Group 2), Bulb Vegetables (Group 3), and Head
and Stem Brassica (Subgroup 5A) and Section 3 Registration Actions for
Dichlobenil on Rhubarb, Caneberries (Subgroup 13A), Bushberries
(Subgroup 13B) and Associated Berry Commodities, DP Number 439722, S.
Piper and D. Rate, 03/10/08.

Occupational and Residential Risk Assessment of Metabolite BAM (to
Support Request for Registration of Fluopicolide on Brassica, Bulb
Vegetables, and Root
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㄀$摧䖓êഀDrinking 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.

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