UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: February 10,2013 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Fluopicolide Human Health Risk Assessment Seeping Document in Support of 

Registration Review. 

PC Code: 027412 (Fluopicolide), 027402 

(BAM) DP Barcode: 0405060 

Decision No.: 469292 Registration No.: NA 

Petition No.: NA Regulatory Action: Registration Review 

Risk Assessment Type: Single Chemical 

Aggregate Case No.: NA 

TXRNo.: NA 

MRIDNo.:NA 

FROM: 

THROUGH: 

TO: 

CAS No.: 239110-1 5-7 

40 CFR: 180.627 

Danette Drew, Chemist/Risk Ass.essor ?"'1-~L.L-~......- '--J"'--

Alexandra LaMay, Biologist c::{..=:::z;;.-z!IV' 

John Liccione, Toxicologist 5~~~~~L.,.___.....e 

Risk Assessment Branch V N 

Health Effects Division (7509P) 

Michael S. Metzger, Chief 

7

. J (} ~ L( Risk Assessment Branch V {[L~ /-

Health Effects Division (7509P 

Russell Wasem, Chemical Review Manager 

Pesticide Re-Evaluation Division (7508P) 

Office of Pesticide Programs 

Attached is the Health Effects Division's (HED) human health risk assessment seeping 

(status update) document for fluopicolide to support the registration review process. 

Page 1 of 35 
Page 2 of 35

Executive Summary

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

human health risk assessments for the herbicide fluopicolide, 2,6-dichloro-N-[3-chloro-5-

(trifluoromethyl)-2-pyridylmethyl]benzamide, to determine the scope of work necessary to 

support the registration review process. HED has considered the currently labeled use patterns 

(labels) as well as the available toxicity and exposure information for fluopicolide. The most 

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

then-proposed uses on brassica leafy greens, potatoes, sugar beets, and carrots and to allow crop

rotation to wheat (D384431).

Fluopicolide is formulated as a liquid/suspension concentrate and is registered for use on a wide 

variety of food crops. Fluopicolide is also registered for use on non-agricultural sites such as 

ornamental plants, lawns, recreational areas, parks, golf courses, athletic fields, commercial and 

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

180.627. The residue of concern for tolerance enforcement is parent fluopicolide. Residues of 

concern for risk assessment include parent fluopicolide and, depending on the crop, one or more 

of the following metabolites: PCA, P1X and BAM. Residues of concern in livestock 

commodities and in drinking water are fluopicolide and BAM. (See Table 1. Summary of 

Fluopicolide Residues of Concern and Table A.3 Chemical Names and Structures of Regulated 

Fluopicolide Metabolites.)

The Codex and U.S. residue definitions for fluopicolide are harmonized and both express 

determination of parent fluopicolide. The Codex maximum residue levels (MRLs) and U.S. 

tolerance levels for many commodities are not harmonized, mainly because of differences in 

commodity group definitions.

BAM (2,6-dichlorobenzamide; PC code 027402), the toxic degradate/metabolite of fluopicolide

is also a degradate/metabolite of the herbicide dichlobenil (2,6-dichlorobenzonitrile; PC code 

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

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

database, toxic effects and points of departure. The most recent hazard and exposure estimates 

for BAM are summarized within this fluopicolide scoping document. More information 

regarding BAM hazard and exposure, including outstanding data requirements, can be found in 

the 5/16/12 dichlobenil registration review scoping document (D396248). 

The fluopicolide toxicology database is sufficient for the characterization of a wide variety of 

toxic effects, including potential carcinogenic, mutagenic, developmental, and reproductive. 

However, immunotoxicity testing is required for fluopicolide as part of the new data requirement 

under 40 CFR Part 158.

The BAM toxicology database is adequate except for a special study to evaluate olfactory 

toxicity following oral administration of BAM (for details, see D396248, Dichlobenil, Human 

Health Assessment Scoping Document in Support of Registration Review). Once outstanding 

data are received for BAM the 10X FQPA safety factor (retained for oral exposures) for the lack 

of this special study will be reevaluated.
Page 3 of 35

The HED Hazard and Science Policy Council (HASPOC; TXR. 0056544) recently met 

(12/19/12) to discuss the need for a 28-day inhalation study for fluopicolide; previous 

assessments used toxicity points of departure (PODs) from an oral study to assess inhalation 

exposure. The HASPOC determined that, based on a weight of evidence (WOE) approach, a 28-

day inhalation toxicity study is not required at this time and that the use of the oral study POD is 

protective for assessing inhalation exposures to fluopicolide.

The residue chemistry database is incomplete. Residue chemistry studies are required for storage 

stability, processing, and field rotational crops (see “Data Requirements for Fluopicolide”

section of this document).

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

metabolite BAM. Updated dietary exposure assessments for fluopicolide or BAM may be 

necessary under registration review if the toxicological PODs, FQPA safety factors or other 

uncertainty factors change, or percent crop treated estimates increase significantly, or there are 

significant changes in the estimated drinking water concentrations based on the Ecological Fate 

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

The residential exposure database for fluopicolide is complete, with the exception of a 

requirement for a chemical specific turf transferable residue (TTR) study (in accordance with the 

updated Part 158 data requirements). Previous residential handler and post-application 

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

estimates of concern. However, the residential post-application Margins of Exposure (MOEs)

for adults and children contacting a treated lawn were not at least 10 times the level of concern 

(i.e. MOEs were <1000 and the LOC is 100), thus triggering the need for a chemical specific 

TTR study (as per the Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and 

Dislodgeable Foliar Residue (DFR) Studies. 6/7/2012, Exposure Science Advisory Council).

Residential handler exposure was not evaluated for BAM because the metabolite BAM is 

believed to form slowly in plants and soil after the product containing the parent (fluopicolide) 

has been applied. However, there is a potential for dermal (adults and children) and incidental 

non-dietary ingestion (for children) exposure to BAM during post-application activities on 

fluopicolide-treated lawns. The short-/intermediate-term dermal MOEs for adults and children

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

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

An updated residential handler (fluopicolide) and post-application (fluopicolide or BAM) 

assessment may be required under registration review as a result of the 2012 revisions to HED’s 

Residential Exposure Standard Operating Procedures (SOPs). In addition, revised residential 

assessments may be needed if toxicological PODs or uncertainty factors change or other new 

data are received by the Agency that impact exposure estimates.

In addition, a quantitative residential post-application exposure assessment has not been 

performed as a result of pesticide drift or volatilization from neighboring fluopicolide-treated 
Page 4 of 35

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

review. 

There were no aggregate (combined food, drinking water, and residential exposures) risks of 

concern for fluopicolide or for BAM. If significant changes are made to the previous 

fluopicolide or BAM residential or dietary risk assessments, revised aggregate risk assessments 

may be performed under registration review.

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

risk estimates of concern. An updated handler and post-application assessment may be necessary 

under registration review of fluopicolide or BAM if warranted by any significant changes in 

exposure assessment methodology, toxicological PODs or uncertainty factors.

Chemical Use Profile

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

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

mildews (Plasmopara, Pseudoperonospara, Peronospora, and Bremia), late blight 

(Phytophthora), and some Pythium species. Fluopicolide appears to interfere with mitosis and 

cell division resulting in the rapid destabilization of fungal cell structures; this pesticidal mode of 

action has been characterized as novel and unique and unlike the known modes of action of other 

registered fungicides. In the plant, fluopicolide is a mesosystemic fungicide; it translocates 

toward the stem tips via the xylem but it does not translocate toward the roots.

Fluopicolide is formulated as a liquid/suspension concentrate and is registered for use on 

currants, grapes, huckleberries, nut trees, pome fruits, flavoring and spice crops, cucurbits, 

eggplant, tomatoes and other fruiting vegetables, leafy and stem vegetables (like spinach , 

broccoli etc), root crop vegetables, okra, onions, sugar beets and turnips. Permanent tolerances 

for residues of fluopicolide are established under 40 CFR 180.627. 

Fluopicolide is also registered for use on non-agricultural sites such as forest trees, herbaceous 

plants, ornamental plants, ornamental lawns and turf, ornamental woody shrubs and vines, 

ornamental trees, lawns, recreational areas, parks, golf courses, athletic fields, commercial and 

industrial areas. Fluopicolide may be applied by air or ground equipment.

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

Hazard Identification/Toxicology

Fluopicolide

The toxicity database for fluopicolide is complete except for immunotoxicity testing. This is a 

new data requirement under 40 CFR Part 158 as a part of the data requirements for registration 

of a pesticide (food and non-food uses).
Page 5 of 35

Technical grade fluopicolide has low acute toxicity via oral, dermal and inhalation routes of 

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

The subchronic and chronic oral toxicity studies in rats and mice revealed liver toxicity in both 

species. Kidney and thyroid toxicity were observed in rats only. Fluopicolide is not neurotoxic, 

carcinogenic, nor mutagenic. Developmental toxicity in the rabbit occurred only at doses that 

caused severe maternal toxicity (including death). In the rat, developmental effects were seen 

only at high dose levels (700 mg/kg/day) in the presence of maternal toxicity. Similarly, 

offspring effects (body weight, kidney) occurred only at levels causing toxicity in parents of the 

multi-generation reproductive toxicity study. There is no evidence of increased quantitative 

susceptibility of rat or rabbit fetuses to in utero or post-natal exposure to fluopicolide. 

No toxic effects were observed in studies in which fluopicolide was administered by the dermal 

routes of exposure. An inhalation toxicity study is not available. The Hazard and Science Policy 

Council (HASPOC; TXR. 0056544) met on December 19, 2012 to discuss the need for this 

inhalation study. The HASPOC has determined that, based on a weight of evidence (WOE) 

approach, a 28-day inhalation toxicity study is not required at this time. This approach 

considered all of the available hazard and exposure information including (1) the 

physical/chemical properties of fluopicolide, including its potential to volatilize (8.03 x 10-7 Pa 

vapor pressure); (2) the low acute inhalation toxicity; (3) the primary target organs of 

fluopicolide are the liver and hematopoietic system following repeat oral exposure; (4) the use of 

an oral POD for fluopicolide results in screening level occupational/residential inhalation MOEs 

>40,000. 

No appropriate endpoint was identified for the acute dietary (general population, including 

infants and children) exposure scenarios. The toxicological profile for fluopicolide suggests that 

increased durations of exposure do not significantly increase the severity of observed effects. 

Therefore, the rabbit developmental and rat chronic/carcinogenicity studies were considered cocritical for endpoint selection for all routes (dietary, incidental oral, dermal and inhalation) and 

durations of exposure (with the exception of acute exposures).

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

factor to 1X because the toxicity database is sufficient for endpoint selection, there is no 

evidence of quantitative susceptibility following in utero and/or postnatal exposure in the rabbit 

and rat developmental toxicity studies or in the 2-generation rat reproduction study, there is low 

concern for the qualitative susceptibility observed in the rat developmental toxicity study 

because the offspring effects (reduced growth and skeletal defects) and late-term abortions are 

well characterized and accompanied by maternal toxicity near the limit dose, and the exposure 

assessments are unlikely to underestimate risk.

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

Appendix B.

BAM 

In the subchronic and chronic oral toxicity studies in the rat and dog, respectively, body weight 

change was the toxicological effect most often observed at the LOAEL. In the combined chronic 
Page 6 of 35

toxicity/carcinogenicity study in the rat, toxicologically significant changes in body weight were 

also observed at the LOAEL, as were eosinophilic foci in the liver. BAM-mediated olfactory 

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

was no evidence of increased susceptibility to offspring following pre-natal exposure to rabbits 

in a developmental toxicity study with BAM.

Appropriate endpoints were identified for the acute dietary (general population, including infants 

and children) from a single oral dose in the in vivo mouse erythrocyte micronucleus assay; acute 

dietary for females 13-49 based on effects observed on a developmental toxicity (rabbit) study; 

chronic dietary based on a chronic toxicity (dog) study; incidental oral based on a 90-day oral 

study in rat; inhalation and dermal endpoints are based on the dichlobenil toxicity studies (in the 

absence of route specific studies for BAM, studies from parent compound dichlobenil were 

selected). 

The 10X FQPA safety factor has been retained as a database uncertainty factor for acute dietary, 

chronic dietary and incidental oral exposures to account for the lack of a special oral toxicity 

study with thorough examination of the olfactory system. An oral toxicity study in the rat with a 

focus on the examination of the olfactory system after 1, 7, 14 and 28 days of exposure will be 

required to assess the potential of olfactory toxicity following acute and subchronic oral 

exposure (D396248, Dichlobenil. Human Health Assessment Scoping Document in Support of 

Registration Review). The FQPA factor has been reduced to 1X for dermal and inhalation 

exposures, since the olfactory endpoint of concern has been measured in dermal and inhalation 

studies.

BAM is not mutagenic or clastogenic in submitted genotoxicity studies. EPA has assumed that 

BAM’s potential for carcinogenicity is similar to parent dichlobenil (Group C, possible human 

carcinogen) and therefore has determined that the cPAD will adequately account for all chronic 

effects, including carcinogenicity, likely to result from exposure to BAM. 

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

B.

Conclusions: The fluopicolide toxicology database is sufficient for the characterization of a wide 

variety of toxic effects, including potential carcinogenic, mutagenic, developmental, and 

reproductive. However, immunotoxicity testing is required as part of the new data requirement 

under 40 CFR Part 158. For BAM, outstanding data requirements (special olfactory toxicity 

studies) and associated rationale can be found in D396248. Once outstanding data are received 

for BAM the 10X FQPA safety factor for the lack of the special study will be reevaluated.

Dietary Exposure

Residue Chemistry

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

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

processing study is required for aspirated grain fractions. Limited field rotational crop studies 
Page 7 of 35

are required for small grains, soybean, corn, rice and oilseed. See the “Data Requirements for 

Fluopicolide” section of this document for details.

Dietary Assessment

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

water are shown in Table 1. Separate risk assessments were conducted for the fluopicolide 

metabolite, BAM. There is a complete hazard database available for BAM and separate 

endpoints for risk assessment have been selected from that data. All other metabolites 

referenced below are assumed to have equivalent toxicity to the parent compound and are 

included with the parent compound in dietary risk assessment. 

Table 1. Summary of Fluopicolide Residues of Concern.

Matrix Residues included in 

Risk Assessment

Residues included in 

Tolerance Expression

Plants

Primary Crops

All primary crops 

except Tuberous and 

Corm Vegetables

Fluopicolide (parent) and 

BAM

Fluopicolide

Tuberous and Corm 

Vegetables

Fluopicolide (parent), 

PCA, and BAM

Rotational Crops

All rotational crops 

except cereal grains

Fluopicolide (parent) and 

BAM

Fluopicolide

Cereal grains - grain for 

human food 

Fluopicolide (parent), 

PCA, P1X and BAM

Cereal grains -

forage/hay/straw and 

grain for livestock feed

Fluopicolide (parent) and 

BAM 

Livestock

Fluopicolide (parent) and 

BAM Fluopicolide

Drinking Water Fluopicolide (parent) and 

BAM Not applicable

Fluopicolide

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

metabolites indicated in Table 1 above except BAM (the BAM metabolite was assessed 

separately), was performed in 2010 to support the established uses and Section 3 requests for use

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

Wheat (D381050, D. Davis, 8/19/10). An acute dietary assessment was not conducted because 

an endpoint attributable to a single dose has not been identified for fluopicolide. A chronic 

dietary (food and drinking water) exposure and risk assessment was conducted using the Dietary 

Exposure Evaluation Model DEEM-FCIDTM, Version 2.03. That assessment is considered 
Page 8 of 35

highly conservative as it included tolerance level residues or maximum field trial residue levels 

for all crops, assumed 100% crop treated and used empirical or default DEEM processing 

factors. Estimated drinking water concentrations (EDWCs) from the last fluopicolide Drinking 

Water Assessment (DWA) (R. Miller, D370764, 6/20/10) were incorporated directly into the 

dietary assessment. Chronic surface water and groundwater EDWCs were based on 

PRZM/EXAM and SCI-GROW models, respectively, and reflected aerial application to Florida 

carrots (the use pattern resulting in the highest EDWCs). 

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

established and then-proposed uses of fluopicolide resulted in an estimated exposure to the 

general U.S. Population which is equivalent to 7.9% of the chronic population adjusted dose 

(cPAD). The most highly exposed subgroup is children 1 – 2 years of age with an estimated 

exposure equivalent to 13% of the cPAD. 

BAM

BAM (2,6-dichlorbenzamide) is a metabolite of concern for two active ingredients, fluopicolide 

and dichlobenil; therefore, the BAM dietary assessment includes residues of BAM in food and 

drinking water from uses of both pesticides. The last dietary assessment for BAM was 

conducted to support new uses of fluopicolide (D. Davis, D381051, 09/09/2010). The 

assessment was partially refined: residue values for BAM from field trials conducted either with 

fluopicolide or dichlobenil were incorporated into the risk assessment and percent crop treated 

data, where available, were used. The EDWC for BAM used in the dietary assessment was 

modeled from the established dichlobenil uses since these provided higher residue levels than 

those from fluopicolide uses (EFED, D340773, J. Angier, 8/29/07). The EDWC for groundwater 

(which was higher than the surface water) was based on SCIGROW modeling of dichlobenil use 

on turf/nutsedge.

Acute and chronic dietary (food and water) risk estimates for BAM are not of concern. For the 

acute dietary assessment the estimated risk is 12% of the aPAD for the general U.S. population. 

All infants and females, the two population subgroups with the highest estimated risk had 

exposures that resulted in estimated acute dietary risks equivalent to 28% of the aPAD for each 

subgroup. For the chronic dietary assessment the U.S. population has an estimated risk of 30% 

of the cPAD. All infants, the most highly exposed population subgroup, had a chronic dietary 

(food and water) exposure that resulted in an estimated risk of 93% of the cPAD. A significant 

portion of that risk comes from the drinking water component of the assessment which is based 

on conservative modeled water residues. The population subgroup, all infants has a chronic 

dietary exposure from food alone that is equivalent to only 6.5% of the cPAD.

Conclusions: Currently there are no dietary (food and water) risk estimates of concern for 

fluopicolide or the metabolite BAM. Updated dietary exposure assessments for fluopicolide and 

BAM may be necessary under registration review if the toxicological PODs or FQPA safety 

factors change, percent crop treated estimates increase significantly, or there are significant 

changes in the estimated drinking water concentrations based on EFED’s updated drinking water 

assessment to be performed under registration review. 
Page 9 of 35

The residue chemistry database is incomplete. Residue chemistry studies are required for storage 

stability, processing, and limited field rotational crops. See the “Data Requirements for 

Fluopicolide” section of this document for details.

Residential Exposure

Fluopicolide

Residential Handler Exposure

Fluopicolide is a fungicide registered for use on herbaceous plants, ornamental plants, 

ornamental lawns and turf, ornamental woody shrubs and vines, ornamental trees, recreational 

areas, parks, athletic fields, and golf courses. The uses on turf and ornamental plants do not 

prohibit homeowners from using the products, therefore, residential handlers may apply the 

products; short-term dermal and inhalation exposure to fluopicolide while mixing, loading, and 

applying products may occur. MOEs for residential lawn application were not of concern 

(MOEs > LOC). 

Since the previous 2010 fluopicolide assessment, the Health Effects Division’s 2012 Standard 

Operating Procedures for Residential Pesticide Exposure Assessment has updated exposure 

assessment methodology for residential exposure scenarios, including methodology for adult 

handler exposure assessment. An updated residential handler assessment may be needed under 

registration review as a result of these revisions.

Residential Post-Application Exposure

For post-application exposure, dermal exposure is likely for adults and children entering treated 

lawns and playing golf or contacting treated plants; children may also experience incidental oral 

exposure during post-application activities on treated turf. Post-application exposure and risks 

for treated lawns were previously assessed for fluopicolide (D384431). No turf transferable 

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

assessment. Risks were not of concern for all scenarios. It was concluded that recreational 

exposures to turf (including playing golf) are expected to be similar or less than exposure 

assessed for treated lawns, and are therefore not of concern.

In accordance with the updated Part 158 data requirements (2007), a turf transferable residue 

(TTR) study is required for all occupational (e.g., sod farms, golf courses, parks, and recreational 

areas) or residential turf uses. As part of the recent revision to the Health Effects Division’s 2012 

Standard Operating Procedures for Residential Pesticide Exposure Assessment, HED analyzed 

all of the available TTR data and selected new liquid and granular default values for the fraction 

of the application rate available for transfer after a turf application (FAR). This default is 1% for 

formulations applied as liquids which are the case with fluopicolide. Of the available TTR 

studies submitted to the Agency, the maximum FAR value seen using a liquid product was 6.1% 

or 6.1 times higher than the default residue transfer value. Therefore, the HED has decided that a 

calculated MOE of approximately 10 times higher than the level of concern (e.g., an MOE > 

1,000 if the LOC = 100) using the default residue transfer values would provide an adequate 
Page 10 of 35

margin of safety for any potentially higher residues seen in a chemical-specific TTR study 

(Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar 

Residue (DFR) Studies. 6/7/2012, Exposure Science Advisory Council). A TTR study is 

required for fluopicolide at this time since the dermal MOEs for adults and children contacting a 

treated lawn are <1,000.

Since the previous 2010 fluopicolide assessment, the Health Effects Division’s 2012 Standard 

Operating Procedures for Residential Pesticide Exposure Assessment has updated exposure 

assessment methodology for residential exposure scenarios, including adult and children 

exposure to treated turf and golf courses. An updated residential handler assessment may be 

needed under registration review as a result of these revisions.

Residential bystander inhalation exposures resulting from off-site transport (e.g., spray drift or 

volatilization) may occur as a result of agricultural applications of fluopicolide. The Agency is 

in the process of evaluating these types of exposures and may, as appropriate, develop policies 

and procedures to identify the need for and, subsequently, the way to incorporate postapplication inhalation exposure into the Agency's risk assessments. The need for a bystander 

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

Although a quantitative residential post-application inhalation exposure assessment has not been 

performed as a result of pesticide drift from neighboring fluopicolide-treated agricultural fields, 

an inhalation exposure assessment should be performed for flaggers, and may be considered 

representative of a worst-case inhalation (drift) exposure.

BAM

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

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

There is a potential for short-term non-occupational exposure to BAM during post-application 

activities. Dermal exposure is possible for adults and children entering treated lawns; children 

may also experience exposure via incidental non-dietary ingestion during post-application 

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

BAM is a metabolite/degradate which forms slowly, these scenarios were assessed assuming that 

BAM is present at levels which reflect high-end measurements observed in the plant metabolism 

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

The short-/intermediate-term dermal MOEs for adults and children and incidental oral MOE for 

children are greater than their respective LOCs (dermal MOEs > 100 and oral MOEs >1000) and 

are therefore not of concern.

Conclusions: The residential exposure database for fluopicolide and BAM is complete, with the 

exception of the TTR study data requirement for fluopicolide. Previous residential handler and 

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

concern. 

An updated residential exposure assessment may be needed during registration review as a result 

of the 2012 revisions to HED’s Residential Exposure Standard Operating Procedures (SOPs). In 
Page 11 of 35

addition, revised residential assessments may be needed if toxicological PODs change or other 

new data are received by the Agency that impact exposure estimates.

In addition, a quantitative residential post-application exposure assessment has not been 

performed as a result of pesticide drift or volatilization from neighboring fluopicolide-treated 

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

review. An inhalation exposure assessment should be performed for flaggers, and may be 

considered representative of a worst-case inhalation (drift) exposure.

Aggregate Risk Assessment

Fluopicolide

Aggregate (food, drinking water, and residential exposures) exposure assessments were 

performed for fluopicolide in the 2010 risk assessment. An acute aggregate assessment was not 

conducted because an endpoint attributable to a single dose was not identified for fluopicolide.

A chronic aggregate dietary (food and drinking water only) assessment was performed and there 

were no risk estimates of concern.

Short- and intermediate-term aggregate risks assessments were performed which combined 

residential exposures to fluopicolide from lawn uses with average dietary exposure estimates. 

The lawn uses are expected to result in higher exposures than the other turf uses (e.g. golf course 

use). The short- and intermediate-term aggregate risk estimates (for adult handlers and for both 

adults and children contacting treated lawns) for fluopicolide were below HED’s level of 

concern. 

BAM

Aggregate (food, drinking water, and residential exposures) exposure assessments were 

performed for BAM in 2008 BAM risk assessment (D354111). The acute and chronic aggregate 

dietary (food and drinking water only) assessments were performed and there were no risk 

estimates of concern.

Short- and intermediate-term aggregate risks assessments were performed which combined 

residential post-application exposures to BAM (from lawn uses of fluopicolide) with average 

BAM dietary exposure estimates. The lawn uses are expected to result in higher exposures than 

the other turf uses (e.g. golf course use). The short- and intermediate-term aggregate risk 

estimates (for adults and children) for BAM were below HED’s level of concern. 
Page 12 of 35

Conclusion: There were no aggregate (food, drinking water, and residential exposures) risks of 

concern for fluopicolide or for BAM. If significant changes are made to the previous 

fluopicolide or BAM residential or dietary risk assessments, revised aggregate risk assessments 

may be performed under registration review.

Cumulative Risk Assessment

Unlike other pesticides for which EPA 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 fluopicolide (parent) and any other substances. For the purposes of this tolerance action, 

therefore, EPA has not assumed that fluopicolide (parent) has a common mechanism of toxicity 

with other substances. For information regarding EPA’s efforts to determine which chemicals 

have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals,

see the policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

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

Occupational Exposure

Fluopicolide

Occupational Handler Exposure

Fluopicolide is a fungicide registered for use on currants, grapes, huckleberries, nut trees, pome 

fruits, flavoring and spice crops, cucurbits, eggplant, tomatoes and other fruiting vegetables, 

brassica vegetables (leafy and stem vegetables like spinach , broccoli etc), leafy vegetables, root 

crop vegetables, bulb vegetables, okra, onions, sugar beets and turnips. Fluopicolide is also 

registered for use on forest trees, Christmas tree plantations, herbaceous plants, ornamental 

plants, ornamental lawns and turf, ornamental woody shrubs and vines, ornamental trees, 

recreational areas, parks, athletic fields, golf courses, commercial and industrial areas. 

Fluopicolide is formulated as a suspension concentrate. Occupational handler exposure 

scenarios include mixing/loading, applying by aerial, groundboom, airblast, or handheld 

equipment, mixing/loading/applying with handheld equipment, and flagging. These handler 

scenarios have been previously assessed in D347228 and D326082. Handler risks were not of 

concern with label-required PPE (baseline plus chemical-resistant gloves).

Recommended unit exposures for occupational handler assessments have generally been derived 

only from the Pesticide Handlers Exposure Database (PHED). However, recently both the 

Outdoor Residential Exposure Task Force (ORETF) and the Agricultural Handler Exposure Task 

Force (AHETF) have produced pesticide handler exposure monitoring data that the Agency is 

using in place of PHED (http://www.epa.gov/pesticides/science/handler-exposure-data.html). As 

more reliable data become available, the Agency will continue to replace existing data. 

Reviewers should incorporate new exposure monitoring data, as necessary, during registration 

review.
Page 13 of 35

An updated occupational handler assessment may be required under registration review if 

warranted by any significant changes in exposure assessment methodology, toxicological PODs

or uncertainty factors.

Occupational Post-Application Exposure

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

on lettuce. These data were used to assess post-application exposure for workers entering treated 

fields and satisfy the DFR data requirement under 40 CFR Part 158. All worker risks were not 

of concern on the day of application. 

Recommended transfer coefficients for occupational post-application assessments are derived 

from Agricultural Reentry Task Force (ARTF) exposure monitoring studies

(http://www.epa.gov/pesticides/science/post-app-exposure-data.html). These transfer 

coefficients have been updated in 2012 based on a reanalysis and submission of new monitoring 

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

registration review.

An updated occupational post-application assessment may be required under registration review 

if warranted by any significant changes in exposure assessment methodology, toxicological 

endpoints or points of departure, or uncertainty factors.

BAM

Handler exposure was not evaluated because the metabolite BAM is believed to form slowly in 

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

There is a potential for short- and intermediate-term occupational dermal exposure to BAM 

during post-application activities. These scenarios were previously assessed. Plant metabolism 

data were available which include surface residues of BAM. These residues, which were 

assumed to be dislodgeable, were used in conjunction with the fluopicolide DFR data (MRID 

46708641) to provide residue estimates for BAM on crops and ornamentals. Because turf 

transferable residue (TTR) data were not available, turf residues were estimated using default

assumptions. Since BAM is a metabolite/degradate which forms slowly, post-application worker 

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

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

assessment. The results of the occupational post-application exposure and risk assessment 

indicate that for potential BAM exposure as a result of fluopicolide use, MOEs for agricultural, 

turf, and ornamental uses are greater than 100 and therefore, are not of concern (D345920 and 

D347230).

Recommended transfer coefficients for occupational post-application assessments are derived 

from Agricultural Reentry Task Force (ARTF) exposure monitoring studies

(http://www.epa.gov/pesticides/science/post-app-exposure-data.html). These transfer 

coefficients have been updated in 2012 based on a reanalysis and submission of new monitoring 
Page 14 of 35

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

registration review.

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

of concern. An updated handler and post-application assessment may be necessary under 

registration review of fluopicolide or BAM if warranted by any significant changes in exposure 

assessment methodology, toxicological PODs or uncertainty factors. 

Public Health and Pesticide Epidemiology Data

For fluopicolide, the OPP Incident Data System (IDS) and the Centers for Disease Control and 

Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event 

Notification System for Occupational Risk-Pesticides (SENSOR) databases were consulted for 

incident data (D405059, 10/16/12). 

The Agricultural Health Study (AHS) is a high quality, prospective epidemiology study 

evaluating the link between pesticide use and various health outcomes including cancer. 

Fluopicolide is not included in the AHS, and therefore this study does not provide information 

for this report.

Because there are no incident cases reported for fluopicolide in either the Main or Aggregate 

IDS, no cases are identified in the SENSOR database, and fluopicolide is not included in the 

AHS, there does not appear to be a concern at this time that would warrant further investigation. 

The Agency will continue to monitor the incident information and if a concern is triggered, 

additional analysis will be included in the risk assessment.

Tolerance Assessment and International Harmonization

Currently, the tolerance expression for fluopicolide is expressed as “fluopicolide [2,6-dichloroN -[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]benzamide]”. HED has recommended that 

the tolerance expression for fluopicolide be revised under 180.627(a)(1) to read as follows

(D384663, 12/9/10):

Tolerances are established for residues of the fungicide fluopicolide [2,6-dichloro-N-[[3-

chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]benzamide], including its metabolites and 

degradates, in or on the commodities in the table below. Compliance with the tolerance 

levels specified below is to be determined by measuring only fluopicolide [2,6-dichloroN-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]benzamide] in or on the commodity.

The Codex and U.S. residue definitions are harmonized and both express determination of parent 

fluopicolide. The Codex maximum residue levels (MRLs) and U.S. tolerance levels for grapes 

and cucurbit vegetables are harmonized. The residue levels are not harmonized for brassica 

vegetables, bulb vegetables, fruiting vegetables or leafy vegetables. Much of this discrepancy is 

because of differences in commodity definitions (e.g. U.S. tolerances are established at 5.0 ppm 

on Brassica, head and stem, subgroup 5A whereas Codex MRLs are established at 2 ppm on 

Flowerhead brassicas (includes broccoli; broccoli, Chinese and cauliflower), 7 ppm on cabbages, 
Page 15 of 35

head, and 0.2 ppm on brussel sprouts). Canada also has MRLs established for residues of 

fluopicolide on several commodities, many which are harmonized with U.S. tolerances, and a 

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

Canada MRLs.

Human Studies

Past fluopicolide risk assessments rely in part on data from studies in which adult human 

subjects were intentionally exposed to a pesticide to determine their dermal and inhalation 

exposure. Many such studies, involving exposure to many different pesticides, comprise generic 

pesticide exposure databases such as the PHED, the Agricultural Reentry Task Force (ARTF) 

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

reviewed all the studies supporting these multi-pesticide generic exposure databases, and has 

found no clear and convincing evidence that the conduct of any of them was either 

fundamentally unethical or significantly deficient relative to the ethical standards prevailing at 

the time the research was conducted. All applicable requirements of EPA’s Rule for the 

Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no 

regulatory barrier to continued reliance on these studies.

Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse 

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and 

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, 

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and 

chronic studies that assess growth, developmental and reproductive effects in different 

taxonomic groups. As part of its reregistration decision, EPA reviewed these data and selected 

the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard 

database. However, as required by FFDCA section 408(p), Flupicolide is subject to the 

endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 

EPA has developed EDSP to determine whether certain substances (including pesticide active 

and other ingredients) may have an effect in humans or wildlife similar to an effect produced by 

a “naturally occurring estrogen, or other such endocrine effects as the Administrator may 

designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect.
Page 16 of 35

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 

2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, 

which contains 58 pesticide active ingredients and 9 inert ingredients. Flupicolide is not among 

the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. 

Accordingly, as part of registration review, EPA will issue future EDSP orders/data call-ins, 

requiring the submission of EDSP screening assays for flupicolide. For further information on 

the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test 

guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/.

Data Requirements for Fluopicolide

Toxicology

870.7800 - Immunotoxicity testing -This study is a new data requirement under 40 CFR Part 

158.

Residue Chemistry

860.1380 Storage Stability

Additional storage stability data are required to support the Brassica head and stem, bulb, and 

root vegetable, and leafy vegetable crop field trials. Storage stability studies with a 

representative root or tuber vegetable (reflecting analysis of roots and tops) and a Brassica

vegetable must be conducted. The requested data for a root or tuber vegetable may be translated 

to bulb vegetables. The required studies should reflect the storage conditions of samples from 

the crop field trials and should include storage intervals of up to 47 months for the root or tuber 

vegetable and 45 months for the Brassica vegetable. Additionally, storage stability data are 

needed for celery and spinach reflecting a storage interval of 38 months. One study should be 

conducted on any representative leafy vegetable. If residues are found to be unstable in any 

representative commodity, additional storage stability data studies will normally be required on 

additional commodities of that group [see OPPTS 860.1380(c)(5)(ii)(D)]. 

860. 1520 Processed Food and Feed

Since residues concentrate in wheat milled byproducts, residue data and a tolerance are required 

for aspirated grain fractions (AGF). The Agency had recommended setting the AGF tolerance at 

0.07 ppm based on the wheat processing data; however, confirmatory residue data on AGF is 

required. 

860.1900 Field Accumulation in Rotational Crops

Limited field trials at two sites per crop as described in OCSPP Guideline 860.1900 Field 

Accumulation in Rotational Crops should be conducted on the following crops:

Small Grain – the registrant has proposed conducting a limited field rotational crop study 

in wheat. HED concurs that a study should be conducted in a small grain. Data from the 

wheat rotational crop study can be translated to other small grains (oats, barley, etc.).
Page 17 of 35

Soybean - the registrant is proposing to conduct a limited rotational crop study in 

soybeans. HED concurs that a limited field rotation study in soybeans should be 

conducted and that this data may be translated to other legumes.

Corn – the registrant has proposed to submit data reflecting a 30-day PBI in corn and to 

establish tolerances for inadvertent residues in corn if required. HED has no objection to 

submission of data on corn to support a 30-day PBI, however if the registrant decides not 

to pursue a 30-day PBI in corn, a limited field rotational study for corn will be required to 

determine the appropriate PBI which is ≤ 12 months.

Rice – a limited field rotational study for rice is required. Alternately, in lieu of 

generating data, the registrant may chose to prohibit rotation to rice on the label.

Oilseed – a limited field rotational study in a representative oilseed is required. The 

registrant may conduct the study in rape (canola varieties only), sunflower, or cotton.

Occupational and Residential Exposure

875.2100 -Turf transferable residue (TTR) data for fluopicolide.

Data Requirements for BAM (From D396248)

Special Oral Toxicity Study (including examinations at 1, 7, 14 and 28 days) in the rat. The 

study should address olfactory toxicity for both dichlobenil and BAM. [See Appendix C of 

memo D396248 for Data Requirement Rationale.]

References

S. Recore, 10/16/12, Fluopicolide: Review of Human Incidents, D405059.

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

Support of Registration Review, D396248.

D. Davis, 3/23/11, Fluopicolide. Confirmatory Data Requirements and Revised Label 

Recommendation to Support Proposed New Uses on Potatoes, Sugar Beets, and Carrots and 

Addition of Rotational Wheat Use with a 30-Day PBI. D387817.

D. Davis et al, 12/9/10, Fluopicolide and its Metabolite, 2,6-Dichlorobenzamide (BAM). 

Amended Human Health Risk Assessment to Support New Section 3 Uses on Brassica Leafy 

Greens Subgroup 5B, Potatoes, Sugar Beets, Carrots and to Allow Rotation to Wheat, D384431

D. Davis, 9/9/10, 2,6-Dichlorobenzamide (BAM) Acute and Chronic Aggregate Dietary (Food 

and Drinking Water) Exposure and Risk Assessment to Support New Section 3 Uses of 

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

Allow Rotation to Wheat.; D381051, D381052
Page 18 of 35

D. Davis, 8/19/10, Fluopicolide Chronic Aggregate Dietary (Food and Drinking Water) 

Exposure and Risk Assessment to Support New Section 3 Uses on Brassica Leafy Greens 

Subgroup 5B, Potatoes, Sugar Beets, Carrots and Rotational Wheat. D381050.

K. O’Rourke, 10/9/07, Occupational and Residential Risk Assessment to Support Request for 

Registration of Fluopicolide on a Variety of Crops, Residential Turf and Ornamentals, D326082.

K. O’Rourke, 10/9/07, Occupational and Residential Risk Assessment of Metabolite BAM (to 

Support Request for Registration of Fluopicolide on a Variety of Crops, Residential Turf and 

Ornamentals). D345920.

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

Registration of Fluopicolide on Brassica, Bulb Vegetables, and Root and Tuber Vegetables. 

D347228.

K. O’Rourke, 12/13/07, Occupational and Residential Risk Assessment of Metabolite BAM (to 

Support Request for Registration of Fluopicolide on Brassica, Bulb Vegetables, and Root and 

Tuber Vegetables), D347230.

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

and S. Smearman. 

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

Degradate of Dichlobenil, D340773.
Page 19 of 35

Appendix A

Table A.1 Fluopicolide Nomenclature.

Chemical structure

Empirical Formula C14H8Cl3F3N2O

Common name Fluopicolide

Company experimental name AE C638206 

IUPAC name 2,6-dichloro-N-[3-chloro-5-(trifluoromethyl)-2-pyridylmethyl]benzamide 

CAS name 2,6-dichloro-N-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]benzamide 

CAS Registry Number 239110-15-7 

End-use products (EPs) V-10161 4SC Fungicide (39.5% fluopicolide; EPA File Symbol No. 59639-RUN)

V-10161 Premix Fungicide (5.54% fluopicolide and 55.4% propamocarb; EPA 

File Symbol No. 59639–RUE)

Chemical Class Fungicide

Known Impurities of Concern None

Table A.2 BAM Nomenclature

Chemical Structure

Empirical Formula C7H5Cl2NO

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

Cl

Cl

N

H

N

O

F Cl 3C

Cl

Cl

H2N

O
Page 20 of 35

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

Common name/code Chemical name Chemical structure

BAM

AE C653711

2,6-dichlorobenzamide

PCA

AE C657188

3-chloro-5-trifluoromethylpyridine2-carboxylic acid 

P1X

AE 1344122

3-methylsulfinyl-5-

trifluoromethylpyridine-2-carboxylic 

acid

Table A.4 Physicochemical Properties of Fluopicolide.

Parameter Value Reference

Molecular Weight 383.59 *

Melting point/range 149 C MRID 46474015

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

Density 1.65 g/cm3 (30 °C) MRID 46474016

Water solubility (20 C) 2.86 mg/L at pH 4

2.80 mg/L at pH 7

2.80 mg/L at pH 9 

MRID 46474021

Solvent solubility (g/L at 20 C) n-Hexane: 0.20

Ethanol: 19.2

Toluene: 20.5

Ethyl acetate: 37.7

Acetone: 74.7

Dichloromethane: 126

Dimethyl sulfoxide: 183 

MRID 46474022

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

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

9.8 MRID 46474017

Octanol/water partition coefficient 

Log(KOW) 

Log POW = 3.26 at pH 7.8 and 22 ± 1 C MRID 46474018

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

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

In methanol: 203 and 271

In methanol/HCl: 202 and 270

In methanol/NaOH: 219 and 271 

MRID 46474014

*The molecular weight was calculated from the Periodic Table.

Cl

Cl

H2N

O

N

F Cl 3C

OH

O

N

F3C

OH

O

SOCH3
Page 21 of 35

Table A.5. Physiochemical Properties of BAM.

Parameter Value References*

Molecular Weight 190.03 g/mol Product Chemistry 

(HSDB, 2002)

Melting point/range Not available

pH Not available

Density Not available

Water solubility (pH 7, 20°C) 2700 mg/L Product Chemistry 

(HSDB, 2002)

Solvent solubility (20°C to 25°C) Not available

Vapor pressure (25 C) 3.26 x 10-5 mm Hg Product Chemistry 

(HSDB, 2002)

Dissociation constant, pKa Not available

Octanol/water partition coefficient, 

logPOW (25°C) Kow = 30 mL/g** HSDB, 2002

UV/visible absorption spectrum Not available
Page 22 of 35

Appendix B: Toxicity Profile for Floupicolide and BAM

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

Formulations

Guideline 

No.

Study Type MRID(s) Results Toxicity 

Category

870.1100 Acute oral [rat] Fluopicolide

Technical 98.3% (AE C638206)

Formulation SC 40 (AE C638206)

Formulation SC61 (AE B066752)

46708601

46709903

46709803

LD50≥ 2000 mg/kg (f)

LD50 ≥ 2000 mg/kg (m/f)

LD50 ≥ 2000 mg/kg (m/f)

III

III

III

870.1100 Acute oral [rat] Metabolites

2,6-dichlorobenzamide (BAM)

1,3-chloro-5 (trifluoromethyl)

pyridine-2-carboxylic acid (PCA)

42940201

46708602

46708603

LD50 ≥ 1538/1144 mg/kg (m/f)

LD50 ≥ 2000/300 mg/kg (m/f)

LD50≥2000 mg/kg (m/f)

III

II

III

870.1200 Acute dermal [rat]

Technical 97.7% (AE C638206)

Formulation SC40 (AE C638206)

Formulation SC61 (AE B066752)

46708605

46709904

46709804

LD50 ≥ 5000 mg/kg

LD50 ≥ 4000 mg/kg

LD50 ≥4000 mg/kg

IV

III

III

870.1300 Acute inhalation [rat]

Technical (AE C638206)

Formulation SC40 (AE C638206)

Formulation SC61 (AE B066752)

46708606

46709905

46709805

LC50 ≥ 5.16 mg/L

LC50 ≥ 1.789 mg/L

LC50 ≥ 3.195 mg/L

IV

III

IV

870.2400 Acute eye irritation [rabbit]

Technical 97.7% (AE C638206)

Formulation SC40 (AE C638206)

Formulation SC61 (AE B066752)

46708607

46709906 

46709806

slight conjuctival irritation

chemosis/corneal opacity in both 

studies

IV

III

III

870.2500 Acute dermal irritation [rabbit]

Technical 97.7% (AE C638206)

Formulation SC40 (AE C638206)

Formulation SC61 (AE B066752)

46708650

46709907

46709807

None (PDII = 0.00)

slight (PDII = 0.08)

slight (PDII = 0.25)

IV

IV

IV

870.2600 Skin sensitization [guinea pig]

Technical 97.7% (AE C638206)

Formulation SC40 (AE C638206)

Formulation SC61 (AE B066752)

46708608

46709908

46709808

Negative (Magnusson-Kligman)

Negative (Buehler)

Negative (Modified Buehler)

nonsensitizer

Table B.2 Acute toxicity profile for metabolite 2,6-dichlorobenzamide (BAM)

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

870.1100/Acute oral toxicity (mouse) 42940201 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
Page 23 of 35

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

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3050 28-day dietary 

toxicity (mouse)

46708609 (2000)

Acceptable/Guideline

M/F: 0/0, 0.95/1.19, 

10.4/12.9, 100/129, 

980/1242 mg/kg/day 

NOAEL = 980/1242 mg/kg/day; the limit 

dose).

The LOAEL was not observed. 

870.3050 28-day dietary 

toxicity (rat)

46708610 (2000)

Acceptable/Guideline 

M/F: 0/0, 1.8/1.8, 

17.4/17.9, 174/184, and 

1720/1820 mg/kg/day

NOAEL = 17.4/17.9 mg/kg/day in 

males/females).

The LOAEL = 174/184 mg/kg/day (M/F) based 

on decreased body weight gain and food 

conversion in females and nephrotoxicity in 

males. 

870.3050 28-day dietary 

toxicity (rat)

AE 1344122 

(Fluopicolide 

metabolite)

46708611 (2003)

Acceptable/Guideline 

M/F: 0/0, 1.5/1.7, 

14.9/16.8, 151.6/167.1, 

1495.3/1615.5 mg/kg/day

NOAEL = 151.6/167.1 mg/kg/day.

LOAEL = 1495.3/1615.5 mg/kg/day based on 

decreased body weights and body weight gains 

in both sexes, and nephrotoxicity in females. 

870.3050 28-day dietary 

toxicity (rat)

AE C657378 (a 

Fluopicolide 

metabolite)

46708612 (2003) 

Acceptable/Guideline 

M/F: 0/0, 1.6/2.1, 

16.2/20.4, 159.2/230.6, 

and 1775.0/1930.8 

mg/kg/day

NOAEL = 159.2/230.6 mg/kg/day.

LOAEL = 1775.0/1930.8 mg/kg/day based on 

decreases in body weight and body weight gain 

(males); increased absolute (females) and 

relative liver weight (both sexes) and relative 

kidney weight (males); increased cholesterol 

(both sexes); and histopathological effects in 

the liver (females), the kidneys (males), and 

thyroid (both sexes).

870.3050 28-day oral 

toxicity (dog)

46708613 (2000)

Acceptable/Non-guideline 

0, 10, 100, 1000 

mg/kg/day

NOAEL = 1000 mg/kg/day (limit dose).

LOAEL was not observed. 

870.3100 90-Day oral 

toxicity (rat)

46474112 (2000)

Acceptable/guideline

M: 0, 7.4, 109, 1668 

mg/kg/d

F: 0, 8.4, 119, 1673 

mg/kg/day

NOAEL = 109 mg/kg/day for males; 8.4 

mg/kg/day for females

LOAEL = 1668 mg/kg/day for males and 119 

mg/kg/day for females based on hypertrophy of 

the zona glomerulosa in the adrenal gland 

(M/F), decreased cellularity of the bone 

marrow (M/F), and trabecular hyperostosis of 

the bone joint (M)

870.3100 90-Day oral 

toxicity (mouse)

46474114 (2000)

Acceptable/guideline

M/F: 0, 5.5, 53, 545 or 

1092 mg/kg/day

NOAEL = 1092 mg/kg/day (M/F)

LOAEL = not identified
Page 24 of 35

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

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 90-Day oral 

toxicity (mouse)

46474116 (2001)

Acceptable/guideline

M: 0, 10.4, 37.8, 161, 770 

mg/kg/d

F: 0, 12.6, 52.8, 207, 965 

mg/kg/day

NOAEL = 770 mg/kg/day for males; 207 

mg/kg/day for females

LOAEL = not identified for males; 965 

mg/kg/day for females based on increased 

incidence of liver oval cell proliferation

870.3150 90-Day oral 

toxicity (dog)

46474118 (2000)

Acceptable/guideline

M&F: 0, 5, 70, 1000 

mg/kg/day

NOAEL = 1000 mg/kg/day (M/F)

LOAEL = not identified (M/F)

870.3200 21/28-Day dermal 

toxicity (species)

46708614 (2003)

Acceptable Guideline

0, 100, 250, 500, 1000 

mg/kg/day

NOAEL = 1000 mg/kg/day

LOAEL > 1000 mg/kg/day

No local or systemic toxicity observed

870.3700a Prenatal 

developmental in 

(rat)

Pilot study

46708615 (2000)

Acceptable/non-guideline

F: 500, 1000 mg/kg/day 

(GD 7-20)

NOAEL/LOAEL not determined. Only four 

animals/group. Purpose of study was to 

determine high-dose level for 46474120.

870.3700a Prenatal 

developmental in 

(rat)

46474120 (2001)

Acceptable/guideline

F: 0, 5, 60, 700 mg/kg/day 

(GD 7-20)

Maternal NOAEL = 60 mg/kg/day

LOAEL = 700 mg/kg/day based on decreased 

body weight gain

Developmental NOAEL = 60 mg/kg/day

LOAEL = 700 mg/kg/day based on delayed 

fetal growth and delayed ossification

870.3700b Prenatal 

developmental in 

(rabbit)

Pilot study

46708616 (2000)

Acceptable/non-guideline

F: 25, 50, 100, 250, 500, 

or 1000 mg/kg bw/day

(GD 6-28)

Maternal NOAEL = 25 mg/kg/day

LOAEL = 50 mg/kg/day based on reduced 

defecation and abortion in a single dose

Developmental NOAEL = 1000 mg/kg/day

LOAEL = not observed

870.3700b Prenatal 

developmental in 

(rabbit)

46474122 (2001)

Acceptable/guideline

F: 0, 5, 20, 60 mg/kg/day 

(GD 6-28)

Maternal NOAEL = 20 mg/kg/day

LOAEL = 60 mg/kg/day based on death, lateterm abortion/premature delivery, decreased 

food consumption and weight gain

Developmental NOAEL = 20 mg/kg/day

LOAEL = 60 mg/kg/day based on 

abortion/premature delivery, decreased fetal 

body weight and crown-rump length
Page 25 of 35

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

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3800 Reproduction and 

fertility effects

(rat)

46474124 (2003)

46474125 (additional 

data, 2004)

46474126 (range-finding, 

2002)

Acceptable/guideline

M: 0, 7.4, 36.4, 144.6 

mg/kg/d

F: 0, 8.1, 41.0, 159.7 

mg/kg/day

Parental/Systemic NOAEL = 36.4/41.0 

mg/kg/day (M/F)

LOAEL = 144.6/159.7 mg/kg/day (M/F) based 

on kidney toxicity in males and females and 

decreased weight gain in females.

Reproductive

mg/kg/day (M/F)

LOAEL = not identified.

Offspring NOAEL = 36.4/41.0 mg/kg/day 

(M/F)

LOAEL = 144.6/159.7 mg/kg/day (M/F) based 

on decreased body weight and weight gain.

870.4100b Chronic toxicity 

(dog)

44674128 (2002)

Acceptable/guideline

M&F: 0, 70, 300, 1000 

mg/kg/day

mg/kg/day (F)

LOAEL = 1000 mg/kg/day based on decreased 

body weight gain (M); not identified (F)

870.4200b Carcinogenicity

(mouse)

46474130 (2003)

Acceptable/guideline

M: 0, 7.9, 64.5, 551.0 

mg/kg/d

F: 0, 11.5, 91.9, 772.3 

mg/kg/day

NOAEL = 64.5/91.9 mg/kg/day (M/F)

LOAEL = 551.0/772.3 mg/kg/day (M/F) based 

on decreased body weight and weight gain and 

liver lesions.

no evidence of carcinogenicity

870.4300 Chronic/ 

Carcinogenicity

(rat)

46474139 (2003)

Acceptable/guideline

M: 0, 2.1, 8.4, 31.5, 109.4 

mg/kg/day

F: 0, 2.8, 10.8, 41.0, 142.2 

mg/kg/day

NOAEL = 31.5/41.0 mg/kg/day (M/F)

LOAEL = 109.4/142.2 mg/kg/day based on 

decreased body weight gain (M/F) and thyroid 

toxicity (M).

no evidence of carcinogenicity
Page 26 of 35

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

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.5100 

Gene Mutation

(Salmonella 

typhimurium)

46474146 (2001)

Unacceptable/guideline

1.6- 5000 μg/plate

46474202 (2001)

Acceptable/guideline

1.6- 5000 μg/plate

46474148 (2001)

Acceptable/guideline

1.6- 5000 μg/plate

46474144 (2001)

Acceptable/guideline

1.6- 5000 μg/plate

46474142 (2004)

Acceptable/guideline

AE638206 (batch mixture 

of PP/241067/1 and 

PP/241024)

5 - 5000 μg/plate

negative (non-mutagenic) Upgradeable if purity 

for test material is given. 

negative (non-mutagenic)

negative (non-mutagenic)

negative (non-mutagenic

positive (mutagenic)

870.5300 Gene mutation

(Chinese hamster 

lung cells)

46474204 (2000)

Acceptable/guideline

AE638206 (batch mixture 

of PP/241067/1 and 

PP/241024)

1.2- 3820 μg/mL

negative (non-mutagenic)

870.5375 Cytogenetics 46474208 (2001)

Acceptable/guideline

1.22 to 625 μg/mL

46474206 (2004)

Acceptable/guideline

AE638206 (batch mixture 

of PP/241067/1 and 

PP/241024)

3.2 to 100 μg/mL

negative for chromosome aberrations

positive for aberrations without S9 activation
Page 27 of 35

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

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.5395 Micronucleus

(mouse)

46474214 (2003)

Acceptable/guideline

150, 300 or 600 

mg/kg/day

46474210 (2005)

Acceptable/guideline

AE638206 (batch mixture 

of PP/241067/1 and 

PP/241024)

200, 600 or 2000 

mg/kg/day

46474212 (2005)

Acceptable guideline AE 

C638206 (Batch No. OP 

2050046 at 2000 

mg/kg/day

negative at doses up to 600 mg/kg

negative at doses up to 2000 mg/kg 

negative at dose of 2000 mg/kg
Page 28 of 35

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

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.5550 Unscheduled 

DNA Synthesis

(rat hepatocytes)

42169839 (1989)

Acceptable/guideline

negative at concentration up to 300 μg/mL in 

cultured rat hepatocytes 

(no OPPTS 

no./ FIFRA

test 

guideline 

84-2)

Other 

Genotoxicity 

Unscheduled 

DNA synthesis 

(rat hepatocytes)

46474216 (2000)

Acceptable/guideline

AE638206 (batch mixture 

of PP/241067/1 and 

PP/241024)

600 or 2000 mg/kg

negative at concentrations up to 2000 mg/kg in 

hepatocytes from treated rats

870.6200a Acute 

neurotoxicity 

screening battery

(rat)

46474218 (2002)

46474219 (range-finding, 

2002)

Acceptable/guideline

M/F: 0, 10, 100, 2000 

mg/kg

NOAEL = 100 mg/kg (M/F)

LOAEL = 2000 mg/kg (M/F) based on 

transiently lowered body temperature.

870.6200b Subchronic 

neurotoxicity 

screening battery

46474221 (2002)

46474222 (positive 

control, 2002)

Acceptable/guideline

M: 0, 15.0, 106.6, 780.6 

mg/kg/day

F: 0, 18.0, 125.2, 865.8 

mg/kg/day

NOAEL = 106.6/18.0 mg/kg/day (M/F)

LOAEL = 780.6/125.2 mg/kg/day based on 

decreased body weight gain, food consumption, 

and food efficiency.

870.6300 Developmental 

neurotoxicity

None

870.7485 Metabolism and 

pharmacokinetics

(rat)

46474242 (2004)-main 

studies

46474241 (2001)

46474244 (2003)

46474226 (2003)

46474239 (2003)

rapid absorption, metabolism and excretion; 

main metabolites were oxidative Ndealkylation cleavage products. Primary route 

of excretion is fecal and urinary with little 

accumulation in the tissues.

870.7485 Metabolism and 

pharmacokinetics

(rat)

46708632 (2002)

Acceptable Non-guideline

Most of the metabolites observed were 

derivatives of AE C638206 fitting well with the 

prior known metabolites, implying cysteine or 

N-acetyl-cysteine introduction on the phenyl 

ring from gluthione conjugation, hydroxylation, 

or other conjugations.

870.7485 Metabolism and 

pharmacokinetics

(rat)

AE C657188 

(PCA)

46708636 (2002)

Acceptable Guideline

AE C657188 (PCA) showed high (87%) 

absorption but low (14 – 21%) metabolism. 

Excretion is mainly through the urine, with a 

minor portion in the feces.
Page 29 of 35

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

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.7485 Metabolism and 

pharmacokinetics

(rat)

AE C653711 (2,6-

dichlorobenzamide

46708633 (2003)

46708634 (2003)

46708635 (2003)

Acceptable Guideline

Absorption: 50-79%. Metabolized extensively 

to 18 identified compounds. The majority of 

the radioactivity was associated with a 

mercapturic acid conjugate of hydroxylchlorobenzamide (15-5-26.2%), present in the 

urine Excretion mainly through urine and 

feces. 

870.7600 Dermal 

penetration

(rat)

46708638 (2003)

Acceptable Guideline

1.43, 659 ug/cm2skin

In vivo study

Dermal Penetration rate: 37%

870.7600 Dermal 

penetration

(comparative)

46708637 (2003)

Acceptable Non-guideline

1.9, 744 ug/cm2skin

In vitro study

Rat skin dermal penetration rate is 7.8 times 

greater than human skin.

Table B.4 Subchronic, Chronic, Other Toxicity Profile for metabolite, 2,6-dichlorbenzamide

(BAM)

Guideline No./

Study Type

MRID No. (Year)/Doses/ 

Classification

Results

870.3100

90-day oral 

(rat; dietary)

00067654 (1967)

0, 50, 180, 600, or 2300 ppm 

(equal to 0, 4, 14, 49, or 172 

mg/kg/day)

Acceptable/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 

42940202 (1971), 44043601 

(1996), 44052901 (1996)

NOAEL = 6.5 (M) and 4.7 mg/kg/day (F)

LOAEL = 19 mg/kg/day (M) and 8.5 mg/kg/day (F) based on 
Page 30 of 35

Table B.4 Subchronic, Chronic, Other Toxicity Profile for metabolite, 2,6-dichlorbenzamide

(BAM)

Guideline No./

Study Type

MRID No. (Year)/Doses/ 

Classification

Results

Chronic 

Toxicity/ 

Carcinogenicity 

oral (rat; 

dietary)

0, 60, 100, 180, or 500 ppm 

[equal to 0, 2.2/2.8, 3.6/4.7, 

6.5/8.5, or 19/25 mg/kg/day 

(M/F)]

Acceptable/Guideline

decreased body weight and body weight gain (≥ week 26) and 

an increased incidence of hepatocellular alteration 

(eosinophilic foci)

Borderline statistically significant (P=0.049) increased 

incidence of hepatocellular adenomas at 25 mg/kg/day (F 

only); dosing considered adequate (M&F)

870.3700

Developmental 

toxicity oral 

(rabbit; gavage)

43003601 (1986), 43265201 

(1994)

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

Acceptable/Guideline

Maternal NOAEL= 30 mg/kg/day

Maternal LOAEL= 90 mg/kg/day based on increased 

incidences of clinical signs (late abortion, thin appearance) 

and decreased (severe) body weight gain and food 

consumption during dosing

Developmental NOAEL = 30 mg/kg/day 

Developmental LOAEL = 90 mg/kg/day based on increased 

incidences of late abortion and skeletal (bipartite interparietal 

bone) and visceral (postcaval lung lobe agenesis) anomalies

870.3800

3-generation 

reproduction 

oral (rat; 

dietary)

42940204 (1971)

0, 60, 100, or 180 ppm 

(equivalent 0, 4.5, 7.5, or 13.5 

mg/kg/day) 

Acceptable/Non-Guideline

(upgradable if individual 

animal data is included)

Parental NOAEL = 13.5 mg/kg/day

Parental LOAEL was not observed. 

Reproductive NOAEL = 13.5 mg/kg/day

Reproductive LOAEL was not observed.

Offspring NOAEL = 13.5 mg/kg/day

Offspring LOAEL was not observed.

Non-guideline 

(literature)

Adult mouse 

olfactory study 

(single 

injection; i.p.)

Brittebo et al. (1991); no 

MRID

0, 25, 50, or 100 mg/kg/day 

(i.p.)

Acceptable/Non-guideline

Decreased periodic acid-Schiff (PAS) staining of contents of 

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

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

epithelium and necrosis of Bowman’s glands observed at 100 

mg/kg/day (sustained)

870.5100

In vitro

bacterial 

reverse 

mutation 

(Ames test)

43003603 (1992)

At concentrations up to 5000 

g/plate (-/+ activation) in S. 

typhimurium

Acceptable/Guideline

Negative with or without activation.

870.5395

In vivo mouse 

erythrocyte 

micronucleus 

assay

43003602 (1993), 43747101 

(1995)

0, 250 mg/kg 

Acceptable/Guideline

Negative. 

Lethargy observed in dose-range finding (pilot) study at 100 

mg/kg/day (=LOAEL; NOAEL not observed); clinical signs 

worsened with increasing dose

870.5550

In vitro 

43003604 (1993)

Negative.
Page 31 of 35

Table B.4 Subchronic, Chronic, Other Toxicity Profile for metabolite, 2,6-dichlorbenzamide

(BAM)

Guideline No./

Study Type

MRID No. (Year)/Doses/ 

Classification

Results

Unscheduled 

DNA synthesis 

(rat 

hepatocytes)

At concentrations up to 1000 

μg/ml

Acceptable/Guideline

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

Residential and Occupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment Study and Toxicological Effects

Acute Dietary 

(all 

populations)

An endpoint attributable to a single dose was not identified from the available data.

Chronic 

Dietary (all 

populations)

Maternal

NOAEL=20 

mg/kg/day

UFA=10x

UFH=10x

FQPA SF = 1X

Chronic RfD = 

0.2 mg/kg/day

cPAD = 0.2 

mg/kg/day

Developmental Toxicity Study in Rabbits

LOAEL (maternal) = 60 mg/kg/day based on 

death, abortions/ premature deliveries, 

decreased food consumption and body 

weight gain.

Co-critical: Chronic/Oncogenicity Study 

in Rats

NOAEL = 31.5 mg/kg/day. 

LOAEL = 109.4 mg/kg/day based on 

decreased body weight gain and increased 

thyroid weight and increased incidence of 

thyroid lesions.

Incidental 

Oral 

IntermediateTerm

(1 - 6 months)

Maternal 

NOAEL = 20 

mg/kg/day

UFA=10x

UFH=10x

FQPA SF = 1X

MOE = 100 

(occupational)

MOE = 100 

(residential)

Developmental Toxicity Study in Rabbits

LOAEL (maternal) = 60 mg/kg/day based on 

death, abortions/ premature deliveries, 

decreased food consumption and body 

weight gain.

Dermal ShortIntermediateand LongTerm (1-30 

days, 1-6 

months, and 

>6 months)

Maternal 

NOAEL = 20 

mg/kg/day

UFA=10x

UFH=10x

FQPA SF = 1X

37% dermal 

absorption

MOE = 100 

(occupational)

MOE = 100 

(residential)

Developmental Toxicity Study in Rabbits

LOAEL (maternal) = 60 mg/kg/day based on 

death, abortions/ premature deliveries, 

decreased food consumption and body 

weight gain.

Co-critical: Chronic/Oncogenicity Study 

in Rats

NOAEL = 31.5 mg/kg/day.

LOAEL = 109.4 mg/kg/day based on 

decreased body weight gain and increased 

thyroid weight and increased incidence of 

thyroid lesions.
Page 32 of 35

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

Residential and Occupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment Study and Toxicological Effects

Inhalation 

ShortIntermediateand Longterm (1-30 

days, 1-6 

months, and 

>6 months)

Maternal 

NOAEL = 20 

mg/kg/day

UFA=10x

UFH=10x

FQPA SF = 1X

(inhalation and 

oral toxicity are 

assumed to be 

equivalent)

MOE = 100 

(occupational)

MOE = 100 

(residential)

Developmental Toxicity Study in Rabbits

LOAEL (maternal) = 60 mg/kg/day based on 

death, abortions/ premature deliveries, 

decreased food consumption and body 

weight gain.

Co-critical: Chronic/Oncogenicity Study 

in Rats

NOAEL = 31.5 mg/kg/day.

LOAEL = 109.4 mg/kg/day based on 

decreased body weight gain and increased 

thyroid weight and increased incidence of 

thyroid lesions.

Cancer (oral, 

dermal, 

inhalation)

Classification: “Not Likely to be Carcinogenic to Humans”.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to 

mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL 

= no observed adverse effect level. LOAEL = lowest observed adverse effect level. 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. PAD = population adjusted dose (a = acute, c = chronic). RfD = 

reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Table B.6 Summary of Toxicological Doses and Endpoints for 2,6-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
Page 33 of 35

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/day3based on nasal 

degeneration

Cancer Classification: 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

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/m3from 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/m3from 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].
Page 34 of 35

Appendix C: International Residue Limits 

Fluopicolide (PC Code 027412; 10/15/12)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex2

40 CFR 180.627

(a) fluopicolide [2,6-dichloro- N -

[[3-chloro-5-(trifluoromethyl)-2-

pyridinyl]methyl]benzamide] 

2,6-dichloro-N-[[3-

chloro-5-

(trifluoromethyl)-2-

pyridinyl]methyl]benza

mide

Fluopicolide. The 

residue is fat soluble.

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

US Canada Mexico1 Codex2

Brassica, head and stem, 

subgroup 5A

5.0 2 Flowerhead brassicas 

(includes broccoli; 

broccoli, Chinese and 

cauliflower)

7 cabbages, head

0.2 brussel sprouts

Grape 2.0 1.4 2 grapes

7 grape pomace, dry

Grape, raisin 6.0 4.1 raisins 10 dried grapes 

(=currants, raisins and 

sultanas)

Potato, processed waste 0.05

Vegetable, brassica (cole) 

leafy subgroup 5B

18 30 leafy vegetables

Vegetable, bulb, crop group 

3-07

7.0 1 onion, bulb

10 onion, Welsh

Vegetable, cucurbit, group 9 0.50 0.5 balsam apples, balsam 

pears, cantaloupes, chayote 

fruit, Chinese cucumbers, 

Chinese waxgourds, citron 

melons, cucumbers, edible 

gourds and muskmelons 

(other than those listed in 

this item), pumpkins, 

summer squash, 

watermelons, west Indian 

gherkins, winter squash

0.5 Fruitng vegetables, 

cucurbits

Vegetable, fruiting, group 8 1.60 1.6 African eggplants, bell 

peppers, bush tomatoes, 

coconas, currant tomatoes, 

eggplants, garden 

huckleberries, goji berries; 

groundcherries, martynias, 

naranjillas, nonbell 

peppers, okras, pea 

eggplants, pepinos, 

roselles, scarlet eggplants, 

sunberries, tomatillos, 

tomatoes, tree tomatoes

1 Fruitng vegetables, 

other than cucurbits

7 peppers chili, dried

Vegetable, leafy, except 

brassica, group 4

25 16 head lettuce, leaf lettuce 20 celery

30 leafy vegetables
Page 35 of 35

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex2

Vegetable, leaves of root and 

tuber, group 2

15.0 30 leafy vegetables

Vegetable root, subgroup 1A 0.15

Vegetable, tuberous and corm 

subgroup 1C

0.02 0.02 arracacha, arrowroot, 

cassava roots, chayote 

roots, Chinese artichokes, 

chufa, edible canna, ginger 

roots, Jerusalem 

artichokes, lerens, sweet 

potato roots, tanier corms, 

taro corms, turmeric roots, 

true yam tubers, yam bean 

roots 

Completed: M. Negussie; 10/18/2012

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

2

* = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = 

processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the 

fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.

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

dichloro- N -[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]benzamide], including its metabolites and 

degradates, in or on the commodities in the table in this paragraph. Compliance with the tolerance levels specified 

below is to be determined by measuring only fluopicolide [2,6-dichloro- N -[[3-chloro-5-(trifluoromethyl)-2-

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

Commodity

Parts per

million

Wheat, aspirated grain fractions 0.07

Wheat, forage 0.20

Wheat, grain 0.02

Wheat, hay 0.50

Wheat, milled byproducts 0.07

Wheat, straw 0.50