Flurnetralin Human Health Risk Assessment DP No. D427465 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

MEMORANDUM 

Date: December 15, 2015 

WASHINGTON, D.C. 20460 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Flumetralin : Human Health Risk Assessment for Registration Review. 

PC Code: 12300 I 

Decision No.: 505305 

Petition No.: NA 

Risk Assessment Type: Single Chemical 

Aggregate 

TXR No.: A 

MRID No.: A 

FROM: 

THROUGH: Danette Drew, Chemist, and 

Michael S. Metzger, Chief, 

HED (7509P) 

DP Barcode: 427465 

Registration No.: I 00- 1228. I 00-640, 400-600 

& 19713-649 

Regula tory Action: Registration Review 

CascNo.: 4119 

CAS No.: 62924-70-3 

40 CFR: NA 

TO: Katherine St. Clair, Risk Manager Reviewer 

Cathryn Britton, Risk Manager 

Risk Management and Implementation Branch II 

Pesticide Re-Evaluation Division 
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Table of Contents

1.0 Executive Summary.................................................................................................................. 3

2.0 HED Recommendations............................................................................................................ 6

2.1 Data Deficiencies ............................................................................................................. 6

2.2 Tolerance Considerations................................................................................................. 6

2.3 Label Recommendations.................................................................................................. 6

3.0 Introduction............................................................................................................................... 7

3.1 Chemical Identity ............................................................................................................. 7

3.2 Physical/Chemical Characteristics................................................................................... 7

3.3 Pesticide Use Pattern........................................................................................................ 7

3.4 Anticipated Exposure Pathways....................................................................................... 9

3.5 Consideration of Environmental Justice .......................................................................... 9

4.0 Hazard Characterization and Dose-Response Assessment....................................................... 9

4.1 Toxicology Studies Available for Analysis ................................................................... 10

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME).................................... 10

4.3 Toxicological Effects ..................................................................................................... 11

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)....................................... 12

4.5 Toxicology Endpoint and Point of Departure Selections............................................... 13

4.6 Endocrine Disruption ..................................................................................................... 16

5.0 Dietary Exposure and Risk Assessment ................................................................................. 17

5.1 Metabolite/Degradate Residue Profile ........................................................................... 17

5.2 Food Residue Profile...................................................................................................... 19

5.3 Water Residue Profile .................................................................................................... 19

5.4 Dietary Risk Assessment................................................................................................ 20

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ......................................... 21

6.1 Non-Occupational Inhalation Exposure (Tobacco Smoking)........................................ 21

6.2 Residential Handler Exposure........................................................................................ 21

6.3 Post-Application Exposure............................................................................................. 22

6.4 Residential Bystander Post-Application Inhalation Exposure ....................................... 22

6.5 Spray Drift...................................................................................................................... 22

7.0 Aggregate Exposure/Risk Characterization ............................................................................ 24

8.0 Cumulative Exposure/Risk Characterization.......................................................................... 24

9.0 Occupational Exposure/Risk Characterization ....................................................................... 24

9.1 Short- and Intermediate-Term Handler Risk.................................................................. 24

9.2 Short- and Intermediate-Term Post-Application Risk ................................................... 27

10.0 Human Incidence .................................................................................................................. 27

11.0 References............................................................................................................................. 27

Appendix A. Toxicology Assessment........................................................................................... 29

A.1 Toxicology Data Requirements...................................................................................... 29

A.2 Toxicity Profiles............................................................................................................. 30

A.3 Hazard Identification and Endpoint Selection ............................................................... 35

A.4 Executive Summaries..................................................................................................... 37

Appendix B. Physical/Chemical Properties.................................................................................. 51

Appendix C. Review of Human Research .................................................................................... 52

Appendix D. Major Flumetralin Metabolites............................................................................... 53
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1.0 Executive Summary

This assessment has been conducted to address the requirement for a Draft Risk Assessment 

(DRA) to support registration review. As part of Registration Review, the Pesticide Reevaluation Division (PRD) of OPP has requested that HED evaluate the hazard and exposure 

data and conduct occupational and residential exposure assessments, as needed, to estimate the 

risk to human health that will result from the currently registered uses of flumetralin. This 

memorandum addresses and obviates the need for a separate scoping document. 

Background

Flumetralin (2-chloro-N-[2,6-dinitro-4-(trifluoromethyl)phenyl]-N-ethyl-6-

fluorobenzenemethanamine) is used as a plant growth regulator for the control of sucker growth 

on flue-cured, burley, dark, Maryland, and cigar tobacco. Flumetralin is in the 2,6-dinitroaniline 

class of chemicals. There are only three end-use product labels registered with flumetralin as an 

active ingredient. All three are emulsifiable concentrate (EC) products. Flumetralin can be 

applied via motorized field sprayers (groundboom) and hand-held equipment. The maximum 

single application rate per season is 1.2 lbs ai/A, and the three products are generally applied 

once, but can be applied up to 2 times per season. There are currently no registered or proposed 

residential uses of flumetralin.

Hazard Assessment

The toxicology database is complete. The liver is the target organ for flumetralin. Other effects 

were noted on the blood. Developmental toxicity included total litter resorptions, increased postimplantation loss, and skeletal alteration in rabbits and increased runts and skeletal malformation 

in rats; however, endpoints selected for risk assessment were protective of these effects. No 

reproductive toxicity was noted, and the offspring were not more sensitive than the parental 

animals. No systemic toxicity was observed following dermal exposure to rabbits for 21 days up 

to the limit dose; however, dermal irritation was noted at all tested doses. No evidence of 

neurotoxicity, immunotoxicity, mutagenicity, or carcinogenicity was observed. No effects were 

noted in a 6-week study in rats, where rats were exposed to smoke from cigarettes made of 

tobacco treated with flumetralin. In acute lethality studies, flumetralin has low acute toxicity via 

the oral, dermal and inhalation routes of exposure. It is a mild dermal irritant, a dermal sensitizer, 

and a severe eye irritant.

Based on the toxicity, duration of exposure, and uses of flumetralin, the following toxicity 

endpoints were selected:

Acute dietary (general population, including infants and children): No endpoint 

identified.

Acute dietary (females 13-49 years of age): aRfD = 0.50 mg/kg/day derived from a 

NOAEL of 50 mg/kg/day in a rabbit developmental toxicity study. LOAEL = 100

mg/kg/day based on increased incidences of litters with total resorptions, increased postimplantation loss, and an increase in external and skeletal alterations.

Intermediate-term dietary: RfD = 0.116 mg/kg/day derived from a NOAEL of 11.6

mg/kg/day in a dog subchronic oral toxicity study. LOAEL = 92.8 mg/kg/day based on 

clinical signs (weight loss, pyrexia, dehydration, and depression), mortality, hematology, 
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clinical chemistry, and increased myeloid hyperplasia which is representative of all 

durations. 

Dermal: No point of departure was determined, because a systemic dermal hazard was 

not identified.

Inhalation: Same as intermediate-term dietary. Toxicity via the inhalation route was 

considered equivalent to the oral route.

Dietary (Food and Water) Exposure and Risk

Flumetralin is a non-food use pesticide active ingredient since it is only used on tobacco to 

control auxiliary bud (sucker) growth. There is potential for flumetralin to reach drinking water 

sources through its application to tobacco. Updated acute and intermediate-term dietary 

assessments of drinking water were conducted using model-derived estimated drinking water 

concentrations (EDWCs). No hazard was identified for acute dietary exposures to the general 

population but an endpoint was determined for females 13-49 years old. An endpoint was 

selected for the general population for intermediate-term dietary exposures based on a 

subchronic oral toxicity study and is protective of all durations. The estimated acute exposure to 

flumetralin in drinking water resulted in a dietary risk of < 1.0% of the aRfD for females 13-49 

years old at the 95thpercentile and is well below the Agency’s level of concern. The estimated 

intermediate-term dietary margin of exposures (MOEs) to flumetralin in drinking water greatly 

exceed 100 for all population subgroups and are also not of concern. 

 

Residential (Non-Occupational) Exposure and Risk

No inhalation risk assessment was conducted since no systemic toxicity was observed in the

available 6-week smoking study in which rats were exposed to flumetralin by inhalation of 

smoke from cigarettes made of tobacco treated with flumetralin. Because flumetralin is 

registered only for use on field grown tobacco, there are no existing or proposed residential uses 

at this time and therefore no quantitative residential handler or post-application assessment was 

completed. Based on the Agency's current practices, a quantitative post-application inhalation 

exposure assessment was not performed for the use of flumetralin on tobacco.

Spray Drift

A quantitative, non-occupational spray drift assessment was conducted for the registered uses of 

flumetralin. Since flumetralin can be applied via groundboom application equipment to field 

grown tobacco plants, there is potential for indirect exposure related to agricultural spray drift. 

In the absence of an endpoint selected for dermal toxicity, an adult dermal post-application 

exposure assessment for spray drift was not conducted. Incidental oral risk estimates for 

children 1 to <2 years old were calculated. The highest exposure resulted from drift following 

flumetralin applications using groundboom equipment for children 1 <2 years old (margins of 

exposures (MOEs) ≥ 3,400 with a LOC = 100). There were no risks of concern at the field’s 

edge.
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Volatilization/Residential Bystander

Volatilization of pesticides may be a source of post-application inhalation exposure to 

individuals nearby pesticide applications. The agency has developed a Volatilization Screening 

Tool and a subsequent Volatilization Screening Analysis, and the Agency will utilize this 

analysis during Registration Review to determine if data (i.e., flux studies) or further analysis are 

required for flumetralin.

Aggregate

There are no food or residential uses of flumetralin. Therefore, aggregate risks include only 

drinking water contributions, which are not of concern. 

Occupational Exposure and Risk

No chemical-specific handler exposure data were submitted in support of this assessment; 

therefore, HED relied on surrogate data and default assumptions in accordance with standard 

policies. In the absence of an endpoint selected for dermal toxicity, dermal handler and postapplication exposure assessments were not conducted. All occupational handler scenarios for the 

registered uses resulted in inhalation MOEs greater than 100 at baseline (i.e., without respiratory 

protection). The lowest MOE of 3,300 is associated with mixing/loading/applying sprays using a 

backpack sprayer. All other MOEs were significantly higher, ranging from 4,800 to 44,000. No 

additional PPE recommendations are needed on the registered labels. 

Based on the Agency's current practices, a quantitative non-cancer occupational post-application 

inhalation exposure assessment was not performed for flumetralin at this time. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for flumetralin.

Human Studies Review

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data, which include studies from 

PHED 1.1; the AHETF database, and the Lawn & Turf Residential SOP are: (1) subject to ethics 

review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with 

applicable ethics requirements. For certain studies, the ethics review may have included review 

by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their 

use, can be found at the Agency website1. 

 

1 http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html.
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2.0 HED Recommendations

2.1 Data Deficiencies

There are no data deficiencies for the Registration Review eligibility of flumetralin in regards to 

the toxicology, occupational and residential exposure, and chemistry databases. No tolerances 

are required, and label modifications are discussed in Section 2.3.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Because no tolerances are required to support the use of flumetralin on tobacco, an enforcement 

analytical method is not required. 

2.2.2 International Harmonization

International harmonization is not an issue for consideration, because there are no tolerances 

established for flumetralin.

2.2.3 Recommended Tolerances

Flumetralin is only registered for application to commercial tobacco crops and is considered to 

be a non-food use chemical, which does not require the establishment of tolerances.

2.2.4 Revisions to Established Tolerances

There are no tolerances established for flumetralin, and thus no revisions are required.

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

The labeled directions appropriately specify the required patterns of use for treating tobacco to 

control bud (sucker) growth. The available use pattern information is adequate to allow 

evaluation of the residue data for the registered uses on tobacco.

2.3.2 Recommendations from Occupational Assessment

Flumetralin is classified as a Category I acute eye irritant. Under 40 CFR 156.208 (c) (2) (iii), 

active ingredients classified as Acute I for eye irritation are assigned a 48-hour REI. The existing 

product labeling indicates either a 12 or 24-hour REI (depending on the product). HED is 

recommending that the REI be revised on the label to address those concerns.
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3.0 Introduction

3.1 Chemical Identity

Table 3.1. Flumetralin Nomenclature

Chemical structure

Common name Flumetralin

Molecular formula C16H12ClF4N3O4

Molecular weight 421.74

PC Code 123001

IUPAC name N-(2-chloro-6-fluorobenzyl)-N-ethyl-2,6-dinitro-4-(trifluoromethyl)aniline

CAS name 2-chloro-N-[2,6-dinitro-4-(trifluoromethyl)phenyl]-N-ethyl-6-

fluorobenzenemethanamine

CAS registry number 62924-70-3

3.2 Physical/Chemical Characteristics

Flumetralin is the common name for the plant growth inhibitor 2-chloro-N-[2,6-dinitro-4-

(trifluoromethyl)phenyl]-N-ethyl-6-fluorobenzenemethanamine (CAS Name). It is registered for 

use as an outdoor drench to tobacco to control side shoots and is formulated as an emulsifiable 

concentrate (EC). It has an aromatic solvent odor and is stable under normal use and storage 

conditions. The environmental fate and characterization database for flumetralin requires

updating, because water solubility, Kow, and vapor pressure values reported in the submitted 

studies do not agree with those cited in outside sources (D427267, I. Abdel-Saheb, 06/10/2015). 

Based on its Koc, flumetralin is an immobile compound. It is very persistent in aerobic soil,

having a half-life of longer than 3 years as reported in test data acquired using a foreign soil 

matrix. Flumetralin is stable to hydrolysis. Given these data, flumetralin persistence and 

accumulation is expected in the field. A detailed summary of the physical/chemical 

characteristics of flumetralin are presented in Appendix B. 

3.3 Pesticide Use Pattern

There are four end-use product labels registered with flumetralin as the active ingredient, all EC

formulations. The labeled use sites include flue-cured, burley, dark, Maryland, and cigar 

tobacco. Flumetralin can be applied with motorized field sprayers (ie, groundboom applications) 

or with handheld spray equipment. For most use sites/crops, the maximum application rate is 1.2

lb ai/A, although one product has a lower application rate of 0.6 lbs ai/A. Table 3.3 below 

details a summary of direction for use of flumetralin products.

CF3

O2N NO2

N CH3

Cl F
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Table 3.3. Summary of Directions for Use of Flumetralin.

Applic. 

Timing, Type, 

and Equip.

Formulation 

[EPA Reg. 

No.]

Applic. 

Rate (lb 

ai/A)

Max. No. 

Applic. per 

Season

Max. 

Seasonal 

Applic. Rate 

(lb ai/A)

PHI 

(days)

Use Directions and 

Limitations

Tobacco Plants

Motorized field 

sprayers/handheld equipment19713-649 0.6 2 1.2 N/A

Plucker plusTM

 Do not apply more than 

2x per crop

 Hand drop line or 

powered spray 

equipment

 0.012 lbs ai/gallon 

application rate for 

handheld equipment

 Must not be applied >4 

ft. over crop canopy

Motorized field 

sprayers/handheld equipment100-640 1.2 1 1.2 N/A

Prime+®

 Apply 1x/season

 Split application an 

option in NC

 Avoid precision hand 

application equipment

 0.024 lbs ai/gallon 

application rate for 

handheld equipment

 Do not co-apply with 

insecticides or 

fungicides

 Must not be applied >4 

ft. over crop canopy

Motorized field 

sprayers/handheld equipment400-600 1.2 1 1.2 N/A

FLUPRO®

 Apply 1x/season

 Avoid precision hand 

application equipment

 Mix 1 gallon flupro in 

49 gallons of water for 

handheld equipment

 Do not co-apply with 

insecticides or 

fungicides

 Must not be applied >4 

ft. over crop canopy

Motorized field 

sprayers/handheld equipment19713-510 1.2 1 1.2 N/A

Drexalin Plus®

 Apply 1x/season

 Do not exceed 1.2 lbs 

ai/A

 Do not replant treated 

areas to any other crop 

than tobacco within 10 

months of last 

application of this 

product
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Table 3.3. Summary of Directions for Use of Flumetralin.

Applic. 

Timing, Type, 

and Equip.

Formulation 

[EPA Reg. 

No.]

Applic. 

Rate (lb 

ai/A)

Max. No. 

Applic. per 

Season

Max. 

Seasonal 

Applic. Rate 

(lb ai/A)

PHI 

(days)

Use Directions and 

Limitations

Product must be 

applied with coarse 

spray

3.4 Anticipated Exposure Pathways

Since there are no food uses for flumetralin, exposure from food will not occur. The registered 

use patterns could result in residues in drinking water, so there is the potential for exposure from 

drinking water. There are no residential uses of flumetralin; however, there is the potential for 

short-term non-occupational exposure (dermal and incidental oral) to flumetralin as a result of 

spray drift and potentially from field volatilization of applied flumetralin. 

Based on the registered use pattern for flumetralin, short- and intermediate-term dermal and 

inhalation exposures are anticipated for occupational handlers and post-application workers. 

3.5 Consideration of Environmental Justice

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

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

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

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the U.S. Department of 

Agriculture’s (USDA’s) National Health and Nutrition Examination Survey, What We Eat in 

America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food 

uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season 

of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary 

exposure to smaller, specialized subgroups, and exposure assessments are performed when 

conditions or circumstances warrant. Whenever appropriate, non-dietary exposures are 

evaluated, based on home use of pesticide products and associated risks for adult applicators and 

for toddlers, youths, and adults entering or playing on treated areas post-application. Further 

considerations are currently in development, as OPP has committed resources and expertise to 

the development of specialized software and models that consider exposure to bystanders and 

farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

Flumetralin [2-chloro-N-[2, 6-dinitro-4-(trifluoromethyl)phenyl]-N-ethyl-6-fluorobenzene 

methanamine] is in the 2, 6-dinitroaniline class of chemicals. Dinitroanilines selectively inhibit 
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the microtubules of plants and protozoa and do not act on fungal or vertebrate tubulins. 

Flumetralin is a plant growth regulator used only on tobacco for control of axillary bud (sucker) 

growth. 

4.1 Toxicology Studies Available for Analysis

The toxicology database for flumetralin is complete for human health risk assessment. HASPOC 

concluded, by a weight of evidence approach, that 90-day inhalation toxicity, acute 

neurotoxicity, subchronic neurotoxicity (Leshin, 2015, TXR # 0057243), and immunotoxicity 

studies (Rury, 2013, TXR # 0056750) were not required. There are acceptable studies available 

for toxicity endpoint selection, including: 

 subchronic oral toxicity studies in rats and dogs

 chronic oral toxicity studies in rats 

 carcinogenicity studies in rats and mice 

 developmental studies in rats and rabbits 

 reproduction study in rats 

 subchronic dermal toxicity study in rats 

 immunotoxicity study in mice 

 complete mutagenicity study battery 

 metabolism study in rats

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)

There are limited animal metabolism data available on flumetralin. Following single doses of 0.5 

mg/kg and 50 mg/kg, 76% to 86% of the dose was excreted in the urine and feces of rats in 48 

hours. According to the European Food Safety Authority (EFSA Journal 2014, 12(12):3912), 

oral absorption of flumetralin is poor, corresponding to 30% of the administered dose at the high 

dose and 33% at the low dose. Once absorbed, flumetralin is widely distributed, totally 

metabolized, and rapidly excreted, mainly via the feces, with some enterohepatic recirculation.

4.2.1 Dermal Absorption

A dermal absorption study is not available. Quantitation of risk by the dermal route of exposure 

is not required. Although there is a route-specific rabbit repeated dose (21-day) dermal toxicity 

study on flumetralin, a dermal endpoint was not selected since the study did not demonstrate 

systemic toxicity up to the limit dose (1,000 mg/kg/day) and twice the limit dose (2000 

mg/kg/day). Comparing the no-observed-adverse-effect level (NOAEL) from the dermal study 

(2000 mg/kg/day) with that from the rabbit developmental oral toxicity study (50 mg/kg/day) 

suggests minimal dermal absorption (2.5%). A similar comparison with the limit dose results in a 

5% dermal absorption factor. Although runts and skeletal malformations were observed in the rat 

developmental toxicity study (NOAEL = 100 mg/kg/day), the dermal equivalent dose is 4000 

mg/kg/day. Therefore, a dermal assessment is not required.
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4.3 Toxicological Effects

The liver is the target organ for flumetralin, based on the effects seen throughout the toxicology 

database. Liver effects were noted in the chronic oral rat study (increased liver weight and 

hepatocellular eosinophilic cytoplasmic change), the mouse carcinogenicity study (increased 

liver weight), and in the subchronic dog study (increased liver weight, hepatocellular necrosis, 

chronic inflammation, and increased alkaline phosphatase, SGOT, and SGPT). Other common 

findings include decreased hemoglobin, hematocrit, and RBC counts and increased cholesterol 

levels following subchronic (rats and dogs) and chronic (rat) exposure. In dogs, clinical signs of 

toxicity (weight loss, decreased food consumption, pyrexia, dehydration, and depression), which 

were progressive over a period of two to four weeks, occurred in both sexes at the high-dose, 

with two dogs of each sex dying on test (on Days 40 and 128). One male dog at the mid-dose 

level also died following longer exposure (Day 169). Mortality was also observed in the rabbit 

developmental toxicity study (total litter resorptions).

No systemic toxicity was observed in the 21-day rabbit dermal toxicity study at the limit dose 

and twice the limit dose. Dermal irritation was observed at all dose levels (500 mg/kg/day and 

above). 

There were no effects reported in a rat 6-week smoking inhalation study (inhalation of smoke 

from cigarettes made of tobacco treated with flumetralin). 

Developmental toxicity was observed in the rabbit, as evidenced by the increased incidence of 

litters with total resorption, increased post-implantation loss, increased incidence of external 

(flexure of forepaw at the wrist) and skeletal alterations (fused sternebrae and absent ossification 

of the caudal vertebral centers) at 100 and 200 mg/kg/day. Maternal toxicity in the rabbit 

(hemorrhagic discharges in the perineal area and piloerection, decreased body weight, increased 

incidence of negative body weight gains during the dosing period, decreased terminal gravid 

uterine weight, and increased incidence of litters with resorptions) occurred at a lower dose than 

where developmental toxicity occurred. In the rat, a slight increase in runts and skeletal 

malformations were observed at 400 mg/kg/day, where minimal maternal toxicity (decreased 

body weight gain) occurred. Although qualitative susceptibility was observed in the rat study, 

concern is low, since clear NOAELs were established and endpoints selected for risk assessment 

are protective of the developmental effects observed in this study. 

Reproductive toxicity was not observed in the rat following exposure to flumetralin. Decreased 

body weight was observed in the offspring at the high-dose level. In the maternal animal, a slight 

decrease in body weight was observed during the dosing period and throughout gestation and 

lactation at both the mid- and high-dose levels; i.e., maternal toxicity was observed at a lower 

dose than offspring toxicity.

In the rat oral chronic toxicity/carcinogenicity study, there were no clinical signs of toxicity and 

no adverse effect on survival. Decreased body weight was observed in both sexes throughout the 

study, but there were no consistent effects on food consumption. Increased liver weight, an 

increased incidence of hepatocellular eosinophilic cytoplasmic change, decreased hemoglobin, 

hematocrit, and RBC counts, and increased cholesterol levels were observed. In the mouse 

carcinogenicity study, there were no clinical signs of toxicity, and no adverse effects on survival, 
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body weight/gain, food consumption, or hematology parameters. There was an increase in liver 

weight in both sexes at the two highest dose levels. No treatment-related increase in any tumor 

type was observed in rats or mice following long-term exposure to flumetralin. The mutagenicity 

database is adequate, and no mutagenicity was observed in the guideline mutagenicity studies. 

The acute and subchronic neurotoxicity studies are not available on flumetralin, but the Hazard 

and Science Policy Council (HASPOC) recommended that these studies be waived (Leshin, 

2015, TXR# 0057243). No clinical signs indicating neurotoxicity were observed in the 

toxicological database on flumetralin. The decreased motor activity and piloerection in the 

maternal rabbits that displayed total litter resorption are considered to be the result of high dose 

toxicity and not a neurotoxic effect. The immunotoxicity data requirement for flumetralin was 

waived also (Rury, 2013, TXR# 0056750). 

In acute lethality studies, flumetralin has low acute toxicity via the oral, dermal, and inhalation 

routes of exposure. It is a mild dermal irritant, a dermal sensitizer, and a severe eye irritant. 

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

Flumetralin is not a food-use chemical and has no tolerances set. Therefore, FQPA does not apply.

4.4.1 Completeness of the Toxicology Database

The database of toxicology studies for flumetralin is complete and includes developmental toxicity 

studies in the rat and rabbit and a reproductive toxicity study in the rat. 

4.4.2 Evidence of Neurotoxicity

There was no evidence of neurotoxicity from flumetralin exposure in the toxicological database.

No clinical signs indicating neurotoxicity were observed in the chronic toxicity/carcinogenicity 

study in rats, the developmental toxicity studies in rats and rabbits, the reproduction study in rats, 

the carcinogenicity study in mice, or the 21-day dermal toxicity study in rabbits at the limit dose 

and twice the limit dose. The decreased motor activity and piloerection in the maternal rabbits 

that displayed total litter resorption are considered to be the result of high dose toxicity and not a 

neurotoxic effect. The clinical signs observed in the dog (pyrexia and depression) were 

associated with moribund condition and are not considered a neurotoxic effect. Although there 

was an increase in brain weight in females in the chronic rat study, there is little concern for 

neurotoxicity, since there were no histopathology correlates and the risk assessment endpoints 

chosen are protective for these effects. 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is no evidence of increased quantitative susceptibility following in utero exposure to

flumetralin in either the rat or rabbit developmental toxicity study or following in utero and/or pre-

/post-natal exposure to flumetralin in the 2-generation reproduction study in rats. Qualitative 

susceptibility observed in the rat was observed only at a much higher dose than doses selected for 

quantifying risk, so risk assessments are protective for these effects.
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4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database.

4.5 Toxicology Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

A detailed description of the toxicity studies used for selecting toxicity endpoints and points of 

departure for various exposure scenarios is presented in the Appendix A of this document. The 

available hazard database is adequate to characterize any potential for prenatal or postnatal risk 

for infants and children. 

Acute Dietary (females 13+): An acute dietary endpoint (drinking water only) for females 13+ 

was selected from a developmental toxicity study in rabbits with a NOAEL of 50 mg/kg/day. At 

the study LOAEL of 100 mg/kg/day, an increased incidence of litters with total resorptions, 

increased post-implantation loss, and an increase in external and skeletal alterations were 

observed. Uncertainty factors for interspecies extrapolation (10x) and intraspecies variation 

(10x) were applied to the NOAEL to calculate the acute reference dose (aRfD = 0.50

mg/kg/day).

Acute Dietary (General Population, including infants and children): No endpoint attributable to 

a single exposure was identified from the available toxicity database; therefore, an acute dietary

(drinking water only) risk assessment for flumetralin for the general population, including infants 

and children, is not required. 

Intermediate-Term Dietary (All Populations): Due to the use profile, only exposures of 

intermediate term or less (through drinking water only) are expected. The intermediate dietary 

endpoint was from the subchronic oral toxicity study in dogs with a NOAEL of 11.6 mg/kg/day. 

At the study LOAEL of 92.8 mg/kg/day, the following findings were noted: clinical signs 

(weight loss, anorexia, pyrexia, dehydration, and depression), mortality, decreased hematocrit, 

hemoglobin, and mean corpuscular hemoglobin concentration (MCHC), increased mean 

corpuscular volume (MCV), Heinz body formation, methemoglobin concentrations, 

reticulocytosis, cholesterol, and alkaline phosphatase, and an increased incidence of myeloid 

hyperplasia. Uncertainty factors for interspecies extrapolation (10x) and intraspecies variation 

(10x) were applied to the NOAEL.

Incidental Oral (Intermediate-Term): The incidental oral endpoint was from the subchronic oral 

toxicity study in dogs (as for the intermediate-term dietary endpoint), because it provided the 

most sensitive dose and endpoint available (NOAEL of 11.6 mg/kg/day). Further details are the 

same as for the intermediate-term dietary endpoint. 

Dermal: The repeated (21-day) dose dermal toxicity study in rabbits on flumetralin was 

considered for these exposure scenarios because the route of exposure is appropriate. However, a 

dermal endpoint was not selected since the rabbit 21-day dermal toxicity study did not 

demonstrate systemic toxicity up to the limit dose (1,000 mg/kg/day) and twice the limit dose 

(2000 mg/kg/day). Comparing the NOAEL from 21-day dermal toxicity study (2000 mg/kg/day) 
Flumetralin Human Health Risk Assessment DP No. D427465

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with that from the rabbit developmental toxicity study (50 mg/kg/day) suggests minimal dermal 

absorption (2.5%). Comparing the rabbit developmental NOAEL to the limit dose suggests a 5% 

dermal absorption factor. Although external and skeletal alterations/malformations were 

observed in the rat developmental toxicity study (NOAEL 100 mg/kg/day), the dermal 

equivalent dose is 4000 mg/kg/day, well above the limit dose. Therefore, a dermal assessment is 

not required.

Inhalation (short- and intermediate-term): Although a 28-day inhalation toxicity study has not 

been submitted, HASPOC recommended that this study be waived for flumetralin (Leshin, 2015, 

TXR# 0057243). In the absence of a route-specific inhalation study, a subchronic oral toxicity 

study in the dog was selected (as for the intermediate-term dietary endpoint) to assess both shortand intermediate-term inhalation exposure, because it provided the most sensitive dose and 

endpoint available (NOAEL of 11.6 mg/kg/day). Further details are the same as for the 

intermediate-term dietary endpoint. 

4.5.2 Recommendations for Combining Routes of Exposure for Risk Assessment

The same endpoint/POD are used for the oral and inhalation assessments and can be combined.

4.5.3 Cancer Classification and Risk Assessment Recommendation

A formal cancer risk assessment was not conducted, since flumetralin did not produce a 

tumorigenic response in either the rat or mouse carcinogenicity study and mutagenicity was not 

observed in the battery of studies performed on flumetralin. The flumetralin team has classified 

flumetralin as “not likely to be carcinogenic in humans”, based upon bioassays in rats and mice 

that showed no significant tumor response in either specie, and there is no mutagenicity concern.

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Flumetralin for Use in Dietary and NonOccupational Human Health Risk Assessments 

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factors RfD/LOC Study and Toxicological Effects

Acute Dietary 

(Drinking 

water only),

Females 13+

NOAEL = 50 

mg/kg/day

UFA = 10x

UFH = 10x

aRfD = 0.5 

mg/kg/day

Developmental Toxicity – rabbit

LOAEL = 100 mg/kg/day; an increased incidence 

of litters with total resorptions, increased postimplantation loss, and increased incidence of 

external (positional anomaly) and skeletal (fused 

sternebrae and absent ossification of the caudal 

vertebral centers) alterations.
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Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Flumetralin for Use in Dietary and NonOccupational Human Health Risk Assessments 

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factors RfD/LOC Study and Toxicological Effects

Acute Dietary 

(Drinking 

water only),

General 

Population, 

including 

Infants and 

Children

Based on available data, no toxicity is expected to the general population from a single day 

exposure to flumetralin.

Intermediate

Dietary 

(Drinking

water only),

All 

Populations

NOAEL = 

11.6 

mg/kg/day

UFA = 10x

UFH = 10x

RfD = 0.11 

mg/kg/day

Subchronic Oral Toxicity - Dog 

LOAEL = 92.75 mg/kg/day for clinical signs 

(weight loss, pyrexia, dehydration, and depression), 

mortality, hematology/clinical chemistry effects, 

and an increased incidence of myeloid hyperplasia.

Incidental 

Oral 

(IntermediateTerm)

NOAEL = 

11.6 

mg/kg/day

UFA = 10x

UFH = 10x

LOC = 

MOE≤100

Subchronic Oral Toxicity - Dog 

LOAEL = 92.75 mg/kg/day for clinical signs 

(weight loss, decreased food consumption, pyrexia, 

dehydration, and depression), mortality, 

hematology/clinical chemistry effects, and an 

increased incidence of myeloid hyperplasia.

Dermal A dermal assessment is not required due to a lack of hazard.

Inhalation a Oral NOAEL 

= 11.6 

mg/kg/day

toxicity via

inhalation 

route 

considered 

equivalent to 

toxicity via 

oral route

UFA = 10x

UFH = 10x

LOC = 

MOE≤100

Subchronic Oral Toxicity - Dog 

LOAEL = 92.75 mg/kg/day for clinical signs 

(weight loss, decreased food consumption, pyrexia, 

dehydration, and depression), mortality, 

hematology/clinical chemistry effects, and an 

increased incidence of myeloid hyperplasia.

Cancer (oral, 

dermal, 

inhalation)

Classification: “Not Likely To Be Carcinogenic To Humans”. 

1 Explanation of Abbreviations: 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); MOE = margin of exposure. LOC = level of concern. RBC = red blood cell.

a No hazard was identified in a route-specific (inhalation of smoke from tobacco treated with flumetralin) study. 

However, there is no inhalation toxicity study on the a.i.; HASPOC recommended waiving an inhalation toxicity 

study for flumetralin at this time (Leshin, 2015, TXR # 0057243).
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Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Flumetralin for Use in 

Occupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Dermal A dermal assessment is not required, due to a lack of hazard.

Inhalation a

(Short- and 

IntermediateTerm)

Oral 

NOAEL = 

11.6 

mg/kg/day

toxicity via

inhalation 

route 

considered 

equivalent to 

toxicity via 

oral route

UFA = 10x

UFH = 10x

LOC = 

MOE≤100

Subchronic Oral Toxicity - Dog 

LOAEL = 92.75 mg/kg/day for 

clinical signs (weight loss, decreased 

food consumption, pyrexia, 

dehydration, and depression), 

mortality, hematology/clinical 

chemistry effects, and an increased 

incidence of myeloid hyperplasia.

Cancer 

(oral, 

dermal, 

inhalation)

Classification: “Not Likely To Be Carcinogenic To Humans”. 

1 Explanation of Abbreviations: 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); MOE = margin of exposure. LOC = level of concern. RBC = red blood cell.

a No hazard was identified in the route-specific (inhalation of smoke from tobacco treated with flumetralin) study. 

However, there is no inhalation toxicity study on the a.i.; HASPOC concluded that an inhalation toxicity study is not 

required for flumetralin at this time (Leshin, 2015, TXR # 0057243).

4.6 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 for flumetralin, 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), TCVP is subject to the 

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

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

active and other ingredients) may have an effect in humans or wildlife similar to an effect 
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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.

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. A second list of 

chemicals identified for EDSP screening was published on June 14, 20132and includes some 

pesticides scheduled for registration review and chemicals found in water. Neither of these lists 

should be construed as a list of known or likely endocrine disruptors. 

For further information on the status of the EDSP, the policies and procedures, the lists of 

chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our 

website.3

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The nature of the residue in tobacco is adequately understood based on tobacco metabolism 

studies. In the Flumetralin Phase 4 Review, it was concluded that the available metabolism 

studies do not completely characterize the metabolites in green tobacco, cured tobacco, or smoke 

resulting from the maximum registered use of flumetralin. However, additional metabolism data 

would not be expected to significantly enhance the understanding of tobacco residues in light of 

the very high NOAELs in the chronic oral/oncogenicity, developmental toxicity, two-generation 

reproduction, and 6-month smoke inhalation studies compared to the worst case (theoretical) 

human exposure levels via the oral and inhalation routes. Based on the available data, 

flumetralin comprises approximately half the residue in green tobacco. Flumetralin was found to 

comprise no more than 4% of the total residue in cured tobacco in the metabolism studies, but 

this can depend on the conditions used for curing. In cigarettes made from [14C]flumetralin 

treated tobacco, the primary pyrolysis product is 14CO2 (31-61% total radioactivity); flumetralin 

was found in mainstream total particulate matter (TPM) at 0.3% of the radioactivity. In 

cigarettes fortified with [14C]flumetralin, 26% of fortified radioactivity was released as 14CO2

when the cigarettes were smoked; flumetralin was found in mainstream TPM at 15% of the 

fortified radioactivity. 

 

2

See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of

chemicals.

3 http://www.epa.gov/endo/
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For the further characterization of flumetralin, confined rotational crop study data have been 

submitted for determining the nature and amount of residue uptake in rotated crops. Flumetralin 

was found at low trace levels (<5.7% TRR) or not detected in most crops. It was a major 

degradate in only one rotated crop commodity examined, garden beet roots at a 60-day plantback interval (PBI). The major residue components at nearly all PBIs in all rotated crops 

examined were trifluoroacetic acid and the CGA 152604 metabolite (2-chloro-6-fluorobenzyl 

alcohol). Based on chemical structure and exposure considerations, the CGA 152604 conjugate 

metabolite is not considered a residue of toxicological concern. Trifluoroacetic acid (TFAA) 

may be similar or slightly more toxic than parent flumetralin based on a toxicity study in rats. 

As a result, parent flumetralin and TFAA are to be considered residues of concern in rotational 

crops based on exposure and toxicity considerations (D412676, I. Negron-Encarnacion, 

05/22/2014). 

Data pertaining to livestock metabolism are not required to support flumetralin use on tobacco.

5.1.2 Summary of Environmental Degradation

The only information available on the flumetralin degradates were obtained from an anaerobic 

soil metabolism study performed using a foreign soil matrix (U.K.). Flumetralin was found to be 

persistent in surface soils. A major metabolite CGA 275536 was formed under these conditions,

but this metabolite is degraded once aerobic conditions are reverted. 

5.1.3 Comparison of Metabolic Pathways

In anaerobic soil, flumetralin is considered persistent but does appear to degrade via reduction of 

the nitro (NO2) group to aniline (NH2). In tobacco flumetralin was degraded to a large number 

of components; thin layer chromatographic analyses indicated that flumetralin comprised 44% 

TRR in green tobacco but only 4% TRR in cured tobacco. In the pyrolysis study conducted to

characterize the fate of residues in burning cigarettes, flumetralin is the major component in 

tobacco smoke. With regard to rotational crops, parent flumetralin and TFAA are to be 

considered residues of concern in supporting such uses that may require further investigation. 

5.1.4 Residues of Concern Summary and Rationale

There are no uses for flumetralin which require residues of concern to be established for 

tolerance enforcement and risk assessment on food/feed crops and/or livestock. Dietary 

exposure may occur through drinking water. Parent flumetralin only is the residue of concern for

risk assessment for drinking water.
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5.2 Food Residue Profile

The residue chemistry database is complete for supporting the use of the plant growth inhibitor 

flumetralin on tobacco. A tobacco pyrolysis study demonstrated that flumetralin is the primary 

residue of concern in tobacco smoke. Sufficient magnitude of the residue studies were also 

submitted to depict maximum residue levels of flumetralin in treated tobacco leaves (green and 

cured). Because tobacco is a non-food/feed use, this only registered use of flumetralin would not 

contribute to residues on food.

5.3 Water Residue Profile

For risk assessment, drinking water exposure is considered since flumetralin is used outdoors for 

treating tobacco crops. As such, there is potential for flumetralin to reach surface water through 

spray drift and through its persistence in surface soils. The EDWCs used for dietary analyses to 

support registration review were provided by EFED in the memorandum “Drinking Water 

Assessment for the Flumetralin Registration Review” (D427267, I. Abdel-Saheb, 06/10/2015). 

This drinking water assessment completed by EFED was conducted for parent flumetralin only 

since there are no degradates of concern. The resulting EDWCs determined for flumetralin were 

subsequently incorporated into the DEEM-FCID program for analysis in the food categories 

“water, direct, all sources” and “water, indirect, all sources.” 

The EFED assessment was conducted using the Surface Water Concentration Calculator 

(SWCC) for surface water and PRZM-GW for groundwater to estimate EDWCs. It is based on 

the labelled maximum single foliar application rate of 1.2 lbs ai/A applied yearly when tobacco 

plants are in the elongated button to early flower stage, either before or after topping. The 

surface water EDWCs obtained by the current SWCC model were found to be very similar to the 

results generated in the previous 2007 drinking water assessment. The EDWCs for groundwater 

from the new PRZM-GW model were determined to be essentially zero. 

For flumetralin, the SWCC model estimates the 1-in-10-year annual acute concentration in 

surface water sources of drinking water to be 6.10 ppb. For the intermediate-term (exposures 

occurring between 30-180 days), the SWCC model estimated a 1-in-10-year 60-day average of 

0.720 ppb. These models and their descriptions are available at the EPA internet site: 

http://www.epa.gov/oppefed1/models/water/. 

The recommended EDWCs for flumetralin of 6.10 ppb and 0.720 ppb summarized below in 

Table 1 were used in the acute and intermediate-term dietary assessments, respectively.

Table 5.3. Summary of Estimated Surface Water Concentrations for Flumetralin.

Surface Water Conc., ppb 1

Acute (1-in-10 year Peak) 6.10

Intermediate-Term (1-in10-year 60-day avg.) 0.720

1 Previously reported EDWCs of 4.9 ppb and 0.91 ppb were generated using the PRZM/EXAMS model for tobacco 

applications (US EPA 2007; D326448) with a revised PCA factor of 0.87.
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5.4 Dietary Risk Assessment

5.4.1 Overview of Residue Data Used

Given that the only use of flumetralin is on tobacco, there are no food or feed uses that require 

the establishment of tolerances. However, there is potential for flumetralin to reach drinking 

water sources through its application to tobacco which does require a drinking water assessment 

to be performed. The dietary assessment conducted for flumetralin was performed using modelderived EDWCs. 

5.4.2 Percent Crop Treated Used in Dietary Assessment

Percent crop treated information are not relevant for analysis because a food dietary assessment 

is not required for flumetralin. 

5.4.3 Acute Dietary Risk Assessment

The acute dietary (drinking water only) exposure analysis and risk assessment conducted was a 

conservative determination using model-derived EDWCs for all direct and indirect water sources 

provided by the Environmental Fate and Effects Division (EFED). It was conducted for females 

13-49 years old since this is the only population subgroup determined to have an acute 

toxicological endpoint for risk assessment. The acute risk estimate was well below the Agency’s 

level of concern (LOC) (i.e., <100% of the acute reference dose (aRfD)). The estimated risk for 

flumetralin from drinking water is <1.0 % of the aRfD with an exposure of 0.000332 mg/kg/day 

at the 95th percentile.

5.4.4 Intermediate-Term Dietary Risk Assessment

The intermediate-term dietary (drinking water only) exposure and risk assessment is also a 

conservative determination, which uses model-derived EDWCs for all direct and indirect water

sources. Because an intermediate-term dietary endpoint protective for longer durations was 

selected for the general U.S. population and all population subgroups, the chronic DEEM module 

is used for analysis since it works to assess exposure over an extended period. The margin of 

exposure (MOE) for the intermediate-term exposures to flumetralin in drinking water greatly 

exceed 100 for all population subgroups, the LOC for assessment, and therefore are not of 

concern. The most highly exposed population subgroup was all infants < 1 year of age with an 

MOE of 310,000.

5.4.5 Cancer Dietary Risk Assessment

A cancer dietary exposure and risk assessment was not conducted since flumetralin is not likely 

to be carcinogenic to humans.

5.4.6. Dietary Assessment Summary Tables

The results of the acute and intermediate-term drinking water only dietary risk analysis is 

reported in Table 5.4.6. Risks do not exceed the Agency’s level of concern. 
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Table 5.4.6. Drinking Water Only Dietary Exposure and Risk Estimates for 

Flumetralin.

Population Subgroup

Acute Dietary Drinking 

Water Surface Water 

Sources (95th Percentile)

Intermediate-term Dietary 

Drinking Water Surface Water 

Sources

Exposure

(mg/kg/day) % aRfD

Exposure

(mg/kg/day) MOE1

U.S. Population

Not Applicable

0.000015 800,000

All infants (< 1 yr) 0.000039 310,000

Children 1-2 yrs 0.000022 550,000

Children 3-5 yrs 0.000018 660,000

Children 6-12 yrs 0.000013 910,000

Youth 13-19 yrs 0.000011 >1,000,000

Adults 20-49 yrs 0.000015 800,000

Adults 50-99 yrs 0.000015 810,000

Females 13-49 yrs 0.000332 <1.0% 0.000015 800,000

1 The values for the highest exposed population for each type of risk assessment are bolded. HED is not 

concerned if the aRfD is <100%, or if the MOE is greater than the LOC. The LOC for flumetralin intermediateterm exposures is 100.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

6.1 Non-Occupational Inhalation Exposure (Tobacco Smoking)

It is HED policy to assess only acute exposure to pesticide residues in tobacco products as the 

chronic health effects from tobacco use are well documented. The flumetralin tobacco pyrolysis 

study found that 15% and 3.6% of the residue in cured tobacco would be present in smoke as 

parent flumetralin (CGA-41065) and mono-reduced CGA-41065, respectively (Appendix D

Chemical Names & Structures). An acute inhalation exposure assessment to flumetralin was 

therefore performed by HED. The assumptions used in this assessment are discussed below.

The tobacco field trial data resulted in a maximum residue of flumetralin in cured tobacco of 24 

ppm and the tobacco pyrolysis study indicated that 18.6% of the residue in cured tobacco would 

be present in smoke attributable to flumetralin. Based on the tobacco field trial study and the 

tobacco pyrolysis study, an acute smoker inhalation exposure of 0.00096 mg/kg/day for males 

and 0.00112 mg/kg/day for females were determined based on the following assumptions: (1) 24 

ppm maximum residue in tobacco, (2) 18.6% of the residue in tobacco is present in smoke, (3) 1 

gram of tobacco per cigarette, (4) 100% absorption of the residue in smoke, (5) U.S. smoker 

smokes 15 cigarettes per day (U.S. Dept. of Health and Human Services Publication Number 

OM90-2004), and (6) 70/60 kg body weight for males/females. The short-term inhalation 

NOAEL is 11.6 mg/kg/day which when combined with the exposure estimates summarized 

above yields MOEs of ≥10,000, and are, therefore, not of concern. 

6.2 Residential Handler Exposure

HED uses the term “handlers” to describe those individuals who are involved in the pesticide 

application process. There are currently no registered or proposed residential uses for 

flumetralin; therefore, a residential handler assessment was not performed. 
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6.3 Post-Application Exposure

There are currently no registered or proposed residential uses for flumetralin. The potential for 

non-occupational post-application exposure from agricultural applications of flumetralin has 

been addressed below in Section 6.5. 

6.4 Residential Bystander Post-Application Inhalation Exposure

Volatilization of pesticides may be a source of post-application inhalation exposure to 

individuals nearby pesticide applications. The Agency sought expert advice and input on issues 

related to volatilization of pesticides from its FIFRA SAP in December 2009, and received the 

SAP’s final report on March 2, 2010.

4

 The Agency has evaluated the SAP report and has 

developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis.

5

 

During Registration Review, the Agency will utilize this analysis to determine if data (i.e., flux 

studies) or further analysis are required for flumetralin.

6.5 Spray Drift

The flumetralin assessment has been updated from the 2007 HED risk assessment to reflect the 

addition of an incidental oral endpoint for the non-occupational spray drift assessment. 

Off-target movement of pesticides can occur via many types of pathways and it is governed by a 

variety of factors. Sprays that are released and do not deposit in the application area end up offtarget and can lead to exposures to those it may directly contact. They can also deposit on 

surfaces where contact with residues can eventually lead to indirect exposures (e.g., children 

playing on lawns where residues have deposited next to treated fields). The potential risk 

estimates from these residues can be calculated using drift modeling onto 50 feet wide lawns 

coupled with methods employed for residential risk assessments for turf products.

The approach to be used for quantitatively incorporating spray drift into risk assessment is based 

on a premise of compliant applications which, by definition, should not result in direct exposures 

to individuals because of existing label language and other regulatory requirements intended to 

prevent them.6 Direct exposures would include inhalation of the spray plume or being sprayed 

directly. Rather, the exposures addressed here are thought to occur indirectly through contact 

with impacted areas, such as residential lawns, when compliant applications are conducted. 

Given this premise, exposures for children (1 to 2 years old) and adults who have contact with 

turf where residues are assumed to have deposited via spray drift thus resulting in an indirect 

exposure are the focus of this analysis analogous to how exposures to turf products are 

considered in risk assessment. 

In order to evaluate the drift potential and associated risks, an approach based on drift modeling 

coupled with techniques used to evaluate residential uses of pesticides was utilized. Essentially, 

a residential turf assessment based on exposure to deposited residues has been completed to 

address drift from the agricultural applications of flumetralin. In the spray drift scenario, the 

 

4 http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

5 http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219

6 This approach is consistent with the requirements of the EPA’s Worker Protection Standard.
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deposited residue value was determined based on the amount of spray drift that may occur at 

varying distances from the edge of the treated field using the AgDrift (v2.1.1) model and the 

Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of 

Spray Drift Policy. Once the deposited residue values were determined, the remainder of the 

spray drift assessment was based on the algorithms and input values specified in the 2012 

Standard Operating Procedures for Residential Risk Assessment (SOPs). 

A screening approach was developed based on the use of the AgDrift model in situations where 

specific label guidance that defines application parameters is not available7,

8

. AgDrift is 

appropriate for use only when applications are made by aircraft, airblast orchard sprayers, and 

groundboom sprayers. When AgDrift was developed, a series of screening values (i.e., the Tier

1 option) were incorporated into the model and represent each equipment type and use under 

varied conditions. The screening options specifically recommended in this methodology were 

selected because they are plausible and represent a reasonable upper bound level of drift for 

common application methods in agriculture. These screening options are consistent with how 

spray drift is considered in a number of ecological risk assessments and in the process used to 

develop drinking water concentrations used for risk assessment. In all cases, each scenario is to 

be evaluated unless it is not plausible based on the anticipated use pattern (e.g., herbicides are 

not typically applied to tree canopies) or specific label prohibitions (e.g., aerial applications are 

not allowed). Section 6.1 provides the screening level drift related risk estimates. 

In many cases, risks are of concern when the screening level estimates for spray drift are used as 

the basis for the analysis. In order to account for this issue and to provide additional risk 

management options additional spray drift deposition fractions were also considered. These drift 

estimates represent plausible options for pesticide labels.

6.5.1 Combined Risk Estimates from Lawn Deposition Adjacent to Applications

Table 6.5.1. Screening Risk Estimates for Children (1<2 years old) (MOEs) Related to Indirect Exposure (Incidental 

Oral) to Spray Drift from Flumetralin.

Crop/Rate Group Spray Type/ Nozzle 

Configuration

Appl. Rate

(lb ai/A)

TTR1(ug/cm2) At Edge of the Field

Crop Target: Tobacco Plants

Groundboom High Boom Very fine to Fine 1.2 0.133 3,400

The spray drift assessment considers the sentinel population, children 1 to <2 years old, 

incidental oral exposures only because no dermal hazard was identified in the flumetralin 

toxicity database. 

Exposures were considered for 50 feet wide lawns where the nearest side of the property was 

directly adjoining the treated field (at field edge). The highest exposure resulted from drift 

following groundboom flumetralin applications (margins of exposure (MOEs) ≥ 3,400, with a 

LOC = 100). There are no risks of concern at the field’s edge (i.e., assuming a residential lawn 

is directly adjacent to a field where agricultural crops are grown and treated with groundboom 

 

7 http://www.agdrift.com/

8 Note that for many cases the scenarios outlined in the screening approach represent actual use practice so risk 

assessors should be aware and characterize these appropriately.
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equipment). See Table 6.5.1. for detailed results. The risk estimates from the screening level 

spray drift assessment for flumetralin are not of concern.

7.0 Aggregate Exposure/Risk Characterization

The registered flumetralin uses are not anticipated to result in residential exposure, and thus the 

acute and chronic drinking water risk estimates provided in Section 5.4.3 and 5.4.4 represent the 

acute and chronic aggregate exposure.

8.0 Cumulative Exposure/Risk Characterization

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 flumetralin and any other substances, and flumetralin does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this action, therefore, EPA has not 

assumed that flumetralin 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/.

9.0 Occupational Exposure/Risk Characterization

9.1 Short- and Intermediate-Term Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct job functions or tasks related to 

applications and exposures can vary depending on the specifics of each task. Job requirements 

(amount of chemical used in each application), the kinds of equipment used, the target being 

treated, and the level of protection used by a handler can cause exposure levels to differ in a 

manner specific to each application event. 

Based on the anticipated use patterns and current labeling, types of equipment, and techniques 

that can potentially be used, occupational handler exposure is expected from the proposed uses. 

While a ban on aerial application is not explicitly on the label, the label directions prohibit 

application over 4 ft. above the canopy and therefore aerial application is not a viable application 

method. The quantitative exposure/risk assessment developed for occupational handlers is based 

on the following scenarios: 

 Mixer/Loader (M/L) liquids for groundboom application

 Apply liquids via groundboom sprayer

 Mixer/Loader/Applicator (M/L/A) via Backpack sprayer

 M/L/A via Manually-pressurized handwand sprayer

 M/L/A via Mechanically-pressurized handwand sprayer
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Occupational Handler Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the occupational 

handler risk assessments. Assumptions and factors, as well as algorithms used to estimate noncancer exposure and dose for occupational handlers are detailed in the most recent ORE memo 

(Lloyd, 2015, D429299). 

Based on the registered and proposed use pattern for flumetralin (1-2 applications per season), 

short- and intermediate-term exposures are expected, and the POD selected for inhalation risk 

assessment is protective of both exposure durations. Long-term exposures are not anticipated.

The flumetralin product labels direct mixers, loaders, applicators and other handlers to wear:

 Plucker plusTM (EPA Reg. No. 19713-649): long-sleeved shirt and long pants, socks, 

shoes, chemical resistant gloves, and a chemical resistant apron when cleaning 

equipment or mixing and loading

 Prime+® (EPA Reg. No. 100-640): coverall over long-sleeved shirt and long pants, 

chemical resistant gloves, chemical-resistant footwear plus socks, protective eyewear, 

and a chemical-resistant apron, when cleaning equipment or mixing and loading. 

 Flupro® (EPA Reg. No. 400-600): Long-sleeved shirt, long pants, and shoes plus socks

 Drexalin Plus (EPA Reg. No. 19713-510): Long-sleeved shirt, long pants, and shoes plus 

socks

Summary of Occupational Handler Non-Cancer Exposure and Risk Estimates

The exposure scenarios presented in Table 9.1 are considered protective of all existing tobacco 

plant uses. All occupational handler scenarios for the registered uses resulted in inhalation MOEs 

greater than the LOC of 100 at baseline PPE (no respiratory protection). The lowest MOE of 

3,300 is associated with mixing/loading/applying sprays using a backpack sprayer. All other 

MOEs were significantly higher, ranging from 4,800 to 44,000. No additional PPE 

recommendations are needed on the registered labels. 
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Table 9.1. Occupational Short- and Intermediate-term Handler Exposure and Risk Estimates for Flumetralin.

Exposure Scenario

Mitigation 

Levela

Inhalation Unit 

Exposureb

(ug/lb ai)

Applicati

on Ratec

Area Treated 

or Amount 

Handledd

Inhalation 

Dosee

(mg/kg/day)

Inhalation 

MOEf

Mixer/Loader

Liquids for Groundboom 

Application Baseline 0.219 1.2 lb ai/A 200 A/day 0.000263 44,000

Applicator

Sprays for Groundboom 

Application Baseline 0.34 1.2 lb ai/A 200 A/day 0.00041 28,000

Mixer/Loader/Applicator

Liquids for Mechanicallypressurized Handgun 

Applications

Baseline 120

0.05 lb 

ai/gal

1,000 gal/day 0.0024 4,800

Liquids for Backpack 

Sprayer Baseline 140 40 gal/day 0.0035 3,300

Liquids for Manuallypressurized Handwand 

Applications

Baseline 30 40 gal/day 0.00075 15,000

a Level of mitigation: Baseline: long pants, long-sleeved shirt, 

b Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ([September, 2015]);

c Based on registered labels (cited in Section 4.1).

d Exposure Science Advisory Council Policy #9.1.

e Inhalation Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW (80 kg).

f Inhalation MOE = Inhalation NOAEL (11.6 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).
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9.2 Short- and Intermediate-Term Post-Application Risk

HED uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to as reentry exposure). Such exposures may occur when workers enter previously treated areas to 

perform job functions, including activities related to crop production, such as scouting for pests 

or harvesting. Post-application exposure levels vary over time and depend on such things as the 

type of activity, the nature of the crop or target that was treated, the type of pesticide application, 

and the chemical’s degradation properties. In addition, the timing of pesticide applications, 

relative to harvest activities, can greatly reduce the potential for post-application exposure.

No post-application chemical-specific data were submitted in support of this risk assessment. A 

short-term dermal post-application exposure assessment is not required due to the absence of 

systemic toxicity relevant for post-application dermal exposure; no DFR data are required at this 

time.

Restricted Entry Interval

Flumetralin is classified as Toxicity Category III via the dermal route. Flumetralin is mildly 

irritating to the skin and it is not a skin sensitizer. It is classified as a Category I acute eye 

irritant. Under 40 CFR 156.208 (c) (2) (iii), active ingredients classified as Acute I for eye 

irritation are assigned a 48-hour REI. The existing product labeling indicates either a 12 or 24-

hour REI (depending on the product). HED is recommending that the REI be revised on the 

label to address those concerns.

10.0 Human Incidence

Based on the low frequency and low severity of incident cases reported for flumetralin in both 

IDS and SENSOR-Pesticides, there does not appear to be a concern at this time that would 

warrant further investigation (Recore, 2015, D429780). The Agency will continue to monitor the 

incident information and if a concern is triggered, additional analysis will be included in the risk 

assessment.

11.0 References

Abdel-Saheb, I. (2015). D427267. Drinking Water Assessment for the Flumetralin Registration 

Review.

Leshin, J. (2015). TXR# 0057243. Flumetralin: Summary of Hazard and Science Policy Council 

(HASPOC) Meeting of September 3, 2015: Recommendation on the Requirements for 

Neurotoxicity (Acute and Subchronic) Studies & on the Requirement of a Subchronic Inhalation 

Study for Flumetralin. 

Lloyd, M. (2015). D429299, Flumetralin: Occupational and Residential Exposure Assessment 

for Registration Review.
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Negron-Encarnacion, I. D412676. Flumetralin. Abbreviated Review of the Confined Rotational 

Crop Study.

Recore, S. and Evans, E. (2015). D429780. Flumetralin: Tier I (Scoping) Review of Human 

Incidents.

Rury, K. (2013). TXR# 0056750. Dinitroaniline Herbicides: Summary of Hazard and Science 

Policy Council (HASPOC) Meetings: Recommendations on the need for an immunotoxicity 

study.

Savoia, P. (2015). D428883. Flumetralin. Updated Acute and Intermediate-Term Dietary 

Exposure and Risk Assessments of Drinking Water to Support Registration Review.
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Appendix A. Toxicology Assessment

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for the non-food uses for flumetralin are in Table 1. Use of the new guideline 

numbers does not imply that the new (1998) guideline protocols were used.

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity..................................................

870.1300 Acute Inhalation Toxicity..............................................

870.2400 Primary Eye Irritation....................................................

870.2500 Primary Dermal Irritation..............................................

870.2600 Dermal Sensitization .....................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (Rodent) .............................................

870.3150 Oral Subchronic (Non-rodent).......................................

870.3200 21-Day Dermal..............................................................

870.3250 90-Day Dermal..............................................................

870.3465 90-Day Inhalation..........................................................

yes

yes

yes

no

no a

yes

yes*

yes

---

---

870.3700a Developmental Toxicity (Rodent).................................

870.3700b Developmental Toxicity (Non-rodent)..........................

870.3800 Reproduction .................................................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (Rodent).............................................

870.4100b Chronic Toxicity (Non-rodent) .....................................

870.4200a Oncogenicity (Rat) ........................................................

870.4200b Oncogenicity (Mouse)...................................................

870.4300 Chronic/Oncogenicity ...................................................

yes

no

yes

yes

yes

yes

---

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - Bacterial....................

870.5300 Mutagenicity—Gene Mutation - Mammalian ...............

870.5xxx Mutagenicity—Structural Chromosomal Aberrations...

870.5xxx Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

no

yes

yes

870.6100a Delayed Neurotoxicity (Hen) ........................................

870.6200a Acute Neurotoxicity Screening Battery (Rat)................

870.6200b 90-Day Neurotoxicity Screening Battery (Rat).............

870.6300 Developmental Neurotoxicity .......................................

no

no b

no b

no

---

---

---

---

870.7485 General Metabolism......................................................

870.7600 Dermal Penetration........................................................

yes

no

yes

---

870.7800 Immunotoxicity............................................... no c---

 

a not required (Leshin, 2015. HASPOC TXR# 0057243)

 

b not required (Leshin, 2015. HASPOC TXR# 0057243)

 

c not required (Rury, 2013, HASPOC TXR# 0056750)

 CR = conditionally required; * there is a 6 month oral toxicity study in dogs
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A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile - Test Substance 

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [rat] 00093998 LD50 > 5000 

mg/kg

IV

870.1200 Acute dermal [rabbit] 00093999 LD50 = >2000 

mg/kg

III

870.1300 Acute inhalation [rat] 00094002 LC50 = 2.13 

mg/L

III

870.2400 Acute eye irritation [rabbit] 00094000 severe irritant 

[PIS = 55]

I

870.2500 Acute dermal irritation [rabbit] 00104250 mild irritant [PIS 

= 2.82]

IV

870.2600 Skin sensitization [guinea pig] 00094001 positive skin 

sensitizer

N/A

Table A2.2 Flumetralin Subchronic, Chronic, and Other Toxicity Profile

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

Classification /Doses

Results

870.3100 90-Day oral 

toxicity (CDCrl:CD(SD)BR

rat)

00094013 (1981)

Acceptable/guideline

0, 30, 300, or 1500 ppm

0, 1.5, 15, or 75 mg/kg/day 

(standard conversion)

Systemic toxicity NOAEL = 300 ppm (15 

mg/kg/ day)

Systemic toxicity LOAEL = 1500 ppm (75 

mg/kg/day), based on decreased body weight, 

body-weight gain, increased cholesterol (both 

sexes), decreased hemoglobin (both sexes), 

hematocrit (females), and increased BUN 

(males).
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Table A2.2 Flumetralin Subchronic, Chronic, and Other Toxicity Profile

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

Classification /Doses

Results

870.3150 90-Day oral 

toxicity (dog)

00094012 (1981)

Acceptable/guideline

0, 30, 300, 3000 ppm

0, 1.1/1.04; 1.61/14.04; 

92.75/103.37 mg/kg/day

NOAEL = 30 ppm [males 1.1/females 1.04 

mg/kg/day]

LOAEL = 300 ppm [males 11.61/females 14.04 

mg/kg/ day], based on one death (male; day 

169). This animal displayed similar clinical 

signs as were seen at the high dose. 

At the high dose [3000 ppm (males 

92.75/females 103.37 mg/kg/day)], clinical 

signs [weight loss, anorexia, pyrexia, 

dehydration, and depression], which were 

progressive over a period of two to four weeks, 

deaths (both sexes; 3 on day 40; 1 on day 128), 

decreased body-weight/body-weight gain and 

food consumption, decreased hematocrit, 

hemoglobin, and MCHB, increased MCV, 

Heinz body formation and increased 

methemoglobin concentrations, increased 

incidence of myeloid hyperplasia, increased 

cholesterol, and reticulocytosis were observed.

870.3200 21/28- Day 

dermal toxicity 

(NZW rabbit)

00116594 (1982) 

Acceptable/guideline

0, 500, 1000, or 2000 

mg/kg/day

6 hours/day, 5 days/week, 3 

weeks

Systemic toxicity NOAEL = 2000 mg/kg/ day, 

the highest dose tested. 

Dermal toxicity NOAEL not determined. 

Dermal toxicity LOAEL = 500 mg/kg/day, 

based on mild skin irritation. Moderate skin 

irritation was observed at 1000 mg/kg/day and 

2000 mg/kg/day, with the maximum Draize 

scores occurring at study termination [1.55 to 

2.10], indicating the severity increased with 

time of exposure.

870.3465 90-Day 

inhalation 

toxicity 

28-day repeat dose inhalation study not 

required for a.i. (HASPOC TXR# 0057243)

870.3700a Prenatal 

developmental 

(CDCrl:CD(SD)BR

rats)

00094011 (1981)

Acceptable/guideline

0, 100, 400, or 800 

mg/kg/day

GD 6-15 (gavage)

Maternal toxicity NOAEL = 100 mg/kg/day. 

Maternal toxicity LOAEL = 400 mg/kg/day, 

based on decreased body-weight gains.

Developmental toxicity NOAEL = 100 

mg/kg/day

Developmental toxicity LOAEL = 400 

mg/kg/day, based on a slight increase in the 

incidence of external and skeletal 

malformations.
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Table A2.2 Flumetralin Subchronic, Chronic, and Other Toxicity Profile

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

Classification /Doses

Results

870.3700b Prenatal 

developmental 

(Russian 

Chbb:HM rabbit)

43862801 (1995)

Acceptable/guideline

0, 10, 50, 100, or 200 

mg/kg/day

GD 7-19 (gavage)

Maternal toxicity NOAEL = 50 mg/kg/day

Maternal toxicity LOAEL = 100 mg/kg/day, 

based on clinical signs (hemorrhagic discharges 

in the perineal area and piloerection), decreased 

body weight, increased incidene of negative 

body weight gains during the dosing period, 

decreased terminal gravid uterine weight, and 

increased incidence of litters with resorptions

Developmental toxicity NOAEL = 100 

mg/kg/day

Developmental toxicity LOAEL = 200 

mg/kg/day, based on an increased incidence of 

litters with total resorption, increased postimplantation loss, increased incidence of 

external [a position anomaly, flexure of 

forepaw at the wrist] and skeletal alterations 

[fused sternebrae and absent ossification of the 

caudal vertebral centers].

870.3800 Reproduction 

and fertility 

effects

(CD-Crl:CD 

(SD)BR rat)

00149532 (1985)

Acceptable/guideline

0, 300, 1000, or 1500 ppm

0, 24/27; 79/99, or 120/138 

mg/kg/day

Parental toxicity NOAEL = 300 ppm [males 24 

mg/kg/day/females 27 mg/kg/day]. 

Parental toxicity LOAEL = 1000 ppm [males 79 

mg/kg/day/females 99 mg/kg/day], based on a 

slight decrease in body weight during the dosing 

period and throughout gestation and lactation.

Developmental toxicity NOAEL = 1000 ppm 

[males 79 mg/kg/day/females 99 mg/kg/day]

Developmental toxicity LOAEL = 1500 ppm 

[males 120 mg/kg/day/females 138 mg/kg/day], 

based on decreased body weight. 

Reproductive toxicity NOAEL = 1500 ppm 

[males 120 mg/kg/day/females 138 mg/kg/day], 

the highest dose tested.

870.4100a Chronic toxicity

[Sprague-Dawley 

CD] rat

42061603 (1986) 42061604 

(1991)

Acceptable/guideline

0, 30, 300, 1000, or 1500 

ppm [males 1.5, 14.5, 49.8, 

75.2 mg/kg/day; females 

1.9, 19.2, 66.7, 103.9 

mg/kg/day

Systemic toxicity NOAEL = 300 ppm (males 

14.5/females 19.2 mg/kg/day)

Systemic toxicity LOAEL = 1000 ppm (males 

49.8/females 66.7 mg/kg/day), based on 

decreased body weight, body-weight gains, 

decreased thymus weight in males, and 

increased brain weight in females. 

870.4100b Chronic toxicity 

Dog
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Table A2.2 Flumetralin Subchronic, Chronic, and Other Toxicity Profile

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

Classification /Doses

Results

870.4200 Combined 

Chronic/

Carcinogenicity

rat

42061603 (1986) 42061604 

(1991)

Acceptable/guideline

0, 30, 300, 1000, or 1500 

ppm [males 1.5, 14.5, 49.8, 

75.2 mg/kg/day; females 

1.9, 19.2, 66.7, 103.9 

mg/kg/day

Systemic toxicity NOAEL = 300 ppm (males 

14.5/females 19.2 mg/kg/day)

Systemic toxicity LOAEL = 1000 ppm (males 

49.8/females 66.7 mg/kg/day), based on 

decreased body weight, body-weight gains, 

decreased thymus weight in males, and 

increased brain weight in females.

No apparent treatment-related increase in any 

tumor type.

870.4300 Carcinogenicity

mouse

42061601, 41061602

Acceptable/guideline

0, 30, 300, 1000, or 1500 

ppm [0, 4.98, 49.8, 166.6, or 

250 mg/kg/day]

Systemic toxicity NOAEL = 300 ppm (49.8 

mg/kg/day)

Systemic toxicity LOAEL = 1000 ppm (166.6 

mg/kg/day), based on increased liver weights in 

both sexes. 

No apparent, treatment-related, increase in the 

incidence of any tumor type in either sex.

Gene Mutation

870.5100

Salmonella 

typhimurium

TA98, TA100, 

TA1535, 

TA1537, 

TA1538

00094009 (1981)

Acceptable/guideline

Negative

Other Effects 

870.5550

Rat hepatocyte 

DNA repair test 

UDS

42061605 (1982)

Acceptable/guideline

Negative

In vivo mouse 

micronucleus 

assay

870.5395

CD-1 mouse 00094010 (1981)

Acceptable/guideline

Negative

870.6200a Acute 

neurotoxicity 

screening battery 

rat

Waived (HASPOC TXR# 0057243)

870.6200b Subchronic 

neurotoxicity 

screening battery

rat

Waived (HASPOC TXR# 0057243)

870.6300 Developmental 

neurotoxicity

Not required.

870.7485 Metabolism and 

pharmacokinetics

(rat)

00094041 (1982)

Single doses: 0.5 mg/kg & 

50 mg/kg

76% to 86% excreted in urine/feces in 48 hours. 
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Table A2.2 Flumetralin Subchronic, Chronic, and Other Toxicity Profile

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

Classification /Doses

Results

870.7600 Dermal 

penetration (rat)

870.7800 Immunotoxicity Waived (HASPOC TXR# 0056750) 

Special Studies Smoke inhalation 

(rat)

00117622 (1982)

Acceptable/non-guideline

Smoke from cigarettes made 

with tobacco spiked with 0, 

300, 5000, or 15,000 ppm 

flumetralin

4 hours/day, 5 days/week 

(total of 30 exposures) in 6 

weeks

No adverse effects observed at 15,000 ppm 
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A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD) - Females age 13-49

Study Selected: Developmental toxicity study (rabbit)

MRID No.: 43862801

Executive Summary: See Appendix A, Guideline § 870.3700b

Dose and Endpoint for Risk Assessment: NOAEL = 50 mg/kg/day, based on an increased 

incidence of litters with total resorptions, increased post-implantation loss, and increased incidence 

of external (positional anomaly) and skeletal (fused sternebrae and absent ossification of the caudal 

vertebral centers) alterations seen at LOAEL = 100 mg/kg/day..

Comments about Study/Endpoint/Uncertainty Factors: This endpoint is appropriate for the 

population of concern (females of child bearing age) and is considered to be a single dose effect.

There are clearly established NOAELs and LOAELs for the population of concern, there are no 

data gaps in the toxicology database, and the point of departure (POD) is protective of 

susceptibility.

Uncertainty Factor (UF): 100X [10X interspecies extrapolation (UFA), 10X intraspecies 

variability (UFH)]. The level of concern for risk assessment is an MOE below 100. 

A.3.2 Acute Reference Dose (aRfD) - General Population

No appropriate endpoint attributable to a single exposure (dose) was identified.

A.3.3 Intermediate Reference Dose 

Study Selected: Subchronic oral toxicity study (dog)

MRID No.: 00094012

Executive Summary: See Appendix A, Guideline § 870.3150

Dose and Endpoint for Risk Assessment: NOAEL = 11.6 mg/kg/day, based on clinical signs 

(weight loss, pyrexia, dehydration, and depression), mortality, hematology/clinical chemistry 

effects, and an increased incidence of myeloid hyperplasia seen at LOAEL = 92.8 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors: The study is considered appropriate 

for dose and endpoint selection for this dietary exposure assessment since it provides the most 

sensitive endpoint; is the appropriate route of exposure; and is of an appropriate duration of 

exposure (6 months). The chronic rat study shows a similar effect level (LOAEL) and a slightly 

higher NOAEL.

Uncertainty Factor (UF): 100X [10X interspecies extrapolation (UFA), 10X intraspecies 

variability (UFH)]. The level of concern for risk assessment is an MOE below 100. 

A.3.4 Incidental Oral Exposure (Short- and Intermediate-Term)

Study Selected: Subchronic oral toxicity study (dog)

MRID No.: 00094012

Executive Summary: See Appendix A, Guideline § 870.3150
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Dose and Endpoint for Risk Assessment: NOAEL = 11.6 mg/kg/day, based on clinical signs 

(weight loss, pyrexia, dehydration, and depression), mortality, hematology/clinical chemistry 

effects, and an increased incidence of myeloid hyperplasia seen at LOAEL = 92.8 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors: The study is considered appropriate 

for dose and endpoint selection for the incidental oral exposure assessment since it provides the 

lowest no effect dose in the database and is protective of other toxic effects observed. 

Uncertainty Factor (UF): 100X [10X interspecies extrapolation (UFA), 10X intraspecies 

variability (UFH)]. The level of concern for risk assessment is an MOE below 100. 

A.3.5 Dermal Exposure (All Durations) 

Quantitation of risk by the dermal route of exposure is not required. No systemic toxicity occurred 

after exposure to the limit dose (1000 mg/kg/day) and twice the limit dose (2000 mg/kg/day) in a 

rabbit 21-day dermal toxicity study with flumetralin. Comparing NOAELs from the 21-day rabbit 

dermal toxicity study (2000 mg/kg/day) with that from the rabbit oral developmental toxicity study 

(50 mg/kg/day) suggests minimal dermal absorption (2.5%). Comparing the rabbit developmental 

NOAEL to the limit dose results in a 5% dermal absorption factor. Although malformations were 

observed in the rat developmental toxicity study (NOAEL 100 mg/kg/day), the dermal equivalent 

dose is 4000 mg/kg/day.

A.3.6 Inhalation Exposure (All Durations) 

Study Selected: Subchronic oral toxicity study (dog)

MRID No.: 00094012

Executive Summary: See Appendix A, Guideline § 870.3150

Dose and Endpoint for Risk Assessment: NOAEL = 11.6 mg/kg/day, based on clinical signs 

(weight loss, pyrexia, dehydration, and depression), mortality, hematology/clinical chemistry 

effects, and an increased incidence of myeloid hyperplasia seen at LOAEL = 92.8 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors: The study is considered appropriate 

for dose and endpoint selection for the inhalation exposure assessment since it provides the 

lowest no effect dose in the database and is protective of other toxic effects observed. The 

HASPOC determined that a subchronic inhalation toxicity study is not required on flumetralin. 

Uncertainty Factor (UF): 100X [10X interspecies extrapolation (UFA), 10X intraspecies 

variability (UFH)]. The level of concern for risk assessment is an MOE below 100. 
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A.4 Executive Summaries

A.4.1 Subchronic Toxicity

870.3100 90-Day Oral Toxicity - Rat

EXECUTIVE SUMMARY: In a subchronic oral toxicity study [MRID 00094013], CGA-41065 

technical (94.6% a.i.) was administered via the diet to groups of 25 control; 20 [low and mid], and 

25 [high] dose Crl:COBS/CD(SD)BR rats per sex at dose levels of 0, 30, 300, or 1500 ppm [1.5, 

15, 75 mg/kg/day, using standard conversion] for 3 months. The 5 extra rats/sex in the control and 

high-dose groups were maintained on normal feed for a 4-week recovery period following the 90-

day treatment period.

All rats survived until study termination, and there were no signs of toxicity. At 1500 ppm, there 

was a slight decrease in body weight at week 13 [males 91%*/females 94% of control], and bodyweight gains were decreased throughout the study [overall: males 87%/females 92% of control; 

weeks 6-13: males 72%/females 90% of control] in both sexes. Food consumption was comparable 

among the groups for both sexes.

Males at the mid- and both sexes at the high-dose levels displayed statistically-significant 

decreases in hemoglobin concentrations at 13 weeks. Hematocrits were also decreased in both 

sexes at the high-dose level, although only the female values attained statistical significance. 

Hematocrit values were comparable to control following the recovery period. Both sexes at the 

high-dose level displayed increased cholesterol values and high-dose males displayed increased 

BUN values during weeks 6 and 13, although statistical significance was attained only in the males. 

Lactic dehydrogenase was decreased in both sexes at 1500 ppm at both the 6- and 13-week 

intervals, although statistical significance was attained only in males at week 6. Yellow 

discoloration was observed in body fat at necropsy at the high-dose level [both sexes]. Relative 

spleen weights were increased in both sexes at the high dose, and hyalin droplet degeneration in 

the kidney was observed in males at the mid- and high-dose levels. No kidney lesions were 

observed following the recovery phase.

The systemic toxicity NOAEL is 300 ppm [15 mg/kg/ day; standard conversion], based on 

decreased body weight, body-weight gain, increased cholesterol [both sexes], decreased 

hemoglobin [both sexes], hematocrit [females], and increased BUN [males] at the systemic 

toxicity LOAEL of 1500 ppm [75 mg/kg/day].

This subchronic oral toxicity study is classified Acceptable, and it satisfies the guideline [OPPTS 

870.3100; §82-1] requirement for a subchronic oral toxicity study in the rodent. 

870.3100 90-Day Oral Toxicity - Mouse

870.3150 90-Day Oral Toxicity - Dog
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EXECUTIVE SUMMARY: In a 6-month oral toxicity study [MRID 00094012], CGA-41065 

technical (96.4% a.i.) was administered via the diet to groups of 8/sex (control), 6/sex [low and 

mid], and 8/sex [high] dose beagle dogs at dose levels of 0, 30, 300, or 3000 ppm [males 0, 1.1, 

11.61, 92.75 mg/kg/day; females 0, 1.04, 14.04, 103.37 mg/kg/day, respectively] for 6 months. 

The 2 extra dogs/sex in the control and high-dose groups were maintained on normal feed for a 4-

week recovery period following the 6-month treatment period.

There were five treatment-related deaths/moribund sacrifices during the study. Two high-dose 

males and one high-dose female were sacrificed moribund on day 40; one high-dose female was 

sacrificed on day 128; and one mid-dose male died on day 169. All of these dogs displayed similar 

clinical signs [weight loss, anorexia, pyrexia, dehydration, and depression], which were 

progressive over a period of two to four weeks. Blood samples obtained prior to sacrifice showed 

elevated white blood cell counts (primarily neutrophils) and alkaline phosphatase levels (four 

dogs); decreased RBCs, hemoglobin, and hematocrit; elevated lactic dehydrogenase levels three 

dogs]; and markedly decreased glucose levels (two dogs). One low-dose female was sacrificed on 

day 23, but she displayed different clinical signs, and the onset was acute [depression, ataxia, 

labored respiration, pinpoint pupils, apparent abdominal pain, and severe bloody diarrhea]. No 

abnormalities were found in the blood sample of this low-dose female taken prior to sacrifice. 

Body weight was decreased in both sexes [week 26l: males 82%/females 84% of control] at the 

high-dose level. Body-weight gains were decreased significantly at the high-dose level at various 

times throughout the study, especially in males. Negative body-weight gain was observed in both 

sexes at the high-dose level during the 13-26 week interval, and the high-dose males also displayed 

a negative body-weight gain during the first few weeks of treatment. These body-weight effects 

were accompanied by decreased food consumption, which occurred throughout the study in both 

sexes.

White blood cell counts were significantly elevated in both sexes [males at 90 and 180 

days/females at 60, 90, and 180 days] at the high-dose level from day 30 on. Red blood cell counts 

(RBC), hematocrit, and hemoglobin concentrations were lower than the control and other groups 

from day 30 until study termination in both sexes at the high-dose level. Reticulocyte counts were 

significantly higher in both sexes at the high-dose level compared with the control from day 60 on. 

Mean corpuscular hemoglobin concentration (MCHC) was significantly decreased from 60 days 

in high-dose males and from day 30 in high-dose females. Mean corpuscular volume was 

significantly higher than control in both sexes at the high dose at various times during the study. 

Methemoglobin concentration was significantly increased compared to the control throughout the 

study at the high-dose level (both sexes). Both sexes at the high-dose level showed significantly 

higher Heinz body counts from day 60 on, and platelet counts were significantly higher than the 

control from day 30 on.

Alkaline phosphatase levels were markedly elevated from day 30 on in both sexes at the high-dose 

level, and in many instances, the values were reported to be many times the expected normal 

values. Additionally, while the expected decline in alkaline phosphatase levels with increasing age 

occurred in the control and other treatment groups, the elevated level observed in the high-dose 

dogs continued throughout the study. Cholesterol values were increased throughout the study 
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(from day 30) in both sexes at the high-dose level, and the report indicated that a trend of increasing 

cholesterol level with increasing dose was evident. Lactic dehydrogenase (LDH) values were 

increased in both sexes at the high-dose level throughout the study, as were potassium values. 

These latter values were reported to be within the normal limits for these dogs. Both serum 

glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) 

levels were increased at the high-dose level for both sexes, mainly during the latter part of the 

study. Urinalysis parameters were not adversely affected by treatment in either sex. 

At study termination, significantly increased absolute and relative (body and brain) liver weights 

were observed in both sexes at the high-dose level. Absolute spleen weight (females) and relative 

(body and brain) spleen weight (both sexes) were observed at the high-dose level compared to the 

control. 

The histopathological lesion reported in the high-dose level dogs were bile duct proliferation [75% 

of dogs (sexes combined)], bile retention, pericholangeal fibrosis [75%], hemosiderosis, 

hepatocellular necrosis, and chronic inflammation [63%]. One male dog at the mid-dose level 

displayed hepatic congestion, hepatocellular vacuolation, and acute inflammation. None of the 

low-dose or control dogs displayed any of these hepatic lesions. Lymphoid hyperplasia of the bone 

marrow was observed in 75% (of both sexes) of the high-dose dogs compared to none in the control 

and other treatment groups.

Of the dogs that died or were killed in extremis, the lesions in the low-dose dog were characterized 

as acute inflammation of the brain, spinal cord, meninges, intestinal tract, lungs, ovaries, uterus, 

optic nerve, lymph nodes, and bone marrow. This inflammatory response was described as acute 

in nature, consisting primarily of neutrophilic inflammatory cells. Vasculitis was present in several 

tissues and was characterized by the presence of neutrophilic inflammatory cells about and within 

the vessel walls. In this acutely affected dog, there were small focal areas of necrosis and cavitation 

in the brain in addition to the acute inflammatory response. In the high-dose dogs, lesions were 

reported as similar to those listed above but were more chronic in nature and characterized by 

chronic/active inflammatory response in the brain and spinal cord (primarily the meninges), 

spleen, lungs, liver, testes, and spermatic cord, intestinal tract, and bone marrow. In one male, 

there was also infarction of the spleen and testes, which were considered as probably secondary to 

vascular lesions. Testicular degeneration was present in both chronically affected dogs and 

considered as secondary to high fever and/or vascular lesions. Myeloid hyperplasia was evident in 

both the low-dose dog and high-dose dogs that died/sacrificed moribund, but it was most severe at 

the high-dose level. 

The systemic toxicity NOAEL is 30 ppm [males 1.1/females 1.04 mg/kg/day], based on one 

death (male) at the LOAEL of 300 ppm [males 11.61/females 14.04 mg/kg/ day]. This animal 

displayed similar clinical signs as were seen at the next higher dose level, which were 

progressive over a period of 2 to 4 weeks prior to death. At the higher dose [3000 ppm (males 

92.75/females 103.37 mg/kg/day)], deaths (both sexes), decreased body-weight/body-weight 

gain and food consumption, decreased hematocrit, hemoglobin, and MCHB, increased 

MCV, Heinz body formation and increased methemoglobin concentrations, increased 

incidence of myeloid hyperplasia, increased cholesterol, and reticulocytosis were observed.
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This 6-month oral toxicity study is classified Acceptable, and it satisfies the guideline requirement 

[OPPTS 870.3100; §82-1] for a subchronic oral toxicity study in the nonrodent. 

870.3200 21/28-Day Dermal Toxicity – Rat

EXECUTIVE SUMMARY: In a 21-day dermal toxicity study [MRID 00116594], CGA-41065 

technical (94.6%* a.i.) was administered via the skin [abraded and intact] to groups of 10 New 

Zealand White rabbits per sex per dose at 0 [saline], 500, 1000, or 2000 mg/kg/day for 6 hours per 

day, 5 days per week for 3 weeks.

All rabbits survived until study termination, and there were no systemic signs of toxicity or 

ophthalmic changes. Body weights and food consumption were comparable among the groups for 

both sexes, and there were no apparent effects on the hematology and blood chemistry parameters 

monitored. No gross lesions were noted at necropsy, and no statistically-significant differences 

were reported among the groups for absolute/relative (body and brain) organ weights. 

Histopathologic lesions were not reported for liver or kidney [only tissues other than the skin that 

were examined]. 

Skin irritation was noted in all dosed groups following the start of dosing and continuing through 

until study termination. Both intact and abraided sites were irritated and the maximum Draize 

scores occurred at the end of the study [1.55-2.10]. Histopathologic alterations consistent with 

nonspecific dermatitis were observed at all dose levels [abraided and intact skin].

The systemic toxicity NOAEL is 2000 mg/kg/ day, the highest dose tested. The dermal toxicity 

NOAEL was not determined because dermal irritation was observed at all dose levels. The 

dermal toxicity LOAEL is 500 mg/kg/day, based on mild skin irritation. Moderate skin 

irritation was observed at 1000 mg/kg/day and 2000 mg/kg/day, with the maximum Draize 

scores occurring at study termination [1.55 to 2.10], indicating the severity increased with 

time of exposure.

This 21-day dermal toxicity study is classified Acceptable, and it satisfies the guideline [OPPTS 

870.3200; §82-2] for a repeat dose dermal toxicity study in the rabbit. 

870.3465 90-Day Inhalation – Rat

The 28-day inhalation toxicity study is not a data requirement for flumetralin (Leshin, 2015, 

HASPOC TXR# 0057243).
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A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study - Rat

EXECUTIVE SUMMARY: In a developmental toxicity study [MRID 00094011], CGA-41065 

technical (96.4% a.i.) was administered orally via gavage [corn oil] to groups (24/group) of 

pregnant female CD-Crl:CD(SD)BR rats at dose levels of 0, 100, 400, or 800 mg/kg body 

weight/day during gestation days 6 through 15. 

All dams survived until study termination [gestation day 20]. One low-dose female delivered 

prematurely on day 19 of gestation. The only apparent clinical sign related to treatment was the 

discoloration of the urine [dark yellow or yellow-orange], which was observed in treated dams at 

all dose levels [no apparent dose-response] during the dosing period and mainly at the low-dose 

level post dose.

At the two highest dose levels, there was a comparable decrease in the mean body-weight change 

[85%-86% of control] and in the corrected mean body-weight change [62%-63% of control] 

compared to the control. Terminal gravid uterine weight was comparable among the groups. 

Yellow ovarian fat was observed at necropsy.

Pregnancy rate was comparable among the groups, although the 800 mg/kg/day dose group 

displayed the lowest rate; i.e., 79% compared with 83% (control and low dose) and 88% (mid 

dose). The mean number of corpora lutea was comparable among the groups. The number of 

implantations, mean number of implantations, number of fetuses, mean number of fetuses were 

comparable among the groups. There were no dead fetuses, and the number of resorbed fetuses 

was comparable among the groups. Pre-implantation loss and post-implantation loss were 

comparable among the groups. Fetal body weights and the sex ratio were comparable among the 

groups.

The number of runts [external malformation] was slightly increased at the mid- and high-dose 

levels, but there was no dose-response [fetal incidence: 0.4%, 0%, 4.2%, and 2.5%, with increasing 

dose; # litters affected: 1/20 (5%), 0/18, 1/21 (5%), 4/19 (21%)]. Three additional high-dose fetus 

[# litters?] displayed external malformations [hydrocephaly; imperforate anus and vestigial tail; 

small/misshapened head, bilateral; anophthalmia, small ear, microstonia, absent nares and 

vebriasse]. Visceral malformations were observed only at the high-dose level [one fetus with 

intraventricular septal defect, transposition of aortic arch, and partial transposition of great 

vessels]. The incidence of skeletal malformations was increased at the high-dose level [8 fetuses], 

although the total number of fetuses with skeletal malformations was less than in the mid-dose 

group [11 fetuses]; i.e., the high-dose fetuses displayed several malformations each compared to 

one malformation each at the mid-dose level. 

The maternal toxicity NOAEL is 100 mg/kg/day. The maternal toxicity LOAEL is 400 

mg/kg/day, based on decreased body-weight gains.
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The developmental toxicity NOAEL is conservatively set at 100 mg/kg/day, and the 

developmental toxicity LOAEL is 400 mg/kg/day, based on a slight increase in the incidence 

of external and skeletal malformations.

870.3700b Prenatal Developmental Toxicity Study - Rabbit

EXECUTIVE SUMMARY: In a developmental toxicity study [MRID 43862801], CGA-41065 

technical (94.6% a.i.) was administered orally via gavage [an aqueous suspension in 0.5% (w/w) 

sodium carboxy-methylcellulose] to groups (19/group) of pregnant female Russian Chbb:HM 

rabbits at dose levels of 0, 10, 50, 100, or 200 mg/kg body weight/day during gestation days 7 

through 19. 

All does survived until study termination [gestation day 29]. Clinical signs of maternal toxicity 

were observed at the two highest dose levels, which included (1) hemorrhagic discharges in the 

perineal area in 5 high dose (200 mg/kg/day) and 2 high-mid dose (100 mg/kg/day) females during 

gestation days 17-26, and all of these females exhibited total resorptions at necropsy; (2) one highmid dose (100 mg/kg/day) female exhibited swelling in the perineal area during gestation days 17-

26; (3) three high dose (200 mg/kg/day) and 1 high-mid dose (100 mg/kg/day) females exhibited 

piloerection during the last 10 days of the gestation period; and (4) two high dose (200 mg/kg/day) 

females showed decreased locomotor activity near the end of the treatment period (gestation day 

19). 

There was a dose-related decrease in body weight throughout the treatment period at the two 

highest dose levels [gestation day (GD) 19 (200 mg/kg/day, 15% decrease; 100 mg/kg/day, 8% 

decrease)], and terminal body weight was significantly decreased at the highest dose level [12% 

decrease]. Negative body-weight gains were observed at the two highest dose levels during the 

treatment period [GD 16-19 (-55 grams at 100 mg/kg/day and -154 grams at 200 mg/kg/day 

compared to +38 grams in control); GD 7-19 (-40 grams and -245 grams, respectively compared 

to +121 grams in control)]. Additionally, at 200 mg/kg/day, body-weight gains during the posttreatment period [GD 20-29] remained below the control and other dose level groups [53% of 

control], although statistical significance was not attained. Feed consumption was also decreased, 

particularly during GD 12-16 at the 100 mg/kg/day (56% of control) and 200 mg/kg/day (31% of 

control) dose levels. 

Terminal gravid uterine weight was decreased at the 100 mg/kg/day (57% of control) and 200 

mg/kg/day (40% of control) dose levels. Gross necropsy revealed mottled livers in 3 of the highdose females and dilatation of the gall bladders in 2 of the high-dose females.

Pregnancy rate was comparable among the groups, although the 200 mg/kg/day dose group 

displayed the lowest rate; i.e., 74% compared with 79% (control), 89%, 89%, 79%, with increasing 

dose. There were no dead fetuses and no abortions. The two highest dose groups displayed the 

fewest number of litters [10 and 5 litters at 100 mg/kg/day and 200 mg/kg/day, respectively, 

compared to 15-17 in the control and other groups]. The total and mean number of corpora lutea 

and implantations were comparable among the groups. There was a treatment-related increase in 

the total number of resorptions, the number of resorptions per doe, and in the number of litters 
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with total resorptions [5 litters at 100 mg/kg/day and 9 litters at 200 mg/kg/day, compared to no 

litters with total resorptions in any other group]. The two highest dose levels had fewer live fetuses 

[total number and number/doe]. Pre-implantation loss was comparable among the groups [lowest 

at 200 mg/kg/day], but post-implantation loss was increased at 100 mg/kg/day [5-fold; not 

statistically significant] and 200 mg/kg/day [10-fold; statistically significant]. Fetal body weights 

were comparable among the groups. The sex ratio varied from a high % of males in the control 

(61%) to a low % of males at 100 ppm (33%). Since the other groups showed the expected % of 

males [43%, 54%, and 47% at 10, 50, and 200 mg/kg/day, respectively] and there was no doseresponse, the low % of males at 100 ppm is not considered treatment-related. 

The incidence of the anomaly of flexure of the forepaw at the wrist was increased at both the 100 

mg/kg/day (8/48; 17%) and 200 mg/kg/day (3/30; 10%) dose levels compared to the control (2/87; 

2%) group. The incidences of fused sternebrae (anomaly) were increased in a treatment-related 

manner at the 100 mg/kg/day and 200 mg/kg/day dose levels, and the increase was statistically 

significant in the high dose group. There was an increased incidence (# of fetuses) of absent 

ossification of the caudal vertebral centers at the 50 mg/kg/day (35/107, 33%), 100 mg/kg/day 

(19/48; 40%), and 200 mg/kg/day (16/30; 53%) dose levels compared to the control (17/87; 20%). 

The respective litter incidence of this latter finding was 65%, 60%, and 100% compared to the 

control (47%).

The maternal toxicity NOAEL is 50 mg/kg/ day. The maternal toxicity LOAEL is 100 mg 

CGA-41065/kg body weight/day, based on clinical signs (hemorrhagic discharges in the 

perineal area and piloerection), decreased body weight, increased incidence of negative 

body-weight gains during the dosing period, decreased terminal gravid uterine weight, and 

increased incidence of litters with total resportions.

The developmental toxicity NOAEL is 50 mg/kg/day, and the developmental toxicity LOAEL 

is 100 mg/kg/day, based on an increased incidence of litters with total resorption, increased 

post-implantation loss, increased incidence of external [a position anomaly, flexure of 

forepaw at the wrist] and skeletal alterations [fused sternebrae and absent ossification of the 

caudal vertebral centers]. 

This guideline developmental toxicity study is classified Acceptable, and it satisfies the guideline 

[OPPTS 870.3700; §83-3(b)] for a developmental toxicity study in the rabbit. 

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects - Rat

EXECUTIVE SUMMARY: In a 2-generation reproduction study [MRID 00149532, 00145793], 

CGA-41065 technical (99.5% a.i.) was administered orally via the diet to groups of 15 male CDCrl:CD (SD)BR rats and 30 female CD-Crl:CD (SD)BR rats per group at dose levels of 0, 30, 300, 

1000, or 1500 ppm [males: 2.3, 23.7, 78.6, 120 mg/kg/day, respectively; females: 2.7, 27.2, 98.8, 

138.3 mg/kg/day, respectively]. The premating period of dosing was 15 weeks [F0]/18 weeks [F1]. 
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The F1 parents were bred twice. Mating was accomplished by cohabitating one male with two 

females for up to 14 days [F0]/21 days [F1].

Although there were several deaths, there was no dose response. All of the control animals 

survived, but 2 F0 females at 30 ppm and 1500 ppm, 1 F0 female at 1000 ppm, 1 F1 male at 30 

ppm and 300 ppm, 2 F1 males at 1500 ppm, 1 F1 female at 300 ppm and 1000 ppm, and 2 F1 

females at 1500 ppm died. The only clinical sign noted was an orange coloration of the urine and 

fat tissue, which is attributed to the test material color [yellow-orange crystals].

Premating Period - F0 parental animals: During the pre-mating period, F0 males at the 1000 

ppm [93% of control] and 1500 ppm [94% of control] dose levels displayed a slight decrease 

(statistical significance not attained) in body weight at week 15 compared to the control. During 

the same period, the F0 females at these two dose levels displayed a slight, statistically-significant, 

decrease [92% of control] in body weight compared to the control. During the initial week of 

treatment (week 0-1), F0 males at both the 1000 ppm [83% of control] and 1500 ppm [83% of 

control] dose levels and F0 females at the 1500 ppm [87% of control] dose level displayed a 

decrease in body-weight gain, but statistical significance was not attained. Body-weight gains were 

decreased throughout the pre-mating period for both sexes [males 91%-94% of control; females 

87%-92%] at these two dose levels, although only females displayed a dose-response. Food 

consumption initially was lower in both sexes at the two highest dose levels [week 1: males 85%-

87% of control; females 88% of control] and remained slightly lower, especially in males [91%-

93% of control] at week 15. Since no treatment-related differences in food efficiency were 

reported, the reduced consumption suggests a palatability problem. F1 parental animals: There 

was a dose-related decrease in body weight during the 0-1 week interval, which was statisticallysignificant at 1000 ppm in F1 females [90% of control] and in F1 males [84% of control] and F1 

females [86% of control] at 1500 ppm. F1 males at 1500 ppm displayed a lower body weight 

throughout the pre-mating period compared to the control [91%-92% of control], although 

statistical significance was not attained. F1 females displayed a dose-related, statisticallysignificant, decrease in body weight throughout the premating period [week 18, 92% and 91% of 

control at 1000 ppm and 1500 ppm, respectively]. There were no significant differences in bodyweight gain overall for either sex, although the magnitude of the decrease was 89% of control in 

males at 1500 ppm and 94% of control in females at both the 1000 ppm and 1500 ppm dose levels. 

Food consumption initially was lower in both sexes at the highest dose level [week 1: males 88% 

of control; females 89% of control] and remained slightly lower, especially in females [90%-91% 

of control] at the two highest dose levels at week 18. Since no treatment-related differences in food 

efficiency were reported, the reduced consumption suggests a palatability problem. 

F0 maternal animals: All dose groups displayed a lower body weight on gestation day 0 and 

throughout gestation compared to the control, with statistical significance being attained at all time 

points at the low- [92%-94% of control] and high-dose [87%-95% of control] levels and from 

gestation day 7 on at 1000 ppm. Body weights at delivery were significantly lower at all dose 

levels compared with the control [92%, 94%, 91%, 87% with increasing dose], although a true 

dose response was not demonstrated. Overall body-weight changes during gestation were 

decreased at 1000 ppm [69% of control] and 1500 ppm [78% of control], although there was no 

dose-response and statistical significance was not attained. During the gestation day 0-7 interval, 
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there was a dose-related decrease in body-weight gain compared to control [94%, 91%, 82%, and 

81% of control, with increasing dose]. During lactation, body weights were decreased initially 

[lactation day 7] at the two high-dose levels [92%* and 91%* of control with increasing dose] and 

at the highest dose on lactation day 14 [90%* of control] and 21 [91% of control]. The 1500 ppm 

dose females displayed the lowest gain during the lactation days 7 to 14 (55% of control) and 7-

21 [0.7 gram vs 1.2 grams in the control]. However, overall, the treated dams displayed increased 

body-weight gains compared to the control.

F1 maternal animals: F2a litters: Decreased body weight was observed throughout gestation at 

the 1000 ppm [89%*-91% of control] and 1500 ppm [88%*-89%* of control] dose levels 

compared to the control, and the delivery body weight was decreased [90% and 87% of control, 

respectively] at these two dose levels also, although statistical significance was not attained. At 

the 1500 ppm dose level, overall body-weight gain during gestation was decreased compared to 

control [79% of control], although statistical significance was not attained. During lactation, there 

was a dose-related decrease in body weight at 1000 ppm [91%*-94%* of control] and 1500 ppm 

[89%*-91%* of control]. F2b litters: Decreased body weights were observed at 1000 ppm [86%*-

89%*] and 1500 ppm [88%*-89%*] dose levels during gestation. Body-weight gains, ranging 

from 50% to 92% of control, were decreased at all dose levels throughout gestation, but there was 

no dose-response. However, dams at the 1500 ppm dose level displayed the lowest overall gain 

[56% of control]. Throughout lactation, the dams at 1500 ppm displayed decreased body weights 

[90%-92% of control], and statistical significance was attained on lactation days 14 [91%*] and 

21 [92%*]. There was no treatment-related change in overall body-weight gain during lactation. 

Gravid uterine weight data were not provided. Gross necropsy revealed no treatment-related 

effects other than the finding of orange fat tissue, which is attributed to the compound color.

There was no treatment-related effect on pregnancy rate. Female fertility index ranged from75% 

to 96.2%, and the male fertility index ranged from 80% to 100%. Although there was no apparent 

adverse effect on the mating index, the 30 ppm group displayed the lowest mating index % for 

each litter [F1a (52.1%); F2a (45.6%; F2b (51.9%)] compared with the % in the control and other 

treatment groups for all litters [56.2%]. Parturition index was 100% for all groups except F0 (F1a 

litters) dams at 30 ppm (95.7%), and F1 (F2a) dams at 300 ppm (94.4%) and 1500 ppm (96%). 

There was no treatment-related change in body-weight gain during lactation. There was no 

treatment-related effect on the number of dead fetuses, and there were no abortions. Mean gestation 

length was comparable among the groups/all litters. Litter size was comparable among the groups 

[all three litters], and the sex ratio was comparable among the groups for all litters.

Pup body weights were comparable among the groups at birth. However, at the 1500 ppm dose 

level, body weights were slightly lower than control values throughout lactation [lactation days 0-

4: 87%, 94%, 81% of control; lactation days 0-21: 89%, 92%, 81% of control for F1a, F2a, and 

F2b pups, respectively]. On lactation day 21, both sexes at 1500 ppm displayed slightly lower body 

weights than the controls [males: 93%, 93%, and 87% of control/females: 93%, 95%, 86% of 

control, for the F1a, F2a, and F2b pups, respectively]. F1a weanling organ weights were 

comparable among the groups, but terminal body-weight data were not provided. F2b pup body 

weights at terminal sacrifice were decreased at the 1500 ppm dose level for both sexes [males 
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75%/females 50% of control], although statistical significance was not attained. Changes in organ 

weights were noted at this dose level also, which included a slight decrease in brain weight [males 

92%/females 91% of control], and decreased in liver weight [males 84%/females 78% of control], 

and kidney weight [males 71%/females 70% of control], the latter two being attributable to the 

lower body weight. The 1500 ppm F2b weanling females also displayed a large increase in uterus 

weight [0.114 gram] compared to the control [0.054 gram] and other dose groups [0.048-0.058 

gram].

Reproductive toxicity was not observed in this study, based on the parameters examined. It is to 

be noted that several parameters in the current protocol that measure reproductive effects, such 

as age of vaginal opening and preputial separation; anogenital distance for F2 pups; 

implantations sites; estrous cycle length and periodicity (F1 weanlings); and sperm measures, 

were not evaluated. These are included in the new protocol, which was not in effect at the time of 

the study.

The parental toxicity NOAEL is 300 ppm [males 24 mg/kg/day/females 27 mg/kg/day]. The 

parental toxicity LOAEL is 1000 ppm [males 79 mg/kg/day/females 99 mg/kg/day], based on 

a slight decrease in body weight during the dosing period and throughout gestation and 

lactation.

The developmental toxicity NOAEL is 1000 ppm [males 79 mg/kg/day/females 99 

mg/kg/day], and the developmental toxicity LOAEL is 1500 ppm [males 120 

mg/kg/day/females 138 mg/kg/day], based on decreased body weight. 

The reproductive toxicity NOAEL is 1500 ppm ppm [males 120 mg/kg/day/females 138 

mg/kg/day], the highest dose tested.

This two generation reproduction study is classified Acceptable/non-guideline, but it satisfies the 

guideline requirements [OPPTS 870.3800; §83-4] for a reproductive toxicity study in the rat. It is 

classified non-guideline because mating was two females to one male. 

A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity – Rat

See 870.4200a, below.

870.4100b Chronic Toxicity - Dog
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A.4.5 Carcinogenicity

870.4200a Carcinogenicity Study - rat

EXECUTIVE SUMMARY: In a combined chronic toxicity/carcinogenicity study [MRID 

42061603], flumetralin (96% a.i.) was administered via the diet to groups of 90 (control), 60 [lowand two mid-], and 80 [high-] dose Sprague-Dawley CD rats per sex at dose levels of 0, 30, 300, 

1000, or 1500 ppm [males 1.5, 14.5, 49.8, 75.2 mg/kg/day; females 1.9, 19.2, 66.7, 103.9 

mg/kg/day, respectively] for 2 years. Ten/sex of the control group were used in the pre-study 

clinical laboratory studies. At 52 weeks, 10 rats/sex from the control and high-dose groups were 

randomly selected and maintained on normal feed for a 5-week recovery period. The interim 

sacrifice at 52 weeks was performed on 10 rats/sex from the control and high-dose groups. 

There was no adverse effect on survival of either sex; females displayed a dose-related increase in 

survival with increase in dose. There were no treatment-related signs of toxicity in either sex. The 

only observation related to treatment was urine discoloration [orange], which can be attributed to 

the test material [an orange granular solid].The 1500 ppm males displayed a slight, but statisticallysignificant, decrease in body weight by week 29 [96% of control], and the deficit in body weight 

continued throughout the study [84% of control at week 103]. Males at 1000 ppm displayed a 

slight, statistically-significant, decrease in body weight by week 75 [93% of control], which by the 

end of the study was 89% of control but not statistically-significant. Females at the 1000 ppm and 

1500 ppm dose levels displayed decreased body weight from week one on [week 1: 97% of control 

(both groups); week 15: 91% and 89% of control, respectively; week 103: 82% and 75% of control, 

respectively].Decreased body-weight gains were observed in males at the 1000 ppm and 1500 ppm 

dose level throughout the study. During weeks 29-37, males at 1500 ppm displayed a 49% deficit 

in body-weight gain. Overall, body-weight gains at 1000 ppm were 86% of control and those at 

1500 ppm were 80% of control. Females at 300 ppm displayed a slight decrease in body weight 

[91% of control] at week 103, but statistical significance was not attained. Females at the 1000 

ppm and 1500 ppm displayed a dose-related decrease in body weight throughout the study [week 

15: 91% and 89% of control, respectively; week 33: 91% and 86%, respectively; week 103: 82% 

and 75% of control, respectively]. Decreased body-weight gains were observed in females 

throughout the study at 1000 ppm and 1500 ppm [weeks 0-1: 94% and 91% of control, 

respectively; weeks 2-15: 84% and 81% of control, respectively; weeks 0-103: 77% and 67% of 

control, respectively; 88% of control at 300 ppm]. There were no consistent differences in food 

consumption in males to account for the decrease in body weight. For the females, decreased 

consumption in food was observed from week 1, suggesting a palatability problem. 

There were no ocular changes observed in either sex. There were decreases in erythrocyte count, 

hemoglobin, and hematocrit, although the significance of these is not apparent. However, similar 

decreases were observed in the 90-day rat study and in the 6-month dog study. Increased 

cholesterol was reported, which is also a finding in the 90-day rat and 6-month dog studies. The 

urinalysis parameters monitored were comparable among the groups for both sexes. 

Males displayed increased liver weights at the two highest dose levels, although there was no doseresponse. Thymus weights were decreased in both sexes at the 1500 ppm dose level and in males 
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at 1000 ppm. Both sexes displayed an increased incidence of hepatocellular eosinophilic 

cytoplasmic change [males 7%, 15%, 16%; females 8%, 24%, 17% at 300 ppm, 1000 ppm, and 

1500 ppm, respectively, compared to 0% in control males and <2% in control females]. The 

incidence of several tumor types was increased, but there was no dose-response. For example, at 

30 ppm (the lowest dose tested), a statistically-significant increase was observed in the adrenal 

medulla [pheochromocytomas: 12.3%, 29.8%*, 18.9%, 12.1%, 27.3% with increasing dose] in 

males. Also at 30 ppm in females, there was a statistically-significant increase in mammary gland 

adenocarcinomas and combined adenomas/adenocarcinomas, but there was no dose-response 

[<2%, 21.4%*, 12.3%, 14.5%, 12.3% with increasing dose. The control incidence was low [1 

adenoma compared to the historical control 12.7%]. Hepatocellular carcinoma was observed in 2 

females at 1500 ppm compared to none in the control and other treatment groups.

The systemic toxicity NOAEL is 300 ppm [males 14.5/females 19.2 mg/kg/day], based on 

decreased body weight, body-weight gains, decreased thymus weight in males, and increased 

brain weight in females at the systemic toxicity LOAEL of 1000 ppm [males 49.8/females 

66.7 mg/kg/day].

This combined chronic toxicity/carcinogenicity study is classified Acceptable, and it satisfies the 

guideline requirement [OPPTS 870.4300; §83-5] for a combined chronic toxicity/carcinogenicity 

study in the rodent. 

870.4200b Carcinogenicity (feeding) - Mouse

EXECUTIVE SUMMARY: In a carcinogenicity study [MRID 42061601], flumetralin (96% a.i.) 

was administered via the diet to groups of 70 CD-1 mice/sex/group at dose levels of 0, 30, 300, 

1000, or 1500 ppm [0, 4.98, 49.8, 166.6, or 250 mg/kg/day] for 95 weeks. An additional 10 

mice/sex/group were sacrificed after 12 months for interim studies. 

There were no apparent, treatment-related, effects on survival in either sex, and there were no 

treatment-related signs of toxicity in either sex. The only observation related to treatment was urine 

discoloration [orange], which can be attributed to the test material [an orange granular solid]. There 

were no treatment-related effects on body weight, body-weight gain, or food consumption in either 

sex, and the hematology parameters monitored were comparable among the groups in both sexes.

Increased absolute and relative liver weights were observed in both sexes at the two highest dose 

levels [1000 ppm and 1500 ppm]. There was no apparent, treatment-related, increase in the 

incidence of any tumor type in either sex.

The systemic toxicity NOAEL is 300 ppm [49.8 mg/kg/day], based on increased liver weights 

in both sexes at the systemic toxicity LOAEL of 1000 ppm [166.6 mg/kg/day].

This carcinogenicity study is classified Acceptable, and it satisfies the guideline [OPPTS 

870.4200; §83-2] for a carcinogenicity study in the mouse. 

A.4.6 Mutagenicity
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Gene Mutation

Guideline 870.5265, gene mutation

MRID 00094009 (1981)

Acceptable/guideline

100-10000 μg/plate (+/- S9l); 20000 μg/plate (+/- S9; repeat TA 1538, 

TA98). negative response in strains TA1535, TA1537, TA100 with and 

without metabolic activation

strains TA1535 and TA98 produced one-fold increases in mutation 

frequency; repeated up to 20000 μg/plate; produced dose-related increase 

in mutation rates w/ & w/out S9

Cytogenetics

Guideline 870.5385, Micronucleus 

assay (mouse)

MRID 00094010 (1986)

acceptable/guideline

two doses @ 3500 mg/kg [24 hours apart]

negative for structural chromosomal aberrations

toxic signs, 2 deaths

Other Genotoxicity

Guideline 870.5550, hepatocyte/DNA 

repair test (rat) - UDS

MRID 42061605 (1982)

acceptable/guideline

did not induce unscheduled DNA synthesis in cultures treated up to limit 

dose [5000 μg/mL]

A.4.7 Neurotoxicity

870.6100 Delayed Neurotoxicity Study - Hen

870.6200 Acute Neurotoxicity Screening Battery

The acute neurotoxicity study data requirement for flumetralin was waived (Leshin, 2015, 

HASPOC TXR# 0057243).

870.6200 Subchronic Neurotoxicity Screening Battery

The subchronic neurotoxicity study data requirement for flumetralin was (Leshin, 2015, 

HASPOC TXR# 0057243).

870.6300 Developmental Neurotoxicity Study

A.4.8 Metabolism

870.7485 Metabolism - Rat

There are no absorption, distribution, metabolism, or excretion data available on flumetralin. 

870.7600 Dermal Absorption - Rat
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A.4.9 Immunotoxicity

870.7800 Immunotoxicity

The immunotoxicity data requirement for flumetralin was waived (Rury, 2013, HASPOC TXR#

0056750). 

A.4.9 Special/Other Studies 

EXECUTIVE SUMMARY: In a subacute (6-week) inhalation study [MRID 00117622], CGA41065 technical (96.4%* a.i.) was administered via inhalation (smoke) to groups of 10 Fischer 344 

rats/sex/dose level. Doses consisted of smoke from cigarettes made with tobacco spiked with test 

material at 300, 5000, or 15000 ppm. The control was exposed to smoke from cigarettes containing 

no test material. The animals were exposed for approximately 4 hours/day, 5 days/week for a total 

of 30 exposures in 6 weeks. At study termination, four groups of 2 rats/sex were exposed once to 

the smoke of 18 cigarettes of each tobacco-spike level for plasma nicotine analyses.

The parameters evaluated were mortality, moribundity, appearance, behavior, body weight, food 

consumption, clinical pathology studies, absolute and relative organ weights, gross pathology, and 

histopathology. 

No adverse, treatment-related, findings were reported. All rats survived until study termination. 

With the exception of some eye irritation and urogenital area staining, there were no signs of 

toxicity. A slight [96% of control] decrease in body weight was noted in the mid- and high-dose 

males compared to control males at week 6, but there was no dose-response. Males at the highdose level displayed a negative [-0.4 gram] body-weight gain compared to no gain in the control 

males during the first week. Overall [weeks 0-6], body-weight gain was decreased at all dose levels 

in the males [90%, 76%, 78% of control with increasing dose]. Female body weight and bodyweight gains were comparable among the groups. 

At study termination, organs weights were comparable among the groups for both sexes. No 

histopathology findings were reported. 

Chamber concentrations of flumetralin were not detected in the control and low-dose [300 ppm] 

groups. At 5000 ppm and 15000 ppm, the overall mean chamber concentrations were 1.15 μg/L ± 

0.22 μg/L and 3.74 μg/L ±0.98 μg/L, respectively.

The systemic toxicity NOAEL is 15000 ppm [3.74 μg/L/day], the highest concentration tested.

This 6-week smoke inhalation study is classified Acceptable/non-guideline, and it does not satisfy 

any guideline requirement.
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Appendix B. Physical/Chemical Properties

Physicochemical Properties of Flumetralin

Parameter Value Reference

Melting point/range 101-103 C Agrochemicals Handbook 1

pH Not available

Density Not available

Water solubility 0.07 ppm at 20 C Pesticide Manual 2

Solvent solubility Not available

Vapor pressure 0.032 mPa at 25 C Pesticide Manual 2

Dissociation constant, pKa Not available

Octanol/water partition coefficient, 

Log(KOW)

5.45 at 25 C Pesticide Manual 2

UV/visible absorption spectrum Not available

1 Agrochemicals Handbook, 2nd Edition, RSC, Nottingham, UK 1987 (www.arsusda.gov/acsl/services/ppdb).

2 Pesticide Manual, 10th Ed., British Crop Protection Council, and The Royal Society Of Chemistry, 1994 

(www.arsusda.gov/acsl/services/ppdb).
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Appendix C. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data include studies from the 

Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler 

Exposure Task Force (AHETF) database, and the Residential SOPs (lawns and turf). These data 

are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant 

with applicable ethics requirements. For certain studies that review may have included review 

by the Human Studies Review Board. Descriptions of data sources as well as guidance on their 

use can be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html. 
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Appendix D. Major Flumetralin Metabolites

Chemical Names and Structures of Major Flumetralin Metabolites.

Common name/code Chemical name Chemical structure

CGA-41065 2-Chloro-N-[2,6-dinitro-4-

(trifluoromethyl)phenyl]-Nethyl-6-

fluorobenzenemethanamin

C16H12ClF4N3O4

Mono-ReducedCGA-41065

2-Chloro-N-[2-amino-6-nitro-4-

(trifluoromethyl)phenyl]-Nethyl-6-fluorobenzenemethanamine

C16H14ClF4N3O2