Flurnetralin Human Health Ri sk Assessme nt DP No. D427465

UNITED STATES ENVIRONMENTA L PRO TECT ION AGENCY

MEMORANDUM

Dat e: December 15

, 2015 WASH INGT ON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

SUB J EC T : F lu metra lin : Human Health Risk Assessment for Registration Review.

P C Co d e: 12300 I

D ecis ion No.: 505305

Petitio n No.: NA
Ri s k Assess m en t Ty p e: Sing l e Che mical Aggregate
TXR No.: A
MRID No.: A

FROM:

THROUGH: Danette Drew

, Chemist

, and
Michael S. Metzger, Chief

, 

### H

ED (7509P) DP Barcode: 427465

R eg i s tration No.: I 00

- 1228

. I 00-640

, 400-600
& 19 7 13-649

R eg ul a t ory Act i on: Registration Review

CascNo. : 4119

CAS No.: 62924- 7 0-3
40 CFR: NA

TO: Katherine St. C l air

, Risk Manager Reviewer
Cat hr y n Britton, Risk Manager
Risk Management and Implementation Branch II
Pesticide Re-Evaluation DivisionFlumetralin Human Health Risk Assessment DP No. D427465

Page 2 of 53 

## 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

................................ ................................ ............... 53Flumetralin Human Health Risk Assessment DP No. D427465

Page 3 of 53 1.0 Executiv e 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 Re

evaluation 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 th at 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

- (triflu o romethyl)phenyl]

- N

- ethyl

- 6

- flu o robenzenemethan amine ) 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 m otorized 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 post

implantation loss, and skeletal alteration in rabbits and increased runts and skeletal malformation in rats; however, end points selected for risk assessment were protective of these effects. No reproductive toxicity was noted, and the offspring w ere not more sensitive than the parental
animals. No systemic toxicity was observed following dermal exposure to rabbits for 21 day s up to the limit dose; however, dermal irritation was noted at all tested dose s. No evidence of neurotoxicity, immunotoxicity, mutagenicity, or carcinogenicity w as observed. No effects were
noted in a 6

- week study in rats, wh ere 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 to xicity endpoints were selected: Acute dietary ( general p opulation, including i nfants and c hildren ) : No endpoint
identified

. Acute dietary ( f

emales 13

- 49 years of age ) : aRfD = 0.50 mg/kg/day derived from a
NOAEL of 5 0 mg/kg/day in a ra bbi t developmental toxicity study . LOAEL = 10 0 mg/kg/day based on increased incidences of litters with total resorptions, increased post

implantation loss, and an increase in external and s keletal alterations

. Intermediate

- term dietary: RfD = 0. 1 16 mg/kg/day derived from a NOAEL of 1 1.6 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), morta lity, hematology,Flumetralin Human Health Risk Assessment DP No. D427465

Page 4 of 53 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 inh a lation 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 t hrough its application to tobacco. Updated a cute and intermediate

- term dietary assessments of drinking water were conducted using model

- derive d 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 intermed iate

- 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 95 t h percentile 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 mad e of tobacco treated with flumetralin. Because flumetralin is registered only for use on field grown tobacco, t here 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 condu cted 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 a n endpoint selected for dermal toxicity

, an adult dermal post

- application exposure assessment for spray drift was n ot conducted

. I ncidental oral risk estimates for children 1 to <2 years old were calculated. The highest exposure resulted from drift following
flumet ralin 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.Flumetralin Human Health Risk Assessment DP No. D427465

Page 5 of 53 Volatilization/Residential Bystander

Volatilization of pesticides may b e a source of post

- application inhalation exposure to individuals nearby pesticide applications. The agency has developed a Volatilization Screening Tool and a subsequent Vo latilization Screening Analysis, and the Agency will utilize this analysis d uring 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 o f this assessment ; therefore, HED relied on surrogate data and default assumptions in accordance with standard poli cies. In the absence of a n endpoint selected for dermal toxicity , dermal handler and post

application exposure assessment s were not conducte d

. All occupational handler scenarios for the registered uses resulted in inhalation MOEs greater than 100 at baseline ( i.e., without respirator y protection )

. The lowest MOE of 3,300 is associated with mixing/loading/applying sprays using a backpack spra yer. All other MOEs were significantly higher, ranging from 4

, 8 00 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 ne ed 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 o ther 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 re quirements. 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 website 1

.

1 http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

.Flumetralin Human Health Risk Assessment DP No. D427465

Page 6 of 53 2.0 HED Recommendations

2.1 Data Defic iencies

There ar e no data deficiencies for the Registration R eview eligibility of flumetralin in regards to the toxicology, occupational and residential exposure, and chemistry databases. No tolerances are required , and label modifications are discussed i n S ection 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

I nternational 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 n on

- 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 assi gned 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.Flumetralin Human Health Risk Assessment DP No. D427465

Page 7 of 53 3.0 Introduction

3.1 Chemical Identity

Table 3.1. Flumetralin Nomenclature

Chemical structure

Common name Flumetralin

Molecular formula C 16 H 12 ClF 4 N 3 O 4 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

- fluoro b enzenemethanamine
CAS registry number 62924

- 70

- 3

3.2 Physical/Chemical Characteristics

Flumetralin is the c ommon 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 a n emulsifiable concentrate (EC). It has an aromatic solvent odor and is s table under normal use and storage
conditions

. The environmental fate and characterization database for flumetralin require s updating

, because water solubility, K ow , 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 K oc , 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 foreig n 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 s ummary of direction for use of flumetralin products.Flumetralin Human Health Risk Assessment DP No. D427465

Page 8 of 53 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/hand

held equipment 19713

- 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

 0.0 12 lbs ai/gallon application rate for handheld equipment

 Must not be applied >4 ft. over crop canopy

Motorized field sprayers/hand

held equipment 100

- 640 1.2 1 1.2 N/A Prime+®

 Apply 1x/season

 Split application an option in NC

 Avoid precision hand application equipment

 0.0 24 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/hand

held equipment 400

- 600 1.2 1 1.2 N/A FLUPRO®

 Apply 1x/season

 Avoid precision hand application equipment

 M ix 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/hand

held equipment 19713

- 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 productFlumetralin Human Health Risk Assessment DP No. D427465

Page 9 of 53 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 flumetra lin ; 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 Population s," ( 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

- estab lished 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 assess ments 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, specialize d 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, y ouths, 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 byst anders 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

- (trifluo ro methyl)phenyl]

- N

- ethyl

- 6

- fluorobenzene
meth anamine] is in the 2, 6

- dinitroaniline class of chemicals. Dinitroanilines selectively inhibitFlumetralin Human Health Risk Assessment DP No. D427465

Page 10 of 53 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

, includ ing :

 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 stu dy in rats

 subchronic dermal toxicity study in rats

 immunotoxicity study in mice

 complete mutagenicity study battery

 metabolism study in rats

4.2 Absorpt ion, Distribution, Metabolism, and E xcretion (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),

o ral 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 ente rohepatic 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 s tudy (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 compari son 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.Flumetralin Human Health Risk Assessment DP No. D427465

Page 11 of 53 4.3 Toxicological Effects

The liver is the target organ for flumetr alin, 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 d ecreased hemoglobin, hematocrit, and RBC counts and increased chol esterol 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 perio d 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
d evelopmental 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 repo rted 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 m aternal toxicity (decreased body weight gain) occurred. Although qualitative susceptibility was observed in the rat study, concern is low, since clear NOAELs were established a nd 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 offspri ng 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 w as 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,Flumetralin Human Health Risk Assessment DP No. D427465

Page 12 of 53 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 ava ilable on flumetralin, but the Hazard and Science Policy Council (HASPOC) recommended that these studies be waived ( Leshin

, 2015

, TXR# 00 57243 ). No clinical signs indicating neurotoxicity were observed in the toxicological database on flumetralin. The decr eased 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 ( Rur y, 2013, TXR # 0056750).

In acute lethality studies, f lumetralin 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 include s 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 ef

fect. 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 co ncern 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 incr eased quantitative susceptibility following in utero exposure to flumetralin in either the rat or rab bit 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

.Flumetralin Human Health Risk Assessment DP No. D427465

Page 13 of 53 4.4.4 Residual Uncertainty in the Exposure Database

There are no resid ual 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 vari ous exposure scenarios is presented in the A ppendix 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 5 0 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 = 0.5 0 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 flum etralin 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 interme diate dietary endpoint was from the subchronic oral toxicity study in dog s 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 ( MCH C) , 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 dog s (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 tox icity 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

Page 14 of 53 with that from the rabbit developmental toxicity stud y (50 mg/kg/day) suggests minimal dermal absorption (2.5%). Comparing the rabbit developmental N OAEL to the limit dose suggests a 5% dermal absorption factor. Although external and skeletal alterations/malformations were observed in the rat developmental t oxicity 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
be en submitted, H ASPOC 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 end point) to assess both short

and 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 Recom mendations 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

t umorigenic 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
flumetral in as “not likely to be carcinogenic in humans ”

, based upon bioassays in rats and mice that showed no significant tumor response in either s pecie , and there is no mutagenicity concern

.

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Hu man Risk
Assessment

Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Flumetralin for Use in Dietary and Non

Occupational 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 UF A = 10x

UF H = 10x aRfD = 0.5

mg/kg/day Developmental Toxicity

– rabbit

LOAEL = 100 mg/kg/day; 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 cente rs) alterations.Flumetralin Human Health Risk Assessment DP No. D427465

Page 15 of 53 Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Flumetralin for Use in Dietary and Non

Occupational 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 UF A = 10x

UF H = 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 (Intermediate

Term) NOAEL =

11.6 mg/kg/day UF A = 10x

UF H = 10x LOC =

MOE≤100 Subchronic Oral Toxicity

- Dog

LOAEL = 92.75 mg/kg/day for clinical s igns (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 UF A = 10x

UF H = 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 (P O D) = 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. UF A = extrapolation from animal to human (inters pecies). UF H = potential variation in sensitivity among
membe rs of the hu man population (int r a species ); 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 toxi city study on the a.i.; HASPOC recommended waiving an inhalation toxicity study for flumetralin at this time ( Leshin, 2015, TXR # 00 57243 )

.Flumetralin Human Health Risk Assessment DP No. D427465

Page 16 of 53 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
Intermediate

Term) Oral

NOAEL =
11.6 mg/kg/day

toxicity via
inhalation

route considered equivalent to toxicity via
oral route UF A = 10x

UF H = 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 Carc inogenic To Humans”.

1 Explanation of Abbreviations: Point of Departure (P O D) = 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. UF A = extrapolation from animal to human (inters pecies). UF H = potential variation in sensitivit y among membe rs of the human population (int r a species ); 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, t here 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 # 00 57243 )

.

4.6 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numero us 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 sys temic 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 Disru ptor 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 effectFlumetralin Human Health Risk Assessment DP No. D427465

Page 17 of 53 produced by a “naturally occurring estroge n, 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 su bstance 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 EDS P 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 betwee n 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, 2013 2 and 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 screen ing 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 flu metralin . However, a dditional metabolism data
would not be expected to significantly enhance the understanding of tobacco residues in light of the very high NO A ELs 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 [ 14 C]flumetralin treated tobacco, the primary pyrolysis product is 14 CO 2 (31

- 61% to tal radioactivity); flumetralin was found in mainstream total particulate matter (TPM) at 0.3% of the radioactivity. In cigarettes fortified with [ 14 C]flumetralin, 26% of fortified radioactivity was released as 14 CO 2 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/Flumetralin Human Health Risk Assessment DP No. D427465

Page 18 of 53 For the further characterization of flumetralin, confined rotational crop study data have been submitted for determining the nature and amou nt 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 plant

back interval (PBI). Th e 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
metabo lite 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 Enviro nmental Degradation

The only information available o n 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 metabol ite 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 reducti on of the nitro (NO 2 ) group to aniline (NH 2 ). In tobacco f lumetralin was degraded to a large number of components ; t hin layer chromatographic analyses indicated that flumetralin comprised 44% TRR in green tobacco but only 4% TRR in cured tobacco. I n the pyrolysis study conducted to
characteriz e 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. P arent flumetralin only is the res idue of concern for risk assessment for drinking water.Flumetralin Human Health Risk Assessment DP No. D427465

Page 19 of 53 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/fee d 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 i s 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 flumetrali n 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 af ter 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 esse ntially 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. The se model s and their description s are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/

.

The recommended EDWCs for flu m etralin 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 Flu metralin

. 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.Flumetralin Human Health Risk Assessment DP No. D427465

Page 20 of 53 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 re quire a drinking water assessment to be performed. T he dietary assessment conducted for flumetralin wa s performed using model

derived 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 d etermined to have an acute toxicological endpoint for risk assessment. The acute r isk estimate was well be low the Agency’s
level of concern (LOC) ( i.e. , <100% of the acute reference dose ( aRfD )) . Th e estimate d risk for
flumetralin f

rom drinking water is <1.0 % of the aRfD with an exposure of 0.000332 mg/kg/day
at the 95 th 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 the refore 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

.Flumetralin Human Health Risk Assessment DP No. D427465

Page 21 of 53 Ta ble 5.4.6

. Drinking Water Only D ietary Exposure and Risk Estimates for
Flu metralin

.

Population Subgroup Acute Dietary Drinking
Water Surface Water Sources (95 th Percentile) Intermediate

- term Dietary Drinking Water Surface Water

Sources Exposure (mg/kg/day) % aRfD Exposure (mg/kg/day) MOE 1 U.S. Population

Not Applicable 0.0 00015 800,000 All infants (< 1 yr) 0.000039 3 10 ,000
Children 1

- 2 yrs 0.000022 55 0 ,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 intermediate

term exposures is 100.

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

6.1 Non

- O ccupational Inhalation Exposure (Tobacco Smo king)

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 flu metralin (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 t obacco field trial study and the tobacco pyrolysis study, an acute smoker inhalation exposure of 0.00096 mg/ k g/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

.Flumetralin Human Health Risk Assessment DP No. D427465

Page 22 of 53 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 a ddr essed below in Secti on 6.5

.

6.4 Residential Bystander Post

- A pplication Inhalation Exposure

Volatilization of pesticides may be a source of post

- application inhalation exposure to
individuals nearb y pesticide applications. The A gency sought expert advice and input on issu es 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 A gency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilizatio n Screening Analysis

. 5

D uring Registration Review, the A gency will utilize this analysis to determ ine if data (i.e., flux studies) or further analysis are required for flumetralin

.

6.5 Spray Drift

T h e 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 off

target and can lead to exposures to those it may directly contact. They can also deposit on
surfaces where contact with residues ca n 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 me thods 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 e xposures 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 thoug ht 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 assume d 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 ap proach 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 agricultur al 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.Flumetralin Human Health Risk Assessment DP No. D427465

Page 23 of 53 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
Resi dential 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 available 7

, 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 rep resent 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 t o 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 lev el 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 addition al 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) TTR 1 (ug/cm 2 ) 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 No te 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.Flumetralin Human Health Risk Assessment DP No. D427465

Page 24 of 53 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 t he

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 flumet ralin 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 subst ances. 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 c ommon 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

- T erm 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 depe nding 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 speci fic 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 applica tion 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 spr ayer

 M/L/A via Manually

- pressurized handwand sprayer

 M/L/A via Mechanically

- pressurized handwand sprayerFlumetralin Human Health Risk Assessment DP No. D427465

Page 25 of 53 Occupational Handler Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the occupational
h andler risk assessments. A ssumption s and factor s, as well as algorithms used to estimate non

cancer exposure and dose for occupational handlers are detailed in the most recent ORE memo (L loyd

, 2015

, D 429299 ).

Based on the registered and proposed use pa ttern 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 flumetral in 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 Estim ates

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.Flumetralin Human Health Risk Assessment DP No. D427465

Page 26 of 53 Table 9

. 1. Occupational Short

- and Intermediate

- term Handler Exposure and Risk Estimates for Flumetralin.

Exposure Scenario Mitigation
Level a Inhalation Unit

Exposure b
(ug/lb ai) Applicati

on Rate c Area Treated

or Amount
Handled d Inhalation

Dose e (mg/kg/day) Inhalation
MOE f

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 Mechanically

pressurized 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 Manually

pressurized 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 label s ( cited in Section 4.1 ).
d Exposure Science Advisory Council Policy #9.1.

e Inhalation Dose = Dermal Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW ( 80 kg).
f Inhalation MOE = Inhalation N OAEL ( 11.6 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).Flumetralin Human Health Risk Assessment DP No. D427465

Page 27 of 53 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 be en previously treated with a pesticide (also referred to as re

entry 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 h arvesting. 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, th e 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

- app lication 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 th e 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 assign ed 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 Inha lation Study for Flumetralin.

Lloyd, M. (2015)

. D 429299

, Flumetralin: Occupational and Residential Exposure Assessment for Registration Review.Flumetralin Human Health Risk Assessment DP No. D427465

Page 28 of 53 Negron

- Encarnacion, I. D412676. Flumetralin. Abbreviated Review of the Confined Rotational Crop Study.

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

.

Rury, K. (2013). TXR# 005 6750. 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 Wat er to Support Registration Review.Flumetralin Human Health Risk Assessment DP No. D427465

Page 29 of 53 Appendix A

. Toxicology Assessment

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for the non

- food uses for f lumetralin 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 ( R odent)

................................ ............. 870.3150 Oral Subchronic ( N on

- 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 ( R odent)

................................ . 870.3700b Developmental Toxicity ( N on

- rodent)

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

................................ ................................ . yes
yes
yes yes

yes
yes
870.4100a Chronic Toxicity ( R odent)

................................ ............. 870.4100b Chronic Toxicity ( N on

- rodent)

................................ ..... 870.4200a Oncogenicity ( R at)

................................ ........................ 870.4200b Oncogenicity ( M ouse)

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

................................ ................... yes

no
yes
yes
yes yes

--- yes
yes
yes

870.5100 Mutagenicity

— Gene Mutation

- B acterial

.................... 870.5300 Mutagenicity

— Gene Mutation

- M ammalian

............... 870.5 xxx Mutagenicity

— Structural Chromosomal Aberrations

... 870.5xxx Mutagenicity

— Other Genotoxic Effects

....................... yes
yes
yes
yes yes

no
yes
yes

870.6100a Delayed Neurotox icity ( H en)

................................ ........ 870.6200a Acute Neurotox icity Screening Battery ( R at)

................ 870.6200b 90

- Day Neuro toxicity Screening Battery ( R at)

............. 870.6300 Develop mental Neuro toxicity

................................ ....... no

no b

no b

no ---

---

---

---

870.7485 General Metabolism

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

................................ ........................ yes

no yes

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

---

a no t required (Leshin, 2015. HASPOC TXR# 0057243)

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

c not required ( Rury, 2013, H ASPOC TXR# 0056750)
CR = conditionally required; * there is a 6 month oral toxicity study in dogsFlumetralin Human Health Risk Assessment DP No. D427465

Page 30 of 53 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 LD 50 > 5000 mg/kg IV

870.1200 Acute dermal [rabbit] 00093999 LD 50 = >2000 mg/kg III

870.1300 Acute inhalation [rat] 00094002 LC 50 =  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. ( Y ear)/
Classification /Doses Results

870.3100 90

- Day oral

toxicity ( CD

Crl: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).Flumetralin Human Health Risk Assessment DP No. D427465

Page 31 of 53 Table A2.2 Flumetralin Subchronic, Chronic
, and Other Toxicity Profile

Guideline No. Study Type MRID No. ( Y ear)/
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 [we ight 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, hemogl obin, 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 ( CD

Crl: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.Flumetralin Human Health Risk Assessment DP No. D427465

Page 32 of 53 Table A2.2 Flumetralin Subchronic, Chronic
, and Other Toxicity Profile

Guideline No. Study Type MRID No. ( Y ear)/
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 ute rine 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 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].

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/fem ales 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

DogFlumetralin Human Health Risk Assessment DP No. D427465

Page 33 of 53 Table A2.2 Flumetralin Subchronic, Chronic
, and Other Toxicity Profile

Guideline No. Study Type MRID No. ( Y ear)/
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.

N o apparent, treatment

- related, increase in the incidence of any tumor type in either sex.

Gene Mutation

870.5100 Salmonella

typhimurium
TA98, TA100, TA1535, TA1537,
TA 1538 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.Flumetralin Human Health Risk Assessment DP No. D427465

Page 34 of 53 Table A2.2 Flumetralin Subchronic, Chronic
, and Other Toxicity Profile

Guideline No. Study Type MRID No. ( Y ear)/
Classification /Doses Results

870.7600 Dermal

penetration (rat)

870.7800 Immunotoxicity W aived (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 ppmFlumetralin Human Health Risk Assessment DP No. D427465

Page 35 of 53 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 litter s 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.

. Comment s 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 ( UF A ) , 10X intraspecies variability ( UF H ) ]. 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 : Subc hronic oral toxicity study (d og )
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, h ematology/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.
Unc ertainty Factor (UF) : 100X [ 10X interspecies extrapolation ( UF A ) , 10X intraspecies variability ( UF H )]

. The level of concern for risk assessment is an MOE below 100.

A.3.4 Incidental Oral Exposure (Short

- and Intermediate

- Term)

Study Selected : Subc hronic oral toxicity study (d og )
MRID No. : 00094012 Executive Summary : See Appendix A, Guideline § 870. 3150Flumetralin Human Health Risk Assessment DP No. D427465

Page 36 of 53 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 ( UF A ) , 10X intraspecies variability ( UF H ) ]. 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 : Subc hronic oral toxicity study (d og )
MRID No. : 00094012 Executive Summary : See Appe ndix 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 myeloi d 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 i nhalation toxicity study is not required on flumetralin. Uncertainty Factor (UF) : 100X [ 10X interspecies extrapolation ( UF A ) , 10X intraspecies variability ( UF H ) ]. The level of concern for risk assessment is an MOE below 100.Flumetralin Human Health Risk Assessment DP No. D427465

Page 37 of 53 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 pe riod 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 body

weight 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 lev els 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 comp arable 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 m ales. 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 leve l [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 systemi c 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

- DogFlumetralin Human Health Risk Assessment DP No. D427465

Page 38 of 53 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 obtaine d 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 l evels (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
abnormal ities 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 th e 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/female s 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 hig h

- 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 fro m 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 contr ol and other treatment groups, the elevated level observed in the high

- dose dogs continued throughout the study. Cholesterol values were increased throughout the studyFlumetralin Human Health Risk Assessment DP No. D427465

Page 39 of 53 (from day 30) in both sexes at the high

- dose level, and the report indicated that a tren d 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 nor mal 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 wer e 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 (bod y 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, pericholan geal 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 t he 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 prima rily 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 nec rosis 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 th e 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, bu t 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 cons umption, 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.Flumetralin Human Health Risk Assessment DP No. D427465

Page 40 of 53 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 o n 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 we re 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 irr itated 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/ d ay, 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 ).Flumetralin Human Health Risk Assessment DP No. D427465

Page 41 of 53 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

pr egnant 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 gestat ion. 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

- d ose 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 wei ght 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 o f 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 s lightly 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 skele tal 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 toxic ity LOAEL is 400 mg/kg/day, based on decreased body

- weight gains.Flumetralin Human Health Risk Assessment DP No. D427465

Page 42 of 53 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 s keletal 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 surv ived 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 high

mid 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 t he 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 post

treatment period [GD 20

- 29] remained below the control and other dose level groups [53% of control], although statisti cal 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 high

dose females and dilatation of the gall bladders in 2 of the high

- dose females.

Pregnancy rate was comparable among the groups, althou gh 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 tota l number of resorptions, the number of resorptions per doe, and in the number of littersFlumetralin Human Health Risk Assessment DP No. D427465

Page 43 of 53 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 d ose 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/k g/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 [4 3%, 54%, and 47% at 10, 50, and 200 mg/kg/day, respectively] and there was no dose

response, 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 in creased 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 n egative 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/da y, 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 CD

Crl: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].Flumetralin Human Health Risk Assessment DP No. D427465

Page 44 of 53 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

consump tion 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 foo d 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 statistically

significant 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 n ot attained. F1 females displayed a dose

- related, statistically

significant, 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 body

wei ght 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 d ose 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], a lthough 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. Du ring the gestation day 0

- 7 interval,Flumetralin Human Health Risk Assessment DP No. D427465

Page 45 of 53 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 h igh

- 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) an d 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 c ontrol], 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 tre atment

- 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 fro m 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 amo ng 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; lactat ion 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, f or 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 [malesFlumetralin Human Health Risk Assessment DP No. D427465

Page 46 of 53 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] co mpared 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 reproductiv e 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], b ased 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 guid eline 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, belo w.

870.4100b Chronic Toxicity

- DogFlumetralin Human Health Risk Assessment DP No. D427465

Page 47 of 53 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 [low

and 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 discolo ration [orange], which can be attributed to the test material [an orange granular solid].The 1500 ppm males displayed a slight, but statistically

significant, decrease in body weight by week 29 [96% of control], and the deficit in body weight
continued th roughout 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. Femal es 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 w ere 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 st udy [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, althoug h 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 urinalysi s 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 dose

response. Thymus weights were decreased in both sexes at the 1500 ppm dose level an d in malesFlumetralin Human Health Risk Assessment DP No. D427465

Page 48 of 53 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 con trol 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/da y] 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 o nly 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 MutagenicityFlumetralin Human Health Risk Assessment DP No. D427465

Page 49 of 53 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 frequ ency; 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 avai l ab l e on flumetralin.

870.7600 Dermal Absorption

- RatFlumetralin Human Health Risk Assessment DP No. D427465

Page 50 of 53 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], CGA

41065 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 materi al. 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, fin dings 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

m ales compared to control males at week 6, but there was no dose

- response. Males at the high

dose 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 w as decreased at all dose levels in the males [90%, 76%, 78% of control with increasing dose]. Female body weight and body

weight 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.Flumetralin Human Health Risk Assessment DP No. D427465

Page 51 of 53 Appendix B. Physical/Chemical Properties

Physicoche mical 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, pK a Not available
Octanol/water partition coefficient, Log(K OW ) 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, a nd The Royal Society Of Chemistry, 1994 (www.arsusda.gov/acsl/services/ppdb).Flumetralin Human Health Risk Assessment DP No. D427465

Page 52 of 53 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 Agricu ltural 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 s tudies 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.go v/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

.Flumetralin Human Health Risk Assessment DP No. D427465

Page 53 of 53 Appendix D. Major Flumetralin Metabolites

Chemical Names and Structures of Major Flu metralin Metabolites.

Common name/code Chemical name Chemical structure

CGA

- 41065 2

- Chloro

- N

- [2,6

- dinitro

- 4

-

(trifluoromethyl)phenyl]

- N

ethyl

- 6

- fluorobenzenemethanamin

C 16 H 12 ClF 4 N 3 O 4

Mono

- Reduced

CGA

- 41065 2

- Chloro

- N

- [2

- amino

- 6

- nitro

- 4

-

(trifluoromethyl)phenyl]

- N

ethyl

- 6

- fluoro

benzenemethanamine

C 16 H 1 4 ClF 4 N 3 O 2