UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

MEMORANDUM

DATE: August 15, 2013 OFFICE OF CHEMICAL SAFETY AN D POLLUTION PRE V ENTION

SUBJECT: FLUTHIACET-METHYL. Human Health Assessment Scoping Document in Support of Registra t ion Review.

PC Code: 108803 Decision No.: 480370 Petition No.: NA DP Barcode: D412789 Registration No.: NA

Risk Assessment Type: NA
TXRNo .: NA MRIDNo.:NA Regulatory Action: Registration Re v i ew Case No.: NA CAS No.: 1173 3 7-19 -6 40 CFR: § 180 .551

FROM: Kris t in Rury,

## Biolo~ist 

# \(7**~ ~**  

# ./
Nancy Dodd, C hemi s t

### 7'~~~ Shei la Healy

, Toxico l ogist



## . 11/' 11

_ ./ Vincent Chen

, Toxicologist**"~ ---** **~L---** Risk Assessmen t Branch III (RAB Ill) Health Effects Division (7509P) Offtce of Pesticide Programs

THROUGH: Chr i stine Olinger

, Branch Chief 

# r!A%

Risk Assessment Bran ch III (RAB 

# /j

Health Effects Division (7509P) Office of Pesticide Pro grams

TO: Ricardo Jones
, Chemical Review Manager Risk Management and Implementation Branch I (RM IB 1) Pesticide Re- Eval uation Division (PRD) (7508P) Office of Pesticide Programs

Exe cutive Summary 

# -

The HED Registration Review Team has eva luated the human health assessments and da tabase for the herbi c id e fluthiacet-methyl to determine w h ether sufficient data are available and if any updates are needed to the human health risk assessments support Registration Review. Fluthiacet -methyl is currently registered for use on field corn, pop corn, sweet corn, co tton, and soybean. Use offluthiacet-methyl is pending on cereal grains (crop gro u p 15)

, except rice and

on dried shelled peas and beans

, except soybean (subgroup 6C) (EPA Notice of Filing: EPA

- HQOPP

- 2011

- 0873). To evaluate the scope of work necessary to support Registration Revi ew,

Page 1 of 19HED has considered the previous finalized human-health risk assessments conducted for this chemical (S. Winfield, D269687, 12/21/2005) as well any updates to the toxicity

, exposure, and
usage databas es, and current Agency science policy and risk assessment methodologies.

The toxicology database for fluthiacet-methyl is complete. The HED Hazard Science Policy Council (HASPOC) gran ted a waiver for th e subchronic inhalation toxicity study for fluthiacetmeth yl (TXR#0053783).

Subchronic and chronic studies in the rat , mouse, and dog indicate tha t the liver and erythropoietic system are the primary targets from repeat-dose oral exposure to fluthiacetmethyl; hepatotoxicity a nd adverse changes in hematolo g ical parameters were frequent fmdings throughout th e toxicology database and ar e the basis for non-cancer endpoints. With repeated dosing, the data show that the mouse is the most sensitive mammalian species. Increased
to x icit y with increased duration is evident in the fluthiacet-methyl toxicity databas e. Because of the completeness of the toxicity database and the lack of developmental suscep tibility and neurotoxici ty, the Food Quality Protection Act (FQPA) safety factor is red uc ed to IX. Fl uthiacet-methyl is a likely human carcinogen. A cancer risk assessment was conducted using a linear low-do se approach (Qt* 

## = 0.207 (mg/kg/day)" 1 ) based on male mouse combined (adenomas/carcinomas) liver tumor rates. Fluthiacet-me thyl has low acute toxicity (Toxicity Category III-IV) v ia the oral, dermal, and inhalation routes of exposure. Fluthiace t- methy l is not acutely toxic or irritating to the skin or eyes, and i s not a d erma l sensitizer.

A new dietary ex posure and aggregate risk assessment will be needed in t he registration review
process to incorporat e updat ed es timated drinking water concentrations (EDWCs) into the chronic and cancer dietary exposure assessments.

A residential handler assessment will not be needed for Registration Re v iew because there are no residential uses of fluthiacet- m ethy l. However, the Agency will conduct a spray drift assessment during Registration Re v iew and examine the need for a volatilization assessmen t for fluthiacetmeth yl based on the potential for exposure to bystanders from agricultural applications.

Occupational exposure to fluthiacet-methyl ma y need to be reassessed based on current Occupational and Residential Exposure (ORE) policies and stan dar d inputs.

Introduction

Fluthiacet-methyl is an herbicide belonging to the imine chemical family. Its pesticidal mode of action includes inhibition of protoporphyrinogen-oxidase leading to plant cell membrane damage (lipid peroxidation) in susceptible weeds when exposed to light. An approp r ia te mode of action in mamma ls has no t been e lucidated.

The mo st recent h uman health risk assessment for fluthiacet-methyl wa s finalized in 2005 for use

on cotton (D269687

, S. Winfield, 12/21/2005). A new use risk assessment is pending for fluthiacet-methyl use on cereal grains, except rice and dried peas and bean s, except soybean. The only registered us es of fluthiacet-me t hyl are on field, pop , and sw ee t corn; cotton; and soybean. Refer to Attachment 1 (Table 1) for the chemical identity offl uthiacet-methyl.

Page 2 of 19

### Page 3 of 19

Hazard Identification/Toxicology

Fluthiacet

- methyl has low acute toxicity (Toxicity Category III

- IV) by oral, dermal, and inhalation routes of exposure. It is not a dermal irritant or sensitizer. With repeated dosing, the available data show that the mouse is the most sensitive mammalia n species. The primary targets of fluthiacet

- methyl toxicity are the erythropoietic system and liver. Common red blood cell effects observed throughout the toxicology database include decreased mean corpuscular volume, mean corpuscular hemoglobin, erythr ocyte counts, hemoglobin and hematocrit. Hepatotoxic effects, such as increased liver weight and clinical chemistry and histological perturbations, were also seen across species and duration. Fluthiacet

- methyl is rapidly absorbed and extensively metaboli zed. Nearly complete fluthiacet

- methyl excretion occurred predominantly via fece s; no significant accumulation of fluthiacet

- methyl was observed in any tissue.

Fluthiacet

- methyl is classified as a “L ikely H uman C arcinogen ” . There was an increase in the trend toward pancreatic exocrine adenomas and pancreatic islet cell adenomas in male rats and an increase in the number of mice with hepatocellular adenomas, carcinomas and/or combined adenomas/carcinomas, in long

- term carcinogenicity studies. There is n o concern for mutagenicity. The unit risk, Q 1 * 

### (mg/kg/day) - 1 

### , of fluthiacet

- methyl based upon male mouse liver combined adenoma and carcinoma tumor rates and is 0.207 in human equivalents. Cancer dermal doses were adjusted for dermal absorption because t he Q 1 

### * is based on an oral study (dermal absorption factor = 31%). The dermal absorption factor was estimated based on a comparison of the lowest observed adverse effect levels (LOAELs)/no observed adverse effect levels (NOAELs) established from similar e ndpoints observed in an oral reproductive study and a 21

- day dermal toxicity study in the same species (rats). In the oral reproductive toxicity study in rats, the parental NOAEL of 31.8 mg/kg/day and the LOAEL of 313 mg/kg/day was based on decreased body weight/weight gain and hepatic pathology. In the 21

- day dermal toxicity study, the systemic toxicity NOAEL was 1000 mg/kg/day, the highest dose tested. A ratio of the LOAEL/NOAEL from the oral and dermal studies indicated an approximate upper bound dermal absorption rate of 31.3% ( i.e., oral LOAEL of 313 mg/kg/day ÷ dermal NOAEL of 1000 x 100 = 31.3%). Since there was no LOAEL in the dermal study, and this calculation was based on the dermal study’s NOAEL (highest dose tested), this dermal absorption rate is considered conservative.

Fluthiacet

- methyl is not identified as an acute or subchronic neurotoxicant. The results of the
two

- generation reproduction and developme ntal toxicity studies indicate that fluthiacet

- methyl is not a significant develop mental or reproductive toxicant and there is no indication of increased susceptibility in young rats following in utero exposure in the toxicology database . In the prenatal developmental study with rabbits

, exposure did not result in maternal toxicity up to the limit dose of 1,000 mg/kg/day. However, developmental toxicity was seen at 1,000 mg/kg/day (NOAEL = 300 mg/kg/day) as an increase in irregular sternebrae; a reversibl e effect attributed to a delay in fetal development. The occurrence of developmental toxicity at a dose at which no maternal toxicity was noted indicates an apparent susceptibility. However, HED has determined that the apparent susceptibility is not robus t for the following reasons:

### Page 4 of 19

T he increased incidence of irregular sternebrae was not statistically significant when compared to concurrent controls; The increase occurred primarily at the limit dose (1,000 mg/kg/day); It was the only anomaly observed in the study (i.e., a single variation); and The dose response was not strong since there was only a small increase in the litter incidences between the low

- dose (5 mg/kg/day) and the high

- dose (1,000 mg/kg/day).

Based on the hazard and exposure data, the fluthiacet

- methyl risk assessment team has recommended that the FQPA Safety Factor be reduced to 1X because there is an adequate
to xicity database for fluthiacet

- methyl and exposure data are complete or are estimated based on data that reasonably account f or potential exposures. Although developmental susceptibility was

seen following in utero and/or postnatal exposure in the developmental toxicity studies in rats or rabbits and in the 2

- generation rat reproduction study , the points of departure ( PODs ) sel ected for risk assessment lower and are protective of this susceptibility . There are no residual uncertainties concerning pre

- and postnatal toxicity and no neurotoxicity concerns. The chronic and cancer dietary (food and drinking water) exposure assessme nts are conservative. The dietary and residential assessments are based on reliable data and will not underestimate exposure/risk. Based on these data and conclusions, the FQPA Safety Factor can be reduced to 1X.

Conclusions: The toxicology database of fluthiacet

- methyl is currently considered to be adequate. Therefore, the PODs and endpoints of concern, and the safety/uncertainty factors are unlikely to change during Registration Review

. Dietary Exposure

HED previously recommended that the Appeal EC product label ( EPA Reg. No. 279

- 9532 ) be revised stating that application may not be made to cotton grown in Arizona or California because c otton crop field trial data from Region 10 had not been submitted. Revised use directions were received as reque sted by HED (D327905, L. Cheng, 8/25/2006 ) , but the label has not been revised to prohibit use in Arizona or California

. In absence of a revised label, cotton field trial data from Region 10 must be submitted.

The nature of the residue in plants and livestock has been defined, and adequate enforcement methods are available. Adequate storage stability, field trial, and rotational crop data are available.

An acute endpoint attributable to a single dose was not identified; therefore, an acute dietary exposure assessment was not conducted. The previous chronic and cancer dietary exposure
assessment s incorporated some refinements and did not show risks of concern for the general U.S. population or any of the population subgroups (S. Winfield, D269687

, 12/21/2005)

. However, the Registration Review risk assessment will include a revised dietary exposure assessment to incorporate updated EDWCs due to change s in drinking water models and modeling

.

Conclusions: A new chronic dietary (food and drinking water) exposure and risk assessment will be needed during R egistration R eview to incorporate updated EDWCs

.

### Page 5 of 19

Residential Exposure

Residential Handlers A residential handler exposure assessment will not be need ed for Registration Review becaus e there are no registered residential uses of fluthiacet

- me t h yl.

Residential Post

- Application The Agency has not considered residential post

- application exposure for fluthiacet

- methyl since there are no registered residential uses at this time. Resident ial exposures from off

- site transport (e.g., spray drift or volatilization) may occur as a result of fluthiacet

- methyl applications to agricultural fields . The Agency will conduct a spray drift assessment and examine the need for a volatilization assessme nt for fluthiacet

- methyl during Registration Review.

Conclusions: R esidential handler and conventional residential post

- application assessment s will not be conducted during Registration Review; however, the Agency will conduct a spray drift
assessment an d examine the need for a volatilization assessment for fluthiacet

- methyl during Registration Review.

Aggregate Risk Assessment

In the most recent human health risk assessment ( S. Winfield, D269687, 12/21/2005 ), an acute aggregate risk assessment was not conducted because an endpoint attributable to a single dose was not identified . Short

- and intermediate

- term aggregate risk assessments were not performed because residential exposure, which is combined with the dietary exposure for aggregate assessments, is not expected. The chronic and cancer aggregate assessment s consist of the food and drinking water dietary assessment (refer to the Dietary Exposure section).

Conclusions : Aggregate exposure to fluthiacet

- methyl i s equivalent to the dietary exposure to fluthiacet

- methyl. N ew chronic and cancer dietary risk assessments will be conducted during Registration Review to incorporate updated EDWCs

. Occupational Exposure

Fluthiacet

- methyl is currently registered for use on field corn , pop corn, sweet corn , cotton , and soybean. Use of fluthiacet

- methyl is pending on cereal grains (crop group 15), except rice and on dried shelled peas and beans, except soybean (subgroup 6C). There is potential for short

- and intermediate

- term occupational exposure to fluthiacet

- methyl during handling (mixing, loading, and applying) and post

- application activities.

Occupational Handlers Occupational handler inhalation exposure and risk assessm ents were conducted for a water dispersible granular (WDG) fluthiacet

- methyl formulation on sweet corn, field corn, pop corn, and cotton (J. Arthur, D264699, 08/21/2001) , a liquid formulation on sweet corn, field corn, pop corn, and cotton (J. Arthur, D278 121, 08/21/2001), and a liquid formulation on cotton (B. O’Keefe, D321648, 10/11/2005)

. A dermal POD has not been selected for fluthiacet

- methyl based on the lack of dermal, systemic, neurological, and developmental toxicity following

### Page 6 of 19

fluthiacet

- methyl ex posure. Therefore, dermal non

- cancer occupational handler and post

application exposure assessment s w ere not conducted. Fluthiacet

- methyl is considered “likely to be carcinogenic to humans” and an assessment of potential cancer risk was conducted using a linear low

- dose approach . A Q 1 

### * of 0.207 (mg/kg/day) - 1 

### was used to estimate cancer risk following fluthiacet

- methyl exposure. Cancer dermal doses were adjusted for dermal absorption because the Q 1 

### * is based on an oral study (dermal absorption factor = 3 1%).

Occupational exposure is expected to be short

- and intermediate

- term in duration. The registered fluthiacet

- methyl labels require occupational handlers to wear long

- sleeved shirts, long pants, shoes, socks, and chemical resistant gloves ; some labels require protective eyewear and gloves

. Applications can be made with ground

, aerial, or chemigation equipment.

The occupational inhalation margins of exposure (MOEs) ranged from 9
, 9 00 to 400,000 and were not of concern ( LOC of 100) without a respirator. For cotton, all dermal and inhalation cancer risk estimates ranged from 7.9x10 - 7 

### to 8.4x10 - 4 

### at baseline, assuming the maximum application rate, and 30 days of exposure per year. For the scenarios that were assessed with gloves, all cotton dermal and in halation cancer risk estimates ranged from 1.3x10 - 6 

### to 7.8x10 - 6



### . For the other agricultural commodities, a ll dermal and inhalation cancer risk estimates ranged from 2.5x10 - 7 

### to 1.6x10 - 5 

### at baseline for private handlers (assumed exposed for 10 days per
yea r). All dermal and inhalation cancer risk estimates ranged from 2.0x10 - 7 

### to 2.7x10 - 6 

### for private handlers with the addition of the personal protective equipment ( PPE ) required on the label (gloves). All dermal and inhalation cancer risk estimates ranged from 7.5x10 - 7 

### to 4.7x10 - 5 

### at baseline for commercial handlers (assumed exposed 30 days per year). All dermal and inhalation cancer risk estimates ranged from 6.1x10 - 7 

### to 8.2x10 - 6 

### for commercial handlers with the addition of the PPE required on the label ( gloves).

Although an occupational exposure assessment has been conducted to estimate exposure risk estimates for all existing uses of fluthiacet

- methyl, all of the assessment s w ere not conducted based on current occupational exposure policies and registered application rates ; some assessments were conducted using application rates less those specified on currently registered labels . Therefore, a new occupational handler risk assessment may be needed during Registration Review.

Occupational Post

- Application Occupational non

- cancer post

- application exposure was not quantitatively assessed because a dermal endpoint was not selected for fluthiacet

- methyl based on the lack of dermal, systemic, neurological, developmental, and route

- specific toxic ity. However, occupational post

application cancer risks were assessed . C hemical

- specific dislodgeable foliar residue data have not been submitted for fluthiacet

- methyl

. Therefore, the exposure assessments use HED’s default assumption that 25% of the ap plication is available for transfer on the day of application and the residues dissipate at a rate of 10% each following day. For all uses of fluthiacet

- methyl, the occupational cancer risk estimates ranged from 8.7x10 - 8 

### to 2.3x10 - 6 

### using a 30

- day average dose.

Labels of r egistered fluthiacet

- methyl products require restricted entry intervals ( REI s ) of 12 and 24 hours.

### Page 7 of 19

Chemical

- specific residue data were not submitted for fluthiacet

- methyl; however, based on the lack of route

- specific dermal toxicity , a dislodgeable foliar residue (DFR) study is not required at this time.

Based on the Agency's current practices, a quantitative occupational post

- application inhalation exposure assessment has not been performed for fluthiacet

- methyl at this time.

Co nclusions: There is sufficient information available to assess occupational handler and post

application exposures. However, the occupational handler exposure scenarios were not assessed based on current ORE policies and registered application rates

. An up

- to

- date occupational handler and post

- application assessment may be needed during Registration Review to account for the changes in these po licies and to assess all the registered uses

. Endocrine Disruptor Screening Program (EDSP)

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxici ty, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturati on, 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 most recent registration decision for fluthiacet

- methyl

, 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), fluthiacet

- methyl is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 cons ists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- relate d effects caused by the substance, and establish a dose

- response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of

### Page 8 of 19

chemicals identified for EDSP screening was published on June 14, 2013 1 

### and includes some pesticides schedul ed for Registration Review and chemicals found in water

. Fluthiacet

- methyl is not among the groups of pesticide active ingredients to be screened under EDSP. Accordingly, as part of Registration Review, EPA will issue future EDSP orders/data call

- ins, req uiring the submission of EDSP screening assays for fluthiacet

- methyl. For further information on the status of the EDSP, the policies and procedures, the list s of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit o ur website. 2



### Public Health and Pesticide Epidemiology Data

The evaluation of the OPP Incident Data System (IDS) indicated that no incidents were identified in the main IDS Uni ted States from January 1, 2008 through June 11, 2013 for the single chemical fluthiacet

- methyl or products containing fluthiacet

- methyl and other active ingredients (S. Recore, D 413851 , 08/07/2013) . In the aggregate IDS from January 1, 200 8 to June 11, 2013 , there were 2 reported incidents involving fluthiacet

- methyl

. Because the se aggregate results fall within the categories reported as counts (which includes minor, unknown or no effects), there is no unique report that provides details about the incident and single chemical incidents are not distinguished from multiple chemical incidents; however, a high frequency of incidents indicates there is a high potential for exposure and vice versa. For fluthiacet

- methyl

, there appears to be a low potential for exposure. The evaluation of the Sentinel Event Notification System for Occup ational Risk (SENSOR) Pesticides database from 1998

- 2009 indicated that no incidents were identified involving fluthiacet

- methyl. Fluthiacet

- methyl is not included in the Agricultural Health Study (AHS), and therefore, the AHS does not provide information for this report. There does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the incident information . I f a concern is triggered, an additional analysis will be included in the risk a ssessment.

Tolerance Assessment and International Harmonization

Tolerances are established for plant commodities under 40 CFR §180.551(a)(1) for residues of fluthiacet

- methyl and under 40 CFR §180.551(a)(2) for combined residues of fluthiacet

- methyl and its acid metabolite. No livestock tolerances are established.

There are no Codex or Canadian maximum residue limits (MRLs) established for fluthiacet

methyl; therefore, there is no harmonization issue at this time.

Environmental Justice

Potential a reas of environmental justice concerns, to the extent possible , w ill be considered in th e registration review , in accordance with US Executive Order 12898 , "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations ," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

1 See http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of chemicals.
2 http://www.epa.gov/endo/

### Page 9 of 19

As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- establis hed 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 r esidential setting. Extensive data on food consumption patterns are compiled under the National Health and Nutrition Examination Survey, What We Eat in America (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a
pes ticide. These data are analyzed and categorized by subgroups based on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances war rant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluated. Further conside rations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specif

ic subgroups

.

Cumulative

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 fluthiacet

- methyl and any other substances and fluthiacet

- methyl does not appear to produce a toxic metabolite produced by other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulat ive effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

Human Studies

The risk assessment s which have been previously conducted for fluthiacet

- methyl rel ied in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposur e databases such as the Pesticide Ha ndlers Exposure Database (PHED), the Outdoor Residential Exposure Task Force (ORETF), and the Agricultural Reentry Task Force (ARTF) Database

. EPA has reviewed all the studies supporting these multi

- pesticide generic ex posure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards prevailing at the time the research was conducted. A ll applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied , and t here is no regulatory barrier to continued reliance on these studies

.

### Page 10 of 19

Data Deficiencies

No additional toxicity or occupational and residential exposure data are needed to support the registered uses of fluthiacet

- methyl at this time.

Residue Chemistry

HED previously recommended that the Appeal EC product label ( EPA Reg. No. 279

- 9532 ) be revised stating that application may not be made to cotton grown in Arizona or California because c otton crop field trial data from Region 10 had not been submitted.

. Revised use directions were received as requested by HED (D327905, L. Cheng, 8/25/2006 ) , but the label has not been revised to prohi bit use in Arizona or California

. In absence of a revised label, cotton field trial data from Region 10 must be submitted.

### Page 11 of 19

References

Memoranda Relevant to Registration Review of Fluthiacet

- methyl

Author DP / TXR # Date Title

Risk Assessment K. Rury D395413 05/08/2103 (pending) Fluthiacet

- Methyl: Human Health Aggregate Risk Assessment for a

Proposed Use on Cereal Grains (except rice), and Dried Shelled Pea and Bean (except soybean) S. Winfield D269687 12/21/2005 Fluthiacet

- Methyl: Human Health Risk A ssessment for Proposed Use on Cotton. W. Wassell D277296 09/04/2001 Fluthiacet

- Methyl (CGA

- 248757; ActionTM) on Sweet Corn, Field Corn, and pop Corn Human Health Risk Assessment. M. Nelson D250978 03/17/1999 Fluthiacet

- Methyl (CGA

- 248757; ActionTM) on Soybeans Human Health Risk Assessment. Residue Chemistry N. Dodd D395413 10/25/2012 Fluthiacet

- methyl. Petition for the Establishment of Permanent Tolerances and Registration for Use on the Cereal Grain Group 15, except Rice and the Dried Shelled Pea and Bean, except Soybean, Subgroup 6C. Summary of Analytical Chemistry and Residue Data. L. Cheng D379917,

D379919 08/31/2010 Fluthiacet

- methyl: Addition of Pre

- plant Burn

- down Application for Field, Pop and Sweet Corn and Soybean and Reduction of Pre

harvest Interval for Corn (Field and Pop) Grain and Fodder. L. Cheng D327905 08/25/2006 Fluthiacet

- methyl. Petition for Establishment of Tolerances for Use on Cotton. Submission of Additional Information Pertaining to Directions for Use, Storage Sta bility in Livestock, Submittal of Analytical Reference Standards, and Proposed Tolerances. M. Doherty D304795 11/22/2005 Fluthiacet

- Methyl. Petition for Establishment of Tolerances for Use on Field Corn, Sweet Corn, Pop Corn, and Cotton. Submission of Residue Analytical Method, Multiresidue Method, and Crop Field Trial Data for Cotton. W. Wassell D234717 02/20/2001 Flut hiacet

- methyl in/on Field Corn, Sweet Corn, Pop Corn, and Cotton. Evaluation of Metabolism Data, Magnitude of Residue Data, and Analytical Methodology. W. Wassell D272221 02/06/2001 Fluthiacet

- methyl in/on Field Corn, Sweet Corn, Pop Corn, and Cotton. Conclusions of the 10/31/2000 Meeting of the Metabolism Assessment Review Committee. M. Nelson D231864,

D235468 05/12/1998 F luthiacet

- Methyl o n Soybeans. Residue Chemistry Disciplinary Review. Dietary Exposure Assessment N. Dodd D397228 04/10/2013 Fluthiacet

- methyl Chronic and Cancer Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Action on the Cereal Grain Group 15, except Rice and the Dried Shelled Pea and Bean, except Soybean, Subgroup 6C S. Winfield D323703 12/05/2005 Fluthiacet

- methyl: Chronic and Cancer Dietary Exposure Assessments for the Section 3 Registration Action of Fluthiacet

methyl on Cotton. W. Wassell D277295 08/28/2001 Chronic and Cancer Tier 2 Dietary Exposure Analyses for the use of Fluthiacet

- methyl in/on Sweet Corn, Pop Corn and Field Corn. W. Cutchin D250980 11/23/1998 Dietary Exposure Analysis for Action (Fluthiacet

- methyl) in/on Soybeans. W. Cutchin D252075 01/13/1999 Dietary Exposure Analysis for Action (Fluthiacet

- methyl) in/on Soybeans. Occupational Residential Exposure

### Page 12 of 19

Memoranda Relevant to Registration Review of Fluthiacet

- methyl

Author DP / TXR # Date Title

K. Rury D297229 04/11/2013 (pending) Fluthiacet

- Methyl: Occupational and Residential Exposure

Assessment for Proposed use on Cereal Grains (except rice) and Dried Shelled Pea and Bean (except soybean). B O’Keefe D321648 10/11/2005 Occupational Risk Assessment to Support Request for a Section 3 Registration of Fluthiacet

- Methyl on Cotton. J. Arthur D278121 09/05/2001 Occupational and Residential Risk Assessment to Support Request for a Section 3 Registration of Fluthiacet

- Methyl on Sweet Corn, Field Corn, and Pop Corn. J. Arthur D264699 08/21/2001 Occupational and Residential Risk Assessment to Support Request for a Section 3 Registration of Fluthiacet

- methyl on Sweet Corn, Field Corn and Pop Corn. Toxicology J. Van Alstine 0053783 09/14/2012 Fluthiacet

- methyl: Summary of Hazard and Science Policy Council (HASPOC) Meeting of March 29, 2012 and July 12, 2012: Recommendations on the requirement of a 28

- day immunotoxicity study and a subchronic inhalation toxicity study. Incident Report S. Recore D413851 08/07/2013 Fluthiacet

- Methyl: Tier I Review of Human Incidents



### Attachment s 1. Chemical Identity Table 2. Tolerance /MRL Summary Table 3 . Endpoint Selection Table 4. Toxicity Profile Tables

### Page 13 of 19 Attachment 1 Chemical Identity Table

Table 1. Fluthiacet

- Methyl Nomenclature

. Chemical structure

Common name f luthiacet

- methyl Company experimental name CGA

- 248757
IUPAC name {2

- chloro

- 4

- fluoro

- 5

- [( EZ )

- 5,6,7,8

- tetrahydro

- 3

- oxo

- 1 H ,3 H

- [1,3,4]thiadiazolo[3,4

-
a ]pyridazin

- 1

- ylideneamino]phenylthio}acetic acid, methyl ester
CAS name 2

- [[2

- chloro

- 4

- fluoro

- 5

- [(tetrahydro

- 3

- oxo

- 1 H ,3 H

- [1,3,4]thiadiazolo[3,4

- a ]pyridazin

- 1

- ylidene)amino]phenyl]thio]acetic acid, methyl ester CAS registry number 117337

- 19

- 6
Chemical structure of CGA

- 300402 ( fluthiacet; acid metabolite)

2

- [[2

- chloro

- 4

- fluoro

- 5

- [(tetrahydro

- 3

- oxo

- 1 H ,3 H

- [1,3,4]thiadiazolo[3,4

- a ]pyridazin

- 1

- ylidene)amino]phenyl]thio]acetic acid
Chemical structure of CGA

- 300403

{[2

- chloro

- 4

- fluoro

- 5

- (1

- oxo

- 3

- thioxo tetrahydro

- 1H

- [1,2,4]triazolo[1,2

- a ]pyridazin

- 2(3H)

- yl)phenyl]thio}acetic acid

### Page 14 of 19 Attachment 2 Tolerance /MRL Table

Fluthiacet

- methyl (108803; Date of Request 06

- 27

- 2013)

Table 2. Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 Codex [ 40 CFR §180.551] (a) General. (1) fluthiacet

methyl, acetic acid [[2

- chloro

- 4

- fluoro

- 5

- [(tetrahydro

- 3

- oxo

- 1 H ,3 H

- [1,3,4]thiadiazolo[3,4

- α]pyridazin

- 1

- ylidene)amino]phenyl]thio]

- methyl ester None None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 1 Codex Corn, field, forage 0.050 Corn, field, grain 0.010
Corn, field, stover 0.050 Corn, pop, grain 0.010 Corn, pop, stover 0.050 Corn, sweet, forage 0.050 Corn, sweet, kernel plus cob with husks removed 0.010

Corn, sweet, stover 0.050 Soybean, seed 0.01 

### Pending Tolerances Grain, cereal, group 15

, except rice 0.02

Grain, cereal, forage, fodder, and straw, group 16 0.05

Pea and bean, dried shelled, except soybean, subgroup 6C 0.02

Vegetable, foliage of legume, except soybean, subgroup 7A 0.05

US [ 

### 40 CFR §180.551 ] Canada Mexico 1 Codex (2) combined residues of the herbicide fluthiacet

methyl and its acid metabolite: acetic acid, [[2

- chloro

- 4

- fluoro

- 5

- [tetrahydro

- 3

- oxo

- 1H,3H

- [1,3,4]thiadiazolo[3,4

- α]pyridazin

- 1

- ylidene)amino]phenyl]thio]

- methyl ester, and its acid metabolite, acetic acid, [[2

- chloro

- 4

- fluoro

- 5

- [(tetrahydro

- 3

- oxo

- 1H,3H

- [1,3,4]thiadiazolo[3,4

- α]pyridazin

- 1

- ylidene)a mino]phenyl]thio] None None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 1 Codex Cotton, gin byproducts 0.20 Cotton, undelinted seed 0.020 Completed: M. Negussie; 07/02/13
2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

### Page 15 of 19 Attachment 3

Summary of Toxicity Endpoints and Points of Departure of Fluthiacet

- methyl

Table 3

. Summary of Toxicological Doses and Endpoints for Fluthiacet

- Methyl for Use in Dietary and

Occupational Human Health Risk Assessments

Exposure/ Scenario Point of

Departure Uncertainty/

FQPA Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects

Acute Dietary (General Population including Infants and Children) No adverse effect attributable to a single dose was identified; therefore, no dose/endpoint was

selected for this exposure scenario.

Chronic Dietary (All Populations) NOAEL=

0.1 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Chronic RfD =

0.001 mg/kg/day

cPAD = 0.001 mg/kg/day 18

- month Carcinogenicity

- Mouse

LOAEL = 1.0 mg/kg/day based on non

neoplastic liver findings , including ( centrilobular cell degeneration and necrosis, histiocytic pigmentation, karyomegaly and chronic active inflammation)

. Dermal Short

and Intermediate

Term (1

- 30 days and 1

- 6 months ) No dermal or systemic toxicity was seen at the Limit

- Dose following repeated dermal

applications to rats. There are no developmental or neurotoxicity concerns.

Inhalation Short

- and Intermediate Term (1

- 30 days and 1

- 6 months) NOAEL =

1.3 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x LOC for MOE =

100 90

- day oral study

- Mouse

LOAEL = 66 mg/kg/day based on effects in the erythropoietic system and liver (including changes in clinical chemistry and histopathology) in mice.

Cancer (oral, inhalation and dermal) Q 1 * = 0.207 (mg/kg/day) - 1 18

- month Carcinogenicity

- M ouse The CARC recommended a linear low

- dose approach (Q 1 *) for human risk characterization and determined that extrapolation should be based on the combined hepatocellular tumors (adenomas and carcinomas) in male mice at dose levels ≥ 10 mg/kg/day. Toxicity via the inhalation route is assumed to be equivalent to that via the oral route . NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (inter

- species). UF H = potential variation in sensitivity among members of the human population (intra

- species). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern.

### Page 16 of 19 Attachment 4

Toxicity Profile for Fluthiacet

- methyl

Table 4.1 . Acute Toxicity of Fluthiacet

- M ethyl Technical

.
OPPTS No. Study Type MRID Results Toxicity Category 870.1100 Acute Oral

- Rats 43348411 LD 50 > 5,000 mg/kg IV 870.1200 Acute Dermal

- Rats 43348412 LD 50 > 2,000 mg/kg III 870.1300 Acute Inhalation

- Rats 43348413 LC 50 > 5 mg/L IV 870.2400 Primary Eye Irritation

Rabbits 43348414 Minimal eye irritant III

870.2500 Primary Skin

Irritation

- Rabbits 43348415 Non

- irritant IV

870.2600 Dermal Sensitization

Guinea pigs 43348416 Not a ski n sensitizer N/A

Table 4. 2. Toxicity Profile of Fluthiacet

- M ethyl Techni cal

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

870.3100 Subchronic oral

toxicity study in
rats 43348423 (1993 )/

Acceptable/ Guideline Doses (M/F) : 0, 0.60/0.69

, 6.19/6.80

, 216/249, 427/490 , or 1,224/1,424 mg/kg/day NOAEL = 6.19 mg/kg/day LOAEL = 216 mg/kg/day based on decreased body weight gains as well as changes in clinical pathology parameters, liver weight and microscopic pathology in rats

. 870.3100 Subchronic oral

toxicity study in mice 43357804 (19 92 )/

Acceptable/ Guideline Doses (M/F) : 0, 0.13/0.17, 1.3/1.6, 66/83 , or 6 55/782 mg/kg/day NOAEL = 1.3 mg/kg/day LOAEL = 66 mg/kg/day based on effects on the erythropoietic system (↓ Hb, HCT, MCV, MCHC, M:E ratio and ↑ in bone marrow granulopoiesis and extramedullary hematopoiesis) and the liver ( changes in absolute and relative liver weights, sorbitol dehydrogenase, alanine aminotransferase, aspartate

a minotransferase, 5'nucleotidase and bile acids, accompanied by fatty changes, chronic inflammation, ka ryomegaly, single cell necrosis and ceroid/lipofuscin pigmentation). 870.3150 6

- week oral

toxicity study in nonrodents

- dogs 43348427 (1993 )/

Acceptable/ Nonguideline Doses (M/F) : 0, 18.1/19.6, 75.1/77.7, 236/232

, 709/766 or 1 ,943/2,126 mg/kg/day (capsule) NOAEL = 77.7 mg/kg/day LOAEL = 232 mg/kg/day based on decreased body weight gain (↓44%).

870.3200 2 8

- day dermal

toxicity in rats 4 3348424 (1993 )/

Acceptable/ Guideline Doses: 0, 10, 100, or 1000 mg/kg/day NOAEL = 100 0 mg/kg/day

, the highest dose tested (HDT).

### Page 17 of 19

Table 4. 2. Toxicity Profile of Fluthiacet

- M ethyl Techni cal

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

870.3 465 90

- day inhalation

study in rats This data requirement has been waived ( J. Van Alstine, TXR 00 53783 , 0 9/14 /12 )

870.3 700 Developmental

toxicity in rats 4 3348426 (1993 )/

Acceptable/ Guideline Doses: 0, 5

, 300 or 1000 mg/kg/day Maternal NOAEL = 1,000 mg/kg/day, HDT Developmental NOAEL = 1,000 mg/kg/day

870.3700 Developmental

toxicity study in rabbits 4 3348425 (1993 )/

Acceptable/ Guideline Doses: 0, 5

, 300 or 1000 mg/kg/day Maternal NOAEL = 1,000 mg/kg/day, HDT Developmental NOAEL = 300 mg/kg/day Developmental LOAEL = 1000 mg/kg/day based on slight non

- significant increased incidence of irregularly shaped sternebrae attributed to a delay in fetal development

.

870.3800 Two

- Generation

reproduction study in rats 4 3830016 (1994 )/

Acceptable/ Guideline Doses (M/F) : 0, 1.59/1.78

, 31.8/36.2 or 313/369 mg/kg/day Parental/Systemic NOAEL = 1.59 mg/kg/day Parental/Systemic N OAEL = 31.8 mg/kg/day b ased on reduction in body weights/gains and liver histopathology

. Reproductive NOAEL = 31.8 mg/kg/day Reproductive LOAEL = 313 mg/kg/day b ased on decreases in mean litter body weights (↓5

- 14%)

. 870.4100 Chronic oral

toxicity study in dogs 43830014 (199 4 )/

Acceptable/ Guideline Doses (M/F) : 0, 0. 351/0.313

, 4.19/5.00

, 57.6/30.3 , or 582/145 mg/kg/day (capsule). NOAEL (M/F) = 57.6 /30.3 mg/kg/day LOAEL (M/F) = 582 /145 mg/kg/day b ased on effects observed in the erythropoietic system and liver including, decreased MCV and MCHC and increased (magnitude and /or severity ) hepatocyte degeneration, leukocytosis, Kupffer cell pigmentation and intracytoplasmic pigmentation. 870.4300 Combined

Chronic/ Carcinogenicity in
rats 13830017 (199 5 )/

Acceptable/Guideline Doses (M/F) : 0, 0.2/0.2

, 2.1/2.5

, 130/154 , or 219/368 mg/kg/day NOAEL = 2.1 mg/kg/day LOAEL = 130 mg/kg/day based on decreased body weight, liver toxicity, pancreatic toxicity and microcytic anemia

. And uterine toxicity (hemorrhage and inflammation)

.

There was an increase in the trend toward pancreatic exocrine adenomas and pancreatic islet cell adenomas in males at 130 and 219 mg/kg/day, respectively

. 870.4200 Carcinogenicity

study in mice 43830015 (1995 )/

Acceptable/ Guideline Doses (M/F) : 0, 0.1/0.1

, 1.0/1.2

, 10/12 , or 32/37 mg/kg/day NOAEL = 0.1 mg/kg/day LOAEL = 1.0 mg/kg/day b ased on non

- neoplastic liver findings including

, centrilobular cell degeneration and necrosis, histiocytic pigmentation, karyomegaly and chronic active inflammation.

T here was an increase in the number of mice with hepatocellular adenomas, carcinomas and/ or

### Page 18 of 19

Table 4. 2. Toxicity Profile of Fluthiacet

- M ethyl Techni cal

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

adenomas/carcinomas at doses ≥ 10 mg/kg/day. 870.6200a Acute

neurotoxicity in
rats. 43830012 (1995)/

acceptable/Guideline 0, 10, 1,000 or 2,000 mg/kg. NOAEL = 2,000 mg/kg/day, with no effects at HDT.

870.6200b Subchronic

neurotoxicity study in rats. 43830013 (199 5 )/

Acceptable/ Guideline Doses ( M /F) : 0, 0.576/0.562

, 556/668 , or 1,128/1,354 mg/kg/day NOAEL = 0.576 mg/kg/day in males and 1,345 mg/kg/day in females (HDT) LOAEL = 556 mg/kg/day in males b ased on decreased body weight (↓9

- 16%), body weight gain (↓ 27

- 33%) and food consumption (↓6

- 19%) in males

. 870. 7485 Metabolism and

pharmacokinetics in rats 43830018

- 20 (199 5 )/

Acceptable/ Guideline Doses: 1.0 or 200 mg/kg Fluthiacet

- methyl was absorbed rapidly at both low and high dosages in both male and female rats. Repeated oral dosing had no effect on extent of absorption. Tissue levels of radioactive fluthiacet

- methyl in single and repeated low dose groups did not exceed 0.018 ppm in any tissue. At the s ingle high dose, female rats showed higher levels of radioactivity in tissues than males except for muscle, brain, fat and plasma. Excretion in males was predominantly in feces for all dose groups, with between 67 to 87% of administered radioactivity excre ted by this route. In females, the percentage of administered radioactivity in urine across all dose groups 40 to 48% was approximately equivalent to the percent excreted in feces, 39 to 52%. The greater fecal excretion in males was based on a greater pe rcentage excretion in bile for males, 37% vs. females 19%. 870. 7800 Immunotoxicity 48943902 (2012)/ Acceptable/Guideline Doses: 0, 1.8, 5.8, 18.9 or 57.4 mg/kg/day NOAEL = 57.4 mg/kg/day, with no effects at HDT.

870.5100 Mutagenic

- Ames

( Salmonella typhimurium and E scherichia Coli ) 43348429 (1990)/

Acceptable/Guideline Fluthiacet

- methyl was negative for mutagenic/genotoxic effects in bacterial cells.

870.5300 Gene mutation in

Chinese Hamster V79 cells 43348433 (1992)/

Acceptable/Guideline Fluthiacet

- methyl was negative for mutagenic/genotoxic effects in cultured mammalian cells. 870.5300 In vivo

micronucleus test in rat hepatocytes 43348435 (1993)/

Acceptable/Guideline Fluthiacet

- methyl did not cause DNA damage in primary rat hepatocytes.

870.5375 In vitro

cytogenetic test in human lymphocytes 43348432 (1993)/

Acceptable/Guideline In vitro cytogenetic assays demonstrated that fluthiacet

- methyl is clastogenic both in the presence and absence of S9 activation.

870.5375 In Vitro

Clastogenic ity Chinese Hamster Ovary Cells 43348434 (1993)/

Acceptable/Guideline In vitro cytogenetic assays demonstrated that fluthiacet

- methyl is clastogenic both in the presence and absence of S9 activation.

### Page 19 of 19

Table 4. 2. Toxicity Profile of Fluthiacet

- M ethyl Techni cal

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

870.5375 Chromosome

Aberration in Cultured CHL Cells 43348431 (1991)/

Acceptable/Guideline In vitro cytogenetic assays demonstrated that fluthiacet

- methyl is clastogenic both in the presence and absence of S9 activation.

870.5395 Mutagenic

-

M icronucleus Assay

- Mouse 43348436 (1991)/

Acceptable /Guideline Fluthiacet

- methyl was negative for micr onuclei induction in mouse bone marrow . However, a significant increase in micronuclei was seen in stimulated rat liver cells following in vivo exposure. 870.5500 Bacterial DNA

damage test 43348428 (1990)/

Acceptable /Guideline Fluthiacet

- methyl did not cause lethal DNA damage in E. coli

. 870.55 5 0 Unscheduled DNA

synthesis in mammalian cells 43348430 (1992 )/

Acceptable /Guideline Fluthiacet

- methyl was negative for in vitro induction of unscheduled DNA synthesis