UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

DATE: August 15, 2013 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

SUBJECT: FLUTHIACET-METHYL. Human Health Assessment Scoping Document in Support of 

Registration 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 Review 

Case No.: NA 

CAS No.: 117337-19-6 

40 CFR: §180.551 

FROM: Kristin Rury, Biolo~ist \(7 ~ ~ ./ 

Nancy Dodd, Chemist 7'~~~ Sheila Healy, Toxicologist .11/' 11 _./ 

Vincent Chen, Toxicologist "~ ---~L---

Risk Assessment Branch III (RAB Ill) 

Health Effects Division (7509P) 

Offtce of Pesticide Programs 

THROUGH: Christine Olinger, Branch Chief r!A% 

Risk Assessment Branch III (RAB /j 

Health Effects Division (7509P) 

Office of Pesticide Programs 

TO: Ricardo Jones, Chemical Review Manager 

Risk Management and Implementation Branch I (RMIB 1) 

Pesticide Re-Evaluation Division (PRD) (7508P) 

Office of Pesticide Programs 

Executive Summary 

-

The HED Registration Review Team has evaluated the human health assessments and database 

for the herbicide fluthiacet-methyl to determine whether 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, cotton, and 

soybean. Use offluthiacet-methyl is pending on cereal grains (crop group 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 Review, 

Page 1 of 19 
HED 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 databases, and current Agency science policy and risk assessment methodologies. 

The toxicology database for fluthiacet-methyl is complete. The HED Hazard Science Policy 

Council (HASPOC) granted a waiver for the subchronic inhalation toxicity study for fluthiacetmethyl (TXR#0053783). 

Subchronic and chronic studies in the rat, mouse, and dog indicate that the liver and 

erythropoietic system are the primary targets from repeat-dose oral exposure to fluthiacetmethyl; hepatotoxicity and adverse changes in hematological parameters were frequent fmdings 

throughout the toxicology database and are the basis for non-cancer endpoints. With repeated 

dosing, the data show that the mouse is the most sensitive mammalian species. Increased 

toxicity with increased duration is evident in the fluthiacet-methyl toxicity database. Because of 

the completeness of the toxicity database and the lack of developmental susceptibility and 

neurotoxicity, the Food Quality Protection Act (FQPA) safety factor is reduced to IX. 

Fluthiacet-methyl is a likely human carcinogen. A cancer risk assessment was conducted using a 

linear low-dose approach (Qt* = 0.207 (mg/kg/day)"1

) based on male mouse combined 

(adenomas/carcinomas) liver tumor rates. Fluthiacet-methyl has low acute toxicity (Toxicity 

Category III-IV) via the oral, dermal, and inhalation routes of exposure. Fluthiacet-methyl is not 

acutely toxic or irritating to the skin or eyes, and is not a dermal sensitizer. 

A new dietary exposure and aggregate risk assessment will be needed in the registration review 

process to incorporate updated estimated drinking water concentrations (EDWCs) into the 

chronic and cancer dietary exposure assessments. 

A residential handler assessment will not be needed for Registration Review because there are no 

residential uses of fluthiacet-methyl. However, the Agency will conduct a spray drift assessment 

during Registration Review and examine the need for a volatilization assessment for fluthiacetmethyl based on the potential for exposure to bystanders from agricultural applications. 

Occupational exposure to fluthiacet-methyl may need to be reassessed based on current 

Occupational and Residential Exposure (ORE) policies and standard 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 appropriate mode of action 

in mammals has not been elucidated. 

The most recent human health risk assessment for fluthiacet-methyl was 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 beans, except soybean. 

The only registered uses of fluthiacet-methyl are on field, pop, and sweet corn; cotton; and 

soybean. Refer to Attachment 1 (Table 1) for the chemical identity offluthiacet-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 mammalian 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, erythrocyte 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 metabolized. Nearly complete fluthiacet-methyl excretion occurred

predominantly via feces; no significant accumulation of fluthiacet-methyl was observed in any 

tissue.

Fluthiacet-methyl is classified as a “Likely Human Carcinogen”. 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 no concern for 

mutagenicity. The unit risk, Q1

*

(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 the Q1* 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 endpoints 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 developmental toxicity studies indicate that fluthiacet-methyl is 

not a significant developmental 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 reversible 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 robust for the following reasons:
Page 4 of 19

The 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 

toxicity database for fluthiacet-methyl and exposure data are complete or are estimated based on 

data that reasonably account for 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) selected 

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 assessments 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 cotton 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 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 

assessments 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 changes in drinking water models and 

modeling. 

Conclusions: A new chronic dietary (food and drinking water) exposure and risk assessment 

will be needed during Registration Review to incorporate updated EDWCs. 
Page 5 of 19

Residential Exposure

Residential Handlers

A residential handler exposure assessment will not be needed for Registration Review because 

there are no registered residential uses of fluthiacet-methyl. 

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. Residential 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 assessment for fluthiacet-methyl during Registration Review.

Conclusions: Residential handler and conventional residential post-application assessments will 

not be conducted during Registration Review; however, the Agency will conduct a spray drift 

assessment and 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 assessments consist of the food 

and drinking water dietary assessment (refer to the Dietary Exposure section). 

Conclusions: Aggregate exposure to fluthiacet-methyl is equivalent to the dietary exposure to 

fluthiacet-methyl. New 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 assessments 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, D278121, 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 exposure. Therefore, dermal non-cancer occupational handler and postapplication exposure assessments were 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 Q1* 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 Q1* is based on an oral study (dermal absorption factor = 31%).

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 9,900 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 7.9x10-7to 8.4x10-4at 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 inhalation cancer risk estimates ranged from 1.3x10-6to 7.8x10-6. 

For the other agricultural commodities, all dermal and inhalation cancer risk estimates ranged 

from 2.5x10-7to 1.6x10-5at baseline for private handlers (assumed exposed for 10 days per 

year). All dermal and inhalation cancer risk estimates ranged from 2.0x10-7to 2.7x10-6for 

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 7.5x10-7to 4.7x10-5

at baseline for commercial handlers (assumed exposed 30 days per year). All dermal and 

inhalation cancer risk estimates ranged from 6.1x10-7to 8.2x10-6for 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 assessments were 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 toxicity. However, occupational postapplication cancer risks were assessed. Chemical-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 application 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 8.7x10-8to 2.3x10-6using a 30-day average

dose. 

Labels of registered fluthiacet-methyl products require restricted entry intervals (REIs) 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. 

Conclusions: There is sufficient information available to assess occupational handler and postapplication 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 policies 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, neurotoxicity, developmental, 

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

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

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

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

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

taxonomic groups. As part of its 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 consists of a battery of 11 screening assays to identify the potential of a 

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

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

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

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

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

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

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

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

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of 
Page 8 of 19

chemicals identified for EDSP screening was published on June 14, 20131and includes some 

pesticides scheduled 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, requiring the 

submission of EDSP screening assays for fluthiacet-methyl. For further information on the status 

of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines 

and the Tier 1 screening battery, please visit our website.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 United 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, D413851, 08/07/2013). In the aggregate IDS from January 1, 2008 to 

June 11, 2013, there were 2 reported incidents involving fluthiacet-methyl. Because these 

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 Occupational 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. If a 

concern is triggered, an additional analysis will be included in the risk assessment.

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

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, will be considered in the 

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-established procedures. In line with OPP policy, HED estimates 

risks to population subgroups from pesticide exposures that are based on patterns of that 

subgroup’s food and water consumption, and activities in and around the home that involve 

pesticide use in a residential setting. Extensive data on food consumption patterns are compiled 

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 

pesticide. 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 warrant. 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 considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary 

patterns among specific subgroups.

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 

cumulative effects of such chemicals, see the policy statements released by EPA’s Office of 

Pesticide Programs concerning common mechanism determinations and procedures for 

cumulating effects from substances found to have a common mechanism on EPA’s website at 

http://www.epa.gov/pesticides/cumulative/.

Human Studies

The risk assessments which have been previously conducted for fluthiacet-methyl relied in part 

on data from studies in which adult human subjects were intentionally exposed to a pesticide to 

determine their dermal and inhalation exposure. Many such studies, involving exposure to many 

different pesticides, comprise generic pesticide exposure databases such as the Pesticide 

Handlers 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 exposure databases, and has found no clear and 

convincing evidence that the conduct of any of them was either fundamentally unethical or 

significantly deficient relative to the ethical standards prevailing at the time the research was 

conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of 

Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued 

reliance on these studies.
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 cotton 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 prohibit 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 Assessment 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 Preharvest 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 Stability 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 Fluthiacet-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 Fluthiacet-Methyl on 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 Fluthiacetmethyl 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

Attachments

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 fluthiacet-methyl

Company experimental name CGA-248757

IUPAC name {2-chloro-4-fluoro-5-[(EZ)-5,6,7,8-tetrahydro-3-oxo-1H,3H-[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-1H,3H-[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-1H,3H-[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-thioxotetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazin-2(3H)-

yl)phenyl]thio}acetic acid

N

N

S

O

N Cl

F

SCH2COOCH3

N

N

S

O

N Cl

F

SCH2COOH

Cl

F

SCH2COOH

N

N

N

O

S
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 Mexico1 Codex

[40 CFR §180.551] (a) General. (1) fluthiacetmethyl, 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 Mexico1 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 Mexico1 Codex

(2) combined residues of the herbicide fluthiacetmethyl 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)amino]phenyl]thio]

None None

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

US Canada Mexico1 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

UFA= 10x

UFH= 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 nonneoplastic liver findings, including 

(centrilobular cell degeneration and 

necrosis, histiocytic pigmentation, 

karyomegaly and chronic active 

inflammation). 

Dermal Shortand 

IntermediateTerm (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

UFA= 10x

UFH= 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)

Q1* = 0.207 (mg/kg/day)-1

18-month Carcinogenicity - Mouse

The CARC recommended a linear low-dose approach (Q1*)

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. UFA = 

extrapolation from animal to human (inter-species). UFH = 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-Methyl Technical.

OPPTS 

No.

Study Type MRID Results Toxicity 

Category

870.1100 Acute Oral- Rats 43348411 LD50 > 5,000 mg/kg IV

870.1200 Acute Dermal- Rats 43348412 LD50 > 2,000 mg/kg III

870.1300 Acute Inhalation- Rats 43348413 LC50 > 5 mg/L IV

870.2400 Primary Eye IrritationRabbits43348414 Minimal eye irritant III

870.2500 Primary Skin 

Irritation- Rabbits

43348415 Non-irritant IV

870.2600 Dermal SensitizationGuinea pigs43348416 Not a skin sensitizer N/A

Table 4.2. Toxicity Profile of Fluthiacet-Methyl Technical.

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 (1992)/ 

Acceptable/Guideline 

Doses (M/F): 0, 0.13/0.17, 

1.3/1.6, 66/83, or 655/782

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

aminotransferase, 5'nucleotidase and bile acids, 

accompanied by fatty changes, chronic

inflammation, karyomegaly, 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 28-day dermal 

toxicity in rats

43348424 (1993)/ 

Acceptable/Guideline

Doses: 0, 10, 100, or 1000 

mg/kg/day

NOAEL = 1000 mg/kg/day, the highest dose tested 

(HDT).
Page 17 of 19

Table 4.2. Toxicity Profile of Fluthiacet-Methyl Technical.

Guideline 

No.

Study Type MRID No. 

(Date)/Classification/ Doses

Results

870.3465 90-day inhalation 

study in rats

This data requirement has been waived (J. Van Alstine, TXR 0053783, 09/14/12)

870.3700 Developmental 

toxicity in rats

43348426 (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

43348425 (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

43830016 (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 NOAEL = 31.8 mg/kg/day 

based on reduction in body weights/gains and liver 

histopathology.

Reproductive NOAEL = 31.8 mg/kg/day 

Reproductive LOAEL = 313 mg/kg/day based on 

decreases in mean litter body weights (↓5-14%).

870.4100 Chronic oral 

toxicity study in 

dogs

43830014 (1994)/ 

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 

based 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 (1995)/ 

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 

based on non-neoplastic liver findings including,

centrilobular cell degeneration and necrosis, 

histiocytic pigmentation, karyomegaly and chronic 

active inflammation.

There 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-Methyl Technical.

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 (1995)/ 

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

based 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 (1995)/ 

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 single 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 excreted 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 percentage 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 

Escherichia 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

Clastogenicity

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-Methyl Technical.

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 -

Micronucleus 

Assay - Mouse 

43348436 (1991)/

Acceptable/Guideline

Fluthiacet-methyl was negative for micronuclei 

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.

870.5550 Unscheduled DNA 

synthesis in 

mammalian cells

43348430 (1992)/ 

Acceptable/Guideline

Fluthiacet-methyl was negative for in vitro 

induction of unscheduled DNA synthesis