Page 2 of 19

Executive Summary

The HED Registration Review Team has evaluated the most recent human health assessments 

and database for the herbicide flazasulfuron to determine whether sufficient data are available 

and whether any updates are needed to support Registration Review. HED has considered the 

most recent human-health risk assessments for flazasulfuron, updates to the toxicity, exposure, 

and usage databases, and current Agency science policy and risk assessment methodologies to 

determine the scope of work necessary to support Registration Review. In addition, HED 

conducted an open literature search to look for new literature relevant to the human health risk 

assessment. The results of the literature search showed that no new information relevant to the 

human health risk assessment has been published.

Flazasulfuron is a sulfonylurea herbicide used to control certain broad-leaf weeds and grasses, 

and acts by inhibiting the acetolactate synthase (ALS) biochemical process, a process not present 

in humans. Flazasulfuron has low acute toxicity. With repeated dosing, the kidney and liver 

were the primary target organs of flazasulfuron toxicity. Subchronic studies in animals indicated 

decreased body weight gain, slight anemia in rats and liver abnormalities in dogs. Flazasulfuron 

is classified as “no evidence of carcinogenicity to humans.” It is negative for mutagenicity in a 

battery of genotoxicity studies. The toxicity and exposure database supported the reduction of 

the FQPA Safety Factor to 1X. 

Sufficient data are available to assess the toxicity of flazasulfuron, with the exception of an 

immunotoxicity study and a subchronic neurotoxicity study. Once these new studies have been 

received and reviewed, the flazasulfuron Registration Review Team recommends that the points 

of departure and safety factors used for risk assessment purposes for flazasulfuron be reexamined. 

Flazasulfuron is currently registered for use on non-residential turf such as golf courses, sod 

farms, athletic fields, commercial lawns and industrial vegetation management areas as well as, 

on Christmas trees. Additionally, it is registered on agricultural food crops including citrus,

grapes and sugarcane.

The residue chemistry database is sufficient to support current and pending registrations of 

flazasulfuron. The nature of the residue in plants and livestock has been defined. Adequate field 

trial, rotational crop data, and storage stability data are available. 

A new risk assessment may be needed depending on the results of the additional data which are 

required and the results of the reevaluation of databases using current policies. Additional 

toxicology studies are required so endpoints may need to be reevaluated. Occupational exposure 

assessments for the turf use may need to be reassessed based on current Occupational and 

Residential Exposure (ORE) policies and exposure data. In addition, the Agency may need to 

consider off-target movement of pesticides into residential settings.
Page 3 of 19

Introduction

HED has evaluated the existing human health risk assessments for flazasulfuron to determine 

whether sufficient data are available and whether a new human health risk assessment is needed 

to support Registration Review. HED has considered the most recent risk assessments for 

flazasulfuron, updates to its toxicity, exposure and usage databases, and current Agency science 

policies and risk assessment methods. The most recent risk assessment for flazasulfuron was 

conducted in 2011 (D372903, C. Walls, 6/12/11). 

Hazard Identification/Toxicology

Flazasulfuron belongs to the pyrimidinylsulfonylurea class of herbicides and controls weeds by 

inhibiting the acetolactate synthase (ALS) biochemical process. Since ALS is a component in 

the synthesis of some essential amino acids, weed survival and growth are inhibited. A direct 

correlation of this mode of action in plants to a mode of action in mammals is not clear because 

ALS is not present in mammals.

In chronic oral studies in the rat, mouse and dog, the target organs were the kidney and liver. 

Observed effects include adverse changes in kidney function (chronic nephropathy) and kidney 

physiology (enlargement, dark color of kidney), increases in liver weight (hepatocellular 

hypertrophy), and adverse effects on liver tissue (increases in inflammatory cell infiltration, 

hepatocellular necrosis, hepatocellular swelling, and bile duct proliferation). Subchronic oral

studies indicated decreased body weight gain, slight anemia in rats and liver abnormalities in 

dogs. Dermal or systemic toxicity was not seen in a subchronic dermal study in rabbits at dose 

levels up to the limit dose.

Developmental toxicity was observed in rats and rabbits at maternally toxic dose levels. 

Reduced fetal weights and delays in ossification are the effects observed in a Sprague-Dawley rat 

developmental study. An earlier developmental rat study (Wistar rats) showed increased 

incidence of visceral malformations (interventricular septal defect). The developmental study in 

rabbits showed increased incidences of abortion at the highest dose tested (450 mg/kg/day). 

Decreases in body weight and chronic nephropathy were observed in offspring in a 2-generation 

rat reproduction study, at dose levels that were toxic to the parental generation. 

There are no quantitative susceptibility concerns based on the developmental and reproductive 

studies. A potential qualitative concern from one rat developmental study (intraventricular septal 

defect seen at minimally toxic maternal dose levels) is addressed by the presence of clear 

NOAELs and LOAELs, and by the selection of regulatory endpoints that are protective of this 

effect. The database is considered sufficient and there are no residual uncertainties. 

Additionally, the available exposure data do not underestimate exposure. 

A transient decrease in motor activity on Day 0 (5 hours post-dosing) was observed at high dose 

levels (>1000 mg/kg) in an acute neurotoxicity study. This observation was associated with a 

systemic effect and not with neurotoxicity.
Page 4 of 19

Upon examination of the toxicity data base, the FQPA factor was reduced to 1X because: a) 

there were no qualitative or quantitative susceptibility concerns based on the developmental and 

reproductive toxicity data and there are no residual concerns regarding prenatal or postnatal 

exposure; b) there is no conclusive evidence of neurotoxicity at dose levels up to the Limit Dose; 

c) there is no evidence of immunotoxicity, as indicated by hematology, lymphoid organ weights 

and histopathology in standard studies; d) there are no residual uncertainties in the exposure 

database.

In vitro and in vivo mutagenicity studies showed no genotoxic potential. The mouse 

oncogenicity study and the rat combined chronic toxicity and carcinogenicity study both showed 

no evidence of carcinogenicity.

Flazasulfuron exhibits low acute toxicity in rats and rabbits. The oral LD50 is greater than 5000 

mg/kg, the acute inhalation LD50 is greater than 4.0 mg/L, and the acute dermal LD50 is greater 

than 2000 mg/kg. All studies are in Toxicity Category III or IV. Flazasulfuron is not irritating to 

the skin or eyes and is not a sensitizer.

In accordance with the revised 40 CFR Part 158 data requirements, studies that are now required 

but missing from the flazasulfuron toxicity data base are an immunotoxicity study (OPPTS 

Guideline §870.7800), and a subchronic neurotoxicity study (OPPTS Guideline §870.6200b). 

OPP is conducting an independent retrospective analysis of more than 120 immunotoxicity 

studies submitted to Agency. Preliminary findings of OPP’s retrospective analysis suggest that 

immunotoxicity studies have not yet provided lower PoDs than are selected from other guideline 

experimental toxicology studies and thus, so far, immunotoxicity studies would not have 

impacted the Agency’s risk assessments. The OPP retrospective analysis is anticipated to be 

completed in the summer of 2012. In the interim, HED recommends that the immunotoxicity 

continue to be required for registration and registration review chemicals.

Toxicity endpoints, points of departure, and safety factors for flazasulfuron risk assessment were 

selected by HED in 2011 for the following exposure scenarios: acute and chronic dietary; shortand intermediate-term incidental oraland short- and intermediate-term inhalation. Quantification 

of dermal risk is not required. No dermal or systemic toxicity was seen following repeated 

dermal applications at the Limit Dose and there are no concerns for neuro-, developmental, or 

reproductive toxicity. Long-term dermal and inhalation endpoints were not identified because

exposure is not anticipated for these scenarios. The toxicity endpoints are presented in 

Attachment 3.

Conclusions: No new toxicity data beyond the subchronic neurotoxicity and immunotoxicity 

studies are required to support the registration review of flazasulfuron. Once all data have been 

received and reviewed, the flazasulfuron Registration Review Team recommends that the points 

of departure and safety factors used for risk assessment purposes for flazasulfuron be reexamined.

Dietary Exposure

The residue chemistry data and drinking water data are adequate to assess dietary exposure. The 
Page 5 of 19

most recent dietary (food and drinking water) exposure assessment was conducted in 2011 

(D378629, K. Rury, 4/12/11) using the Dietary Exposure Evaluation Model DEEM-FCIDTM, 

Version 2.03. This assessment was conducted to support the pending 2012 PRIA action for first 

food uses on citrus, grapes, and sugarcane. The dietary exposure assessment relies on 

conservative inputs (tolerance level residues, 100% crop treated, DEEMTM default processing 

factors) to model exposure to flazasulfuron through food and drinking water. 

The estimated drinking water concentration (EDWC) of flazasulfuron was provided by the 

Environmental Fate and Effects Division (EFED) and incorporated directly into the acute and 

chronic assessments. The EDWC for ground water from the Tier II provisional groundwater 

model (PRZM-GW) using the Delmarva corn scenario was used since it is higher than that for 

surface water. The assessments are based on reliable data and will not underestimate 

exposure/risk.

The acute dietary exposure estimates for food and drinking water are well below HED’s level of 

concern at the 95th percentile for the general U.S. population and all population subgroups (1.1% 

of the aPAD for the general U.S. population and 4.0% of the aPAD for all infants (<1 year old), 

the most highly exposed population subgroup). 

The chronic dietary exposure estimates for food and drinking water are below HED’s level of 

concern for the general U.S. population and all population subgroups (17% of the cPAD for the 

general U.S. population and 54% of the cPAD for all infants (<1 year old), the most highly 

exposed population subgroup). 

HED classified flazasulfuron as “no evidence of carcinogenicity to humans;” therefore, 

quantification of human cancer risk was not conducted. 

The residue chemistry database is sufficient to support current and pending registrations. The 

nature of the residue in plants and livestock has been defined. No tolerances have been 

established for livestock commodities since there is no reasonable expectation that finite residues 

will occur in these matrices. 

Adequate field trial and rotational crop data are available. The magnitude of the residue and 

processing studies are supported by adequate storage stability data for flazasulfuron. 

Residues are not expected to occur in rotational crops since citrus and grapes are not rotated and 

since the proposed sugarcane label contains a 12-month plant-back restriction. The requirement 

of a confined rotational crop study to support the use on sugarcane (the only proposed/registered 

crop which is rotated) has been waived since an adequate 12-month plant-back restriction was 

placed on the proposed label. (This waiver was based on low residues in metabolism studies, no 

detectable residues in field studies, and limited sugarcane acreage.) Adequate enforcement 

methods are available to support tolerances for plants. 

Conclusions: Provided that EFED drinking water estimates do not need revision, a new dietary 

assessment for flazasulfuron may not be required for the purpose of registration review. 

Furthermore, although a new version of DEEM (Version 3.04) will be released, a new dietary 
Page 6 of 19

risk assessment may not be needed since it is anticipated that the changes in the model will not 

affect the risk conclusion.

Residential Exposure

Residential Handlers

Flazasulfuron is currently registered for use on golf courses and other non-residential turf areas 

such as industrial parks, tank farms, sod farms, seed farms, and professionally managed sports 

fields. However, a residential handler exposure assessment is not required because flazasulfuron 

is only applied to use sites that are not treated by residential handlers.

Residential Post-Application 

Based on the current use patterns, there is only potential for post-application dermal exposure for 

recreational golfers. Since a dermal end point was not selected due to lack of observed toxic 

effects, a residential post-application assessment is not necessary. A new risk assessment is not 

needed for the existing uses. 

Aggregate Risk Assessment

Aggregate assessments consider exposures from food, drinking water, and residential uses. In 

the most recent human health risk assessment (D372903, C. Walls, 6/12/11), aggregate risks 

were estimated for the acute (food and drinking water) and chronic (food and drinking water) 

exposure durations. As previously mentioned, these aggregate dietary risks were below HED’s 

level of concern. The short- and intermediate-term aggregate risk assessments were not required 

as no short or intermediate-term dermal toxicity endpoints were identified. 

Conclusions: The aggregate risk assessments include only food and drinking water and will not 

need to be reassessed provided that the drinking water estimates do not change.

Occupational Exposure

Flazasulfuron registration is pending for use on citrus, grapes, sugarcane, Christmas trees, and 

industrial vegetation management areas, and currently registered on golf course and other 

professionally managed turf areas. There is potential for short- and intermediate-term 

occupational exposure to flazasulfuron during handling (mixing, loading, and applying) and 

post-application activities.

Occupational Handlers

Occupational handler exposure and risk assessments were conducted for the pending uses on 

citrus, grapes, sugarcane, Christmas trees, and industrial vegetation management areas and 

registered uses on golf course and other professionally managed turf area. The resulting in risk 

estimates are not of concern (MOEs ranging from 1,400 to 97,000). These assessments were 

based on PHED unit exposure values. However, HED policies have since changed yielding 
Page 7 of 19

updated acreage assumptions as well as updated unit exposure values. New occupational handler 

assessments may be needed for all use patterns.

Occupational Post-Application

There is a possibility for agricultural workers to have post-application dermal exposure to 

flazasulfuron following its uses. However, a dermal hazard was not identified; therefore, postapplication dermal exposures were not assessed.

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

exposure assessment has not been performed for flazasulfuron at this time. However, there are 

multiple potential sources of post-application inhalation exposure to individuals performing postapplication activities in previously treated fields. These potential sources include volatilization 

of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency 

sought expert advice and input on issues related to volatilization of pesticides from its Federal 

Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. 

The Agency received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. If new policies or 

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

post-application inhalation exposure assessment for flazasulfuron.

Conclusions: There is sufficient information available to assess occupational exposure. 

However, the occupational exposure scenarios were not assessed based on current ORE policies. 

An up-to-date occupational assessment may be needed, accounting for the changes in policies 

and unit exposures. 

Public Health and Pesticide Epidemiology Data

The evaluation of the OPP Incident Data System (IDS) indicated no incidents identified in the 

United States for flazasulfuron in either Main or Aggregate IDS, from January 1, 2006 to 

December 14, 2011 (D399369, S. Recore, 02/14/12). Flazasulfuron is not included in the 

Agricultural Health Study (AHS), and therefore, 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 and if a concern is triggered, additional 

analysis will be included in the risk assessment.

 

Tolerance Assessment and International Harmonization

Currently, there are permanent US tolerances established for flazasulfuronare in/on citrus, 

grapes, and sugarcane. There are no Codex, Canadian, or Mexican maximum residue limits 

(MRLs) established for residues of flazasulfuron on plant or livestock commodities. Therefore, 

there are no harmonization issues.
Page 8 of 19

Environmental Justice

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

human health risk assessment, 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).

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED estimates 

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

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

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

by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used 

in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed 

and categorized by subgroups based on age, season of the year, ethnic group, and region of the 

country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups 

and exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures 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.

Endocrine Disruptor Screening Program

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 the most recent registration decision reviewed these data and 

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

hazard database. However, as required by FFDCA section 408(p), flazasulfuron 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 
Page 9 of 19

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. Flazasulfuron 

is not among the group of 58 pesticide active ingredients on the initial list to be screened under 

the EDSP. Accordingly, as part of registration review, EPA will issue future EDSP orders/data 

call-ins, requiring the submission of EDSP screening assays for flazasulfuron. For further 

information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, 

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

http://www.epa.gov/endo/.

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 flazasulfuron and any other substances and flazasulfuron does not appear to produce a toxic 

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

assumed that flazasulfuron has a common mechanism of toxicity with other substances. For 

information regarding EPA’s efforts to determine which chemicals have a common mechanism 

of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements 

released by EPA’s Office of Pesticide Programs concerning common mechanism determinations 

and procedures for cumulating effects from substances found to have a common mechanism on 

EPA’s website at http://www.epa.gov/pesticides/cumulative/.

Human Studies

The previous risk assessments rely in part on data from studies in which adult human subjects 

were intentionally exposed to a pesticide or other chemical. These studies, which comprise the 

PHED, the Outdoor Residential Exposure Task Force (ORETF), and the Agricultural Reentry 

Task Force (ARTF) have been determined to require a review of their ethical conduct, and have 

received that review.

Data Requirements/ Outstanding Deficiencies

Toxicology

870.6200b Subchronic Neurotoxicity Screening Battery

● Under the data requirements as presented in 40 CFR Part 158, a subchronic

neurotoxicity screening study is required.
Page 10 of 19

870.7800 Immunotoxicity

● Under the data requirements as presented in 40 CFR Part 158, an immunotoxicity 

study is required.

References

As shown in References below, only two human health risk assessment have been conducted for 

flazasulfuron. 

Memoranda Relevant to Registration Review of Flazasulfuron

Author Barcode 

(DP#)

Date Title

N. Dodd 394885 11/8/11 Flazasulfuron. Amendment to Review of Analytical 

Chemistry and Residue Data for Use on Citrus, Grapes and 

Sugarcane

C. Walls 372903 6/12/11 Flazasulfuron: Human Health Risk Assessment for Proposed 

Uses on Citrus, Grapes, Sugarcane, Christmas Trees, and 

Industrial Vegetation Management 

K. Rury 378629 4/12/11 Flazasulfuron: Acute & Chronic Aggregate Dietary (Food 

and Drinking Water) Exposure and Risk Assessment for the 

First Food Use, Section 3 Registration Action (Citrus, 

Grapes, and Sugarcane)

C. Walls 378633 3/19/11 FLAZASULFURON: Occupational and Residential 

Exposure/Risk Assessment for Use on Citrus, Grapes, 

Sugarcane, Christmas Trees, and Industrial Vegetation 

Management

E. Holman 386767 2/28/11 Flazasulfuron; Report of the Residues of Concern 

Knowledgebase Subcommittee (ROCKS) 

N. Dodd 372901 2/16/11 Flazasulfuron. Summary of Analytical Chemistry and 

Residue Data for Use on Citrus, Grapes, and Sugarcane

K. 

O’Rourke

316614 11/23/05 Occupational and Residential Risk Assessment to Support 

Request for Registration of Flazasulfuron on Non-Residential 

Turf

G. Burke 303573, 

309442

11/16/05 Flazasulfuron: Human Health Risk Assessment for the 

Proposed Uses on Golf Courses, Sod Farms, Professionally 

Managed Athletic Fields (College and Professional), and 

Commercial Lawns. 

Attachments

1. Chemical Identity Table

2. Tolerance Summary Table

3. Endpoint Selection Table
Page 11 of 19

Attachment 1

Chemical Identity Table

Table 1a. Chemical Identity of Flazasulfuron

Common Name flazasulfuron

IUPAC Name 1-(4,6-dimethoxypyrimidin-2-yl)-3-(3-trifluoromethyl-2-pyridylsulfonyl)urea

Chemical Abstracts Service 

(CAS) Name

N-[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]-3-(trifluoromethyl)-2-

pyridinesulfonamide

PC Code 119011

CAS registry number 104040-78-0

Chemical Class Sulfonylurea herbicide

Chemical Structure

Table 1b. Chemical Names and Structures for Flazasulfuron Metabolites/Degradates

Common name/code Chemical name Chemical structure

ADMP 2-amino-4,6-dimethoxypyrimidine

DTPU N-(4,6-dimethoxy-2-pyrimidinyl)-N-

[3-(trifluoromethyl)-2-pyridinyl]urea

DTPP 4,6-dimethoxy-N-[3-

(trifluoromethyl)-2-pyridinyl]-2-

pyrimidinamine
Page 12 of 19

HTPP 6-methoxy-2-[[3-(trifluoromethyl)-2-

pyridinyl]amino]-4-pyrimidinol

TPSA 3-(trifluoromethyl)-2-

pyridinesulfonamide

2,3-GTF 3-trifluoromethyl-2-pyridylguanidine
Page 13 of 19

Attachment 2

Tolerance/MRL Table

Table 2. Summary of US and International Tolerances and Maximum Residue Limits for 

Flazasulfuron

Residue Definition: 

US Canada Mexico2 Codex

40 CFR 180. xxx:

Plant/Livestock: N-[[(4,6-dimethoxy-2-

pyrimidinyl)amino]carbonyl]-3-

(trifluoromethyl)-2-pyridinesulfonamide

None None

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex

Fruit, citrus, group 10-10 0.01

Grape 0.01

Sugarcane 0.01

Completed: M. Negussie; 02/23/2012

1

Includes only commodities registered in the US. 

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.
Page 14 of 19

Attachment 3

Summary of Flazasulfuron Endpoints Selected for Risk Assessment

Table 3-A. Summary of Toxicological Doses and Endpoints for Flazasulfuron for Use in Residential and 

Non-Occupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute 

Dietary

(all 

populations 

including 

Females 13-

49)

NOAEL =50 

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 1X

Acute RfD = 0.5 

mg/kg

aPAD = 0.5 

mg/kg

Acute neurotoxicity (rat) LOAEL = 

1000 mg/kg/day based on: transient decrease in 

motor activity observed at Day 0 (5 hours postdosing).

Chronic 

Dietary

(all 

populations)

Oral

NOAEL = 

1.3 mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 1X

Chronic RfD = 

0.013 mg/kg/day

cPAD = 0.013 

mg/kg/day

Combined Chronic Toxicity/ Carcinogenicity rats

LOAEL= 13.3 mg/kg/day based on adverse 

change in kidney function (chronic nephropathy)

Incidental 

Oral 

Short-Term

(1 - 30 days) 

and

Intermediate 

Term (1 - 6 

months)

NOAEL = 2 

mg/kg/day

UFA = 10x

UFH = 10x

Residential:

LOC for MOE = 

100

90-Day oral toxicity in (dog)

LOAEL= 10 mg/kg/day based on changes in 

liver (increase in: deposition of brown pigments, 

glutamic pyruvic transaminase, creatine 

phosphokinase, inflammatory cell infiltration, 

microgranulomas).

Dermal 

Short-Term

(1 - 30 days)

and

IntermediateTerm

(1 - 6 

months)

Quantification of dermal risk is not required. No 

dermal or systemic toxicity was seen following 

repeated dermal applications at the Limit Dose 

and there are no concerns for neuro-, 

developmental, or reproductive toxicity

Inhalation 

Short-Term

(1 - 30 days)

And 

IntermediateTerm

(1 - 6 

months)

NOAEL = 2 

mg/kg/day

UFA = 10x

UFH = 10x

Residential:

LOC for MOE = 

100

90-Day oral toxicity in (dog)

LOAEL = 10 mg/kg/day based on changes in 

liver (increase in: deposition of brown pigments, 

glutamic pyruvic transaminase, creatine 

phosphokinase, inflammatory cell infiltration, 

microgranulomas).

Cancer (oral, 

dermal, 

inhalation)

Classification: No evidence of carcinogenicity to humans based on lack of carcinogenic effects in the 

rat and mouse carcinogenicity studies and lack of a mutagenicity concern
Page 15 of 19

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

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = 

population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level 

of concern. N/A = not applicable.

Table 3-B. Summary of Toxicological Doses and Endpoints for Flazasulfuron for Use in 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

Dermal 

Short-Term

(1 - 30 days)

IntermediateTerm

(1-6 months)

Quantification of dermal risk is not required. No 

dermal or systemic toxicity was seen following 

repeated dermal applications at the Limit Dose 

and there are no concerns for neuro-, 

developmental, or reproductive toxicity

Inhalation 

Short-Term

(1 - 30 days)

And 

IntermediateTerm

(1 - 6 

months)

NOAEL = 2 

mg/kg/day

UFA = 10x

UFH = 10x

Occupational:

LOC for MOE = 

100

90-Day oral toxicity in (dog)

LOAEL = 10 mg/kg/day based on changes in 

liver (increase in: deposition of brown pigments, 

glutamic pyruvic transaminase, creatine 

phosphokinase, inflammatory cell infiltration, 

microgranulomas).

Cancer (oral, 

dermal, 

inhalation)

Classification: No evidence of carcinogenicity to humans based on lack of carcinogenic effects in the 

rat and mouse carcinogenicity studies and lack of a mutagenicity concern

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

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = 

population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level 

of concern. N/A = not applicable.
Page 16 of 19

Toxicity Profiles

Table A.3.1 Acute Toxicity Profile - Flazasulfuron 

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

870.1100 Acute oral [rat] 46220908 LD50 > 5000 mg/kg (male and 

females)

IV

870.1200 Acute dermal [rat] 46220909 LD50 > 2000 mg/kg (male and 

females)

III

870.1300 Acute inhalation [rat] 46220910 LC50 > 5 mg/L (male and 

females)

IV

870.2400 Acute eye irritation 

[rabbit]

46220911 Minimal conjunctivitis 

through 48 hours. Free by 72 

hours.

III

870.2500 Acute dermal 

irritation [rabbit]

46220912 No erythema, edema, or 

dermal effects observed at 

application site.

IV

870.2600 Skin sensitization 

[guinea pig]

46220913 Not a sensitizer -

Table A.3.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

870.3100

90-Day oral toxicity 

(rat)

46220920 (1988)

M/F: 0, 40, 200, 1000, 

5000 ppm

M: 0, 2.31, 11.66, 57.1, 

287 mg/kg/day 

F: 0, 2.53, 12.8, 61.5, 309 

mg/kg/day

Acceptable/Guideline

NOAEL (M/F) = 11.66/61.5 mg/kg/day

LOAEL (M/F) = 57.1/309 mg/kg/day based on depression of 

body weight gain (M/F) and slight anemia due to decrease 

in hemoglobin (F).

870.3150

90-Day oral toxicity 

(dog)-capsule

46220921 (1994)

M: 0, 2, 10, 50, 250 

mg/kg/day 

F:0, 2, 10, 50, 100 

mg/kg/day

Acceptable/Guideline

NOAEL (M/F) = 2/10 mg/kg/day

LOAEL (M/F) = 10/50 mg/kg/day based on changes in liver 

(increase in: deposition of brown pigments, glutamic pyruvic 

transaminase, creatine phosphokinase, inflammatory cell 

infiltration, microgranulomas).

870.3200

21-Day dermal 

toxicity (rabbit)

46220922 (1994)

0, 250, 500, 1000 

mg/kg/day

Acceptable/Guideline

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

LOAEL (M/F) = No systemic toxicity was observed at the 

limit dose. No localized dermal effects were observed.
Page 17 of 19

Table A.3.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

870.3700a

Prenatal 

developmental in 

(rat): 

Wistar

46220924 (1988)

0, 100, 300, 1000 

mg/kg/day

Acceptable/Guideline

Maternal NOAEL = 100 mg/kg/day

LOAEL = 300 mg/kg/day based on increase in maternal 

relative liver weight and decreased body weight gain and 

food consumption.

Developmental NOAEL = 100 mg/kg/day

LOAEL = 300 mg/kg/day based on increased incidence of 

visceral malformations (interventricular septal defect).

870.3700a

Prenatal 

developmental in 

(rat): 

Sprague-Dawley

46220925 (1996)

0, 100, 300, 1000 

mg/kg/day

Acceptable/Guideline

Maternal NOAEL = 300 mg/kg/day

LOAEL =1000 mg/kg/day based on transient decreased 

body weight gain and food consumption.

Developmental NOAEL = 300 mg/kg/day

LOAEL = 1000 mg/kg/day based on reduced fetal weights 

and retardation in ossification.

870.3700b

Prenatal 

developmental in 

(rabbit)

46220923 (1988)

0, 50, 150, 450 

mg/kg/day

Acceptable/Guideline

Maternal NOAEL = 150 mg/kg/day

LOAEL = 450 mg/kg/day based on high incidences of 

abortion and decrease in food consumption after initial 

administration.

Developmental NOAEL = 150 mg/kg/day

LOAEL = 450 mg/kg/day based on high incidences of 

abortion. 

870.3800

Reproduction and 

fertility effects

(rat)

46220926 (1995)

0, 200, 2000, 10000 ppm

M: 0, 8.7, 87.5, 473.0 

mg/kg/day

F: 0, 11.7, 124.5, 613.7 

mg/kg/day

Acceptable/Guideline

Parental/Systemic NOAEL (M/F) = 8.7/124.5 mg/kg/day

LOAEL (M/F) = 87.5/613.7 mg/kg/day based on changes in 

kidney parameters (M/F: Bilateral discoloration, 

enlargement, mild nephropathy) and reductions in body 

weight in both generations (F0, F1).

Reproductive NOAEL (M/F) =473.0/613.7mg/kg/day

LOAEL (M/F) =not established.

Offspring NOAEL (M/F) = 87.5/124.5 mg/kg/day

LOAEL (M/F) = 473.0/613.7 mg/kg/day based on reduction 

in lactational body weights of the F1 and F2 offspring.

870.4100b

Chronic toxicity 

(dog)-capsule

46220927 (1995)

M: 0, 0.4, 2, 10, 50 

mg/kg/day

F: 0, 2, 10, 50 mg/kg/day

Acceptable/Guideline

NOAEL = 2 mg/kg/day

LOAEL = 10 mg/kg/day based on changes in liver (increase 

in: inflammatory cell infiltration, hepatocellular necrosis, 

hepatocellular swelling, and bile duct proliferation).

870.4300

Combined Chronic 

Toxicity/ 

Carcinogenicity

(rat)

46220929 (1995)

M: 0, 40, 400, 2000 ppm

F: 0, 40, 400, 4000 ppm

M: 0, 1.3, 13.3, 70.1 

mg/kg/day

F: 0, 1.6, 16.4, 172.6 

mg/kg/day

Acceptable/Guideline

NOAEL = 1.3 mg/kg/day

LOAEL = 13.3 mg/kg/day based on : Adverse change in 

kidney function (chronic nephropathy) and kidney 

physiology (enlargement, dark color of kidney)

no evidence of carcinogenicity
Page 18 of 19

Table A.3.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

870.4200

Carcinogenicity

(mouse)

46220928 (1995)

0, 500, 3500, 7000 ppm

M: 0, 77.3, 552.7, 1053.8 

mg/kg/day

F: 0, 93.7, 659.8, 1208.2 

mg/kg/day

Acceptable/Guideline

NOAEL (M/F) = 77.3/93.7 mg/kg/day

LOAEL (M/F) = 552.7/659.8 mg/kg/day based on decrease 

in body weight, body weight gain, food consumption and an 

increase in liver effects (liver weight and hepatocellular 

hypertrophy).

no evidence of carcinogenicity

870.5500

Salmonella 

typhimurium and 

Escherichia coli

Reverse Mutation 

Assay

46220933 (1987)

0, 20, 50, 100, 200, 500, 

1000 g/ plate (S. 

typhimurium); 0, 100, 

200, 500, 1000, 2000, 

5000 (E. coli) in the 

presence and absence of 

metabolic activation

(+ S9)

Acceptable/Guideline

Flazasulfuron was not cytotoxic with or without S9 

activation in four S. typhimurium strains and one strain of E. 

coli, and did not induce a genotoxic response in any strain.

Negative

870.5300

in vitro Mouse 

Lymphoma 

Mutagenesis Assay

46220930 (1993)

0, 20, 30, 40, 50, 60, 70, 

80, 90, 100, 500 g/ml 

in the presence and 

absence of metabolic 

activation 

(+ S9)

Acceptable/Guideline

There was no evidence of biologically significant induction 

of mutant colonies. 

Negative

870.5375

in vitro 

Cytogenetics Test

46220931 (1988)

0, 3.3 x 10-4, 1.7 x 10-4, 

8.3 x 10-5, 4.1 x 10-5, 

2.1 x 10-5 M, with and 

without metabolic 

activation (+ S9) 

Acceptable/Guideline

Flazasulfuron did not induce chromosome aberrations in 

Chinese hamster lung cells, in the presence and absence of 

S9activation.

Negative

870.5395

in vivo Mammalian 

Erythrocyte 

Micronucleus Test: 

Mouse

46220932 (1995)

0, 1250, 2500, 5000 

mg/kg

Acceptable/Guideline

There was no statistically significant increase in the 

frequency of micronucleated polychromatic erythrocytes in 

mouse bone marrow at any dose or collection time.

Negative

870.6200a

Acute neurotoxicity 

screening battery

(rat)

46220934 (2002)

0, 50, 1000, 2000 

mg/kg/day

Acceptable pending data 

submission /Guideline

NOAEL (M/F) = 50 mg/kg

LOAEL = 1000 mg/kg based on: transient decrease in motor 

activity observed at Day 0 (5 hours post-dosing)
Page 19 of 19

Table A.3.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

870.7485

Metabolism and 

pharmacokinetics

(rat)

46220940 (1994), 

46220941 (1995), 

46220942 (1995), 

46220943 (1995)

single dose: 2, 50 mg/kg

multiple dose: 2 mg/kg

Radiolabel: 

(first ring: Pyridine

second ring: Pyrimidine)

Acceptable/Guideline

Radiolabeled flazasulfuron (Pyridine/Pyrimidine) was 

rapidly distributed and excreted in the urine and feces 

following multiple dosing. Urinary elimination, calculated 

from a total collection of 168 hours, occurred slower in 

males (74/73%) compared to females (90/91%). Fecal 

elimination, calculated from a total collection of 168 hours, 

was greater in males (23/23%) than in females (10/9%). 

Radiolabel was detected at low concentrations in carcass 

(M:1.7/1.1%; F:0.30/0.23%)), blood (M: 0.74/0.35%; F: 

0.16/0.02), liver (M: 0.23/0.14%; F: 0.04/0.04%), and 

kidney (M: 0.13/0.02%; F: 0.02/ <0.005%). Peak plasma 

concentration following single dose administration occurred 

at 6 hours in both sexes.