UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: May 29,2014 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Fluroxypyr Methylheptyl Ester. Human Health Assessment Seeping Document 

in Support of Registration Review. 

PC Code: 128968 DP Barcode D418559 

Decision No.: 488688 Registration Nos.: 

Petition No.: NA Regulatory Action: Registration Review 

Case No.: NA Risk Assessment Type Scoping Document 

TXRNo.:NA CAS No.: 81406-37-3 

MRIDNo.: NA 40 CFR: § 180.535 

FROM: 

THRU: 

TO: 

Seyed Tadayon, Risk Assessor ~ , 1 J/J _ .() 

Matthew Lloyd, CIH; Industrial Hygienis ~~~/. 

Linda Taylor, Ph.D., Toxieo A ist ~~ (__ 

Peter Savoia, Chemist . fbi 

Risk Assessment Branch V d I 

Health Effects Division (7509P) 

Office of Pesticide Programs ~ /J /) 

M. ichael. S. Metzger, Chief 'J J" ,{ 

Risk Assessment Branches V and VII 

Health Effects Division (7509P) 

Office of Pesticide Programs 

Khue Nguyen, Chemical Review Manager 

Pesticide Re-evaluation Division (7508P) 

Office of Pesticide Programs 

Page 1 of20 
EXECUTIVE SUMMARY 

The Health Effects Division (HED) Registration Review Team has considered the most recent 

human-health risk assessment for the herbicide fluroxypyr methylheptyl ester (fluroxypyrMHE); 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. The most recent risk assessment was conducted in September 2012 (S. 

Tadayon, 9/25/2012, D396339), Fluroxypyr. Human Health Risk Assessment to Support 

Proposed New Use on Rice. In addition, HED conducted an open literature search for literature 

relevant to the human health risk assessment. The results of the literature search showed that no 

new information since the 2012 assessment relevant to the human health risk assessment has 

been published. 

Fluroxypyr MHE is an herbicide intended for post-emergent selective control of broadleaf 

weeds. It is currently registered for use on wheat, barley, oats, com, sorghum, fallow cropland, 

range and pasture grasses, pome fruit and millet. Tolerances for combined residues of fluroxypyr 

MHE and its acid metabolite fluroxypyr have been established on food, feed, and livestock 

commodities in connection with the use of fluroxypyr MHE. The agricultural products are 

generally formulated as liquids and granular formulations of fluroxypyr-MHE. There is one 

product (Vista TM) that is formulated as a liquid concentrate and is used primarily on turf (i.e. 

lawns and golf courses) and sod farms. Since fluroxypyr MHE is not a restricted use pesticide it 

is assumed that it could be applied by homeowners in residential settings. 

Fluroxypyr is formulated as fluroxypyr-methylheptyl ester which, after predominantly foliar 

uptake, hydrolyses to fluroxypyr acid, which is the, herbicidally active form of fluroxypyr. 

Toxicity/Hazard 

The toxicity database for fluroxypyr MHE is complete and adequate for characterization of 

potential developmental, reproductive, carcinogenic, mutagenic, neurotoxic, and immunotoxic 

effects. No new data have been received since the last (2012) risk assessment with respect to 

toxicology._However, based on the current 40 CFR Part 158 data requirements, a subchronic 

inhalation toxicity study, and acute and subchronic neurotoxicity studies are now required for 

fluroxypyr MHE. As part of developing the scoping document under registration review, the 

Hazard and Science Policy Council (HASPOC) reviewed the database for fluroxypyr-MHE and 

based on a weight of evidence approach considering all the available hazard and exposure 

information, granted waivers for these studies (TXR No. 0056397, dated August 23, 2012). 

No modifications to the endpoint selections and safety factors are required from the 2012 risk 

assessment during Registration Review. 

Dietary Exposure 

Residue Chemistry 

The residue chemistry database for fluroxypyr MHE is complete and adequate for the purpose of 

supporting the currently registered uses. No new residue chemistry data are required at this time. 

Page 2 of20 
Page 3 of 20

Adequate metabolism (crops, livestock, and rotational crops), storage stability, magnitude of the 

residue, and processing data are available to support the registered uses of the herbicide 

fluroxypyr. Adequate methods are available for the enforcement of all currently established 

tolerances. The residues of concern for dietary risk assessment are fluoxypyr MHE and its acid 

metabolite fluroxypyr. The nomenclature and physiochemical properties of fluroxypyr MHE can 

be found in Appendix B. 

Dietary Assessment

In the most recent dietary risk assessment, an endpoint attributable to a single exposure was not 

identified; therefore, an acute dietary risk assessment was not performed. An unrefined chronic

aggregate dietary food and drinking water exposure and risk assessment was conducted which 

determined chronic risks to be below HED’s level of concern (S.Tadayon, 09/11/2012, 

D405555). Updated dietary exposure assessments for fluroxypyr MHE may be necessary only to 

consider any new estimated drinking water concentrations. 

Residential Exposure

The residential exposure database is adequate. In the last risk assessment (Matthew Lloyd 

D402132; 09/11/2012), the calculated risk estimates did not exceed the level of concern 

(MOE>100). The existing turf uses were reassessed in that document and they reflect updates to 

HED’s 2012 Residential SOPs along with policy changes for body weight assumptions. 

Previous residential post-application assessments, which assessed incidental oral exposures only, 

relied on default assumptions for turf transferrable residues following treatments. 

Aggregate Assessment

In the most recent risk assessment, HED provided updated aggregate exposure and risk estimates 

for food, drinking water and residential exposures. The exposure scenarios aggregated are: 

chronic food and drinking water with short-term incidental oral ingestions in infants and 

children; and chronic food and drinking water with short-term inhalation of adult residential 

handlers. The combined MOE’s for the scenarios examined were below HED’s level of concern 

(i.e. MOE > 100). The need for revised aggregate exposure assessment as part of registration 

review is not anticipated. 

Occupational Exposure

The occupational exposure database is adequate. No dermal hazard has been identified for

fluroxypyr MHE for short- or intermediate-term exposure scenarios; therefore, post-application 

exposure and risks were not quantified for those exposure durations. The MOEs for occupational 

exposures were calculated for short/intermediate term inhalation exposures using standard 

assumptions and unit exposure data. In the last risk assessment (S. Tadayon, D396339; 

09/25/2012), the calculated risk did not exceed the level of concern (MOE>100. Based on the 

previously calculated risk estimates associated with fluroxypyr MHE, HED does not anticipate 

the need to update the occupational exposure risk estimates for fluroxypyr MHE during 

registration review. 
Page 4 of 20

1.0 FORMULATIONS AND USE PATTERNS 

The herbicide fluroxypyr-MHE is currently registered for use in or on field corn, sweet corn, 

sorghum, range and pasture grasses, turf, dry bulb onions, garlic, pome fruits, wheat, barley, oat,

rice and shallots. The most recent risk assessment was performed for the t use of fluroxypyr on 

rice (S. Tadayon, D396339; 09/25/2012). Fluroxypyr is registered for use on residential 

turfgrass and recreational sites, such as golf courses, parks, and sports fields. The agricultural 

products are generally formulated as liquids and granular formulations of fluroxypyr-MHE. 

There is one product (VistaTM) that is formulated as a liquid concentrate and is used primarily on 

turf (i.e. lawns and golf courses) and sod farms. Since fluroxypyr MHE is not a restricted use 

pesticide it is assumed that it could be applied by homeowners in residential settings.

2.0 HAZARD IDENTIFICATION/TOXICOLOGY

The toxicology database for fluroxypyr MHE, which includes studies on both the fluroxypyr acid

metabolite and fluroxypyr methylheptyl ester) is considered complete for characterization of 

potential developmental, reproductive, carcinogenetic, mutagenic, neurotoxic, and immunotoxic 

effects. The acid is the more toxic chemical and the majority of toxicology studies are on the acid. 

For hazard characterization, the parent and acid are considered to be of equal toxicity.

No new toxicity and/or metabolism data have been received since the last risk assessment, 

which did not identify any data deficiencies with respect to toxicology. Based on the current 40 

CFR Part 158 data requirements, a subchronic inhalation toxicity study, and acute and 

subchronic neurotoxicity studies are now be required for fluroxypyr MHE. As part of 

developing a scoping document under registration review, the Hazard and Science Policy 

Council (HASPOC) reviewed the database for fluroxypyr MHE and based on a weight of 

evidence approach considering all the available hazard and exposure information, granted 

waivers for these studies. The subchronic inhalation study is not requires since the use of an oral 

point of departure results in margins of exposure (>3,800) greater than the Agency’s level of 

concern (Target MOE=1000). The neurotoxicity battery are not required since the kidney, not 

the nervous system, is the target organ for fluroxypyr-induce toxicity and there are no evidence 

of neurotoxicity in the chemical class (i.e., pyridyinoxy acid herbicides) (TXR No. 0056397, 

dated August 23, 2012). No modifications to the endpoint selections and safety factors are 

required from the 2012 risk assessment during Registration Review.

The kidney is the target organ for fluroxypyr following oral exposure to rats, mice, and dogs. In 

the rat, increased kidney weight and death were observed in both sexes in the 90-day feeding study, 

and increased kidney weight and chronic progressive glomerulonephropathy were observed in both 

sexes in the chronic study. Increased kidney weight was observed in maternal rat in the 

developmental toxicity study with fluroxypyr, and kidney effects (deaths due to renal failure; 

increased kidney weight, and microscopic kidney lesions) were observed in both sexes in the 2-

generation reproduction study in rats. Although kidney toxicity (early signs of acute tubular 

nephrosis) was observed in dogs in the 28-day feeding study, no kidney effects or other treatment 

related toxicity were seen in the chronic feeding study in dogs at the same doses used in the 28-

day study. Kidney lesions (increased incidences of renal papillary necrosis and regenerative 

nephrosis in females) were observed in mice following long-term exposure. 
Page 5 of 20

An acute endpoint was not identified. No adverse effects were identified following a single oral 

dose, and there are no developmental or neurotoxicity concerns noted in the database.

There was no evidence of increased susceptibility (quantitative/qualitative) following in utero 

exposure to the acid and the ester in rats and rabbits, or following pre and/or postnatal exposure to 

the acid form in rats. Neither developmental toxicity nor reproductive toxicity was observed in 

rats. In rabbits, developmental toxicity was not observed following exposure to fluroxypyr at dose 

levels that resulted in maternal death. Abortions were observed in rabbits following exposure to 

fluroxypyr MHE at the limit dose. There was no evidence of neurotoxicity or neuropathology in 

any of the studies. There were no treatment-related effects on spleen or thymus weights or 

immunotoxic endpoints, based on an enzyme-linked immunosorbant assay (ELISA) for a T-cell 

dependent antibody response to immunization with sheep red blood cells (SRBC). The Food 

Quality Protection Act (FQPA) safety factor has been reduced to 1X. Fluroxypyr is classified “not 

likely to be carcinogenic to humans”, and there is no mutagenicity concern. 

Fluroxypyr has low acute toxicity by the oral and dermal routes of exposure and moderate acute 

toxicity by the inhalation route of exposure, based on lethality studies. Fluroxypyr (MHE) ester is 

less acutely toxic than the acid by the oral route of exposure. Neither chemical is irritating to the 

skin. Fluroxypyr MHE is not a dermal sensitizer; however, it is a mild eye irritant. The acute 

toxicity profiles for fluroxypyr and fluroxypyr MHE technical are contained in Appendix A of this 

risk assessment. 

Conclusions: Conclusions: The toxicity database for fluroxypyr is considered complete. No 

additional toxicological data are required. There are currently no changes expected to the 

toxicological endpoints, points of departure, and safety factors/uncertainty factors for human 

health risk assessment from the 2012 risk assessment.

3.0 DIETARY EXPOSURE

The residues of concern for tolerance setting and risk assessment purposes in plants and livestock 

commodities are fluroxypyr 1-MHE and its metabolite fluroxypyr, free and conjugated, all 

expressed as fluroxypyr. Fluroxypyr is the major component of the residue found in plants. In 

livestock, very low levels of residue transfer to tissues were seen, and fluroxypyr was the sole 

residue identified in livestock tissues. Further, the analytical enforcement method includes a 

hydrolysis step and detects the combined residues of parent and acid, expressed as fluroxypyr 

equivalents. (DP #: D402134, Peter Savoia, 09/11/2012). 

Permanent tolerances are established under 40 CFR §180.535 for the registered uses of 

fluroxypyr MHE on raw agricultural commodities (RACs). A spreadsheet summarizing the 

international residue limits established on fluroxypyr is presented in Appendix C. There are no 

MRLs established on fluroxypyr by Codex or Mexico.

Tolerances have been established for the combined residues of fluroxypyr 1-methylheptyl ester 

[1-methylheptyl ((4-amino-3,5-dichloro-6-fluoro-2-pyridinyl)oxy)acetate] and its metabolite 

fluroxypyr [((4-amino-3,5-dichloro-6-fluoro-2-pyridinyl)oxy)acetic acid] under 40 CFR 180.535. 
Page 6 of 20

A spreadsheet summarizing the international residue limits established on fluroxypyr is 

presented in Appendix C. There are no MRLs established on fluroxypyr by Codex or Mexico. 

Canada has established MRLs on fluroxypyr for a number of RACs which are harmonized with 

those tolerances set by the U.S. Canada does not establish tolerances on livestock feedstuffs. 

Tolerances are established for ruminant commodities by both the U.S. and Canada. These 

tolerances are harmonized except for kidney. Kidney tolerances are not harmonized because 

different livestock diets are followed subsequent to the U.S. registration of fluroxypyr for use on 

grass.

In the prior action (S. Tadayon, D396339; 09/25/2012) which registered the use of fluroxypyr on 

rice, HED noted that 40 CFR 180.535 citation for fluroxypyr inadvertently lists the “Barley, hay” 

commodity twice specifying two different tolerances. The tolerance for barley, hay at 12 ppm is 

an error and should be removed from the federal register. 

In the most recent dietary risk assessment, an endpoint attributable to a single exposure was not 

identified; therefore, an acute dietary risk assessment was not performed. A chronic aggregate 

dietary (food and drinking water) exposure and risk assessment was conducted which determined 

chronic risks to be below HED’s level of concern i.e. < 100% of the chronic population adjusted 

dose (cPAD) for the general population and all population subgroups. The chronic dietary 

exposure for the highest reported exposed population subgroup, all infants (<1 year old), was 

3.5% of the cPAD. Tolerance level residues and 100% crop treated (CT) assumptions were used 

for all commodities.

In the most recent drinking water assessment (DP 396343, Ronald Parker, 08/21/12), the residues

of concern fluroxypyr 1-methylheptyl ester [1-methylheptyl ((4-amino-3,5-

dichloro-6 fluoro-2-pyridinyl) oxy) acetate] and its metabolite fluroxypyr [((4-amino-3,5-

dichloro-6-fluoro 2-pyridinyl) oxy) acetic acid] in ground water were low in comparison

to surface water. The conservative screening-level drinking water assessment for surface water

predicted acute and chronic estimated drinking water concentrations (EDWCs) using the Rice

Model (v1). In this model, EFED assumed pesticide application to a static rice paddy with no 

inflow from rainfall or outflow from seepage, overflow or evaporation. 

Conclusions: The dietary exposure database is adequate to support the existing registrations of

fluroxypyr MHE. Dietary exposure estimates are not of concern. There are no anticipated 

changes to the dietary exposure unless EDWCs are revised to reflect new policies and any 

updated EDWCs are significantly higher than those used in the previous assessment. At this 

time, a new dietary assessment is not anticipated under registration review.

4.0 RESIDENTIAL EXPOSURE

Based on the current registered use pattern, Fluroxypyr-MHE is applied by homeowners to 

residential turf. The existing turf uses were reassessed in the last risk assessment (Matthew Lloyd 

D402132; 09/11/2012). The document reflects updates to HED’s 2012 Residential SOPs along 

with policy changes for body weight assumptions. Based on this update, no currently registered 

products result in any residential handler or post-application risk estimates of concern. 
Page 7 of 20

Residential Handler

Since fluroxypyr-MHE, is not restricted use pesticide, HED previously conducted a residential 

handler exposure assessment for lawn use (Matthew Lloyd D402132; 09/11/2012). Risk 

estimates were not of concern. Short-term residential handler (inhalation only) MOEs ranged

from 3,800 to 1,500,000. 

Residential Post Application 

Quantitative residential dermal post-application risk assessments were not conducted based on 

the absence of toxicity via the dermal route. However, an incidental oral exposure assessment 

for children was conducted in the most recent exposure assessment (Matthew Lloyd D403132; 

09/11/2012). All of the short-term MOEs for these exposures were greater than 100, and thus are 

not of risk concern. Exposure and risk estimates were assessed in accordance with the 2012 

Residential SOPs. In accordance with the updated Part 158 data requirements (2007), a turf 

transferrable residue (TTR) study is required for all residential or occupational turf uses (e.g., 

sod farms, golf courses, parks, and recreational areas). However, a TTR study can be waived for 

fluroxypyr-MHE at this time because post-application incidental oral exposure calculated 

previously (Matthew Lloyd D402132; 09/11/2012) resulted in MOEs greater than10 times the 

level of concern (e.g., an MOE> 1,000 compared to the LOC of 100); therefore, using the default 

residue transfer values provides an adequate margin of safety for any potentially higher residues 

seen in a chemical-specific TTR study. Incidental oral post-application MOEs for children 

ranged from 14,000 to 6,500,000.

Spray Drift

Residential exposures resulting from off-site transport (e.g., spray drift or volatilization) might 

occur as a result of applications of fluroxypyr-MHE. The Agency is in the process of evaluating 

these types of exposures and might, as appropriate, develop policies and procedures to identify 

the need for and, subsequently, the way to incorporate these post-application exposures into the 

Agency’s risk assessments. The need for spray drift and volatilization risk assessment for 

fluroxypyr-MHE will be examined during registration review.

Conclusions: There is sufficient information available to assess residential exposure. All of the 

residential exposure scenarios for the registered uses of fluroxypyr-MHE have been assessed 

adequately in accordance with current policies and the updated Residential SOPs. There are no 

risks of concern. The need for new residential exposure assessments is not anticipated. 
Page 8 of 20

5.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT

In the most recent risk assessment, HED provided updated aggregate exposure and risk 

estimates. A dermal exposure assessment was not conducted, because no systemic toxicity was 

seen at the limit dose (1000 mg/kg) with fluroxypyr-MHE in the 21-day dermal toxicity studies 

and no developmental toxicity was found with prenatal exposure with fluroxypyr-MHE. The 

exposure scenarios aggregated are: chronic food and drinking water with short-term incidental 

oral ingestions in children; and chronic food and drinking water with short-term inhalation of 

adult residential handlers. The toxicity endpoints for short-term incidental oral and inhalation 

exposures were derived from a subchronic dog study with a NOAEL of 100 mg/kg/day. The 

aggregate risks for residential handlers and children are obtained by dividing the NOAEL by the 

sum of the exposure values to calculate the MOE which was then compared to the target MOE of 

100. The combined MOE’s for the scenarios examined were below HED’s level of concern (i.e. 

MOE > 100). 

The residential handler exposure from applying fluroxypyr using a backpack sprayer and

children’s postapplication oral exposure were combined with the chronic dietary exposure from 

the mostly highly exposed adult (General US population) and children’s (all infants <1 year old) 

subpopulations , respectively, to determine aggregate exposure and risk. Despite the numerous 

conservative assumptions in developing these estimates, the MOEs are above the LOC of 100, 

and are not of concern.

Conclusions: Aggregate exposures reflect current policies and adequate toxicity and exposure 

data. The need for a revised aggregate assessment is not anticipated in registration review.

6.0 OCCUPATIONAL EXPOSURE 

Fluroxypyr-MHE may be applied using aerial, groundboom and hand-held spray equipment. The 

personal protective equipment (PPE) required for handlers consists of a single layer of clothing 

(long sleeve shirt, long pants, and socks plus shoes) with no respirator. The Restricted Entry 

Interval for fluroxypyr-MHE is 12 hours because fluroxypyr-MHE is Toxicity Category III for 

acute dermal and primary eye irritation and Toxicity Category IV for primary skin irritation.

The occupational uses of Fluroxypyr-MHE result in short-term (1 - 30 days) and intermediateterm (1 - 6 months) occupational exposures. 

Occupational Handler Exposure

The registrant has not submitted chemical-specific exposure data to estimate handler exposures. 

In the absence of chemical-specific data, it is HED policy to use the best available data to assess 

handler exposures. Sources of such generic (surrogate) handler data include Pesticide Handlers 

Exposure Database Version 1.1 (PHED 1.1), and the Agricultural Handler Exposure Task Force 

(AHETF) database, or other registrant-submitted occupational exposure studies. Some of these 

data are proprietary (e.g., AHETF data), and subject to the data protection provisions of Federal 

Insecticide, Fungicide, and Rodenticide Act (FIFRA).

All short- and intermediate-term MOEs for agricultural handler scenarios are assessed at baseline 
Page 9 of 20

PPE except for aerial applicators, who were assessed with closed cockpit (i.e., engineering

controls) built in. All scenarios have MOEs above 100 and thus are not a risk concern at 

baseline exposure. The inhalation MOE’s ranged from 9,700 to 1,600,000.

Occupational Post-application Exposure

In the absence of toxicity via the dermal route, no quantitative dermal post-application risk 

assessment is required for the occupational uses of Fluroxypyr-MHE. The REI on registered 

labels is considered appropriate based on the toxicity of the technical ingredient. Although HED 

would typically require dislodgeable foliar residue (DFR) studies based on the existing use 

pattern, no studies are required due to a lack of toxicity via the dermal route.

Conclusions: Occupational assessments reflect current policies and adequate toxicity and 

exposure data. The need for updated occupational handler exposure assessments is not 

anticipated as part of registration review. 

7.0 PUBLIC HEALTH AND PESTICIDE EPIDEMIOLOGY DATA 

Based on the low frequency and severity of incident cases reported for both Fluroxypyr-MHE in 

both IDS and SENSOR-Pesticides, 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 (S.Recore, 

D420478, May28, 2014).

8.0 CUMULATIVE RISK ASSESSMENT 

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 fluroxypyr-MHE and any other substances and Fluroxypyr-MHE does not appear to produce 

a toxic metabolite produced by other substances. For the purposes of this action, therefore, EPA 

has not assumed that Fluroxypyr-MHE has a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative.

9.0 HUMAN STUDIES

Past fluroxypyr-MHE risk assessments rely 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) 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 
Page 10 of 20

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.

10.0 DATA REQUIREMENTS

None.
Page 11 of 20

Appendix A: Toxicology Profile 

1.0 Toxicology Data Requirements

Table A.1 Test Technical

Required Satisfied

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

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

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

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

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

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

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rat and mouse) ...................................

870.3150 Oral Subchronic (dog)....................................................

870.3200 21/28-Day Dermal (rat)..................................................

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

870.3465 28-Day Inhalation ..........................................................

yes

yes

yes

CR

noA

yes

yes

yes

yesC

yesA

870.3700a Developmental Toxicity (rat).........................................

870.3700b Developmental Toxicity (rabbit)....................................

870.3800 Reproduction (rat)..........................................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rat) ....................................................

870.4100b Chronic Toxicity (dog)...................................................

870.4200a Carcinogenicity (rat) ......................................................

870.4200b Carcinogenicity (mouse)................................................

870.4300 Chronic/Carcinogenicity (rat) ........................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial .....................

870.5300 Mutagenicity—Gene Mutation - mammalian ................

870.5375 Mutagenicity—Structural Chromosomal Aberrations ...

870.5395 Mutagenicity—Mammalian Erythrocyte Micronucleus.

870.5500 Mutagenicity— Bacterial DNA Damage or Repair Test

870.5550 Mutagenicity—Unscheduled DNA Synthesis.................

yes

yes

yes

yes

noB

noB

yes

yes

yes

yes

NAB

NAB

870.6100a Acute Delayed Neurotoxicity. (hen) ..............................

870.6100b 90-Day Neurotoxicity (hen)...........................................

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

870.6200b 90 Day Neurotoxicity Screening Battery (rat) ...............

870.6300 Developmental Neurotoxicity (rat) ................................

no

no

yesA

yesA

CR

---

---

NAA

NAA

NA

870.7485 General Metabolism (rat)...............................................

870.7600 Dermal Penetration (8-hour), in vivo (male rat).............

yes

CR

yes

yes

870.7800 Immunotoxicity 

(rat)...........................

yes yes

A waived (HASPOC TXR No. 0056397); 

B not required as per 1991 Mutagenicity Test Guidelines 

C This requirement is adequately addressed by the available 21-day dermal toxicity study
Page 12 of 20

2.0 Toxicity Profiles

Table A.2.1. Acute Toxicity of Fluroxypyr Acid and Fluroxypyr 1-Methylheptyl Ester (MHE) Technical

Guideline No. Study Type MRIDs # Results

Toxicity 

Category

870.1100 Acute Oral – rat Acid 40354010 LD50 = 2405 mg/kg III

MHE 40354005 LD50 > 5000 mg/kg IV

870.1200 Acute Dermal – rabbit 

- rat

Acid 40354010 LD50 > 5000 mg/kg III

MHE 40354006 LD50 > 2000 mg/kg III

870.1300 Acute Inhalation Acid 40354011 LD50 > 296 mg/m3

II

MHE 40354004 LD50 > 1.0 gm/m3III

870.2400 Primary Eye Irritation –

rabbit

Acid 49354010 not applicable not applicable

MHE 40354007 mildly irritating III

870.2500 Primary Skin Irritationrabbit

Acid 40354010 non-irritating IV

MHE 40354008 non-irritating IV

870.2600 Dermal Sensitization -

guinea pig

Acid - none not applicable not applicable

MHE 42137335 & 

42540900

not a sensitizer not applicable

Table A2. Toxicity Profile of Fluroxypyr Technical (Fluroxypyr acid and Fluroxypyr MHE)

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.3150

28-day oral toxicity

Dog

MRID 42137340 (1983)/ 

acceptable/

fluroxypyr acid 98% a.i.

0, 20, 50, 150 mg/kg/day in diet

NOAEL = 50 mg/kg/day 

LOAEL= 150 mg/kg/day, based on kidney lesions (early 

signs of acute tubular nephrosis), increased adrenal wts (both 

sexes), decreased testes wts (males)

870.3100

90-Day oral toxicity 

rodents (rats)-Fischer 344

MRID 44080316(1991)/ 

acceptable/ 

fluroxypyr acid 98.9% a.i.

0, 320, 700, 1000 mg/kg/day

NOAEL = 700 mg/kg/day

LOAEL = 1000 mg/kg/day, based on decreased body weight 

gain & testis weight (males), decreased brain weight 

(females), and increased kidney weight (both sexes). There 

were no treatment-related microscopic lesions.

870.3100

90-Day oral toxicity 

rodents (rats)--Wistar

MRID 42164502 (1987)/ 

acceptable/ 

fluroxypyr acid 98.3-98.5% a.i.

0, 80, 750, 1000, 1500 

mg/kg/day

Mean intake: M 79, 721, 924, 

1215; F 81, 755, 969, 1392 mkd

Males

NOAEL = 80 mg/kg/day

LOAEL = 750 mg/kg/day, based on nephrotoxicity and death 

Females

NOAEL = 750 mg/kg/day 

LOAEL = 1000 mg/kg/day, based on nephrotoxicity and 

death 
Page 13 of 20

Table A2. Toxicity Profile of Fluroxypyr Technical (Fluroxypyr acid and Fluroxypyr MHE)

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.3100

90-Day oral toxicity 

rodents (mice) – SPF ICR

MRID 42137337(1988)/ 

acceptable/ 

fluroxypyr acid 99.3% a.i.

0, 200, 500, 2500, 10000 ppm

Male: 0, 27, 67, 336, 1342 

mg/kg/day

Female: 0, 35, 87, 437, 1748 

mg/kg/day

NOAEL = 1342 mg/kg/day (males)/1748 mg/kg/day 

(females)

LOAEL not established.

870.3150

90-Day oral toxicity 

(nonrodents)

NA NA

870.3200

21-Day dermal toxicity

(rabbits)

MRID 42137338(1991)/ 

acceptable/

fluroxypyr MHE 98.5% a.i.

0, 100, 300, 1000 mg/kg/day

NOAEL = 1000 mg/kg/day (HDT)

LOAEL not established.

870.3250

90-Day dermal toxicity

NA NA

870.3465

4-Week inhalation 

toxicity

(rat)

NA NA

870.3700a

Prenatal developmental 

toxicity (rats) - CD

MRID 40244509 (1983) 

acceptable/ 

fluroxypyr acid 99% a.i.

GD 6-19

0, 125, 250, 500 mg/kg/day

Maternal NOAEL = 250 mg/kg/day

LOAEL = 500 mg/kg/day, based on increased kidney weights

(one death).

Developmental NOAEL = 500 mg/kg/day (HDT)

LOAEL not established.

870.3700a

Prenatal developmental 

toxicity (rats) –SpragueDawley

MRID 44094901 (1994) 

acceptable/ 

fluroxypyr MHE 95.8% a.i.

GD 6-15

0, 100, 300, 600 mg/kg/day

Maternal NOAEL = 300 mg/kg/day

LOAEL = 600 mg/kg/day, based on increased maternal 

deaths (days 4, 6, 7, 7, 8, 8, 10, 10) and decreased body 

weight gains and food consumption.

Developmental NOAEL = 600 mg/kg/day (HDT)

LOAEL = not established.

870.3700b

Prenatal developmental 

toxicity (rabbits)

MRID 40354013 (1984) 

acceptable/ 

fluroxypyr acid 95.8% a.i.

0, 25, 100, 250, 400 mg/kg/day

GD 6-19

Maternal NOAEL = 250 mg/kg/day

LOAEL = 400 mg/kg/day, based on increased maternal 

deaths. Due to a large number of maternal deaths in this

group, a dose level of 250 mg/kg/day was added to the study, 

and the 400 mg/kg/day dose level was discontinued early

(terminated on day 9).

Developmental NOAEL = 250 mg/kg/day (HDT)

LOAEL not established.
Page 14 of 20

Table A2. Toxicity Profile of Fluroxypyr Technical (Fluroxypyr acid and Fluroxypyr MHE)

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.3700b

Prenatal developmental 

toxicity (rabbits)

MRID 44080319 (1996) 

acceptable/ 

fluroxypyr MHE 95.8% a.i.

0, 100, 500, 1000 mg/kg/day

GD 7-19

(acid equivalent doses: 69, 346, 

or 693 mg/kg/day)

Maternal NOAEL = 500 mg/kg/day

LOAEL = 1000 mg/kg/day, based on increased abortions

(one doe on GD 25). At 1000 mg/kg/day, 3 does aborted (GD 

22, GD 25, GD 25) and 1 death GD 20.

Developmental NOAEL = 500 mg/kg/day

LOAEL = 1000 mg/kg/day, based on increased abortions

(one doe on GD 25). At 1000 mg/kg/day, 3 does aborted (GD 

22, GD 25, GD 25) and 1 death GD 20.

870.3800

Reproduction and fertility 

effects (rats) – SpragueDawley

MRID 44080321 (1996) 

acceptable/ 

fluroxypyr acid 99% a.i.

0, 100, 500, 750 mg/kg/day (M)

0, 100, 500, 1000 mg/kg/day (F)

Parental/Systemic NOAEL = 100 mg/kg/day (males) /500 

mg/kg/day (females)

LOAEL = 500 mg/kg/day (males)/ 1000 mg/kg/day 

(females), based on kidney effects (both sexes; increased 

kidney weight with microscopic findings) and increased 

deaths (females) due to renal failure.

Reproductive NOAEL = 750 mg/kg/day (Males)/1000 

mg/kg/day (females) (HDT)

LOAEL not established.

Offspring NOAEL = 500 mg/kg/day

LOAEL = 1000 mg/kg/day, based on decreased pup weight 

and body weight gain and slightly lower survival.

870.4100a

Chronic toxicity (rodents)

NA; see 870.4300 NA

870.4100b

Chronic toxicity (dogs)

MRID 40244507(1988)

acceptable/ 

fluroxypyr acid 98%a.i.

0, 20, 50, 150 mg/kg/day

NOAEL = 150 mg/kg/day (HDT)

LOAEL not established.

870.4200a

Carcinogenicity (rats)

NA; see 870.4300 NA

870.4200b

Carcinogenicity (mice)-

CD-1

MRID 44080317 (1991) 

acceptable/guideline

fluroxypyr acid 98.9% a.i.

0, 100, 300, 1000 mg/kg/day

NOAEL = 300 mg/kg/day 

LOAEL = 1000 mg/kg/day, based on decreased body weight 

and body weight gain (males) and increased kidney lesions 

(increased incidences of renal papillary necrosis and 

regenerative nephrosis) in females.

No evidence of carcinogenicity.

870.4300

Combined 

Chronic/carcinogenicity 

(rats)—Fischer 344

MRID 44080322 (1994) 

acceptable/guideline

fluroxypyr acid 99% a.i.

0, 100, 500, 1000 mg/kg/day

NOAEL =100 mg/kg/day

LOAEL = 500 mg/kg/day, based on increased kidney weights 

and chronic progressive kidney glomerulonephropathy (both 

sexes).

No evidence of carcinogenicity.

At 1000 mg/kg/day, 5 male rats died within first 90 days on 

test.
Page 15 of 20

Table A2. Toxicity Profile of Fluroxypyr Technical (Fluroxypyr acid and Fluroxypyr MHE)

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.5100

Bacterial reverse 

mutation

MRID 44080323 (1995) 

acceptable/ 

fluroxypyr MHE 95.8% a.i.

100 - 5000 ug/plate

Negative.

870.5300

In vitro mammalian cell 

gene mutation

MRID 44080324 (1996) 

unacceptable/

fluroxypyr MHE 95.8% a.i.

1.25 - 50 ug/mL

Negative, but did not test a soluble dose.

870.5375

In vitro mammalian 

chromosome aberration 

(HL)

MRID 44080325 (1996) 

acceptable/ 

fluroxypyr MHE 95.8% a.i.

0.42 – 1250 ug/mL

Negative.

870.5395

Mammalian micronucleus 

(mouse)

MRID 44080326 (1996) 

acceptable/ 

fluroxypyr MHE 95.8% a.i.

oral gavage of 225, 450 or 900 

mg/kg

Negative.

870.6200a

Acute neurotoxicity 

screening battery

(rats)

NA NA

870.6200b

Subchronic neurotoxicity 

screening battery

(rats)

NA NA

870.6300

Developmental 

neurotoxicity

(rats)

NA NA
Page 16 of 20

Table A2. Toxicity Profile of Fluroxypyr Technical (Fluroxypyr acid and Fluroxypyr MHE)

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.7485

Metabolism

(Fischer 344 rats)

MRID 44080327 (1996) 

acceptable/ 

fluroxypyr MHE 99% a.i.

Males: 50 mg/kg (labeled) as 

single oral dose

Total recovery of the administered dose was 105%, with the 

principal route of excretion being expired 14CO2, which 

contained approximately 61% of the radioactivity for the 

fluroxypyr MHE. The urine contained approximately 30% 

and the feces contained 5% of the administered dose. At 48 

hours post dose, approximately 7% of the administered dose 

was recovered in the blood, carcass, and skin. Approximately 

52% of the administered dose was absorbed and expired as 

14CO2 within 12 hours post dose, and an additional 18% of 

the administered dose was excreted in the urine within 12 

hours post dose. Based on the percentage of dose in the 

expired 14CO2, urine, and tissues, approximately 90% of the 

dose was absorbed. Once absorbed, it was extensively 

metabolized and rapidly expired as 14CO2 and eliminated in 

the urine with a half-life of 6 hours. Peak plasma 

concentrations of 14C-radioactivity were attained by 7 hours 

post dose.

870.7600

Dermal penetration

NA NA

870.7800

Immunotoxicity (Crl:WI 

(Han) rats)

MRID 48581311 (2011)

Acceptable/guideline

fluroxypyr 99.9%

Males: 0, 80, 250, 750 

mg/kg/day for 29 days

NOAEL = 750 mg/kg/day (highest dose tested; actual dose was 

816 mg/kg/day); no treatment-related decrease in primary 

immune response to SRBCs in male rats; spleen or thymus 

weights comparable to control.
Page 17 of 20

3.0 Fluroxypyr MHE Endpoints and Doses for Risk Assessment

Table A. 3. Summary of Toxicological Doses and Endpoints for Fluroxypyr MHE for Use 

in Human 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)

No adverse effects were identified following a single oral dose and there are no developmental 

concerns noted in the database.

Chronic Dietary

(All populations)

NOAEL= 100 

mg/kg/day

UFA 10x

UFH 10x

FQPA SF = 

1x

chronic RfD 

= 

1 mg/kg/day

chronic 

PAD= 

1 mg/kg/day

Chronic/Carcinogenicity-Rat

LOAEL = 500 mg/kg/day, based on 

kidney effects (increased kidney weights, 

alterations in clinical chemistry 

parameters indicative of impaired renal 

functions, and increase in severity of 

chronic progressive 

glomerulonephropathy in both sexes).

Incidental Oral

(Short- and 

Intermediate 

Term)

NOAEL= 100 

mg/kg/day

UFA 10x

UFH 10x

FQPA SF = 

1x

Residential 

LOC is for 

MOE below 

100 

Chronic/Carcinogenicity-Rat

LOAEL = 500 mg/kg/day, based on 

kidney effects (increased kidney weights, 

alterations in clinical chemistry 

parameters indicative of impaired renal 

functions, and increase in severity of 

chronic progressive 

glomerulonephropathy in both sexes).

Dermal 

(Short- and 

Intermediateterm)

Quantification not required since 21-Day dermal rabbit NOAEL = 1000 mg/kg/day, and there 

are no developmental toxicity concerns.

Dermal 

(Long-term)

Long-term dermal exposure is not expected based on the current use pattern.

Inhalation 

(All durations)

Oral study 

NOAEL= 100 

mg/kg/day 

(inhalation and 

oral toxicity 

assumed to be 

equivalent)

UFA 10x

UFH 10x

FQPA SF = 

1x

Residential 

LOC is for 

MOE below 

100 

Chronic/Carcinogenicity-Rat

LOAEL = 500 mg/kg/day, based on 

kidney effects (increased kidney weights, 

alterations in clinical chemistry 

parameters indicative of impaired renal 

functions, and increase in severity of 

chronic progressive 

glomerulonephropathy in both sexes). 

Cancer (oral) Classified as a “Not Likely” human carcinogen.

UF = uncertainty factor, FQPA SF = Food Quality Protection Act safety factor, NOAEL = no observed adverse 

effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = 

chronic), RfD = reference dose, MOE = margin of exposure, LOC = level of concern, NA = Not Applicable
Page 18 of 20

Appendix B: Chemistry

1.0 Identification of Active Ingredient

Table B.1. Fluroxypyr 1-MHE Nomenclature.

Compound

Common name Fluroxypyr 1-methylheptyl ester

Company experimental name XRM-5316

IUPAC name 1-methylheptyl-4-amino-3,5-dichloro-6-fluoro-2-pyridyloxyacetate

CAS name [(4-amino-3,5-dichloro-6-fluoro-2-pyridinyl)oxy]acetic acid, 1-methylheptyl ester

CAS # 81406-37-3

End-use product/EP 1.5 lb ae/gal EC formulation (StaraneTM Herbicide; EPA Reg. No. 62719-286) 

Fluroxypyr, free acid

Common Name Fluroxypyr

CAS name [(4-amino-3,5-dichloro-6-fluoro-2-pyridinyl)oxy]acetic acid

CAS # 69377-81-7

2.0 Physical and Chemical Properties

Table B.2. Physicochemical Properties of the Fluroxypyr 1-MHE.

Parameter Value

Melting point/range 57.5°C 

pH 6.81 in solution containing 90.1 μg/L

Density 1.30 g/mL at 21°C

Water solubility ( 20 °C) 90.1 μg/L in purified water

294 μg/L in pH 5 buffer

136 μg/L in pH 7 buffer

57.2 g/L in pH 9 buffer

Solvent solubility (20 °C) 6.23 g/100 mL in n-heptane

>200 g/100 mL in xylene

377 g/100 mL in methanol

22.0 g/100 mL in n-octanol

>300 g/100 mL in acetone

Vapor pressure 2.0 x 10-5 kPa at 25 °C

1.0 x 10-5 kPa at 20 °C

Dissociation constant Not applicable

Octanol/water partition coefficient Log(KOW) 4.57 at pH 5

5.04 at pH 7

5.31 at pH 9

UV/visible absorption spectrum Not available

F N

Cl Cl

NH2

O O

CH3

CH3

F N

Cl Cl

NH2

O

OH

O
Page 19 of 20

Appendix C: International Residue Limits (128959 & 128968; 02/06/14)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex

§ 180.535 (a) General. (1) fluroxypyr 

1-methylheptyl ester [1-methylheptyl 

((4-amino-3,5-dichloro-6-fluoro-2-

pyridinyl)oxy)acetate] and its metabolite 

fluroxypyr [((4-amino-3,5-dichloro-6-

fluoro-2-pyridinyl)oxy)acetic acid]

1-methylheptyl [(4-amino-3,5-

dichloro-6-fluoro-2-

pyridinyl)oxy]acetate, including 

the metabolite [(4-amino-3,5-

dichloro-6-fluoro-2-

pyridinyl)oxy]acetic acid

None

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

US Canada Mexico1 Codex

Barley, grain 0.5 0.5

Barley, hay 20.0

Barley straw 12.0

Cattle, fat 0.1 0.1

Cattle, kidney 1.5 0.5

Cattle, meat 0.1 0.1

Cattle, meat byproducts 0.1 0.1 (meat byproducts of cattle, 

except kidney)

Corn, field, forage 1.0

Corn, field, grain 0.02 0.02

Corn, field, stover 0.5

Corn, Sweet, forage 1.0

Corn, sweet, kernel plus cob 

with husk removed 

0.02 0.02

Corn, sweet, stover 2.0

Fruit, pome, group 11 0.02 0.02 apples, Asian pears, azaroles, 

Chinese quinces, crabapples, 

Japanese quinces, loquats, mayhaws, 

medlars, pears, quinces, tejocotes

Garlic, bulb 0.03 0.03dry bulb onions

Goat, fat 0.1 0.1

Goat, kidney 1.5 0.5

Goat, meat 0.1 0.1

Goat, meat byproducts 0.1 0.1 (meat byproducts of goats, except 

kidney)

Grain, aspirated fractions 0.6

Grass, forage 120

Grass, hay 160

Hog, fat 0.1 0.1

Hog, kidney 1.5 0.5

Hog, meat 0.1 0.1

Hog, meat byproducts 0.1 0.1 (meat byproducts of hogs, except 

kidney)

Horse, fat 0.1 0.1

Horse, kidney 1.5 0.5

Horse, meat 0.1 0.1

Horse, meat byproducts 0.1 0.1 (meat byproducts of horses, 

except kidney)

Milk 0.3 0.1
Page 20 of 20

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex

Millet, forage 12.0

Millet, grain 0.5

Millet, hay 20.0

Millet, proso, straw 12.0

Oat, forage 12.0

Oat, grain 0.5 0.5

Oat, hay 20.0

Oat, straw 12.0

Onion, bulb 0.03 0.03

Rice, bran 3.0

Rice, grain 1.5

Shallot, bulb 0.03 0.03dry bulb onions

Sheep, fat 0.1 0.1

Sheep, kidney 1.5 0.5

Sheep, meat 0.1 0.1

Sheep, meat byproducts 0.1 0.1 (meat byproducts of sheep, 

except kidney)

Sorghum, grain, forage 2.0

Sorghum, grain, grain 0.2 0.02

Sorghum, grain, stover 4.0

Wheat, forage 12.0

Wheat, grain 0.5 0.5

Wheat, hay 20.0

Wheat, straw 12.0

Completed: M. Negussie; 02/10/2014

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.