### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D

. C. 20460



### MEMORANDUM

Date: May 29,2014 O F FICE OF
CHEMICAL SAFETY AND
POLLUTION PREVENTION



### SUBJECT: Fluroxypyr Methylheptyl Ester. Human Heal th 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 Hy gienis

## ~~**~ /.**  Linda Taylor, Ph.D.,**Toxi eo**  A 

### is t**~~** 

### (__

Peter Savoia, Chemist

. 

# fbi

Risk Assessment Branch 

# V d I

Health Effec ts 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 Nguye n
, Chemical Review Manager

Pesticide Re-evaluation Division (7508P)

Office of Pesticide Programs

Page 

### 1 of20EXECUTIVE SUMMARY



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

human-health risk assessment for the herbicide fluroxypyr methylheptyl ester (fluroxypyr

MHE); 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. T he most recen t 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 i nformation since the 2012 assessment relevant to th e human health risk assessment has

been published.

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

weeds. It 

### is currently registered for us e 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 i s 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 -m ethylheptyl ester which, after predominantly foliar uptake, hydroly ses 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) ri sk assessment with respect to toxicology._However, based on th e current 40 CFR Part 158 data requiremen t s, a subchronic

inhala tion toxicity study, and acute and s ubchronic neurotoxic i ty studies are now required for fluroxypyr MHE. As part of developing the scoping document under registration revi ew, the

Hazard and Science Policy Council (HASPOC) reviewed the database for fluroxypyr-M HE 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 Registra t ion Review

.

Dietary Exposure

Residue Chemistry



## The residue chemistry database for fluroxypyr MHE 

## is complete and adequate for the purpose of supporting the currently registered us es. No new residue chemis t ry data are required at this tim e.

Page 2 of20

### Page 3 of 20

Adequate metabolism (crops, livestock, and rotational crops)

, storage stability, magnitude of th e 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 f luoxypyr MHE and its acid

metabolite flu r oxypyr. The nomenclature and physiochemical properties of fluroxypyr MHE can be found in Appendix B.

Dietary Assessment

In the most recent dietary risk assessment, a n endpoint attributable to a sin gle exposure w as not identified; therefore, an acute dietary risk assessment was not performed . A n unrefined chronic aggregate dietary food and drinking water exposure and risk assessment w as conducted which

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

D405555 )

. Updated d ietary exposure assessments for f luroxypyr 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

D 402132 ; 0 9 / 11 /20 12 ), the calculated risk estimates did not exceed the level of concern (MOE>100). The existing turf uses were reassessed in th at document and they reflect updates to

HED’s 2012 Residential SOPs a long 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 a ggregate 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

f luroxypyr MHE for short

- or intermediate

- term exposure scena rios ; 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. I n the last risk assessment ( S. Tadayon, D 3 96339 ; 0 9 / 25 /20 12 ), the calculated risk did not exceed the level of concern (MOE>100

. Based on the previously calculated risk estimates associated with f luroxypyr MHE , HED does not anticipate the need to update th e occupational exposure risk estimates for f luroxypyr MHE during registration review.

### Page 4 of 20

1.0 F ORMULATIONS AND 

### U SE 

### P ATTERNS



### 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 flu r ox ypyr on rice ( S. Tadayon, D 3 96339; 09/25/2012 ). Flu r oxyp yr 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 granul ar f ormulations 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.

2.0 H AZARD 

### I DENTIFICATION 

### /T OXICOLOGY



### The toxicology database for flu r oxypyr MHE

, which includes studies on both the fl uroxypyr 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 ma jority of toxicology studies are on the acid. For hazard characterization, t he 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 da ta 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 sco ping document under registration review, the Hazard and Science Policy Council (HASPOC) reviewed the database for fluroxypyr MHE and b ased on a weight of

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

waivers for t hese 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 sinc e 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 2 3 , 201 2). 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 flu ro xypyr following oral exposure to rats, mice, and dogs. In the rat, increased kidney weight and death wer e 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 . In creased kidney weight was observed in maternal rat in the developmental toxi city 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 acut e tubular nephrosis) was observed in dogs in the 28

- day feeding study, no kidney effects or other treatment related toxicity w ere seen in the chronic feeding study in dogs at the same doses used in the 28

- day study

. K idney 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 obs erved in rabbits following exposure to fluroxypyr MHE at the limit dose. There was no evidence of neurotoxicity or neuropathology in any of the studies. T here were no treatment

- related effects on spleen or thymus weights or immunotoxic endpoints, b ased on a n 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 b e carcinogenic to humans ”

, and there i s no mutagenicity concern.

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

tox icity by the inhalation route of exposure, based on lethality studies. F luroxypyr (MHE) es ter is

less acutely toxic than the acid by the oral route of exposure . Neither chemical is irritating to the skin. Fluroxypyr M HE is not a dermal sensitizer; however, it is a mild eye irritant. The acute toxicity profiles for fluroxypyr and fluroxypyr M HE 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

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

health risk assessment from the 2012 risk assessment.

3.0 D IETARY 

### E XPOSURE



### 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, P eter 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)acet ate] 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 esta blished 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

gras s.

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 wa s 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 r esidues 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 assume d pesticide application to a static rice paddy with no

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

Conc lusions: 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 R ESIDENTIAL 

### E XPOSURE



### 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 reflect s updates to HED’s 2012 Resident ial 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 ). R isk

estimates were not of concern. Short

- term residential handler (inhalation only) MOEs range d

from 3,800 to 1,500

, 0 00

.

Residential Post Application

Q uantitative residential dermal post

- application risk assessment s w ere 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 D 403132 ; 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 acc ordance 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 recreat ional 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 than 10 times the level of concern (e.g., an MOE> 1,000 compared to the LOC of 100); therefore, using the default residue transfer values provide s an adequate margin of safety for any potentially higher residues

seen in a chemical

- specific TTR study. Incidental oral post

- application MOEs for children

range d 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 i n 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 nee d 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 assessment s is not anticipated.

### Page 8 of 20

5.0 A GGREGATE 

### E XPOSURE AND 

### R ISK 

### A SSESSMENT



### 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 fluroxy pyr

- 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 childre n; 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

ag gregate risk s 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 compar ed 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 b ackpack 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 numero us 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 ass essment is not anticipated in registration review

.

6.0 O CCUPATIONAL 

### E XPOSURE



### F luroxypyr

- MHE may be applied using aeria l

, 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 f luroxypyr

- MHE is Toxicity Category III for acute dermal and primary eye irritation and Toxicity Category IV for primary skin irritation.

The occupational uses of F luroxypyr

- MHE result in short

- term (1

- 30 days) and intermediate

term (1

- 6 months) occupational exposures.

Occupational Handler E xposure

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 (surro gate) 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 applicato rs, who were assessed with closed cockpit (i.e., engineering controls) built in. All scenarios have MOE s 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 E xposure

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

- application risk assessment is required for the occupational uses of F luroxypyr

- 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 u pdated occupational handler exposure assessments is not anticipated as part of registration review.

7.0 P UBLIC 

### H EALTH AND 

### P ESTICIDE 

### E PIDEMIOLOGY 

### D ATA



### 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 C UMULATIVE 

### R ISK 

### A SSESSMENT



### 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 f luroxypyr

- MHE and any other substances and F luroxypyr

- 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 F luroxypyr

- 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 chemic als, 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/pesticide s/cumulative.

9.0 H UMAN 

### S TUDIES



### Past f luroxypyr

- 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 Ha ndlers Exposure Database (PHED) and the Agricultural Reentry Task Force (ARTF) Database . EPA has reviewed all the studies supporting

these multi

- p esticide 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 cond ucted. A ll

### 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 t here is no regulatory barrier to continued reliance on

these studies

.

10.0 D ATA 

### R EQUIREMENTS



### 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

no A yes

yes

yes

yes C

yes A

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

no B

no B yes

yes

yes

yes
NA B

NA B

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

yes A

yes A

CR ---

--- NA A

NA A

NA

870.7485 General Metabolism (rat)

................................ ............... 870.7600 Dermal Penetration (8

- hour)

, in vivo (male rat)

............. yes
CR yes

yes

870.7800 Immunotoxicity (rat)........................... y es y es

A waived ( HASPOC TXR No. 0056397 ) ;

B not required as per 1991 Mutagenicity Test Guidelines

C This requirement is adequately addressed by the available 2 1

- 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 LD 50 = 2405 mg/kg III

MHE 40354005 LD 50 > 5000 mg/kg IV

870.1200 Acute Dermal

– rabbit

- rat Acid 40354010 LD 50 > 5000 mg/kg III

MHE 40354006 LD 50 > 2000 mg/kg III

870.1300 Acute Inhalation Acid 40354011 LD 50 > 296 mg/m 3 II

MHE 40354004 LD 50 > 1.0 gm/m 3 III

870.2400 Primary Eye Irritation

– rabbit Acid 49354010 not applicable not applicable

MHE 40354007 mildly irritating III

870.2500 Primary Skin Irritation

rabbit 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 A 2. 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)

-- Wi star 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 m g /kg/day, based on nephrotoxicity and death

Females

NOAEL = 750 mg/kg/day

LOAEL = 100 0 m g /kg/day, based on nephrotoxicity and

death

### Page 13 of 20

Table A 2. 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 ( f emales)

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)

– Sprague

Dawley 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/ fluroxyp yr 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 th is 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 A 2. 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 (rabbi ts) 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)

– Sprague

Dawley 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 ( f

emales) LOAEL = 500 mg/kg/day ( m ales)/ 1000 mg/kg/day ( f emales), based on kidney effects ( both sexes; increas ed kidney weight with microscopic findings ) and increased deaths ( females ) due to renal failure. Reproductive NOAEL = 750 mg/kg/day (Ma les)/ 1000 mg/kg/day (f

emales) (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 day s on

test.

### Page 15 of 20

Table A 2. 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 A 2. 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 14 CO 2 , 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

14 CO 2 within 12 hours post dose, and an additio nal 18% of

the administered dose was excreted in the urine within 12 hours post dose. Based on the percentage of dose in the expired 14 CO 2 , urine, and tissues, approximately 90% of the dose was absorbed. Once absorbed, it was extensively

metabolized and rapidly expired as 14 CO 2 and eliminated in

the urine with a half

- life of 6 hours. Peak plasma

concentrations of 14 C

- 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 i n 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 populat i ons) NOAEL= 100

mg/kg/day UF A 10x

UF H 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

I nter mediate

Term ) NOAEL= 100

mg/kg/day UF A 10x

UF H 10x

FQPA SF = 1x Residential

LOC is for

MOE below

1 00 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

Intermediate

term) 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 ) UF A 10x

UF H 10x

FQPA SF = 1x Residential

LOC is for

MOE below

1 00 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 (Starane TM 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(K OW ) 4.57 at pH 5 5.04 at pH 7 5.31 at pH 9 UV/visible absorption spectrum Not available

### 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 Mexico 1 

### 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 Mexico 1 

### 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 Mexico 1 

### 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.