Quizalofop

- ethyl and Quizalofop

- P

- ethyl

Human Health Risk Assessment DP#394192



### Page 3 of 19 HED recommends that the 40 CFR § 180.441 tolerance for residues of quizalofop in sunflower

seeds be revised from 1.9 ppm to 2.0 ppm to account for increases in residues found in a recent sunflower residue chemistry study (MRID 47910507 )

. In addition, based on the revised Table 1

of Guideline 86 0.1000, soybean soapstock and sugar beet tops are no longer important

feedstuff s ; therefore, th ose tolerance s should be removed from 40 CFR § 180.441.

Maximum residue limits (MRLs) for quizalofop have not been established by Mexico or Codex.

Canada MRL s and US tolerances for quizalofop are harmonized for some commodities. Harmonization is not possible for dry beans, edible podded beans, and milk fat since the US

tolerances are lower than the Canadian MRLs. For harmonization of sugar beet commodities,

H ED recommends the establishment of a US tolerance for sugar beet at 0.2 ppm and the removal of the individual US tolerances for sugar beet roots, sugar beet molasses, and sugar beet tops.

Background Quizalofop ethyl and quizalofop

- P

- ethyl are s elective herbicide s used for the control of annual and perennial grasses in crops and non

- croplands (rights

- of

- way, fencerows, etc)

. They can be applied using ground boom equipment and by fixed wing aircraft as broadcast and banded applications. Quizalofop ethyl is a 50/50 racemic mixture of R

- and S

- enantiomer s

. Quizalofop

P

- ethyl is the purified R

- enantiomer , which is the pesticidally active isomer

. HED has determined that the toxicological profile of the 50/50 racemic mixture ( quizalofop ethyl ) and the

R

- ena ntiomer ( quizalofop

- P

- ethyl ) are similar, and that the currently available toxicity and

residue data on quizalofop ethyl are adequate to support risk assessments reflecting uses of either quizalofop ethyl or quizalofop

- P

- ethyl

. The two compounds are collectively referred to as “quizalofop” in this document.

All of the currently registered products are formulated as the R

- enantiomer, quizalofop

- P

- ethyl

. Presently, quizalofop

- P

- ethyl is registered for use on the following food crops : barley, dry beans, canola, crambe

, cotton

, dry and succulent peas

, lentils , mint, rapeseed, snap beans, sorghum, soybean, sugar beets, flaxseed, sunflower

, wheat and pineapple

. Quizalofop

- P

- ethyl is also registered on the following nonfood crops grown for seed on ly : alfalfa, carrots, cabbage, garlic, onion, radish, spinach, Swiss chard and rye. There are no residential uses of quizalofop. Tolerances are established under 40 CFR §180.441for residues of quizalofop ethyl

.

Quizalofop ethyl was first registered in 19 88 and quizalofop

- P

- ethyl was first registered in 1990

. As a result neither chemical was subject to review under the reregistration process under the Federal Insecticide Fungicide and Rodenticide Act (FIFRA) and the Food Quality Protection Act (FQPA) for chemicals registered prior to 1984. Consequently, neithe r a Reregistration Eligibility Decision (RED ) nor a Tolerance Reregistration Eligibility Decision (TRED) was issued.

An HED scoping document in support of registration r eview of quizalofop ethyl and quizalofop

P

- ethyl was completed in 2007 (Eiden, 2007). A subsequent human health risk assessment was performed in 2011 in association with the then

- proposed new uses on sorghum and rapeseed and

is the most recent assessment ( 11/17/11; D384660 and D386678 )

. No outstanding human health data requirements for q uizalofop were identified in either document or in the June 2008 finalQuizalofop

- ethyl and Quizalofop

- P

- ethyl

Human Health Risk Assessment DP#394192



### Page 4 of 19 workplan for the registration review of quizalofop ( http://www.epa.gov/oppsrrd1/registration_review/quizalofop/ index.htm)

.

Toxicology/ Hazard A ssessment Quizalfop is classified as catagory IV for the acute oral, dermal and inhalation toxicity in the rat. It was negative for dermal irritation in the rabbit and a dermal non

- sensitizer in the guinea pig. The liver is the target organ as evidenced by increased liver weight and histopathological changes in the liver. A metabolism study in rats indicated that following oral administration, quizalofop ethyl is readily absorbed from the gastrointestinal tract and is excreted rapidly via urine and feces. The major metabolite of quizalofop ethyl is the corresponding acid. Developmental studies in rats and rabbits and a two

- generation reproduction study in rats showed no evidence (qualitative or quantitative) for increased susceptibility following in utero and/or pre/post

- natal exposure to quizalofop ethyl. The quizalofop ethyl database does not

indicate it to be a neurotoxic chemical since no treatment

- related effects on brain weight or histopathology of the nervous system were observed in studies that measure these endpoints. The

Cancer Peer Review Committee determined that quizalofop ethyl should be classified as Category D (not classifiable as to human carcinogenicity). Mutagenicity studies conducted on quizalofop ethyl did not demonstrate evidence of mutagenic potential. For detailed hazard

chara cterizations, refer to the 2011 risk assessment ( D384660 and D386678).

No toxicity studies have been received since the last human health risk assessment in 2011. The Agency has modified the Pesticide Data Requirements for Assessing Toxicity (40 CFR §15 8.500), which now require submission of acute and sub

- chronic neurotoxicity testing. The

HED Hazard and Science Policy Council ( HASPOC ) recently concluded that , based on a weight

of

- the

- evidence (WOE) approach, acute and sub

- chronic neurotoxicity studies a re not required at this time for quizalofop. This approach included the following considerations: 1) the lack of neurotoxicity in the available toxicology studies for quizalofop; 2) liver toxicity is the primary toxic effect seen in the quizalofop database and provides the most sensitive point of departure (POD) for risk assessment; and 3) the low concern for neurotoxicity in other members of this

cla ss of chemicals (HASPOC meeting, TXR#: 0056481, October 4, 2012). The waiver for the

sub

- chronic inhalation study was also granted by the HASPOC. This WOE approach considered all the available hazard and exposure information for quizalofop, including: (1) the low vapor pressure of quizalofop (8.3 x 10 - 10 

### mm Hg); (2) the low acute inhalation toxicity of quizalof op (Toxicity Category IV); and (3) the use of a conservative oral POD resulting in screening

- level

MOEs for handler exposures ranging from 2,900 to 211,000.

The risk assessment team has re

- evaluated the PODs and uncertainty factors from the most

recent risk assessment, with respect to anticipated exposure pathways and current policies on selecting endpoints and safety factors, including the safety factor for the protection of infants and children (FQPA Safety Factor). The point of departure for the chro nic dietary scenario is based on the lowest NOAEL in the database of 0.9 mg/kg/day from the chronic rat study. A risk assessment for the dermal scenario is not required since the 28

- day dermal study revealed no adverse responses at the limit dose of 2000 m g/kg/day. The acute dietary scenario was not evaluated, since no single

- dose effects were identified in the oral toxicity database. Inhalation scenarios were not assessed since inhalation exposure is not expected

. The toxicity database for quizalofop is adequate in terms of endpoint selection and dose response information to characterize the potential for prenatal or postnatal risk to infants and children. There are noQuizalofop

- ethyl and Quizalofop

- P

- ethyl

Human Health Risk Assessment DP#394192



### Page 5 of 19 concerns and no residual uncertainties for pre

- and postnatal toxicity. The result s of the immunotoxicity study do not impact endpoint selection or safety factors. The quizalofop ethyl database does not indicate it to be a neurotoxic chemical based on a weight

- of

- evidence consideration. Based on the available data, the 10X FQPA SF to a ccount for enhanced sensitivity of infants and children (as required by FQPA) was reduced to 1X. The HED has confidence that the risk assessment conducted with no additional safety factor will provide a reasonable certainty of no harm to the safety of inf ants and children. No changes to the toxicological endpoints, PODs and FQPA safety factors selected in 2011 are warranted. The toxicology profile and endpoint selection table are listed in Appendices B and C.

Residential Exposure and Risk Assessments Qu izalofop is not registered for use in residential settings

. A residential exposure assessment is not required.

Dietary Exposure and Risk Assessments Sufficient residue data are available to assess dietary exposure to quizalofop. A c hronic dietary (food and drinking water) assessment was conducted in association with the most recently registered uses of quizalofop (as q uizalofop

- P

- ethyl) on sorghum and the rapeseed crop group

20A ( Tadayon , 20 11 ). An acute dietary risk assessment was not performed, as an acute endpoint was not identified in the hazard assessment. Similarly a cancer risk assessment was not performed as quizalofop is not classifiable as to human carcinogenicity.

C hildren (1

- 2 years old ) were found to have the maximum chronic dietary risk estimate at 29% of the chronic population adjusted dose (cPAD)

, which is well below HED’s level of concern of

100% of cPAD. The dietary assessment is considered very conservative as it was conducted assuming tolerance level residues and 100% crop treated.

D rinking water concentrations used in the assessment were generated by Pesticide Root Zone

Model

- Exposure Analysis and Modeling System (PRZM

- EXAMS) using the maximum application rate per season for quizalofop ethyl on dry peas in Michigan (Wente, 2011)

. The Environmental Fate and Effects Division (EFED) has reviewed the existing estimated drinking water concentrations (EDWCs) for quizalofop and has determined that given current policies the

EDWCs ma y increase or decrease only slightly (email communication S. Wente to D. Drew 8/14/12)

. D ietary r isk estimates that would include any slightly revised EDWCs would still be considerably below the level of concern

. Results of the quizalofop dietary assessment are
summarized in the table below.

Table 1

. Summary of Chronic Dietary Exposure and Risk for Quizalofop

- P

- ethyl ( Food and D rinking W ater)

Population Subgroup cPAD (mg/kg/day) Chronic

Exposure (mg/kg/day) %cPAD

General U.S. Population

0.009 0.001025 11
All Infants (< 1 year old) 0.002477 28

Children 1

- 2 years old 0.002636 29 *

Children 3

- 5 years old 0.002315 26

Children 6

- 12 years old 0.001590 18

Youth 13

- 19 years old 0.000978 11

Adults 20

- 49 years old 0.000803 9Quizalofop

- ethyl and Quizalofop

- P

- ethyl

Human Health Risk Assessment DP#394192



### Page 6 of 19 Table 1

. Summary of Chronic Dietary Exposure and Risk for Quizalofop

- P

- ethyl ( Food and D rinking W ater)

Population Subgroup cPAD (mg/kg/day) Chronic

Exposure (mg/kg/day) %cPAD

Adults 50+ years old 0.000685 8

Females 13

- 49 years old 0.000767 9



### * Children 1

- 2 years old were the most highly exposed population



### Aggregate Exposure and Risk Assessments Aggregate risk estimates take into account dietary and residential sources of exposure. As there are no registered uses of quizalofop that would result in residential exposure, an aggregate assessment (food, water and residential) is not performed. Chroni c aggregate exposures consist of food and water only and are not of concern (Table 1 )

.

Cumulative Exposure and Risk Assessments 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 quizalofop ( quizalofop ethyl or quizalofop

- P

- ethyl ) and any other substanc es and quizalofop does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that quizalofop has a common mechanism of toxicity with other substances. For informatio n 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 determ inations and procedures for cumulating effects from substances

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

Occupational Exposure and Risk Assessments The occupational exposure and risk assessment address es risks to workers exposed in an occupational setting via the dermal and inhalation routes of exposure. However, for q u iz alofop, quantitative dermal and inhalation risk assessment s we re not conducted, b ased on the combination of low hazard (via dermal an d inhalation routes) and exposure potentials and

because no endpoints or points of departure for dermal or inhalation exposure were identified

. Quizalofop is not toxic via the dermal route (based on the lack of toxicity following repeat dermal exposure an d the lack of concern for developmental/reproductive effects which are not examined in the dermal study) ; therefore, no dermal endpoint was identified . Quizalofop is a Category IV Inhalation Toxicant indicating low toxicity by the inhalation route, it is not volatile, and it has low use rates. All of these factors indicate that use of quizalofop will not lead to inhalation exposures of concern. To support this qualitative assessm ent, HED has at this time, estimated risks from inhalation exposures for workers applying and handling quizalofop products for a number of high acreage crops using a screening

- level analysis. This screening

- level analysis uses maximum use rates, maximum acreage, baseline PPE, updated SOP , and the

c hronic oral RfD to estimate inhalation risks. Risk estimates based on inhalation exposures of pesticide handlers (mixers, loaders, applicators) for barley, flax, sunflower, wheat, cotton, pineapple, and non

- crop areas are all below HED’s level concern. The Margins of Exposure (MOEs) resulting from this screening assessment range from 2900 to 211,000 and are not of concern as they are well above 100 (the level of concern). A 12

- hour Restricted Reentry Interval ( REI) has been established and is reflected on the labels of all registered products.Quizalofop

- ethyl and Quizalofop

- P

- ethyl

Human Health Risk Assessment DP#394192



### Page 7 of 19 Public Health and Incident Reports Quizalofop incidents were analyzed in 2007 (M. Hawkins, 07/31/2007, D342226). There were 8

incidents identified in IDS from 1999 to 20 07; there were 10 incidents identified in Poison Control Center Data from 1993 to 2005; and there were no incidents identified in NIOSH

SENSOR data from 1998 to 2003.

Updated incident analyses of the Main and Aggregate Incident Data System (IDS) from Jan uary 1, 2007 to September 20, 2012, and the National Institute of Occupational Safety and Health Sentinel Event Notification System for Occupational Risks (NIOSH SENSOR) from 1998 to 2008 are consistent with the previous analyses. The results are as follo ws:

From January 1, 2007, to September 20, 2012, there are no incidents reported in either Aggregate IDS or Main IDS that involve quizalofop.

From 1998 to 2008, three cases (which were associated with one drift event) were identified in SENSOR as being associated with quizalofop. In 2005, a mother and her two children were exposed to a product containing quizalofop through drift from a neighbor’s application. All three cases were classified as low in severity. Symptoms reported for all three cases in clude headache, upper respiratory pain/irritation, and shortness of breath. Additionally, the mother reported having a cough.

Based on the continued low frequency and severity of incident cases reported for quizalofop, there does not appear to be a concer n 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 conducted (update provided via 10/9/12 email communication S. Recore to D.

Dre w).

Residue Chemistry and Tolerance Recommendations

R esidue chemistry deficiencies previously identified for quizalofop were recently evaluated along with a recent residue data submission (sunflower residue decline; MRID 47910507 ) ( D371923, Negrón

- Encarnación, 2012) . The deficiencies are resolved with the exception of the following: Recovery data are required f or the metabolites quizalofop acid and quizalofop methyl by using the multiresidue method (860.1360); Storage stability data for quiz alofop p

- ethyl and quizalofop acid in/on field corn and processed commodities are required (860.1380); B ased on the revised version of Table 1 of OPPTS 860.1000 (June 2008), processing studies (860.1520)

are required for cotton, meal; cotton, hulls; cotton gin byproducts; and cotton, refined oil in order to determine if separate tolerances are needed for these processed commodities of cotton; A

reference standard of 2

- methoxy

- 6

- chloroquinoxaline should be sent to the analytical standard repository (860.1650 ). In addition, the livestock grazing restriction on the label for Assure II ( EPA Reg. No. 352

- 541) is impractical and should be removed.

Tolerance Recommendations

The submitted residue decline data for sunflower are adequate to satisfy the previous condition of registration

. R esidues slightly increased over the sampling period. A revised tolerance using

OECD ( Organization for Economic Co

- operation and Development ) calculation procedures isQuizalofop

- ethyl and Quizalofop

- P

- ethyl

Human Health Risk Assessment DP#394192



### Page 8 of 19 proposed to account for this incre ase. In addition, based on the revised Table 1 of Guideline 860.1000, soybean soapstock and sugar beet tops are no longer important feedstuff s ; therefore,

th ose tolerance s should be eliminated from the 40 CFR § 180.441. HED recommends that 40

CFR § 180.44 1 be amended by establishing /removing tolerances for the plant commodities as

listed in T able 2 below.

International Harmonization

The international residue limits table is included in Appendix D. Maximum residue limits for quizalofop have not been established by Mexico or Codex. The Canada and US residue definitions for quizalofop ethyl in plants are similar but not identical ; howev er, both reflect expression of residues as quizalofop ethyl equivalents and the residues of concern, quizalofop ethyl and quizalofop acid, are accounted for either directly or indirectly

.

The Canadian Pest Management Regulatory Agency (PMRA) established MRLs for dry beans, edible podded beans

, sugar beets , flax , and lentils. Harmonization is not possible for dry beans and edible podded beans since the US tolerance is lower than the Canadian MRL. For harmonization of sugar beet commodities, HED recommend s the establishment of a US tolerance for sugar beet at 0.2 ppm and to remove the individual US tolerances for sugar beet roots, sugar

beet molasses, and sugar beet tops ( no longer a significant feedstuff item ) (see T able 2 below )

. The US tolerance and Ca nadian MRL for flax and lentils is equivalent.

The US tolerances and Canadian MRLs values are the identical for all livestock commodities except milk fat

. The US tolerance expression for livestock commodities is based on residues convertible to quizalofop which includes quizalofop ethyl and quizalofop

- methyl. Although the Canadian tolerance expression doesn’t include quizalofop

- methyl, upon communication wi th the PMRA it was noted that the data acquisition methods were the same. Based on this the Canadian MRLs and US tolerances for fat, meat, and meat by products of goat, cattle, hog, horse, poultry and sheep; eggs; and milk are harmonized. The Canadian MRL for milk fat is lower than the US tolerance; therefore, these values cannot be harmonized.

Table 2

. Tolerance Summary for Quizalofop ( 40 CFR § 180.441) Commodity Current

Tolerance (ppm) HED

Recommended Tolerance (ppm) Comments (correct commodity

definition)

Soybean, soapstock 1.0 Remove Not a feedstuff item
Sunflower, seed 1.9 2
Beet, sugar

- 0.2 Beet, sugar, molasses 0.2 Remove Replace with 0.2 ppm tolerance for beet, sugar Beet, sugar, roots 0.1 Remove Replace with 0.2 ppm tolerance for beet, sugar (Harmonize with Canada) Beet, sugar, tops 0.5 Remove Not a feedstuff itemQuizalofop

- ethyl and Quizalofop

- P

- ethyl

Human Health Risk Assessment DP#394192



### Page 9 of 19 Data Requirements

Toxicology There are no outstanding data requirements.

Residue Chemistry The following residue chemistry data remain outstanding . See D371923 for details on residue chemistry data requirements :

860.1200 Directions for Use

The Section (3) label of Assure II (EPA Reg. No. 352

- 541) indicates that grazing of livestock is prohibited in treated areas. This restriction is not considered practical. Based on the most

recent version of the label (dated 04/12/2012)

, this restriction has not yet been removed.

860.1360 Multiresidue Methods

Multiresidue method data (recovery data) for the metabolites, quizalofop acid and quizalofop

- methyl remain outsta nding.

860.1380 Storage Stability

Storage stability data for quizalofop

- P

- ethyl and quizalofop acid in/on field corn and processed commodities ha ve not been received

. T he available wheat storage stability data

w ere tentatively considered adequate to support submitted crop field trial on corn. However,

w hen the storage stability study on corn is submitted, the adequacy of the storage stability

data will be re

- evaluated.

860.1520 Processed Food and Feed

Studies to determine the residues in/on cotton, meal; cotton, hulls; cotton gin byproducts; and

cotton, refined oil are required to determine if separate tolerance s are needed for these

food/feed items.

860.1650 Submittal of Analytical Reference Standards

A ref erence standard of 2

- methoxy

- 6

- chloroquinoxaline should be sent to the analytical standard repository.

Occupational Residential Exposure There are no outstanding data requirements.Quizalofop

- ethyl and Quizalofop

- P

- ethyl

Human Health Risk Assessment DP#394192



### Page 10 of 19 Reference Memoranda

K. Rury, Quizalofop (quizalofop

- ethyl and quizalofop

- P

- ethyl ) : Summary of Hazard and Science Policy Council (HASPOC) Meeting of October 4, 2012 ( T XR No.: 0056481)

I . Negrón

- Encarnación, 12/4/ 2012, Quizalofop

- P

- ethyl. Summary Document to Support Registration Review and Residue Decline Data for Sunflower in Support of the Condition of Registration for Use on Sunflower ( PP# 0F6076), D 371923.

I. Negrón

- Encarnación, 11/17/2011, Quizalofop

- P

- ethyl: Human Health Risk Assessment for New Uses on Sorghum, Rapeseed Crop Group 20 A, and Field Corn , D384 660 and D386678.

S. Tadayon, 10/25/ 201 1, Quizalofop

- P

- ethyl. Revised Chronic Dietary Exposure Assessment to Support Section 3 Registration for use on Corn, Rapeseed and Sorghum, D395387.

S.P. Wente, 07/19/2011 , Drinking water exposure for quizalofop

- P

- ethyl in support of propagation of herbicide

- tolerant field corn and sorghum, D384661.

C. Eiden, 11/7/ 20 07

, Quizalofop

- ethyl (PC 128711) and Quizalofop

- P

- ethyl (PC 128709) Health Effects Division (HED) Problem Formulation for Registration Review. D342230.

M. Hawkins, 7/31/2007, Review of Quizalofop Incident Reports, D342226.

J. Rowland, 10/24/1997, Quizalofop

- ethyl: Report of the Hazard Identification Assessment Review Committee (HIARC). TXR 012373.Quizalofop

- ethyl and Quizalofop

- P

- ethyl

Human Health Risk Assessment DP#394192



### Page 11 of 19 Appendix A

Nomenclature and Physicochemical Properties of Quizalofop

– P

- ethyl

Table A1

. Test Compound Nomenclature

Chemical structure

Common name Quizalofop

- P

- ethyl

Company experimental name Not provided

IUPAC name ethyl (R)

- 2

- [4

- ((6

- chloroquinoxalin

- 2

- yl)oxy)phenoxy]propanoate

CAS name (2R)

- 2

- [4

- [(6

- chloro

- 2

- quinoxalinyl)oxy]phenoxy]propanoic acid, ethyl ester

CAS registry number 100646

- 51

- 3

End

- use product (EP) 0.88 lb ai /gal EC formulation (EPA Reg. No. 352

- 541)

TA BLE A 2. Physicochemical Properties of the Technical Grade Test Compound Quizalofop

- P

- Ethyl.

Parameter Value Reference

Melting point 76.0

- 77.0 C (pure form) CB Nos. 5852 & 5853, 3/29/90, W. Hazel pH 6.6 (1% aqueous slurry)

Density 1.35 g/cm 3 at 20 C (pure form)

Water solubility 0.4 ppm (20 C)

Solvent solubility

acetone
benzene

carbon disulfide

chloroform cyclohexanone

dichloromethane dimethyl sulfoxide

ethanol

n

- hexane

methanol tetrahydrofuran

toluene xylene g/L at 20 oC

650

680

660

1350

440

1970

200

22

5

22

1160

430

360

Vapor pressure 8.3 x 10
- 10 mm Hg (20 C)

Dissociation constant, pK

a Not applicable

Octanol/water partition coefficient log P OW = 4.66

UV/visible absorption spectrum Not availableQuizalofop

- ethyl and Quizalofop

- P

- ethyl

Human Health Risk Assessment DP#394192



### Page 12 of 19 Appendix B Toxicology Profile

B

. 1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for non fo od and food uses for quizalofop are below. Use of

the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Study 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 (rodent)

................................ ............... 870.3150 Oral Subchronic (non

- rodent)

................................ ........ 870.3200 21

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal ........................................................

...... 870.3465 90

- Day Inhalation

................................ .......................... yes

yes

yes CR

CR yes

yes

yes

-

*

870.3700a Developmental Toxicity (rodent)

................................ ... 870.3700b Developmental Toxicity (non

- rodent)

........................... 870.3800 Reproduction

................................ ................................ . yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

................................ .............. 870.4100b Chronic Toxicity (non

- rodent)

................................ ....... 870.4200a Oncogenicity (rat)

................................ .......................... 870.4200b Oncogenicity (mouse)

................................ .................... 870.4300 Chronic/Oncogenicity

................................ .................... 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

— Chromosomal Aberrations in CHO

cells

................................ ................................ ................................ .. 870.5500 Bacterial DNA damage or repair test (recombinant assay in B. subtilis ). 870.5550 Mutagenicity

— Unscheduled DNA synthesis

................. yes

yes

yes

yes

yes yes

yes

yes

yes

yes

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

................................ ....... no

no

yes

yes CR -

-

*

*

-

870.7485 General Metabolism

................................ ...................... 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes

no

yes yes

yes

yes

* Not required (HASPOC decision, October 4, 2012, TXR#: 0056481)Quizalofop

- ethyl and Quizalofop

- P

- ethyl

Human Health Risk Assessment DP#394192



### Page 13 of 19 B. 2 Toxicity Profiles

Table B .2.1 Acute Toxicity Profile of Quizalofop ethyl.

OPPTS

Guidelin

e Study Type MRID Results Toxicity Category

870.1100 Acute oral toxicity / rat 00146669 LD 50 = 1670 mg/kg (M) 1480 mg/kg (F) III

870.1200 Acute dermal toxicity / rat 00146670 LD 50 => 5000 mg/kg IV

870.1300 Acute inhalation toxicity / rat 00146674 LC 50 = 4.8

- 5.8 mg/L IV

870.2400 Primary eye irritation / rabbit 00146671 Not an irritant IV

870.2500 Primary dermal irritation /

rabbit 00146672 Negative IV

870.2600 Dermal sensitization /

guinea pig 00146673 Non

- Sensitizer

--

Table B.2.2 Sub

- chronic, Chronic and Other Toxicities Profile for Quizalofop ethyl.

Guideline No./ Study Type/ MRID Nos.

Doses/Classification Results 1

870.3100

Subchronic Oral

- Rat 00128216 (1982)

(0, 40, 128, 1280 ppm)

M: 0, 2.6, 8.4, 82.9 mg/kg/day F: 0,3.0, 9.7, 93.6 mg/kg/day Acceptable/Guideline NOAEL=8.4/9.7 (M/F) mg/kg/day LOAEL= 89.2/93.6 (M/F) mg/kg/day based on decreased body weight gains, increased liver weight and centrilobular liver cell enlargement.

870.3150

Subchronic Oral

- Dog 00127969 (1982)

(0, 25, 100, 400 ppm) 0, 0.63, 2.5, 10 mg/kg (M/F) (by a standard conversion factor) Acceptable/Guideline NOAEL= 2.5 mg/kg/day LOAEL= 10 mg/kg/day based on increased incidence of testicular atrophy.

870.3200

28

- Day dermal toxicity

- Rabbit 00146677 (1983)

0, 125, 500, 2000 mg/kg/day (M/F) Acceptable/Guideline NOAEL= 2000 mg/kg/day (highest dose tested [HDT])

870.3700a Prenatal, developmental

- Rat 00128206 (1983)

0, 30, 100, 300 mg/kg/day (GD 2 6

- 15) Acceptable/Guideline Maternal: NOAEL= 30 mg/kg/day; LOAEL= 100 mg/kg/day based on decreased body weight gains and food consumption. Developmental: NOAEL= 300 mg/kg/day (HDT).

870.3700b

Prenatal developmental

- NZW Rabbit 3 40370502 (1985)

0, 7, 20, 60 mg/kg/day (GD 7

- 19) Range

- finding study 0, 7, 25, 60, 75 mg/kg/day (GD 7

- 19), Acceptable/Guideline Maternal: NOAEL= 20 mg/kg/day, LOAEL= 60 mg/kg/day based on decreased body weight gains and food consumption. Developmental: NOAEL= 60 mg/kg/day (HDT).

870. 3800 Reproduction and fertility effects

- Rat 00153351 (1985), 40242502

(1987) (0,25, 100, 400 ppm) 0, 1.25, 5.0, 20 mg/kg/day (M/F) (by a standard conversion factor) Acceptable/Guideline Parental/Systemic : NOAEL= 5 mg/kg/day; LOAEL= 20 mg/kg/day based on decreased body weight and body weight gains. Reproductive : NOAEL=5 mg/kg/day; LOAEL= 20 mg/kg/day based on decreased percentage of pup born

alive. Offspring :Quizalofop

- ethyl and Quizalofop

- P

- ethyl

Human Health Risk Assessment DP#394192



### Page 14 of 19 Table B.2.2 Sub

- chronic, Chronic and Other Toxicities Profile for Quizalofop ethyl.

Guideline No./ Study Type/ MRID Nos.

Doses/Classification Results 1

NOAEL=5 mg/kg/day; LOAEL= 20 mg/kg/day based on decreased pup weights.

870.4200a

Chronic Toxicity/ Carcinogenicity

- Rat 00146682 (1985)

(0, 25, 100, 400 ppm)

0, 0.9, 3.7, 15.5 mg/kg/day (M)

0, 1.1, 4.6, 18.6 mg/kg/day (F)

Acceptable/guideline NOAEL= 0.9/1.1 mg/kg/day (M/F), LOAEL= 3.7/4.6 mg/kg/day based on increased incidence of centrilobular enlargement of the liver in both

sexes and mild anemia in males.

Increased incidence, with dose

- related trend, of hepatocellular carcinomas in females o nly.

Cancer classification: Category D (not classifiable as to human carcinogenicity)

870.4100b Chronic toxicity

- dog 00146683(1985)/40242501

(1987)

(0, 25, 100, 400 ppm)

0, 0.625, 2.5, 10 mg/kg/day (M/F)

(by a standard conversion factor)

Acceptable/Guideline NOAEL=10 mg/kg/day (HDT).

870.4200b Carcinogenicity

- mouse 00146684 (1985)

(0, 2, 10, 20, 80, 320 ppm)

0, 0.3, 1.4, 11.4, 45.7 mg/kg/day

(by a standard conversion factor)

Acceptable/Guideline NOAEL=1.4 mg/kg/day; LOAEL=11.4 mg/kg/day based on increased incidence of bilateral testicular atrophy, enlarged liver and histopathology finding indicative of hepatotoxicity in the liver.

Increased incidences of ovarian tumors in females and liver tumors in males at the high

dose.

Cance r classification: Category D (not classifiable as to human carcinogenicity)

870.5100 Mutagenicity

Bacterial 00 128205

0, 10, 100, 250, 500, 1000, 2500 μg (+/

- S9) Negative

870.5375 Mutagenicity

Chromosomal

Aberrations (CHO) 00 128204

0, 125, 250, 500 & 1000 μg/mL (

- S9)

0, 31. 3 , 62.5, 125, 250 & 500 μg/mL (+S9) Negative

DMN Control: Positive

870.5395 Mutagenicity

Micronucleus Assay (Mouse) 00 128203

0, 300, 600, 1200 mg/kg/day Negative

870.5550 Mutagenicity

UDS 00 128202 Negative

870.7485

Metabolism 40328601

Supplementary Metabolism study in rats showed that following oral administration, quizalofop ethyl is readily absorbed from the gastrointestinal tract and is excreted rapidly via urine and feces. The major metabolite of quizalofop ethyl is the

co rresponding acid, which is metabolizedQuizalofop

- ethyl and Quizalofop

- P

- ethyl

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### Page 15 of 19 Table B.2.2 Sub

- chronic, Chronic and Other Toxicities Profile for Quizalofop ethyl.

Guideline No./ Study Type/ MRID Nos.

Doses/Classification Results 1

further.

870.7600

Dermal

Penetration 00146679

0.19, 1.9, or 19 mg/rat, With a10

- hour exposure at doses of 0.19, 1.9, or 19 mg/rat, the absorption was 8.38, 3.27, and 2.9% of the applied dose, respectively

870.7800 Immunotoxicity 48500401(2011)

0, 10, 100, 300, or 600 ppm (0, 2, 20, 55, or 103 mg/kg/day. Acceptable/Guideline. No evidence of immunotoxicity.

1. LOAEL = Lowest observed adverse effect level, NOAEL = No observed adverse effect level.

2

. GD = Gestation Day

3. NZW = New Zealand White RabbitsQuizalofop

- ethyl and Quizalofop

- P

- ethyl

Human Health Risk Assessment DP#394192



### Page 16 of 19 Appendix C

Table C .1. Summary of Toxicological Points of Departure and Endpoints for Quizalofop for Use in Dietary

and Non

- Occupational Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Acute Dietary

– all populations No appropriate endpoint was identified. There were no effects observed in oral toxicity studies

that could be attributed to a single

- dose exposure.

Chronic Dietary (All Populations) NOAEL=

0.9 mg/kg/day UF A = 10x

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

= 0.009 mg/kg/day

cPAD = 0.009 mg/kg/day Chronic toxicity/Carcinogenicity study in

rats. LOAEL = 3.7 mg/kg/day based on

increased incidence of centrilobular enlargement of the liver in both sexes and

mild anemia in males.

Incidental Oral No endpoint was selected as no residential uses are under registration.

Dermal

– all

durations No appropriate endpoint was identified and a risk assessment via this route is not required.

Inhalation

– all

durations No appropriate endpoint was identified and a risk assessment via this route is not required.

Cancer (oral, dermal, inhalation) Category D. Not classifiable as to human carcinogenicity.

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

- response data and used to mark the beginning of extra polation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (inters pecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose.Quizalofop

- ethyl and Quizalofop

- P

- ethyl

Human Health Risk Assessment DP#394192



### Page 17 of 19 Appendix D

International Residue Limits

Quizalofop ethyl (PC Code 128711 ) and Quizalofop

- P

- ethyl (PC Code 128709) ; 09/18/2012 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 1 Codex

40 CFR 180.441:

Plant: quizalofop ethyl residues

convertible to 2

- methoxy

- 6

- chloroquinoxaline, expressed as the stoichiometric equivalent of quizalofop ethyl. ethyl ( RS ) 2

- [4

- (6

- chloroquinoxalin

2

- yloxy)phenoxy] propionate, including the acid metabolites of ( RS )2

- [4

- (6

- chloroquinoxalin

- 2

- yloxy)phenoxy]propanoic acid, all expressed as quizalofop

- ethyl None

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

US Canada Mexico 1 Codex Barley, grain 0.05
Barley, hay 0.05

Barley, straw 0.05
Bean, dry, seed 0.4 0.15 Dry (adzuki beans, beans, blackeyed peas, broad beans, kidney beans, lablab beans, lima beans, moth beans, mung beans, navy beans, pink beans, pinto beans, rice beans, tepary beans, urd beans)

0.05 dry chickpeas, lentils, soybeans
Bean, succulent 0.25 0.05 edible podded (jackbeans, moth beans, runner beans, snap beans, soybeans, sword beans, wax beans, yardlong beans) Beet, sugar, molasses 0.2 0.2 sugar beets 2

Beet, sugar, roots 0.1 0.2 sugar beets
Beet, sugar, tops 0.5 0.2 sugar beets

Cotton, undelinted seed 0.1
Cowpea, forage 3.0
Cowpea, hay 3.0

Crambe, meal 2.0

Flax, seed 0.05 0.05 flax
Gold of pleasure, meal 2.0

Lentil, seed 0.05 0.05 lentils
Pea, dry 0.25 0.05 peas
Pea, field, hay 3.0

Pea, field, vines 3.0

Pea, succulent 0.3 0.05 peas
Peppermint, tops 2.0
Rapeseed, meal 2.0Quizalofop

- ethyl and Quizalofop

- P

- ethyl

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### Page 18 of 19 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 Codex Rapeseed subgroup 20A, except flax, seed 1.5 0.05 flax, Oriental mustard seeds (condiment type), Oriental mustard seeds (oilseed type), rapeseeds (canola) Sorghum, grain, aspirated grain fractions 1.0

Sorghum, grain, forage 0.20
Sorghum, grain, grain 0.20
Sorghum, grain, stover 0.30
Soybean, flour 0.5
Soybean, hulls 0.02
Soybean, meal 0.5
Soybean, seed 0.05
Soybean, soapstock 1.0
Spearmint, tops 2.0

Sunflower, seed 1.9
Wheat, forage 0.05
Wheat, grain 0.05
Wheat, hay 0.05

Wheat, straw 0.05
US [40 CFR §180. 441 (a)(2)] Canada Mexico 1 Codex quizalofop ethyl residues

convertible to quizalofop (2

- [4

- (6

- chloroquinoxalin

- 2

- yl

oxy)phenoxy]propanoic acid), expressed as quizalofop Same as above None

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

US Canada Mexico 1 Codex
Cattle, fat 0.05 0.05

Cattle, meat 0.02 0.02
Cattle, meat byproducts 0.05 0.05
Egg 0.02 0.02

Goat, fat 0.05 0.05

Goat, meat 0.02 0.02
Goat, meat byproducts 0.05 0.05
Hog, fat 0.05 0.05
Hog, meat 0.02 0.02
Hog, meat byproducts 0.05 0.05

Horse, fat 0.05 0.05

Horse, meat 0.02 0.02
Horse, meat byproducts 0.05 0.05

Milk 0.01 0.01

Milk, fat 0.25 0.05Quizalofop

- ethyl and Quizalofop

- P

- ethyl

Human Health Risk Assessment DP#394192



### Page 19 of 19 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 Codex Poultry, fat 0.05 0.05
Poultry, meat 0.02 0.02
Poultry, meat byproducts 0.05 0.05
Sheep, fat 0.05 0.05
Sheep, meat 0.02 0.02
Sheep, meat byproducts 0.05 0.05
MRLs With No US Equivalent Rutabaga roots 0.1

Completed: M. Negussie; 09/18/2012

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

2 Included by I. Negron based on electronic communication with PMRA.

c) Tolerances with regional registrations. Tolerances with regional registration are established for residues of the herbicide quizalofop ethyl, including its metabolites and degradates, in or on the commodities in the following table. Compliance with the tol erance levels specified in the following table is to be determined by measuring only those quizalofop ethyl residues convertible to 2

- methoxy

- 6

- chloroquinoxaline, expressed as the stoichiometric equivalent of quizalofop ethyl, in or on the commodity.

Commodity Parts per million

Pineapple 0.1