UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460



### MEMORANDUM

Date: 20-AUG-2013 OFFICE OF
CHEMICAL SAFETY ANO
POLLUTION PREVENTION



### SUBJECT: Quinoxyfen. Human-Health Risk Assessment for the Proposed Uses on Vegetab l e, Fru iting

, Group 8-10; Fruit, Small Vine Climbing, Except Fuzzy Kiwifruit, Subgrou p 13-07 F; and Berry, Low Growing Subgro up 13 -07 G.

PC Code: 055459
Decision No .: 4 71748
Petition No.: 2E81 17
Risk Assessment Type: Si n gle Chem i caVAggregate
TXRNo.: NA
MRIDNo.: NA DP Barcode: 0410691 Registration No. : 62719-375 Regulatory Action: Sec. 3 R eg i stration Case No. : 7037
CAS No.: 124495-18-7
40 CFR: § 180.588



### F ROM: George F. Kramer, Ph.D.

, Senior

## emis**~~** Jenni fe r R. Tyler, Chemist Monique M. Perron, S.D.

, Toxicologist

R isk Assessment Branch 1 (RAB 1 )
H ea l th Effects Division (HED; 7509 P )



### THROUGH: Dana M. Vogel, Acting Branch Chief,

### RAB**~** Associate Division Direc tor, HED

### (7509P)**~**

TO: Barbar a Madden/Sidney J ackson, RM 05 Registration Division (RD; 7505P)

The HED of the Offic e of Pesticide Programs (O PP) is charged with estimating the risk to human
health from exposure to pesticides. The RD of OPP has requ ested that HED evaluate ha zard and

ex posure data and conduct dietary, occupational

, re s idential, and aggregate exposure assessments, as needed

, to estimate the ri sk to human health that will result from the proposed
Section 3 registration uses of the active ingredient (ai) quinoxyfen (5,7-dichloro-4-(4

- fluorophenoxy)quino li ne) on vegetable, fruiting, group 8-1 0 ; fruit, small vine c li mbing, except fuzzy kiwifruit, subgroup 13-07F; and berry

, low g r ow in g s ubgrou p 1 3-07G.

A summary of the findings and an assessment of human -he alth risk resultin g from the proposed
and registered uses of quinoxyfen are provided i n th i s document. The risk assessment, re sidue chemistry assessment, and dietary exposure assessment were provided by George Kram er ( RAB 1 ); the hazard characterizat i on and endpoint selection by Monique Perron (RAB 1 ); the

occupa t iona l exposure and re sidentia l assessment by Jennifer Tyler (RAB 1 ); and the drinking

water exposure assessment by Karen Milians of the Env ironmental Fate and Effects Division

Page I of32Quinoxyfen Human

- Health Risk Assessment DP#41069l

( EFE D)

.

The most recent human-health risk assessment for quinoxyfen, for a Section 3 registration
request for use on stone fruits crop group 12 (excluding cherry)

, artichoke, and winter squash,

was completed on 22-JAN

- 2009 (B. Hanson

, D351021)

.

Page 2 of32Quinoxyfen Human

- Health Risk Assessment DP# 410691

Page 3 of 32 Table of Contents
1.0 Executive Summary

................................ ................................ ................................ ........... 5
2.0 HED Recommendations

................................ ................................ ................................ .... 7
2.1 Data D eficiencies

................................ ................................ ................................ ............ 7
2.2 Tolerance Considerations

................................ ................................ .............................. 8
2.2.1 Enforcement Analytical Method

................................ ................................ ............... 8
2.2.2 Recommended Tolerances

................................ ................................ ......................... 8
2.2.3 Revisions to Petitioned

- For Tolerances

................................ ................................ .... 8
2.2.4 International Harmonization

................................ ................................ ..................... 9
2.3 Label Recommendations

................................ ................................ ................................ 9
3.0 Introduction

................................ ................................ ................................ ........................ 9
3.1 Chemical Identity

................................ ................................ ................................ ........... 9
3.2 Physical /Chemical Characteristics

................................ ................................ ............... 9
3.3 Pesticide Use Pattern

................................ ................................ ................................ .... 10
3.4 Anticipated Exposure Pathways

................................ ................................ ................. 11
3.5 Consideration of Environmental Justice

................................ ................................ .... 11
4.0 Hazard Characterization and Dose

- Response Assessment

................................ .......... 11
4.1 Toxicology Studies Available for Analysis

................................ ................................ . 11
4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)

............................. 12
4.2.1 Dermal Absorption

................................ ................................ ................................ ... 12
4.3 Toxicological Effects

................................ ................................ ................................ .... 13
4. 3.1 Summary of Toxicological Effects

................................ ................................ ........... 13
4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

............................... 13
4.4.1 Completeness of the Toxicology Database

................................ .............................. 14
4.4.2 Evidence of Neurotoxicity

................................ ................................ ........................ 14
4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

........ 14
4.4.4 Residual Uncertainty in the Exposure Database

................................ ................... 14
4.5 Toxicity Endpoint and Point of Departure Selections

................................ .............. 15
4.5.1 Dose

- Response Assessment

................................ ................................ ...................... 15
4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

..... 16
4.5.3 Cancer Classification and Risk Assessment Recommendation

............................ 16
4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk
Assessment

................................ ................................ ................................ ............................... 16
5.0 Dietary Exposure and Risk Assessment

................................ ................................ ......... 18
5.1 Residues of Concern Summary and Rationale

................................ .......................... 18
5.2 Food Residue Profile

................................ ................................ ................................ .... 19
5.3 Water Residue Profile

................................ ................................ ................................ .. 19
5.4 Di etary Risk Assessment

................................ ................................ .............................. 20
5.4.1 Description of Residue Data Used in Dietary Assessment

................................ .... 20
5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ .............. 20
5.4.3 Acute Dietary Risk Assessment

................................ ................................ ............... 20
5.4.4 Chronic Dietary Risk Assessment

................................ ................................ ........... 20
5.4.5 Cancer Dietary Risk Assessment

................................ ................................ ............. 21
6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

............................. 21
6.1 Residential (Non

- Occupational) Exposure/Risk Character ization

............................. 21
6.2 Residential Bystander Post

- application Inhalation Exposure

................................ ..... 21
6.3 Spray Drift

................................ ................................ ................................ ........................ 22
7.0 Aggregate Exposure/Risk Characterization

................................ ................................ .. 22
7.1 Acute Aggregate Risk

................................ ................................ ................................ ... 22Quinoxyfen Human

- Health Risk Assessment DP# 410691

Page 4 of 32 7.2 Chro nic Aggregate Risk

................................ ................................ .............................. 22
8.0 Cumulative Exposure/Risk Characterization

................................ ............................... 23
9.0 Occupational Exposure/Risk Characterization

................................ ............................ 23
9.1 Short

- and Intermediate

- Term Handler Risk

................................ ........................... 23
9.2 Short

- and Intermediate

- Term Post

- Application Risk

................................ ............. 25
9.2.1 Dermal Post

- Application Risk

................................ ................................ ................. 25
9.2.2 Inhalation Post

- Application Risk

................................ ................................ ............ 25
10.0 References

................................ ................................ ................................ ......................... 26 Appendix A. Toxicology Profile and Executive Summaries

................................ .................. 27
A.1 Toxicology Data Requirements

................................ ................................ ................... 27
A.2 Toxicity Profiles

................................ ................................ ................................ ............ 28 Appendix B. Physical/Chemical Properties

................................ ................................ ............. 31 Appendix C. Review of Human Research

................................ ................................ ................ 32Quinoxyfen Human

- Health Risk Assessment DP# 410691

Page 5 of 32 1.0 Executive Summary

Background : Quinoxyfen is a systemic quinoline fungicide. Its proposed mode of action is the
inhibition of GTP

- binding proteins (G

- proteins) affecting intracellular signaling. Quinoxyfen was developed for the control of powdery mildews on a variety of crops.

Perm anent tolerances are established for residues of quinoxyfen per se [40 CFR §180.588 (a)] in/on cherries (0.30 ppm); grapes (0.60 ppm); hop, dried cones (3.0 ppm); lettuce, head (7.0 ppm); lettuce, leaf (19 ppm); pepper, bell (0.35 ppm); pepper, nonbell (1. 7 ppm); strawberry (0.90 ppm); pumpkin (0.30 ppm); squash, winter (0.30 ppm); and melon subgroup 9A (0.08 ppm).

The Interregional Research Project Number 4 (IR

- 4) has submitted a Section 3 request to register
a 22.58% ai suspension

- concentrate (SC) formulation ( Quintec ® , EPA Reg. No. 62719

- 375 ) for

use on vegetable, fruiting, group 8

- 10; fruit, small vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F; and berry, low growing subgroup 13

- 07G . The end

- use products are p roposed
for 4 to 5 foliar spray applications at 0.098

- 0. 11 lb ai/A/application with minimum retreatment intervals (RTIs) of 7

- 21 days, for maximum seasonal rates of 0. 39

- 0.54 lb ai/A. The proposed
label allow s for applications via aerial and/or groundboom equipment, depending on the crop. Preharvest intervals (PHIs) of 1

- 14 days are proposed. The rotational crop plantback intervals (PBIs) are 30 days for all non

- labeled crops. In conjunction with this petition, IR

- 4 has requested the establishment of pe rmanent tolerances for the residues of the fung icide quinoxyfen
in or on the commodities summarized in Table 2.2.2.

Hazard Assessment : The primary target organs affected by quinoxyfen are the liver and kidney. The most sensitive species was the rat. Li ver effects were seen in the subchronic rat and mouse studies as well as the chronic dog study. Subchronic effects observed in rats and mice at high doses included increased liver weights, hepatocellular hypertrophy, and individual cell hepatocellular nec rosis. Chronic effects observed in the dog included increased liver weights, increased alkaline phosphatase levels, and increased incidence of very slight to slight microscopic hepatic lesions. Kidney effects were only noted in the rat combined
chronic/c arcinogenicity study that resulted in an increased severity of chronic progressive glomerulonephropathy in males. Body

- weight decrements were noted in the rat and/or mouse subchronic, chronic and carcinogenicity studies as well as the rabbit developmental and rat reproduction studies.

Oral rat and rabbit developmental studies showed no increased qualitative or quantitative susceptibility of offspring to quinoxyfen in utero . In the rabbit developmental toxicity study, maternal and developmental toxicity were observed at the highest dose tested ( lowest

- observed
adverse

- effect level ; LOAEL = 200 mg/kg/day). Maternal effects included inanition, clinical signs, decreased body weight and body

- weight gains, decreased food consumption, and increased
incidence of abortion late in pregnancy. Developmental toxicity was evidenced as increased incidence of abortion late in pregnancy. No maternal or developmental toxicity was observed in the rat developmental study up to the limit dose of 1000 mg/kg/day. In the tw o

- generation rat reproduction study, no parental effects were observed up to the highest dose tested (100 mg/kg/day) while first

- generation pup weights were reduced at the same dose. There is apparent quantitative susceptibility when looking at the two

- ge neration reproductive study in isolation, but when using a weight

- of

- evidence approach that puts the offspring findings in the two

- generation reproduction toxicity study in context with the full toxicological database there is no concern forQuinoxyfen Human

- Health Risk Assessment DP# 410691

Page 6 of 32 susceptibility to offspring since it is anticipated that parental toxicity would have been observed
at the same dose.

Quinoxyfen was categorized as having low acute toxicity via the inhalation, oral, and dermal routes (Toxicity Category III or IV). It is a mild eye irritant (Toxicity Category III) and classified as a dermal sensitizer, but not a dermal irritant.

There is no evidence of carcinogenicity based on studies in rats or mice. Quinoxyfen did not show evidence of mutagenicity in in vitro or in vivo studies

.

No evidence of neurotoxicity or neuropathology was seen in any of the submitted studies.

An immunotoxicity study submitted since the most recent risk assessment showed no evidence of immunotoxicity up to the highest dose tested

.

The RAB1 risk assessment team for quinoxyfen determined that the Food Quality Protection Act (FQPA) Safety Factor (SF) should be reduced to 1X for all exposure scenarios for the following

reasons (see Section 4.4 for a full discussion ) : the toxicological database is adequate for FQPA assessment, there is no evidence of neurotoxicity, there is low concern for offspring susceptibility , and there is no uncertainty in the exposure database , as discussed in Section 4.4.

Food Residue Profile: The nature of the residue in plants is adequately understood in the subject crops . Organization for Economic Co

- operation and Development (OECD) tolerance

calculation procedures and the submitted residue data sets were used to calculate the HED

recommended tolerances. Th ere is an adequate residue analytical method for the purposes of
tolerance enforcement. The submitted magnitude of the residue data are adequate and there are no residue chemistry issues that would preclude establishing unconditional tolerances for
residu es of quinoxyfen , as outlined in Table 2.2.2.

Exposure/Risk Assessment Characterization: No toxic effects attributable to a single (i.e., acute) exposure to quinoxyfen have been identified; therefore, an acute dietary exposure
assessment has not been con ducted. A chronic risk assessment w as conducted for dietary exposure based on the existing and proposed uses. The assessment directly incorporated drinking water estimates. Assumptions for the chronic assessment included tolerance

- level
residues and 100 % crop

- treated (CT) for registered and proposed uses, and Dietary Exposure Evaluation Model (DEEM) 7.81 default processing factors (where provided). A cancer dietary assessment was not conducted because quinoxyfen is classified as “not likely to be carcin ogenic to humans.” The chronic dietary risk estimates are below HED’s LOC (<100% of the cPAD) for the general U.S. population and all population subgroups. The most highly exposed population subgroup is children 1

- 2 years old with a risk estimate of 8.5% of the cPAD.

There are no registered or proposed residential uses for quinoxyfen ; therefore, a residential

exposure assessment was not conducted.

Short

- and intermediate

- term assessments, which are used to evaluate aggregate dietary and residential exposures, were not performed because there are no registered or proposed residential

non

- food uses. Since there are no residential uses, the chronic ag gregate risks are made up only of dietary sources (food and drinking water) and the dietary exposure analys i s represent s chronic aggregate exposure. Quinoxyfen is classified as “ n ot l ikely to be c arcinogenic to h umans”;Quinoxyfen Human

- Health Risk Assessment DP# 410691

Page 7 of 32 therefore, a c ancer aggregate risk assessment w as not performed. The chronic aggregate risk estimates do not exceed the HED’s level of concern (LOC) for the general U.S. population and all population subgroups.

Base d on the proposed use patterns, short

- and intermediate

- term occupational exposures are expected. There are no short

- and intermediate

- term dermal endpoints or points of departure (PODs); therefore, a quantitative dermal handler assessment was not conducted. In addition, the
short

- and intermediate

- term inhalation PODs are the same; therefore, estimates for short

- term durations are protective of longer

- term. Chronic occupational exposure is not expected for the proposed uses. As quinoxyfen is classified as “not likely” to be carcinogenic to humans, a
cancer risk assessment is not necessary. A margin of exposure (MOE) ≥ 100 is adequate to protect occupational pesticide hand lers from inhalation exposures.

For the scenarios where baseline data are available, all short

- and intermediate

- term inhalation risk estimates for occupatio nal handlers are above the LOC ( MOE ≥ 100 ) with baseline protection (i.e., long

- sleeved shirt, long pants, shoes, and socks). Only engineering control data (i.e., enclosed cockpits) are available for aerial application scenarios. All inhalation risk
estim ates for occupational aerial applicators are above the LOC ( MOE ≥ 100 ) with baseline clothing and enclosed cockpits.

In the absence of a short

- and intermediate

- term dermal POD, a quantitative short

- and
intermediate

- term dermal post

- application exposure a ssessment was not conducted. Based on the Agency's current practices, a quantitative non

- cancer occupational post

- application inhalation exposure assessment was not performed for quinoxyfen at this time. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post

- application inhalation exposure assessment for quinoxyfen

.

Quinoxyfen is classified in acute T oxicity C ategory III for acute dermal and primary eye
irritation. It is classified in Toxic ity Category IV for acute oral, acute inhalation and primary
skin irritation and classified as a dermal sensitizer. The Worker Protection Standard (WPS)
interim restricted

- entry i nterval (REI) of 12 hours is sufficient to protect workers.

This risk asses sment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. Please refer to Appendix C for a discussion of the human study data used in this risk assessment.

2.0 HED Recommendati ons

Pending submission of a revised Section F (see Section 2.2.2) , there are no other residue chemistry, occupational, or toxicology data deficiencies that would preclude the establishment of permanent tolerances for residues of quinoxyfen and it metaboli tes and degradates as outlined in
Table 2.2.2.

2.1 Data Deficiencies

860.1550 Proposed Tolerances

The petitioner is requested to submit a revised Section F specifying the following:Quinoxyfen Human

- Health Risk Assessment DP# 410691

Page 8 of 32 Revised tolerance expression, as presented in Section 2.2.2. Revised tolerance levels, as presented in Table 2.2.2.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate gas chromatography/mass

- selective detector (GC/MSD) method is available for enforcing quinoxyfen tolerances (DowElanco Pr ocedure ERC95.26); a successful petition method validation (PMV) has been completed (Memo, E. Kolbe, 5/11/06; D285350). The lowest level of method validation (LLMV) was 0.01 ppm. Samples from the submitted field and processing studies were analyzed using a high

- performance liquid chromatography/mass spectrometry (HPLC/MS) method derived from Dow AgroSciences Report RF 98

- 200 dated 5/31/99; method entitled “Determination of Residues of Quinoxyfen Applied as EF

- 1295 in Hops.” The LLMV was 0.01 ppm for quin oxyfen in all tomato matrices.

2.2.2 Recommended Tolerances

In accordance with the most recent guidance concerning tolerance expressions, HED recommends that the tolerance expression for 40 CFR § 180.588 be changed as indicated below.

CFR §180.588 (a ) General. Tolerances are established for residues of the fungicide quinoxyfen, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring o nly quinoxyfen (5,7

- dichloro

- 4

- (4

- fluorophenoxy)quinoline).

The proposed uses and the submitted data support the following permanent tolerances for
residues of quinoxyfen in or on the commodities summarized in Table 2.2. 2

.

Note to RD: With the establishment of these tolerances, the tolerances for the following commodities should be deleted from 40 CFR §180.588 (a): grape; pepper, bell; pepper, nonbell; and strawberry.

Table 2.2.2. Tolerance Summary for Quinoxyfen

.

Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments; Correct Commodity Definition Vegetable, fruiting, group 8

- 10 1.7 1.7

Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F 0.60 2.0

Berry, low growing, subgroup 13

- 07G 0.90 1.0

2.2.3 Revisions to Petitioned

- For Tolerances

HED is recommending increases in the proposed tolerances for residues of quinoxyfen in/on the berry, low growing subgroup 13

- 07G and the fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F in order to harmonize with the Codex maximum resid ue limits (MRLs; seeQuinoxyfen Human

- Health Risk Assessment DP# 410691

Page 9 of 32 Section 2.2.4)

.

2.2.4 International Harmonization

Codex MRLs are established for residues of quinoxyfen per se in/ on grapes, strawberries, and peppers. HED is recommending increases in the proposed U.S. tolerances for residues of quinoxyfen in/on the berry, low growing subgroup 13

- 07G and the fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F in order to harmonize with the Codex MRLs. Harmonization of the proposed U.S. tolerance for residues of quinoxyfen in/on the vegetable, fruiting, group 8

- 10 (1.7 ppm) with the Codex MRL for peppers (1 ppm) is not possible as the
U.S. tolerance would need to be re duced significantly (residue data from field trials conducted in the U.S. show that the Codex MRL is too low).

Harmonization with the Canadian MRL for grapes (0.5 ppm) is not possible because harmonization with the Codex MRL necessitates a higher toleranc e (2.0 ppm) for residues of quinoxyfen in/on the fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F.

2.3 Label Recommendations

T he proposed label (Quintec ® ; EPA Reg. No 62719

- 375 ) lists the maximum application rate for tomato as 6 oz pr oduct/gal, which equates to 0.098 lb ai/A [(6 oz product/gal) x (1 gal/128 oz) x (2.08 lb ai/gal) = 0.098 lb ai/A]. This rate differs from Section B of the petition, which lists the maximum application rate for tomatoes as 0.13 lb ai/A. HED requests clar ification of the intended application rate for tomatoes.

3.0 Introduction

3.1 Chemical Identity

Table 3.1. Quinoxyfen Nomenclature.

Chemical Structure

Common name Quinoxyfen
Company name Not applicable

Chemical class Quinoline fungicide

IUPAC name 5,7

- dichloro

- 4

- quinolyl 4

- fluorophenyl ether

CAS name 5,7

- dichloro

- 4

- (4

- fluorophenoxy)quinoline

CAS # 124495

- 18

- 7

End

- use product/EP 2.08 lb ai/gal SC formulation; Quintec ® (EPA Reg. No 62719

- 375)Quinoxyfen Human

- Health Risk Assessment DP# 410691

Page 10 of 32 3.2 Physical/Chemical Characteristics

Quintec ® is a protectant fungicide used to control powdery mildew infections on grapes and hops. Quintec ® cannot control existing or latent infections; therefore, the pesticide must be applied before infections occur. Quinoxyfen has chemical properties that imply that it may be persistent in the environment under certain conditions. However, once it is in the soil, the studies show quinoxyfen is immobile to slightly mobile depending on the soil type. Quinoxyfen is rapidly metabolized under aquatic conditio ns, but more stable under terrestrial conditions. The water solubility and the Kd / Koc values indicate quinoxyfen is fairly insoluble and will adsorb tightly to soil particles. Its vapor pressure is 1.2 x 10 - 5 Pa at 20 oC. A summary of the physicochemica l properties can be found in Appendix B.

3.3 Pesticide Use Pattern

There is currently one quinoxyfen end

- use product (EP) registered to Dow AgroSciences LLC
for use on food/feed crops: Quintec ® , a 22.58% ai SC (EPA Reg. No. 62719

- 375). IR

- 4 is

suppor ting the use of Quintec ® on vegetable, fruiting, group 8

- 10; fruit, small vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F; and berry, low growing subgroup 13

- 07G. Example labels were provided and the proposed use directions are summarized in Table 3 .3.1

.

Table 3.3.1. Summary of Proposed Use Directions for Quinoxyfen.

Application Timing, Type and Equipment Formulation [EPA reg. No.] Single

Rate (lb ai/A) Max Number

Applications per Season Max. Seasonal

Application Rate (lb ai/A) PHI

(Days) Use Directions

and
Limitations 1
Vegetable, Fruiting, Group 8

- 10 Directed foliar applications Ground equipment Quintec ®
[62719

- 375] 0.098 4 0.39 3 The minimum

r etreatment interval (RTI)
is 7

- 14 days. Fruit, Small Vine Climbing, Except Fuzzy Kiwifruit, Subgroup 13

- 07F Directed foliar applications Ground equipment Quintec ®
[62719

- 375] 0.11 5 0.54 14 The minimum
RTI is 7

- 21 days. Berry, Low Growing Subgroup 13

- 07G Directed foliar applications Ground equipment Quintec ®
[62719

- 375] 0.098 4 0.39 1 The minimum
RTI is 10

- 14 days.

1 Crops having quinoxyfen tolerances may be replanted at any time, all other crops require a 30

- day PBI.

Conclusions : The proposed use patterns are adequate to allow evaluation of the residue data submitted in support of this petition.

It should be noted that the proposed label (Quintec ® ) lists the maximum application rate for tomato as 6 oz product/gal, which equat es to 0.098 lb ai/A [(6 oz product/gal) x (1 gal/128 oz) x (2.08 lb ai/gal) = 0.098 lb ai/A]. This rate differs from Section B of the petition, which lists the maximum application rate for tomatoes as 0.13 lb ai/A. HED requests clarification of the
inten ded application rate for tomatoes. For the purposes of this risk assessment, HED assumed the proposed label rate to be correct.Quinoxyfen Human

- Health Risk Assessment DP# 410691

Page 11 of 32 3.4 Anticipated Exposure Pathways

RD has requested that HED evaluate hazard and exposure data and conduct dietary, occupation al, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from the proposed Section 3 registration uses of quinoxyfen on vegetable, fruiting, group 8

- 10; fruit, small vine climbing, except fuzzy k iwifruit, subgroup 13

- 07F; and berry, low growing subgroup 13

- 07G

. Humans may be exposed to quinoxyfen in food and drinking water, since quinoxyfen may be applied directly to growing crops and application may result in quinoxyfen reaching surface and grou nd water sources of drinking water. There
are no residential uses of quinoxyfen , so exposure in residential or non

- occupational settings is not likely. In an occupational setting, applicators may be exposed while handling the pesticide prior to applicati on, as well as during application. There is also a potential for post

- application exposure for workers re

- entering treated fields.

This risk assessment considers all of the aforementioned exposure pathways based on the proposed new uses of quinoxyfen , but also considers the existing registered uses as well.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U. S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations,” (http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf). As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to
well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumptio n, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture (USDA) under the National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA; 2003

- 2008) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of t he country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

Quinoxyfen is a quinoline fungicide that acts by inhibiting GTP

- binding proteins (G

- proteins) in intracellular signaling.

4.1 Toxicology Studies Available for Analysis

This assessment includes summaries from the most recent human

- health risk assessment f orQuinoxyfen Human

- Health Risk Assessment DP# 410691

Page 12 of 32 quinoxyfen (B. Hanson, 22

- JAN

- 2009; D351021). The toxicological database for quinoxyfen is adequate for hazard characterization, toxicity endpoint selection, and FQPA SF evaluation. An immunotoxicity study (MRID# 48106301) has been submitted since the last risk assessment and the results incorporated into the current assessment. An in vivo dermal penetration study (MRID# 47830401) has been submitted and classified as acceptable/non

- guideline. In the absence of any further information, the results of this study can be used for risk assessment

purposes.

The classification of the rat metabolism study (MRID # s 45360605 and 45360606) has been changed from unacceptable/upgradable to acceptable/non

- guideline (M. Perron, 26

- MAR

- 2013;
TXR# 0056612 ) since the l ast risk assessment. It is suitable at this time for risk assessment in the absence of any further data. If a need for additional metabolic information for quinoxyfen arises that may affect future risk assessments, then the classification of this study m ay be
reevaluated

.

HED previously requested a 28

- day inhalation study to characterize the effects of quinoxyfen via the inhalation route. The HED Hazard and Science Policy Council (HASPOC) concluded

, using a weight

- of

- evidence approach

, that the 28

- day inhalation study was not required at this time (K. Rury, 20

- MAR

- 2013; TXR# 0056609).

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)

Following oral administration of radiolabeled quinoxyfen ([2

- Quinoline

14 C] XDE

- 795), peak plasma concentrations occurred within 0.5

- 1.5 hours for all treatment groups. Plasma clearance of radioactivity was biphasic with a half

- life ≤1 hour for the rapid/primary phase and 15

- 19 hours for the slower/secondary phase at the low dose . At the higher dose of 500 mg/kg, the
clearance half

- life values increased to 2

- 3 hours and 18

- 22 hours for the rapid and slow phases, respectively, suggesting saturation of clearance at this higher dose level. In the bile

- duct

cannulated male rats, 14.3% dose was found in t he feces at 10 mg/kg and 57.3% dose at 500 mg/kg, indicating that the fraction unabsorbed increases with the higher dose level tested. Within 24 hours of dosing, 68

- 85% dose was recovered in the excreta of all groups. Quinoxyfen was extensively metaboliz ed in rats with major metabolites identified in the urine, bile, and feces. The major routes of elimination were through the urine and feces for both radiolabels of quinoxyfen (45

- 49% urine and 38

- 40% feces for [Phenyl

- U

14 C] XDE

- 795; 13

- 20% urine and
66

- 78% feces for [2

- Quinoline

14 C] XDE

- 795). Concentrations of radioactivity were detected in the kidneys, liver, ovaries, perirenal fat, gastrointestinal (GI) tract, and carcass. Generally, tissue concentrations of radioactivity were slightly lower in the males than females and lower in the 10

- mg/kg group than the 500

- mg/kg group.

4.2.1 Dermal Absorption

A dermal

- absorption factor of 34% was identified from t he maximum systemic absorption observed in the rat dermal penetration study (MRID# 47830401). A dermal

- absorption factor was not needed for this risk assessment because no dermal endpoint was chosen ( Section 4.5.1).Quinoxyfen Human

- Health Risk Assessment DP# 410691

Page 13 of 32 4.3 Toxicological Effects

4.3.1 Summa ry of Toxicological Effects

The primary target organs affected by quinoxyfen are the liver and kidney. The most sensitive species was the rat. Liver effects were seen in the subchronic rat and mouse studies as well as the chronic dog study. Subchronic effects observed in rats and mice at high doses included increased liver weights, hepatocellular hypertrophy, and individual cell hepatocellular necrosis. Chronic effects observed in the dog included increased liver weights, increased alkaline phosphatase levels, and increased incidence of very slight to slight microscopic hepatic lesions. Kidney effects were only noted in the rat combined chronic/carcinogenicity study that resulted in an increased severity of chronic progressive glomerulonephropathy in m ales. Body

- weight decrements were noted in the rat and/or mouse subchronic, chronic

, and carcinogenicity studies as well as the rabbit developmental and rat reproduction studies.

Oral rat and rabbit developmental studies showed no increased qualitative or quantitative susceptibility of offspring to quinoxyfen in utero . In the rabbit developmental toxicity study, maternal and developmental toxicity were observed at the highest dose tested (LOAEL = 200 mg/kg/day). Maternal effects included inanition, cl inical signs, decreased body weight and body

- weight gains, decreased food consumption, and increased incidence of abortion late in pregnancy. Developmental toxicity was evidenced as increased incidence of abortion late in pregnancy. No maternal or develo pmental toxicity was observed in the rat developmental study up to the limit dose of 1000 mg/kg/day. In the two

- generation rat reproduction study, no parental effects were observed up to the highest dose tested (100 mg/kg/day) while first

- generation pup

w eights were reduced at the same dose. There is apparent quantitative susceptibility when looking at the two

- generation reproductive study in isolation, but when using a weight

- of

evidence approach that puts the offspring findings in the two

- generation rep roduction toxicity study in context with the full toxicological database there is no concern for susceptibility to offspring since it is anticipated that parental toxicity would have been observed at the same dose (see section 4.4.3)

.

Quinoxyfen was cat egorized as having low acute toxicity via the inhalation, oral, and dermal routes (Toxicity Category III or IV). It is a mild eye irritant (Toxicity Category III) and classified as a dermal sensitizer, but not a dermal irritant.

There is no evidence of carcinogenicity based on studies in rats or mice. Quinoxyfen did not show evidence of mutagenicity in in vitro or in vivo studies.

No evidence of neurotoxicity or neuropathology was seen in any of the submitted studies.

An immunotoxicity study submitted since the most recent risk assessment showed no evidence of immunotoxicity up to the highest dose tested

.

4.4 Safety Factor for Infants and Children (FQPA SF)

The RAB1 risk assessment team for quinoxyfen determined that the FQPA SF should be reduced to 1X for all exposure scenarios for the following reasons: the toxicological database is adequate for FQPA assessment, there is no evidence of neurotoxicity, there is low concern for offspring susceptibility , and there is no uncertainty in the exposure database.Quinoxyfen Human

- Health Risk Assessment DP# 410691

Page 14 of 32 4.4.1 Completeness of the Toxicology Database

The existing toxicological database is adequate for characterizing quinoxyfen toxicity and quantification of hazard for dietary and occupational exposures. The developmental toxicity studies in rats and rabbits, two

- generation reproduction toxicity study in rats, and acute and subchronic neurotoxicity studies are available to assess potential fetal/offspring se nsitivity.

4.4.2 Evidence of Neurotoxicity

There is no evidence of neurotoxicity from quinoxyfen exposure. A developmental neurotoxicity study was not required since there was no evidence of neurotoxicity or neuropathology in the acute or subchronic neu rotoxicity studies or any other submitted study.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

In isolation, there is evidence of increased quantitative susceptibility in the two

- generation reproduction toxicity study. N o parental effects were observed up to the highest dose tested (100 mg/kg/day) while first

- generation pup weights were reduced at the same dose. Concern is low
since: 1) the effects in pups are well characterized with a clear no

- observed adverse

- effect l evel (NOAEL) ; 2) the pup effects are only noted in the first

- generation offspring; and 3) the doses and endpoints selected for risk assessment are protective of the pup effects noted in the rat reproduction study. Additionally, taking into consideration t he full toxicological database, there would be no susceptibility to offspring since assessments to parental animals are intentionally
limited in the two

- generation reproduction study to avoid stressing dams and affecting the rearing and care of offspring. If additional evaluations had been performed on parental animals
in the two

- generation reproduction study, including histopathology and organ weight assessments, then it is expected that the kidney and liver effects observed in the rat subchronic
oral stu dy and in the interim (12 months) and final sacrifices of the rat chronic toxicity/carcinogenicity study would have been seen at the 100

- mg/kg/day dose in the reproduction study. Therefore, when using a weight

- of

- evidence approach that puts the offspring findings in the two

- generation reproduction toxicity study in context with the full toxicological database there is no concern for susceptibility to offspring since it is anticipated that parental toxicity would have been observed at the same dose.

In utero exposure in developmental studies did not display quantitative or qualitative evidence of increased susceptibility of rat or rabbit offspring.

4.4.4 Residual Uncertainty in the Exposure Database

The chronic dietary food exposure assessment utilizes existing and proposed tolerance

- level residues, DEEM 7.81 default processing factors (where provided), and 100% CT information for all commodities. By using these screening

- level assessments, actual exposures/ris ks will not be
underestimated.

The dietary drinking water assessments utilize water concentration values generated by the FQPA Index Reservoir Screening Tool (FIRST) model . The resulting screening

- level estimated drinking water concentrations (EDWCs) pro vide conservative, health

- protective, high

- end
estimates of water concentrations that will not likely be exceeded.Quinoxyfen Human

- Health Risk Assessment DP# 410691

Page 15 of 32 There are no registered residential uses of quinoxyfen ; therefore, residential exposures are not anticipated.

4.5 Toxicity Endpoint and P oint of Departure Selections

Changes were made to the occupational toxicity endpoints since the last risk assessment. A dermal endpoint was not selected therefore occupational dermal exposures were not assessed. Additionally, the subchronic oral and the two

- generation reproduction toxicity stud ies in rats
were considered co

- critical studies for occupational inhalation exposures. The PODs, uncertainty factors (UFs) , and toxicity endpoints are presented in Table 4.5.4.1 (dietary and non

occupational asses sments) and Table 4.5.4.2 (occupational assessments).

4.5.1 Dose

- Response Assessment

Acute Dietary Endpoint (all populations): There were no effects observed attributable to a single
dose for the general population (including infants and children) or females 13

- 49 years of age; therefore, an endpoint was not selected for this exposure scenario

. There were no effects seen in the acute neurotoxicity study up to the limit dose. Abortions observed in the rabbit developmental study were not considered an appropriate endpoint for females 13

- 49 years of age because abortions occurred late in pregnancy in the presence of substantial maternal toxicity.

Chronic Dietary Endpoint (all populations): The chronic reference dose (cRfD) was established
based on th e NOAEL (20 mg/kg/day) from the rat combined chronic toxicity/carcinogenicity study. The LOAEL of 80 mg/kg/day is based on increases in severity of chronic progressive glomerulonephropathy in the males and minimal decreases in body weight and body

- weight gain in both sexes. The NOAEL of 20 mg/kg was chosen because the study and endpoint are appropriate for the route and duration of exposure. The cRfD of 0.2 mg/kg/day is derived from the NOAEL of 20 mg/kg/day and a 100

- fold uncertainty factor ( 10X for int erspecies extrapolation, 10X for intraspecies variation

, and 1X for FQPA SF). For reasons outlined in Section 4.4, the FQPA SF has been reduced to 1X for this exposure scenario.

Short

- and Intermediate

- Term Incidental Oral Exposure: There are no registered or proposed residential uses for quinoxyfen. Therefore, an endpoint for incidental oral exposure was not
selected.

Short

- and Intermediate

- Term Dermal Endpoints: A dermal endpoint was not selected. Dermal endpoints were chosen in previous risk assessments; however

, reevaluation of the full toxicological database yielded no dermal hazard. Since there is no concern for enhanced sensitivity/susceptibility to offspring from quinoxyfen exposure (as discussed in Section 4.4.3),
the effects of concern in adults and offspring are adequately assessed in the dermal toxicity study
where no adverse dermal or systemic effects were observed up to the limit dose (1000 mg/kg/day).

Short

- and Intermediate

- Term Inhalation Endpoints: The subchronic oral and two

- generation reproduction toxicity stud ies in rats were chosen as co

- critical studies for the short

- and
intermediate

- term occupational inhalation scenarios

. The LOAEL of 100 mg/kg/day in the subchronic oral study was based on decreased body

- weight gain in females, increased liver weights in males and slight hepatocellular hypertrophy in both sexes. The LOAEL of 100 mg/kg/day in the two

- generation reproduction study was based on decreased first generation pupQuinoxyfen Human

- Health Risk Assessment DP# 410691

Page 16 of 32 weights. The NOAE L in the subchronic oral study (10 mg/kg/day) is lower than the NOAEL in
the two

- generation reproduction study (20 mg/kg/day), but this is a reflection of dose selection. Therefore, the NOAEL from the two

- generation reproduction study of 20 mg/kg/day is

p rotective of effects seen in both studies. The LOC for inhalation exposure scenarios is for MOEs <100 (10X for interspecies extrapolation and 10X for intraspecies variation ). For inhalation exposure scenarios, 100% absorption of the oral dose should be a ssumed.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

For occupational risk

, only inhalation exposure s are of concern . Currently

, there are no registered residential uses of quinoxyfen

.

4.5.3 Cancer Classification and Risk Assessment Recommendation

The Agency classified quinoxyfen as “not likely to be carcinogenic to humans” by all routes of exposure based upon lack of evidence of carcinogenicity in rats and mice; therefore, a cancer risk assessment is not required.

4 .5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk
Assessment

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Quinoxyfen for Use in Dietary and Non

Occupational Human

- Health Risk Assessments.

Exposure/
Scenario POD Uncertainty/ FQPA Safety
Factors RfD, PAD, LOC

for Risk
Assessment Study and Toxicological Effects Acute Dietary (All Populations) Not

applicable Not applicable Not applicable No adverse effects attributable to a single dose were observed. As a result,
no hazard was identified and an endpoint was not selected to assess this exposure scenario. Chronic Dietary (All Populations) NOAEL =
20 mg/kg/day UF A = 10X

UF H = 10X

FQPA SF = 1X Chronic RfD =

0.2 mg/kg/day

cPAD = 0.2 mg/kg/day Combined chronic

toxicity/carcinogenicity (rat)

LOAEL = 80 mg/kg/day based on increases in severity of chronic progressive glomerulonephropathy in the males and decreases in body weight and body

- weight gain in both sexes.Quinoxyfen Human

- Health Risk Assessment DP# 410691

Page 17 of 32 Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Quinoxyfen for Use in Dietary and Non

Occupational Human

- Health Risk Assessments.

Exposure/
Scenario POD Uncertainty/ FQPA Safety
Factors RfD, PAD, LOC

for Risk
Assessment Study and Toxicological Effects

Incidental Oral
Short

- Term (1

- 30 days) an d
Intermediate

Term (1

- 6 months)

Dermal Short

Term (1

- 30 days)
and Intermediate

Term (1

- 6 months)

Inhalation Short

Term (1

- 30 days)
and Intermediate

term (1

- 6 months) Not

applicable Not applicable Not applicable No exposure is expected because there

are no residential uses. As a result, these exposure scenarios were not
assessed.

Cancer (oral, dermal, inhalation) Classified as “not likely to be carcinogenic to humans” based on the absence of carcinogenicity

in rats or mice

.

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no

- obs erved adverse

- effect level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. FQPA SF = FQPA Safety Factor. PAD = population

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

Table 4.5. 4 .2. Summary of Toxicological Doses and Endpoints for Quinoxyfen for Use in Occupational
Human

- Health Risk Assessments. Exposure/
Scenario POD UFs LOC for Risk
Assessment Study and Toxicological Effects

Dermal
Short

- Term (1

- 30 days) and
Intermediate

Term (1

- 6 months) Not

applicable Not applicable Not applicable A dermal endpoint was not selected. As a result, dermal exposure scenarios
were not assessed.

Inhalation
Short

- Term (1

- 30 days) and
Intermediate

term (1

- 6 months) NOAEL =

20 mg/kg/day

Inhalation

absorption
factor =
100% UF A = 10X

UF H = 10X Occupational

LOC for MOE =
100 90

- day oral toxicity (rat)

LOAEL = 100 mg/kg/day based on decreased body

- weight gain in females, increased liver weights in males and slight hepatocellular hypertrophy (centrilobular and midzonal) in both

sexes

.

Two

- generation reproduction toxicity study (rat)

LOAEL = 100 mg/kg/day based on a
decrease in first

- generation pup weights

.Quinoxyfen Human

- Health Risk Assessment DP# 410691

Page 18 of 32 Table 4.5. 4 .2. Summary of Toxicological Doses and Endpoints for Quinoxyfen for Use in Occupational
Human

- Health Risk Assessments. Exposure/
Scenario POD UFs LOC for Risk
Assessment Study and Toxicological Effects Cancer (oral, dermal, inhalation) Classified as “not likely to be carcinogenic to humans” based on the absence of carcinogenicity

in rats or mice

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no

- observed adv erse

- effect level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. MOE = margin of exposure. LOC = level of concern.

5.0 Dietary Exposure and Risk Assessment

An overview of the metabolism and environmental degradation of quinoxyfen can be found in
the 22

- JAN

- 2009 human

- health risk assessment (B. Hanson, D351021)

.

5.1 Residues of Concern Summary and Rationale

Plants (Primary Crops): Based on acceptable cucumber, grape, sugar beet, and tomato metabolism studies, the natur e of the residue in plants is adequately understood in the subject crops. The HED Metabolism Assessment Review Committee (MARC) has determined that the residue of concern for purposes of tolerance enforcement and risk assessment is the parent compound onl y (D227383, G. Kramer

, 26

- MAR

- 2003)

.

Plants (Rotational Crops): Dow AgroSciences previously submitted the results of limited rotational crop field trials for quinoxyfen on radish roots and tops, mustard greens, and on wheat grain, forage, hay, and straw conducted at a total seasonal application rate of ~0.39 lb ai/A (1 X). The study showed residues of quinoxyfen, 2

- oxo

- quinoxyfen, and DCHQ are each below 0.01 ppm at the 30

- day PBI and at all other PBIs that were examined. The proposed 30

- day PBI on the product labels is appropriate.

Livestock: There are no livestock feed items associated with the subject crops. Therefore, data requirements related to livestock (e.g., metabolism studies, methods, magnitude of the residue) are not pertinent to this petition.

Drinking Water: Environmental fate data suggest that parent is persistent in the environment and is stable to hydrolysis at pH 7 and 9, only susceptible to hydrolysis under acidic conditions (pH 4). The three major metabolites are: DCHQ (86% applied dose in hydrolysis at pH 4 in 4 days, 3% at pH 7 in 21 days), C FBPQ (91% in aqueous photolysis), and 3

- OH

- quinoxyfen (62% applied dose in aerobic soil metabolism). Under typical environmental pH ranges, DCHQ is not likely to be found in drinking water sources in substantial quantities; therefore, it can be
excluded a s a residue of concern. CFBPQ degraded rapidly as the aqueous photolysis study continued, with an estimated half

- life of 7 hours, and can also be excluded as a residue of
concern. 3

- OH

- quinoxyfen is stable in soil and there is a possibility of accumulati on with multiple applications. Due to the lack of soil partitioning data on this metabolite, there is uncertainty concerning its mobility. Because hydroxylation (the addition of the 3

- OH) is assumed to increase mobility relative to quinoxyfen, it is pres umed to have the potential to reach drinking water sources in significant quantities. Based on the structure similarity, this metaboliteQuinoxyfen Human

- Health Risk Assessment DP# 410691

Page 19 of 32 might have similar toxicity as the parent. Therefore, MARC recommends that for risk assessment, parent and 3

- OH

- quino xyfen are the residues of concern (D227383, G. Kramer

, 26

- MAR

- 2003 ).

Table 5.1. Summary of Metabolites and Degradates to be included in Risk Assessment and Tolerance Expression 1

.

Matrix Residues Included in Risk Assessment Residues Included in Tolerance Expression for Compliance Monitoring

Plants Subject

Crop s 2 Quinoxyfen Quinoxyfen

Rotational Crop Not Applicable 3 Not Applicable 3

Drinking Water Quinoxyfen and 3

- OH

- quinoxyfen Not Applicable

1 Memo, G. Kramer

, 20

- AUG

- 2013 ; D407728

. 2 For future new uses (i.e., on small grains), additional metabolism data may be required.

3 The following potential residues of concern were identified: quinoxyfen, 2

- oxo

- quinoxyfen, and DCHQ . None of these residues were found in the limited rotational crop field trials at a 30

- day PBI. Provided a 30

- day PBI is specified on the quinoxyfen labels and use rates are 0. 39 lb ai/A or below for annual crops , residues in rotational crops are not currently of concern for the risk assessment or for tolerance setting

.

5.2 Food Residue Profile

The submitted field trial residue data for tomatoes are adequate. The field trial data reflect the proposed use pattern; an adequate number of trials were conducted in the appropriate geographic regions; and samples were analyzed for the residue of concer n using validated data

- collection methods. The storage intervals were also validated. Using the OECD tolerance calculation procedures for the residue data indicate that the requested tolerance level for vegetable, fruiting, group 8

- 10 is appropriate. In addition , the previously submitted data on strawberries and grapes are adequate to support the expansion to the low

- growing berry 13

- 07G crop subgroup and the small fruit vine climbing subgroup 13

- 07F, except fuzzy kiwifruit, respectively.

The newly subm itted tomato and the previously submitted grape processing studies are also adequate. Separate tolerances are not required for residues in/on any of the processed fractions.

Dow AgroSciences previously submitted the results of limited rotational crop field trials for quinoxyfen on radish roots and tops, mustard greens, and on wheat grain, forage, hay, and straw (1X the proposed rate). The study showed all residues of concern were 0.01 ppm at the 30

- day
PBI and at all other PBIs that were examined. Th e proposed 30

- day PBI is appropriate.

5.3 Water Residue Profile

EFED provided Tier 1 ground and surface EDWCs for quinoxyfen and t he major transformation product

, 3

- OH

- quinoxyfen (Memo, K

. Milians

, 04

- 23

- 13 ; D 407730 ). Quinoxyfen is proposed for use by b oth aerial and ground application, with a single maximum application rate of 0.107
lbs ai /A (6.6 fl oz ai /A/application Quintec ® ) and a seven day minimum re

- application interval, for a maximum total application rate of 0.54 lbs ai /A/year (33 fl oz ai /A/yea r Quintec ® ). Because the new uses are proposed at lower maximum application rates than those for previously
assessed uses, EFED refers to the last assessment, dated October 20, 2008 (D351023).

The last drinking water assessment for quinoxyfen focused on the use on stone fruit group 12 (excluding cherries), artichokes, winter squash, pumpkins, and edible gourds. EDWCs wereQuinoxyfen Human

- Health Risk Assessment DP# 410691

Page 20 of 32 estimated using the FIRST model for surface water and the SCI

- GROW model for groundwater (EDWCs using PRZM

- GW were negligible, and th us do not supersede the SCI

- GROW EDWCs)

. In that assessment ( D351023 ), EDWCs were determined based on an annual application rate of 0.57 lb ai /A (five applications at 0.114 lb ai /A, with a re

- application interval of seven days), and an annual application rate of 0.52 lb ai /A (four applications at 0.13 lb ai /A,
with a re

- application interval of six days).

Table 5.3 . Tier I EDWCs Resulting From Applications of Quinoxyfen.

Use Pattern (Surface Water/FIRST model) Use (modeled rate) Acute (ppb) Chronic (ppb) Groundwater (SCIGROW) ppb

Surface water
Stone Fruits (FIRST) Aerial spray

(0.13lb ai /A x 4 applic.; total of 0.52

lb/A/yr) 9.3 0.66 3.1 x 10 - 3

Surface water
Cherries (FIRST) Orchard air blast spray

(0.114 lb ai /A x 5 applic.; total of

0.57 lb/A/yr) 9.9 0.62 3.4 x 10 - 3

Values in bold show the highest EDWCs, which are recommended for use in dietary risk assessment.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

A chronic dietary

- exposure and risk assessment was conducted using DEEM

- FCID, ver. 3.16 which incorporates consumption data from the USDA NHANES/WWEIA; 2003

- 2008. The assessments were performed for the general U.S. population and all population subgroups. The unrefined chronic analysis assumed DEEM 7.81 default concentration factors, and tolerance

level residues for all commodities. The drinking water estimate fr om the existing U.S. uses was incorporated directly into the dietary assessment using the concentration for surface water generated by the FIRST. The resulting screening

- level EDWC estimate of 0. 0006 6 ppm was used for the chronic assessment.

5.4.2 Perc ent Crop Treated Used in Dietary Assessment

The chronic dietary analys i s assumed 100% CT for all commodities.

5.4.3 Acute Dietary Risk Assessment

No toxic effects attributable to a single (i.e., acute) exposure to quinoxyfen have been identified;
ther efore, an acute dietary exposure assessment has not been conducted.

5.4.4 Chronic Dietary Risk Assessment

The chronic dietary risk estimates (food + water) were 2.4% of the cPAD for the general U.S. population and 8.5% of the cPAD for the most highly e xposed population subgroup (children 1

- 2 years old) and are thus below HED’s level of concern (>100% cPAD). A summary table of dietary exposure and risk for quinoxyfen can be found in Section 5.4.6. Although further refinement to the analysis is not requ ired at this time, future assessments could be refined using average field trial values, use of empirical processing factors, incorporation of % CT data, orQuinoxyfen Human

- Health Risk Assessment DP# 410691

Page 21 of 32 monitoring data.

5.4.5 Cancer Dietary Risk Assessment

A cancer dietary assessment was not performed because quinoxyfen was classified as “not likely to be carcinogenic to humans.”

5.4.6 Summary Table

Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure Risk for Quinoxyfen. *

Population Subgroup Acute Dietary (95 th Percentile) Chronic Dietary Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD General U.S. Population N/A N/A 0.006582 3.3 All Infants (<1 year old) N/A N/A 0.005601 2.8
Children 1

- 2 years old N/A N/A 0.016903 8.5
Children 3

- 5 years old N/A N/A 0.014353 7.2
Children 6

- 12 years old N/A N/A 0.007967 4.0
Youth 13

- 19 years old N/A N/A 0.005047 2.5
Adults 20

- 49 years old N/A N/A 0.005882 2.9
Adults 50

- 99 years old N/A N/A 0.005669 2.8
Females 13

- 49 years old N/A N/A 0.005907 3.0 *The values for the highest exposed population for each type of risk assessment are bolded.

6.0 Residential (Non

- Occupational) Exposure/Risk

6.1 Residential Exposure/Risk Characterization

There are no registered or proposed uses of quinoxyfen that result in residential exposures. Therefore, residential exposure is not expected, and no residential risk assessment was performed.

6.2 Residential Bystander Post

- A pplication Inhalation Exposure

Based on the Agency's current pr actices, a quantitative post

- application inhalation exposure assessment was not performed for quinoxyfen at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV) and the low proposed use rate (0.11 lb ai/A). However, vola tilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungic ide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 1 . The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are developed, then the Agency may revisit the need for a quantitative post

- application inhalation exposure assessment for quinoxyfen

.

1 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlQuinoxyfen Human

- Health Risk Assessment DP# 410691

Page 22 of 32 6. 3 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for quinoxyfen . The Agency has been working with the Spray Drift Task Force, EPA Regio nal Offices, and State Lead Agencies for pesticide regulation and other parties to develop the best spray

- drift

management practices (see the Agency’s Spray Drift website for more information 2 . The Agency has completed its evaluation of the new database s ubmitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT ® computer model to its risk assessments for pesticides applied by air, orchard airblast an d ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray

- drift

- management practices to reduce
off

- target drift with specific products with significant risk estimates associated with drift.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sourc es are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

Fo r quinoxyfen, an aggregate exposure risk assessment was performed for chronic aggregate exposure (food and drinking water). Short

- and intermediate

- term assessments, which are used to evaluate aggregate dietary and residential exposures, were not performe d because there are no registered or proposed residential non

- food uses. Quinoxyfen is classified as “ n ot l ikely to be

c arcinogenic to h umans”; therefore, cancer aggregate risk assessments were not performed.

7.1 Acute Aggregate Risk

No toxic effects attributable to a single (i.e., acute) exposure to quinoxyfen have been identified; therefore, an acute aggregate risk assessment has not been conducted.

7.2 Chronic Aggregate Risk

The chronic aggregate risk assessment takes into accou nt average exposure estimates from dietary consumption of quinoxyfen (food and drinking water). The chronic dietary exposure estimates are not of concern to HED (<100% cPAD) for the general U.S. population and all population subgroups (see Table 5.4.6). The dietary exposure assessment assumed 100% CT, DEEM 7.81 default concentration factors, and tolerance

- level residues for all commodities , and a Tier 1 chronic surface water EDWC generated by the FIRST model

.

2 Available: http://www.epa.gov/opp00001/factshe ets/spraydrift.htmQuinoxyfen Human

- Health Risk Assessment DP# 410691

Page 23 of 32 8.0 Cumulative Exposure/Risk Characteriz ation

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 quinoxyfen and any other substances and quinoxyfen does not appear t o produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore,
EPA has not assumed that quinoxyfen has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to dete rmine 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 cumul ating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

An occupational exposure assessment of the proposed uses was provided in a HED
memorandum dated 01

- AUG

- 2013 (Memo, J. Tyler; D4 1 0 694 ). For the proposed use sites, there is a potential for short

- and intermediate

- term occupational exposure to quinoxyfen during mixing, loading, applying, and other handling tasks, as well as during post

- application activities.
There are no short

- and interme diate

- term dermal endpoints and PODs; therefore, quantitative dermal handler and post

- application assessments were not conducted. Only inhalation handler exposure was assessed. Additionally, since the same endpoint and POD were selected for short

and in termediate

- term inhalation durations, short

- term inhalation exposure and risk estimates are considered to be protective of potential longer

- term exposure and risk. Chronic exposure is not expected for the proposed agricultural uses.

9.1 Short

- and Interm ediate

- Term Handler Risk

The scenarios assessed for occupational handlers include mixing/loading liquids to support aerial, airblast, and groundboom applications, applying sprays with aerial, airblast, and groundboom equipment, and flagging for liquid aer ial applications.

It is the policy of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical

- specific data, include Pesticide Handlers Exposure Database (PHED) 1 .1, the Agricultural Handler Exposure Task Force (AHETF) database, the Outdoor Residential Exposure Task Force (ORETF) database, or other registrant

- submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subjec t to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures,” are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate

R eference Table 3 ”, which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website 4

.

Estimates of inhalation exposure were calculated for various levels of p ersonal

- protective equipment (PPE). Results are presented for “baseline,” defined as a single layer of clothing

3 Available: http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdf

4 Available: http://www.epa.gov/pesticides/science/handler

- exposure

- data.htmlQuinoxyfen Human

- Health Risk Assessment DP# 410691

Page 24 of 32 consisting of a long

- sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as well as baseline with various lev els of PPE as necessary (e.g., gloves, respirator, etc). The proposed product label involved in this assessment directs applicators and other
handlers to wear a long

- sleeved shirt and long pants, socks, shoes, and chemical

- resistant gloves made of waterpr oof material.

Table 9.1.1 provides a summary of the estimated inhalation exposures and risks to occupational pesticide handlers. An MOE ≥100 is adequate to protect occupational pesticide handlers from inhalation exposure. For the scenarios where baselin e data are available, all inhalation risks for occupational handlers are above the LOC ( MOE ≥100 ) with baseline protection (i.e., long

sleeved shirt , no respirator , long pants, shoes, and socks) . Only engineering control data (i.e., enclosed cockpits) are available for aerial application scenarios. All inhalation risks for occupational aerial applicators are above the LOC ( MOE ≥100 ) with baseline clothing and enclosed cockpits

.

The Agency matches quantitative occupational exposure assessment with appropr iate characterization of exposure potential. While HED presents quantitative risk estimates for human flaggers where appropriate, agricultural aviation has changed dramatically over the past two decades. According to the 2012 National Agricultural Aviati on Association (NAAA) survey of their membership, the use of Global Positioning System (GPS) for swath guidance in agricultural aviation has grown steadily from the mid 1990s. Over the same time period, the use of human flaggers for aerial pesticide appli cations has decreased steadily from ~15% in the late 1990s to only 1% in the most recent (2012) NAAA survey

. The Agency will continue to monitor all available information sources to best assess and characterize the exposure potential for human flaggers in agricultural aerial applications.

Table 9.1.1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Quinoxyfen

.

Exposure
Scenario Crop or Target Inhalation Unit Exposure (μg/lb ai) 1 Maximum

Application
Rate 2 Area Treated

or Amount
Handled Daily 3 Inhalation

Mitigation Level Dose (mg/kg/day) 4 MOE 5

Mixer/Loader Liquids

– Aerial application Fruiting Vegetables (Group 8

-

10B), Low Growing Berry (Subgroup 13

- 07G) Baseline: 0.219 0.098 lb ai/A 350 A 0.0000939 210,000

Liquids

– Groundboom applications 80 A 0.0000215 930,000

Liquids

– Airblast application Small Fruit Vine Climbing

Except Fuzzy Kiwifruit (Subgroup 13

- 07F) 0.11 lb ai/A 40 A 0.0000121 1,700,000

Applicator
Aerial applications Fruiting Vegetables (Group 8

-

10B), Low Growing Berry (Subgroup 13

- 07G) Eng. control:
0.0049 0.098 lb ai/A 350 A 0.0000021 9,500,000

Groundboom applications Baseline: 0.34 80 A 0.0000344 600,000

Airblast applications Small Fruit Vine Climbing

Except Fuzzy Kiwifruit (Subgroup 13

- 07F) Baseline: 4.71 0.11 lb ai/A 40 A 0.000259 77,000

Flagger

Flagger Fruiting Vegetables (Group 8

-

10B), Low Growing Berry (Subgroup 13

- 07G) Baseline: 0.35 0.098 lb ai/A 350 A 0.00015 130,000Quinoxyfen Human

- Health Risk Assessment DP# 410691

Page 25 of 32 Table 9.1.1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Quinoxyfen

.

Exposure
Scenario Crop or Target Inhalation Unit Exposure (μg/lb ai) 1 Maximum

Application
Rate 2 Area Treated

or Amount
Handled Daily 3 Inhalation

Mitigation Level Dose (mg/kg/day) 4 MOE 5
Mixer/loader/Applicator

Liquids

– Mechanically

pressurized handgun Small Fruit Vine Climbing

Except Fuzzy Kiwifruit (Subgroup 13

- 07F) Baseline: 3.9 0.0037 lb ai/gal 1,000 gal 0.00018 110,000

Fruiting Vegetables (Group 8

- 10B), Low Growing Berry (Subgroup 13

- 07G) 0.0033 lb ai/gal 1,000 gal 0.000161 120,000

1 Unit Exposures are taken from “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table,” September 2012

. 2 Based on proposed Quintec ® label (Reg. No. 62719

- 375).

3 Units Treated are taken from “Standard Values for Daily Acres Treated in Agriculture”; ExpoSAC SOP No. 9.1, revised 25 September 2001.

4 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/ A or gal) × Area Treated or Amount Handled (A or gal/day) ÷ BW (80 kg).

5 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). Inhalation NOAEL = 20 mg/kg/day.

9.2 Short

- and Intermediate

- Term Post

- Application Risk

HED uses the t erm post

- application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re

entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post

- application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post

- application exposure.

9.2.1 Derma l Post

- Application Risk

In the absence of a short

- and intermediate

- term dermal POD, a quantitative short

- and
intermediate

- term dermal post

- application exposure assessment was not conducted.

REI : Quinoxyfen is classified in Toxicity Category III for ac ute dermal and primary eye
irritation. It is classified in Toxicity Category IV for acute oral, acute inhalation and primary
skin irritation and classified as a dermal sensitizer. The WPS Interim REI of 12 hours is sufficient to protect workers.

9.2.2 I nhalation Post

- A pplication Risk

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for quinoxyfen at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV) and the low proposed use rate (0.11 lb ai/A). However, there are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential
sources include v olatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009, and received the SAP’s fina l report onQuinoxyfen Human

- Health Risk Assessment DP# 410691

Page 26 of 32 March 2, 2010 5

. The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to identify the need for a nd, subsequently, the way to incorporate occupational post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post

- applicati on inhalation exposure assessment for quinoxyfen.

Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposu re resulting from application of pesticides outdoors is likely to result in higher exposure than post

- application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post

- applicatio n inhalation exposure scenarios.

10.0 References

Previous Risk Assessments: B. Hanson, 22

- JAN

- 2009; D351021. G. Kramer, et al. ; 15

- MAY

2006; D321331

HASPOC Memo: K. Rury, 20

- MAR

- 2013; TXR# 0056609

Chemistry Memo: G. Kramer; 20

- AUG

- 2013 ; D407728

Drinking Water Memo: K. Milians, 23

- APR

- 2013; D407730

Dietary Memo: G. Kramer; 20

- AUG

- 2013 ; D410693

Occupational Exposure Memo: J. Tyler; 01

- AUG

- 2013 ; D4 1 0 694

List of Appendices: Appendix A. Toxicology Profile and Executive Summaries Appendix B. Physical/Chemical Properties Appendix C. Review of Human Research

cc: G. Kramer, M. Perron

, J

. Tyler RDI: RAB1 ( 29

- M A Y

- 2013)
G.F. Kramer:S10957:PY

- S:(703)305

- 5079:7509P:RAB1

5 Available: http://www.epa.gov/scip oly/SAP/meetings/2009/120109meeting.htmlQuinoxyfen Human

- Health Risk Assessment DP# 410691

Page 27 of 32 Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

Study requirements (40 CFR § 158.340) for food use of quinoxyfen are presented 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 Acute Eye Irritation

................................ ....................... 870.2500 Acute Dermal Irritation

................................ ................. 870.2600 Skin Sensitization

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

yes
yes
yes
yes
yes 870.3100 90

- Day Oral Toxicity in Rodents

................................ .. 870.3150 90

- Day Oral Toxicity in Nonrodents

............................. 870.3200 21/28

- Day Dermal Toxicity

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

- Day Dermal Toxicity

................................ ................ 870.3465 90

- Day Inhalation Toxicity

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

no

no 1 yes

yes
yes

--

-- 870.3700a Prenatal Developmental Toxicity (rodent)

..................... 870.3700b Prenatal Developmental Toxicity (nonrodent)

............... 870.3800 Reproduction and Fertility Effects

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

yes
yes 870.4100a Chronic Toxicity (rodent)

................................ .............. 870.4100b Chronic Toxicity ( nonrodent)

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

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

................................ ................ 870.4300 Combined Chronic Toxicity/Carcinogenicity

................ yes
yes
yes
yes
yes yes 2

yes
yes 2

yes
yes 870.5100 Mutagenicity

— Bacterial Reverse Mutation Test

.......... 870.5300 Mutagenicity

— Mammalian Cell Gene Mutation Test

.. 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations

.. 870.5xxx Mutagenicity

— Other Genotoxic Effects

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

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

................. 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

............... 870.6300 Developmental Neurotoxicity

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

no yes

yes

-- 870.7485 Metabolism and Pharmacokinetics

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

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

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

no
yes no 3

-- yes

1 HED HASPOC concluded that the 28

- day inhalation study was not required at this time (K. Rury, 20

- Mar

- 2013; TXR#0056609).

2 The combined chronic toxicity/carcinogenicity study satisfies the requirement of the study.

3 Study is classified as acceptable/non

- guideline. The data reported in the study is suitable to inform risk assessment in the absence of any further data.Quinoxyfen Human

- Health Risk Assessment DP# 410691

Page 28 of 32 A.2 Toxicity Profiles

Table A.2. Subchronic, Chronic, and Other Toxicity Profile

- Quinoxyfen.

Guideline No. Study Type MRID No. (year)/
Classification /Doses Results

870.3100 90

- Day Oral

Toxicity in Rodents (rat) 45406705, 45406702

(1992) Acceptable/guideline 0, 10, 100, 250 mg/kg/day NOAEL = 10 mg/kg/day. LOAEL = 100 mg/kg/day based on decreased body weight gain in females, increased liver weights in males and slight hepatocellular hypertrophy (centrilobular and midzonal; both sexes).
870.3100 90

- Day Oral

Toxicity in Rodents (mouse) 45406701 (1992)

Acceptable/guideline 0, 10, 50, 100, 250 mg/kg/day NOAEL = 100 mg/kg/day. LOAEL = 500 mg/kg/day based on increased liver weights, individual cell hepatocellular necrosis and hepatocellular hypertrophy in both sexes.
870.3150 90

- Day Oral

Toxicity in Non

Rodent (dog) 45406706 (1992)

Acceptable/guideline
when combined with

range

- finding studies 0, 10, 50, 100 mg/kg/day Range

- finding studies: 45406703 (1992) 0, 100, 500, 1000 mg/kg/day 45406704 (1993) 0, 250 mg/kg/day NOAEL = 100 mg/kg/day.
LOAEL = not e stablished.

870.3200 28

- Day Dermal

Toxicity (rat) 45360516 (2000)

Acceptable/guideline 0, 10, 100, 1000 mg/kg/day 6 hr/day; 5 days/wk NOAEL = 1000 mg/kg/day.
LOAEL = not established.

870.3700a Prenatal

Developmental in Rodent (rat) 45360520 (1994)

Acceptable/guideline 0, 100, 300, 1000 mg/kg/day Maternal NOAEL = 1000 mg/kg/day.
LOAEL = not established. Developmental NOAEL = 1000 mg/kg/day.
LOAEL = not established.
870.3700b Prenatal

Developmental in
Non

- Rodent (rabbit) 45360521 (1994)

Acceptable/guideline 0, 20, 80, 200 mg/kg/day Range finding: 45360519 (1993) 0, 100, 300, 600, 1000 mg/kg/day Materna l NOAEL = 80 mg/kg/day. LOAEL = 200 mg/kg/day based on inanition, clinical signs, decreased body weights and body

weight gains, food consum ption and increased
incidence of abortion. Developmenta l NOAEL = 80 mg/kg/day. LOAEL = 200 mg/kg/day based on increased
incidence of abortion.
870.3800 Reproduction and

Fertility Effects (rat) 45360522 (1995)

Acceptable/guideline 0, 5, 20, 100 mg/kg/day Parental/Systemic NOAEL = 100 mg/kg/day.
LOAEL = not established. Reproductive NOAEL = 100 mg/kg/day.
LOAEL = not established. Offspring NOAEL = 20 mg/kg/day. LOAEL = 100 mg/kg/day based on decrease in
first

- generation pup weights.
870.4100a Chronic Toxicity

(rodent) See 870.4300

. See 870.4300

.

870.4100b Chronic Toxicity

(dog) 45360517

Acceptable/guideline 0, 5, 20, 200 mg/kg/day NOAEL = 20 mg/kg/day. LOAEL = 200 mg/kg/day based on increased alkaline phosphatase, increased absolute and relative (to body) liver weights, and increased incidence of very slight to slight microscopic hepatic lesions.Quinoxyfen Human

- Health Risk Assessment DP# 410691

Page 29 of 32 Table A.2. Subchronic, Chronic, and Other Toxicity Profile

- Quinoxyfen.

Guideline No. Study Type MRID No. (year)/
Classification /Doses Results

870.4200a Carcinogenicity (rat) See 870.4300

. See 870.4300

. 870.4200b Carcinogenicity

(mouse) 45406707 (1995)

Acceptable/guideline 0, 20, 80, 250 mg/kg/day NOAEL = 80 mg/kg/day. LOAEL = 250 mg/kg/day based on decreased body weight gain in both sexes.

No evidence of carcinogenicity.

870.4300 Combined Chronic

Toxicity/ Carcinogenicity (rat) 45360523 (1995)

45724201 (2001) Acceptable/guideline 0, 5, 20, 80 mg/kg/day NOAEL = 20 mg/kg/day. LOAEL = 80 mg/kg/day based on increases in severity of chronic progressive glomerulonephropathy in the males and minimal decreases in body weight and body

- weight gain in
the males and females.

870.5100 Bacterial reverse

mutation 45360601 (1993)

Acceptable/guideline Negative for inducing reverse mutation in bacteria exposed to doses up to 5000 ug/plate (

- S9) and 1000 μg/plate (+S9).

870.5300 In vitro mammalian

cell gene mutation 45360602 (1994)

Acceptable/guideline Negative for inducing forward mutation in CHO (mammalian) cells treated up to 20 μg/mL (

- S9) and 80 ug/mL (+S9).

870.5375 In vitro mammalian

chromosome aberration (RL) 45360604 (1994)

Acceptable/guideline Negative up to 100 μg/mL (

- S9 and +S9).

870.5395 Mammalian

micronucleus (mouse) 45360603 (1994)

45724203 (2001) Acceptable/guideline Negative up to 5000 mg/kg.

870.6200a Acute Neurotoxicity

Screening Battery (rat) 45360515 (1999)

Acceptable/guideline 0, 200, 632, 2000 mg/kg NOAEL = 2000 mg/kg.
LOAEL = not established.

870.6200b Subchronic

Neurotoxicity Screening Battery (rat) 45360518 (1995)

Acceptable/guideline 0, 5, 20, 80 mg/kg/day NOAEL = 80 mg/kg/day.
LOAEL = not established.

870.7485 Metabolism and

Pharmacokinetics 45360605 (1995)

45360606 (2001) Acceptable/non

- guideline M&F: 10 or 500 mg/kg (labeled) as single oral dose or 10 mg/kg (labeled) as single oral dose followed by 10 mg/kg/day (unlabeled) orally for 14 days. M: 10 or 500 mg/kg (labeled) single oral dose or 500 mg/kg/day oral

gava ge dose for 3 days. Absorption of labeled quinoxyfen was rapid with maximum plasma concentrations occurring between 0.5 and 1.5 hours. Overall recovery of the dose ranged from 83.5

- 96.2%. Concentrations of radioactivity in the tissues were generally sli ghtly
lower in males than females and in the low

- dose compared to the high

- dose group. The major metabolites identified were an acid labile conjugate
of 4

- fluorophenol and 5,7

- dichloro

- 4

- hydroxyquinoline in the urine, glucuronide and/or sulfate conjugate( s) of two isomers of fluorophenyl ring

- hydroxy

- XDE

- 795 in the bile, and the parent and two isomers of fluorphenyl ring

- hydroxy

- XDE

795 (unconjugated) in the feces. The major route of elimination was through urine in the phenyl

- labeled quinoxyfen and throu gh the feces in the quinoline

labeled quinoxyfen.

Classified as non

- guideline due to several unanalyzed fractions.Quinoxyfen Human

- Health Risk Assessment DP# 410691

Page 30 of 32 Table A.2. Subchronic, Chronic, and Other Toxicity Profile

- Quinoxyfen.

Guideline No. Study Type MRID No. (year)/
Classification /Doses Results

870.7800 Immunotoxicity 48106301 (2010) Acceptable/guideline 0, 20, 100, 250 mg/kg/day NOAEL = 250 mg/kg/day.
LOAEL = not established.Quinoxyfen Human

- Health Risk Assessment DP# 410691

Page 31 of 32 Appendix B. Physical/Chemical Properties

Table B.1. Physicochemical Properties of the Technical Grade Test Compound: Quinoxyfen. 1

Parameter Value Reference
Molecular weight 308.13 g/mol

Smith, Amy J., Group B: Physical and Chemical Properties of Quinoxyfen (DE

- 795) and Supplemental Properties
of 3

- Hydroxy

- XDE

- 795, Dow AgroSciences, LLC, 20 December

2000. Melting point/range 106.0

- 107.5 oC
pH 7.97 (1% solution in water at 22.7 °C)
Density 1.097 g/cm 3 at 20 °C
Vapor pressure 1.2 x 10 - 5 Pa at 20 °C
Log 10 K OW (Log P) 4.66 at 20 °C

Solubility mg/L at 20 °C
Distilled water 0.116 Water (pH 5) 0.128 Water (pH 7) 0.047 Water (pH 5) 0.036

n

- Hexane 9.64
Methanol 21.5 Ethyl acetate 179
Toluene 272
Acetone 116
Dichloromethane 589

Dissociation Constant K
a = 2.77 x 10 - 4 , pK
a = 3.56

1 Refer to D354559, 11/06/08, D. Wilbur

.Quinoxyfen Human

- Health Risk Assessment DP# 410691

Page 32 of 32 Appendix C. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from the PHED 1.1, the AHETF database, and the ARTF database are (1) subj ect to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 6

.

6 http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html