UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C

. 20460

M E MORANDUM

{)ate: 5 / 6 / 13 OFFICE OF C H EMICAL SAFETY AND PO L LUTION PREVENTION

SUBJECT: Hexythiazox

. Human Health Risk Assessment to Support New Uses on Grain Sorghum, Pepper / Eggplant Subgroup 8 -1 OB, Pome Fruit Group 11- 10, Caneberry Subgroup 13-07 A, Small Vine Climbing, Except Fuzzy Kiwifruit Subgroup 13-07F, and Low Growing Berry Subgroup 13-070

.

PC Code: 128849 DP Barcode: 1)404015, 1) 4 01797 Decision No.: 466411, 463688 Registration No.: 10163-250, 1 0163

- 251

, 10163-277 Petition No.: 2F8054, 2 E 8016 Regulatory Action: Section 3 Registration Risk Assessment T ype: Single Chemical Case No.: N/A Aggregate TXRNo.: NA CAS No.: 78587-05-0 MRIDNo. : NA 40 CFR : 40 CFR 180.448

FROM : l)onna S. {)avis, Risk

## Assesso**~** / ")--'
Alexandra LaMay,

### Biolo**g'st** /:(

### ~ L i nda Taylor,**Toxicologist .----;~** **~~....<'~- --**  .......**A< /**  Risk Assessment Branch Health Effects l)ivision (7509P)

THRO U GH: Michael Metzger, Chief

# ~ /) (}

# ~ R i sk Assessment Branch VII

# ~J 

# , !

- Health Effects l)ivision (7509P) '

TO: Olga Od i ott, Risk Manager Mark Suarez, Product Manager Insecticide Branch Registration l)ivision (7505P)

Sidney Jackson, Risk Manager Barbara Madden, Team Leader Risk I ntegration Minor Use

, and Emergency Response Branch Registration l)ivision (7505P)

Page 1 of36He xyt hiazo x H uman H ealt h Ri sk Assessme n t D 404015

Tab le of Contents

1

. 0 Executiv e S ummary

... . . ... . . . .. .. .. . .. ...... . ....... .. . ... . .. .. .. ....... .. .. ................ . ..... .. . ......... . ... . 4

2.0 HED Re com m enda tions

........ . ... . .................. .. . ... . .. .. .. .. . ............................................ 7 2.1 2.2 2.2.1 2.2.2 2.2.3 2

. 2.4 2.3 2.3. 1 2

. 3.2 2.3.3 Dat a Deficiencies

. . .. . ... ........................................ .. .. .. .. .. .. .. .. . ... . ....... .. .. .. .. .. .. .. .. ... . . 7 T olerance Considerations

..... . .................. .. .. .. . .. .. .. .. .. ..................... . ......... . ............ 7 Enf o rcement An al yt i cal Method

.................................................... .. .. .. .. .......... 7 R ecommended Toleran ces

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

- For Tolerances

.. .. .. ...... . . ..................................... . ........ 9 In ternat i o nal Harmo ni zation

........................... .. .. .. .. .. .. .. . ....... ...... ... . ... . ... .. .. . .... 10 Label Recommendations

. . . .. .. . ...................... . ... .. .. . ... . ........... ...... . ... .. .. .. .. ............ 11 Recommendations from R esidue R e views

........ ..................................... ...... .. 11 Rec omme ndations from Occupationa l Assessmen t

. ... .. .. .. .. ....... . ... . .. ....... . ... . . 11 R eco mm endat ions from R es id e ntial Assessment..

......................................... 11

3.0 Introd uction

...................................................... ... . ....... ...................... . .................... 1 1 3.1 Che mi cal Identity

..... . .. .. ................................................................................. . ... 1 2 3 .2 Ph ys i cal / Chemical Characteristics

................ ... . ... .. . .. .. .. .. .. . ............... .. .. ... . ... . .. ... 13 3

. 3 Pe st i ci d e Use Pattern

. .. .. .. . ............................................................................. .. .. . 14 3.4 Anticip ated Ex posure Path ways

... . ... .. .. . ........ .. .. .. .. .. ............ ..... ... . ... .. .. .. ......... .... 1 6 3

. 5 Con s i dera ti on of E n viro nm ental Ju st ic e

................... . .. .. .. .. ... .. .. . ... ............ . . . ... .. . 16

4.0 Hazard Character ization and Do se- R esponse Assessment

.. . ................ . .. ... . .. .. .. .. .. 17 4.1 Hazard Characterizat ion

........................... . ... . .. .. .. .. .. .. .. .. ... . ... . .......... .. .. .. .. ... . ... .. . . 1 7 4. 2 Hazard Profile

.......... . ......................................................................................... 17 4

. 3 D ose-Response Assess men t/Endpoint Se l ectio n

... . ........................................... 17 4.4 FQP A Considerat ions

......................................................................................... 18 4.5 Summary of Toxicologica l Do ses and E ndpoints for Use in Human Risk Assessments and Levels

.. . . .. . .. .... . . . ............ . ............. . . . . .. ... .. . . . ... . ... ... ......... . . . . . . . . . . . . . . . . . . . . . 1 9

5.0 Di etary Exposure/Ris k Characteri za ti o n

.. . ... . ......... . ..... .. .. .. .. ... . .. . ... .. .. . ... .. .. .. .. . . . ... .. 20 5.1 Residue Chemistry Summa ry

........................... . .. .. ............................ .. .. .. .. .. ....... 20 5.2 Dr inking Water R esi due Pr ofile

............ . .... . .. .. .. .. .. .. ........................................... 2 1 5.3 Di etary Exposure and Ri sk

....................................................................... .. .. .. .... 22 5.4 Anticipated Residue and Percen t Crop Treate d (%CT) Information

................. 23

6.0 Res i dential and Other No n-Occupa t i onal Ex posures /Risks

............ . ....... .. .. .. ....... . 23 6.1 Resid en t ia l Handler Exposure and Ri s k

...... .. .. .. .. . .. .. ... . . .... . ... .. ......... . ....... .. ........ 23 6.2 Re sidential Po s t

- application Exposure

................ .. .................... .. .. . .. .. .. .. .. ... . ... . .. 24 6.3 Oth e r

........... .... .. .. .. .. . .. . ... . .. .. .. .. .. .. ...... .. . . ................... . ...... . . .................... .. .. ... . ... . .. 25

7.0 Aggregate Ri sk Assessments and Risk C hara cte riza tion

................. .. ...... .. .. .. .. ... .. . 26 7 .I Ac u te Agg r egate Ri sk

................................... .............. ....................................... 26 7.2 S h o rt

- and Intermediate-Term Aggregate Ri sks

................................................ 26
7

. 3 Long

- Term (C hr onic) Aggregate R i sk

.. .. .. .. .. ... . .. .. .. .............................. .. .. .. ... .. . . 28

P age 2 of36

### Hexythiazox Human Health Risk Assessment D404015

Page 3 of 36 8.0 Cumulative Risk Characterization/Assessment

................................ ..................... 28

9.0 Occupational Exposures and Risks

................................ ................................ ........ 28 9.1 Occupational Handler Risk

................................ ................................ ................ 28 9.2 Occupational Post Application Risk

................................ ................................ .. 30

10.0 Human Studies

................................ ................................ ................................ ....... 31

Appendix A. Toxicology Assessment

................................ ................................ .............. 32

Appendix B: Toxicology Data Requirements

................................ ................................ ... 36

### Hexythiazox Human Health Risk Assessment D404015

Page 4 of 36 1.0 Executive Summary

Hexythiazox, trans

- 5

- (4

- chlorophenyl)

- N

- cyclohexyl

- 4

- methyl

- 2

- oxothiazolidine

- 3

- carboxamide, is an ovicide/miticide used to control mites on a variety of fruit and nut crops. Hexythiazox is a contact pesticide which achieves control of eggs or immature mites via direct contact or contact with treated surfaces.

Gowan Company has submitted PP# 2F8054 requesting the following: A new regionally restricted use limite d to OCSPP Harmonized Test Guideline 860.1500 Regions 6, 7, and 8 on sorghum and establishment of tolerances on grain at 3 ppm, forage at 5 ppm, and stover at 6 ppm. The new use is to be included only on the label for the 1 lb/gal emulsifiable concentrate (EC) formulation (Onager® Miticide, EPA Reg. No 10163

- 277) of hexythiazox

. Increase the milk tolerance from 0.02 ppm to 0.05 ppm to harmonize with Codex. Establish poultry tolerances for meat, meat byproducts, and eggs at 0.05 ppm to harmonize with Codex. Increase livestock meat byproduct tolerances (including kidney and liver) from 0.05 ppm to 0.5 ppm.

The Interregional Research Project No. 4 (IR

- 4) in PP# 2 E8016 is proposing the following: A new use of hexythiazox on the pepper/eggplant subgroup 8

- 10B on the Hexygon DF and Onager® Miticide labels and a tolerance for CSG 8

- 10B at 1.5
ppm. Expansion of the use on the pome fruit group 11 to include all commodities in the updated pome fruit group 11

- 10 on the Savey® 50 DF and Onager® Miticide labels and a t olerance for CG 11

- 10 at 0.25 ppm.
E xpansion of the use on the caneberry sub group 13A to include all commodities in the updated caneberry subgroup 1 3

- 07A on the Savey® 50 DF label and a tolerance for CSG 13

- 07A at 1.0 ppm. Expansion of the use to all membe rs of small fruit, vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F on the Onager® Miticide label based on the current
use on grapes and a tolerance for CSG 13

- 07F at 1.0 ppm. Expansion of the use of all members of the low growing berry subgroup 13

- 0 7G on the Savey® 50 DF label based on the current use on strawberry and a tolerance for CSG 13

- 07G at 3.0 ppm.

The toxicity database for hexythiazox is complete. Hexythiazox is associated with toxicity of the liver and adrenals following subchronic and chronic exposure to dogs, rats and mice, with the dog bei ng the most sensitive species. The prenatal developmental studies in rabbits and rats and the two

- generation reproduction study in rats showed no indication of increased susceptibility to in utero and/or postnatal exposure to hexythiazox. Reproductive toxicity was not observed. There is no concern for neurotoxicity following exposure to hexythiazox. The toxico logy database for hexythiazox does not show any evidence of treatment

- related effects on the immune system. Hexythiazox is classified as “likely to be carcinogenic to humans”; however,

### Hexythiazox Human Health Risk Assessment D404015

Page 5 of 36 s ince the effects seen in the study that serves as the basis for the chronic RfD occurred at doses substantially below the lowest dose that induced tumors, HED concluded that quantification of risk using a non

- linear approach; i.e., RfD, for hexythiazox wil l adequately account for all chronic toxicity, including carcinogenicity, that could result from exposure to hexythiazox.

No acute risk is expected since no hazard was identified in any toxicity study for this duration of exposure. Chronic risk is regul ated based on effects seen in the adrenal glands in a one

- year dog feeding study. Short

- term and intermediate

- term incidental oral and inhalation risks are regulated based on decreased pup body weight during lactation and delays in hair growth and/or eye opening, decreased p arental body

- weight gain and increased liver, kidney, and adrenal weights in the 2

- generation reproduction study in the
rat. For the short

- and intermediate

- term dermal risk assessment, no quantification of risk is required

.

The nat ure and magnitude of the residue in plants, animals and water has been adequately delineated to support the proposed new and expanded uses. The submitted labels are adequate except as follows. The proposed supplemental label for use of Onager® Miticide o n crop subgroup 8

- 10B should be revised to specify minimum spray volumes for ground and aerial application. Additionally, a dequate residue data have not been submitted to support the requested use on crop subgroup 8

- 10B commodities on the Hexygon® DF labe l; therefore, the use on subgroup 8

- 10B commodities should be removed from the Hexygon® DF label. Lastly, the Savey® 50 DF label should be amended to specify a minimum spray volume for aerial application to pome fruit of 10 gallons per acre. An adequate high performance liquid chromatography method with UV detection ( HPLC/UV ) exists to enforce th e required crop and livestock tolerances. A reference standard is available at the EPA National Pesticide Standards Repository

. The number and geographic representation of the submitted grain sorghum and pepper field trial data are adequate to support the requested geographically restricted use on sorghum in Regions 6, 7, and 8 and on the pepper/eggplant subgroup 8

- 10B for the EC f ormulation only. The residue data were generated by a validated data collection method, are supported by adequate storage stability data, and support the requested use pattern. No residue data are required to support the requested label expansions. The submitted data support tolerance of 3, 5, and 6 ppm on sorghum grain, forage, and stover, respectively, a tolerance of 5 ppm on aspirated grain fractions, and a tolerance of 1.5 ppm on the pepper/eggplant subgroup 8

- 10B. HED recommends in favor of the requ ested expansions listed above and tolerances for the new crop groups/subgroups at the same levels as the current tolerances from which they are extrapolated, with the exception of the pome fruit group 11

- 10 tolerance which should be set at 0.4 ppm and the low growing berry subgroup 13

- 0 7G which should be set at 6 ppm, both to harmonize with Codex. Updated dietary burden calculations for livestock indicated that the current livestock tolerances are adequate; however, HED recommends increasing the ruminant m eat by product tolerances to 0.5 ppm and the egg tolerance to 0.05 ppm to harmonize with Codex. All other livestock tolerances are currently harmonized with Codex. The nature of the residue in rotational crops in not adequately understood, however, based on the available confined and limited rotational crop data, HED concludes that

, in light of the 120 day

### Hexythiazox Human Health Risk Assessment D404015

Page 6 of 36 plant

- back interval (PBI) on the label, no additional data with respect to rotational crops are required at this time.

An acute endpoint was not selec ted for hexythiazox; therefore, the Agency conducted only a chronic dietary (food and drinking water) exposure and risk assessment. The chronic dietary risk assessment used tolerance level residues

, assumed 100% crop treated

, included DEEM default process ing factors, and modeled water values . This unrefined assessment resulted in estimated chronic dietar y (food and water) risks of 17 % of the chronic population adjusted dose (cPAD) for the U.S. population an d 82 % of the cPAD for children 1

– 2 years of age , the most highly exposed population subgroup.

Th is action does not include new residential uses; however, hexythiazox is registered for use in residential settings including uses on ornamental plantings, turf, and fruit and nut trees in residential set tings. These uses were reassessed to reflect updates to HED’s 2012 Residential SOPs as well as policy changes for body weight assumptions. Residential handler inhalation margins of exposure ( MOEs ) for all scenarios ranged from 420,000 to 330,000,000; sig nificantly exceed ing the level of concern (LOC) of 100 and are not of

concern . The MOEs for children’s incidental oral exposure to treated turf for all

sce narios ranged from 11,000 to 4, 700,000; greatly exceeding the LOC of 100 and are not of concern.

Since there are no acute endpoints of concern, an acute aggregate risk assessment was not conducted. HED has conducted short

- term, intermediate

- term
, and lon g

- term (chronic) aggregate risk assessments for hexythiazox. Short

- and intermediate

- ter m aggrega te MOEs ranged from 1,300 to 9,8 00; significantly exceeding the LOC of 100 and are not of concern. The long

- term (chronic) aggregate assessment includes only dietary (food and water) exposure as there are no long

- term residential exposure s cenarios. Chro nic dietary risk is not of concern.

A quantitative dermal risk assessment is not required for hexythiazox. Occupational handler inhalation MOEs significantly exceed 100 for all scenarios assessed associated with the new and expanded uses and are not of concern . Further, there were no risks of concern identified for postapplication exposure to hexythiazox associated with these new

uses.

No additional personal protective equipment (PPE) is required

. T he label restricted entry interval (REI) of 1 2 ho urs is appropriate and in compliance Worker Pro tection Standard requirements.

Potential areas of environmental justice concern, 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.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

### Hexythiazox Human Health Risk Assessment D404015

Page 7 of 36 2.0 HED Recommendations

Provided the proposed labels (Section B) are amended as noted in Section 2.3, below, and a revised Section F is submitted as noted in Section 2.2, below, there are no hazard, exposure, or risk considerations that would preclude granting the requested regi onally restricted use on sorghum and the newly proposed use on the pepper/eggplant subgroup 8

- 10B, as well as the necessary tolerances required to support those uses.

Additionally, HED has no objection to the proposed expansions: Expansion of the curren t use on CG 11 to include all commodities in the updated pome fruit group 11

- 10.
E xpansion of the current use on the caneberry sub group 13A to include all commodities in the updated caneberry subgroup 1 3

- 07A

. Expansion of the current use on grapes to all m embers of small fruit, vine climbing, except fuzzy kiwifruit subgroup 13

- 07F. Expansion of the current use on strawberry to all members of the low growing berry subgroup 13

- 07G.

Lastly, Gowan Company has proposed new/increased livestock tolerances. HED h as concluded that the current tolerances are adequate to cover secondary residues in livestock; however, HED is recommending that livestock tolerances be harmonized with Codex in conjunction with these requested new and expanded uses

.

2.1 Data Deficiencies

There are no data deficiencies with respect to toxicology associated with this action.

All residue chemistry data requirements have been adequately addressed with the exception of the need for additional field trial data to support the requested use on crop subgroup 8

- 10B commodities on the Hexygon® DF (10163

- 251) label. Should the registrant desire to support the use of hexythiazox on subgroup 8

- 10B commodities, additional field tria l data will be required, as outlined in S ection 5.3 of this memorandum.

There are no data deficiencies with respect to occupational or residential exposure assessment with this action.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Hexythiazox and its metabolites are not c onsistently recovered through FDA’s multi

residue methods. No data were provided, or are required, for recovery through other common multi

- residue methodology.

An adequate HPLC/UV analytical method is available for the enforcement of tolerances for res idues of hexythiazox and its metabolites containing the PT

- 1

- 3 moiety in crop and

### Hexythiazox Human Health Risk Assessment D404015

Page 8 of 36 livestock commodities. This method is listed in the U.S. EPA Index of Residue Analytical Methods under hexythiazox as method AMR

- 985

- 87.

Briefly, residues are extracted w ith methanol or methanol/water, acidified, partitioned with dichloromethane (DCM) , subjected to base hydrolysis, partitioned with acetonitrile, and re

- partitioned with DCM. The extracts are cleaned up using column chromatography, and the ethyl acetate/hex ane eluate is concentrated and analyzed by HPLC with UV detection. Residues are expressed in terms of hexythiazox using a molecular weight conversion factor of 1.55. The method LOQ is 0.02 ppm.

2.2. 2 Recommended Tolerances

Tolerances currently establish ed under 40 CFR §180.448 comply with the HED Interim Guidance on Tolerance Expressions (S. Knizner, 5/27/09); therefore, no revisions are recommended to the residue definition. Table 2.2.2, below summarizes the recommended tolerance levels and commodity d efinitions required to support the proposed new and expanded uses included in these petitions.

Table 2.2.2 . Tolerance Summary for Hexythiazox

. Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments

( correct commodity definition ) 40 CFR 180.448(a) Tolerance for residues. Aspirated grain fractions

- 5 Grain, aspirated fractions Currently established at 0.5 ppm, increase required due to new use on sorghum Pepper/eggplant subgroup 8

- 10B 1.5 1.5 P epper/ E ggplant subgroup 8

- 10B

Fruit, pome, group 11

- 10 0.25 0.4 Fruit, pome, group 11

- 10 Set to harmonize with Codex. Established tolerance for fruit, pome, group 11 can be removed from 40 CFR and replaced by this crop group tolerance. Caneberry subgroup 13

- 07A 1.0 1 Caneberry subgroup 13

- 07A Established tolerance for caneberry subgroup 13A can be removed from 40CFR and replaced by this subgroup tolerance. Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F 1.0 1 Fruit, small, vine climbing, subgroup 13

- 07F, except fuzzy kiwifruit Established tolerance for grape can be removed from 40CFR and replaced by this subgroup tolerance Berry, low growing, subgroup 13

- 07G 3.0 6 Berry, low growing, subgroup 13

- 07G Established tolerance for strawberry can be removed from 40CFR and

re placed by this subgroup tolerance. Milk 0.05 No change in current tolerance required Milk Currently established at 0.05 ppm

### Hexythiazox Human Health Risk Assessment D404015

Page 9 of 36 Table 2.2.2 . Tolerance Summary for Hexythiazox

. Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments

( correct commodity definition )
Ruminant meat byproducts 0.5 0.5 Cattle, meat byproducts Current tolerance level is 0.2 ppm; Increase to harmonize with Codex. 0.5 Goat, meat byproducts Current tolerance level is 0.2 ppm; Increase to harmonize with Codex. 0.5 Horse, meat byproducts Current tolerance level is 0.2 ppm; Increase to harmonize with Codex. 0.5 Sheep, meat byproducts Current tolerance level is 0.2 ppm; Increase to harmonize with Codex. Egg 0.05 0.05 Egg Current tolerance level is 0.01 ppm; Increase to harmonize with Codex. Poultry, meat 0.05

-- Poultry, meat There is no expectation of finite residues in poultry meat ; therefore a tolerance is not required. Poultry, meat byproducts 0.05 No change in current tolerance required P oultry, meat byproducts Currently established at 0.05 ppm 40 CFR 180.448(c) Tolerances with regional registrations. Grain sorghum, grain 1 3 3 Sorghum, grain, grain Grain sorghum, forage 1 5 5 S orghum, grain, forage Grain sorghum, stover 1 6 6 sorghum, grain, stover



### 2.2. 3 Revisions to Petitioned

- For Tolerances

The registrant did not propose an increase in the aspirated grain fraction tolerance. However, the submitted residue chemistry data show that sorghum residues concentrate in AGF, and that the current AGF tolerance of 0.05 ppm is not adequate to cover resi dues in sorghum AGF. Therefore the Agency is requesting that Gowan Company petition for an increased tolerance of 5 ppm in AGF.

Minor revisions to the petitioned

- for tolerances for sorghum grain, sorghum forage, and sorghum stover to reflect standard Ag ency commodity definitions are requested, no change in the proposed tolerance level is required.

Minor revision to the petitioned

- for tolerance for CSG 13

- 07F to reflect standard Agency commodity definition has been requested, no change in the proposed tolerance level is required.

HED is recommending revision to the proposed tolerance for CG 11

- 10 from the proposed level of 0.25 ppm to 0.4 ppm and to the proposed tolerance for CSG 13

- 07G from 3 ppm to 6 ppm to harmonize with Codex established and prop osed MRLs.

Minor revisions to the petitioned

- for tolerances for ruminant meat byproducts to reflect standard Agency commodity definition have been requested, no change in the proposed tolerance levels are required.

### Hexythiazox Human Health Risk Assessment D404015

Page 10 of 36 The petitioner has requested a new to lerance for residue of hexythiazox on poultry meat; however poultry metabolism and feeding studies demonstrate that there are not likely to be residues in poultry meat; therefore a tolerance on poultry meat is not required.

No revision to the petitione d

- for tolerances for crop subgroup 13

- 07A, or eggs is required. The requested tolerance for milk has already been established with another petition; therefore no change to the established tolerance is required at this time.

2.2. 4 International Harmonization

Codex MRLs for plant commodities are established for eggplant at 0.1 ppm, pome fruit at 0.4 ppm, grapes at 1.0 ppm, and strawberry at 6 ppm (proposed) for residues of hexythiazox and its metabolites containing the PT

- 1

- 3

- moiety, expressed as hexythiazox. There are no Canadian or Mexican MRLs currently established. The International Residue Limit (IRL) status sheet is included as Attachment 3 to this memorandum.

The Agency is currently harmonized with Codex with respect to residue definitio n in plants, and is recommending tolerances for CG 11

- 10 (pome fruit), CSG 13

- 07F (small, vine climbing fruit, except kiwifruit), and CSG 13

- 07G (low growing berry) that are harmonized with the current Codex MRLs for pome fruit, grapes (representative

comm odity of CSG 13

- 07F), and strawberry (representative commodity of CSG 13

- 07G). Therefore; HED

- recommended tolerances for plant commodities are harmonized with Codex established or proposed MRLs with exception of the tolerance for eggplant. Codex has esta blished their current MRL of 0.1 ppm for eggplant based on a use in the Netherlands at a significantly lower application rate than the use current ly proposed in the U.S. The Codex MRL would not cover residues seen in the U.S. field trial data; therefore h armonization with codex with respect to eggplants is not possible at this time.

The Agency is currently harmonized with Codex with respect to the residue definition in livestock commodities. The current milk tolerance of 0.05 ppm is harmonized with the Codex MRL for milk. HED is recommending an increase in the ruminant meat byproduct tolerances to 0.5 ppm and an increase in the current egg tolerance to 0.05 ppm to harmonize with Codex

.
HED has reviewed the poultry metabolism and feeding studies and c oncludes that the use on poultry meat can be classified as 180.6(a)(3), no reasonable expectation of finite residues; therefore the U.S. will not need to set a tolerance for this commodity. The relevant Codex MRL has been set at 0.05 ppm with a footnote t hat states “absent at the limit of quantitation”. Effectively, the Codex MRL acknowledging the absence of residues and the U.S. determination that no tolerance is required results in a harmonized approach to residues in poultry meat.

### Hexythiazox Human Health Risk Assessment D404015

Page 11 of 36 2.3 Label Recomme ndations

2.3.1 Recommendations from Residue Reviews

The following label changes are recommended.

The proposed supplemental label for use of Onager® Miticide on crop subgroup 8

- 10B should be revised to specify minimum spray volumes for ground and aerial application. The submitted residue chemistry data support a minimum spray volume of 20 gallons per acre (GPA) for ground application. Further , the petitioner must revise the directions to reflect a minimum spray volume for aerial applications of 2 GPA fo r crop subgroup 8

- 10B or submit additional data reflecting aerial application to representative commodities of that crop subgroup.

Adequate residue data have not been submitted to support the requested use on crop subgroup 8

- 10B commodities on the Hexyg on® DF label. The use on subgroup 8

- 10B commodities should be removed from the Hexygon® DF label. To support inclusion of these crops on the Hexygon® DF label, the data outlined in Section 3.3 of this memorandum will be required.

The Savey® 50 DF labe l should be amended to specify a minimum spray volume for aerial application to pome fruit of 10 gallons per acre.

2.3.2 Recommendations from Occupational Assessment

No label changes are required based on the occupational assessment.

2.3.3 Recommendati ons f rom Residential Assessment

No label changes are required based on the residential assessment.

3.0 Introduction

Gowan Company has submitted PP# 2F8054 requesting the following: A new regionally restricted use limited to OCSPP Harmonized Test Guideline 860.1500 Regions 6, 7, and 8 on sorghum and establishment of tolerances on grain at 3 ppm, forage at 5 ppm, and stover at 6 ppm. The new use is to be included only on the label for the 1 lb/gal emulsifiable concentrate (EC) formulation (Onager® Miticide, EPA Reg. No 10163

- 277) of hexythiazox

. Increase the milk tolerance from 0.02 ppm to 0.05 ppm to harmonize with Codex. Establish poultry tolerances for meat, meat byproducts, and eggs at 0.05 ppm to harmonize with Codex. Increase livestock meat byproduct tolerances (including kidney and liver) from 0.05 ppm to 0.5 ppm.

### Hexythiazox Human Health Risk Assessment D404015

Page 12 of 36 The Interregional Research Project No. 4 (IR

- 4) in PP# 2 E8016 is proposing the following: A new use of hexythiazox on the pepper/eggplant subgroup 8

- 10B on the Hexygon DF (EPA Reg No. 10163

- 251) and Onager® Miticide (EPA Reg No. 10163

- 277) labels and a tolerance for CSG 8

- 10B at 1.5 ppm. Expansion of the use on the pome fruit group 11 to include all commodities in the updated pome fruit group 11

- 10 on the Savey® 50 DF and Onager® Miticide labels and a tolerance for CG 11

- 10 at 0.25 ppm.
E xpansion of the use on the caneberry sub group 13A to include all commodities in the updated caneberry subgroup 1 3

- 07A on the Savey® 50 DF label and a tolerance for CSG 13

- 07A at 1.0 ppm. Expansion of the use to all members of small fruit, vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F on the Onager® Miticide label based on the current
use on grapes and a tolerance for CSG 13

- 07F at 1.0 ppm. Expansion of the use of all members of the low growing berry subgroup 13

- 07G on the Savey® 50 DF label based on the current use on strawberry and a tolerance for CSG 13

- 07G at 3.0 ppm.

Tolerances are currently established under 40 CFR §180.448 for the combined residues of hexythiazox and its metabolites containing the (4

- chlorophenyl)

- 4

- methyl

- 2

- oxo

- 3

- thiazolidine moiety (expressed as parts per million of the parent compound).

3.1 Chemical Identity

Hexythiazox, trans

- 5

- (4

- chlorophenyl)

- N

- cy clohexyl

- 4

- methyl

- 2

- oxothiazolidine

- 3

- carboxamide, is an ovicide/miticide used to control mites on a variety of fruit and nut crops. Hexythiazox is a contact pesticide which achieves control of eggs or immature mites via direct contact or contact with tre ated surfaces.

The chemical structure and nomenclature of hexythiazox and its common moiety, PT

- 1

- 3 is shown in Table 3.1. The physicochemical properties of the technical grade hexythiazox are presented in Table 3.2.

### Hexythiazox Human Health Risk Assessment D404015

Page 13 of 36 T able 3. 1. Nomenclature of Hexythiazox. Compound

Common name Hexythiazox Company experimental names DPX

- Y5893, NA

- 73
IUPAC name (4 RS ,5 RS )

- 5

- (4

- chlorophenyl)

- N

- cyclohexyl

- 4

- methyl

- 2

- oxo

- 1,3

- thiazolidine

- 3

- carboxamide
CAS name trans

- 5

- (4

- chlorophenyl)

- N

- cyclohexyl

- 4

- methyl

- 2

- oxo

- 3

- thiazolidinecarboxamide

CAS # 78587

- 05

- 0
End

- use product/EP 1 lb/gal EC (EPA Reg. No. 10163

- 277; Onager® Ovicide/Miticide) Compound

(4

- chlorophenyl)

- 4

- methyl

- 2

-
oxo

- 3

- thiazolidine moiety

Common name PT

- 1

- 3 moiety
Chemical name 5

- (4

- chlorophenyl)

- 4

- methyl

- thiazolidin

- 2

- one



### 3.2 Physical/Chemical Characteristics

Table 3.2. Physicochemical Properties of Hexythiazox.

Parameter Value Reference Melting point/range 108.0

- 108.5 °C 00143533 pH Not applicable Density 1.289 at 25 °C 00143533 Water solubility 0.12 ppm 44006301 Solvent solubility g/L chloroform 1379 xylene 362
acetone 160.0 acetonitrile 28.6

n

- hexane 3.9 methanol 20.6 00143533

Vapor pressure <10 - 8 mm Hg at 25 oC 44006301 Dissociation constant, pK a Not applicable Octanol/water partition coefficient Log(P OW ) 560 (average) 0143533, 00146531

UV/visible absorption spectrum (molecular absorption coefficients) Maximum at 223 nm in acetonitrile, no absorption in the visible range. Not available

### Hexythiazox Human Health Risk Assessment D404015

Page 14 of 36 3.3 Pesticide Use Pattern Residue Chemistry Summary Document, D404573, D. Davis, 5/3/13



### Gowan Company has submitted a supplemental label for Onager® Miticide (EPA Reg No. 10163

- 277) which includes proposed regionally restricted use directions for sorghum. The newly proposed use pattern for sorghum is summarized in the table below.

IR

- 4 has submitted supplemental labels for Onager® Miticide (EPA Reg No. 10163

- 277) and Hexygon® DF Ovicide/Miticide (EPA Reg No. 10163

- 251) which include proposed use directions for members of the pepper/eggplant subgroup 8

- 10B. The Hexygon® DF Ovicide/Miticide specifically includes use on green house grown members of the crop subgroup. The proposed new use pattern for crop subgroup 8

- 10B is summarized in the table below.

Tabl e 3.3 . Summary of Proposed Directions for Use of Hexythiazox. Applic. Timing, Type, and Equip. Formulation

[EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per Season Max. Seasonal

Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations
Sorghum

Foliar by ground or air equipment or through chemigation Onager®

Miticide [ 10163

- 277 ] 0.1875 1 0.1875 30 Restricted to use in Regions 6, 7, and 8. Ground spray volume specified as 15

– 20 gal per acre (GPA). Minimum spray volume for air application is 5 GPA. 120 day plant

- back interval Pepper/Eggplant Subgroup 8

- 10B Foliar by ground or air equipment Onager®

Miticide [ 10163

- 277 ] 0.1875 1 0.1875 1 120 day plant

- back interval
Foliar; ground or air not specified Hexygon®

DF [10163

- 251] 0.1875 1 0.1875 1 120 day plant

- back interval



### Additionally, IR

- 4 has submitted supplemental labels which propose the following:

Expand the pome fruit use from the currently registered crop group 11 commodities to commodities in crop group 11

- 10 on the Savey® 50 DF (EPA Reg No. 10163

- 250) and Onager® Miticide labels. The proposed use pattern for crop group 11

- 10 commodities is iden tical to that currently registered on these two labels for crop group 11 commodities.

Expand the caneberry use from the currently registered crop subgroup13A commodities to commodities in crop subgroup13

- 07A on the Savey® 50 DF label. The proposed use pa ttern for crop subgroup 13

- 07A is identical to the use pattern for the currently registered crop subgroup 13A commodities.

### Hexythiazox Human Health Risk Assessment D404015

Page 15 of 36 Establish a use on crop subgroup 13

- 07F on the Onager® Miticide label based on the current registered use on grapes, the represent ative commodity for the 13

- 07F crop subgroup. The use pattern for the 13

- 07F crops is identical to the grape use currently on this label.

Establish a use on crop subgroup 13

- 07G on the Savey® 50 DF label based on the current registered use on strawberry, the representative commodity for the 13

- 7G crop subgroup. The use pattern for the 13

- 07F crops is identical to the strawberry use currently on this label.

Conclusions

. The proposed label directions are adequate to allow evaluation of the residue data relative to those proposed new uses.

The proposed supplemental label for the geographically limited use of Onager® Miticide on sorghum is adequate and supported by the submitted residue data. No revisions to the sorghum use pattern on the Onager® labe l are required.

The proposed supplemental label for use of Onager® Miticide on crop subgroup 8

- 10B should be revised to specify minimum spray volumes for ground and aerial application. The submitted residue chemistry data support a minimum spray volume of 20 gallons per acre (GPA) for ground application. Further , the petitioner must revise the directions to reflect a minimum spray volume for aerial applications of 2 GPA for crop subgroup 8

- 10B or submit additional data reflecting aerial application to representative commodities of that crop subgroup. Provided the Onager® Miticide label is revised to specify appropriate minimum spray volumes, the proposed use is supported by adequate residue data.

Adequate residue data have not been submitted to suppor t the requested use on crop subgroup 8

- 10B commodities on the Hexygon® DF (10163

- 251) label. Available residue data reflect application of the EC formulation only; n o residue data have been provided using the DF formulation. Additional field trial data will be required to support use of this formulation on the pepper/eggplant crop subgroup 8

- 10B as outlined in Section 5.3

.
Provided the Savey® 50 DF label is amended to specify a minimum spray volume for aerial application to pome fruit of 10 gallons pe r acre , as required in the OCSPP Harmonized Test Guideline 860.1500 for aerial application to orchard crops in the absence of aerial application data, the proposed Savey® 50 DF label for CG11

- 10 commodities is acceptable. The proposed Onager® Miticide lab el for CG11

- 10 commodities is acceptable.

The proposed supplemental Savey® 50 DF label for crop sugroup13

- 07A commodities is acceptable.

The proposed supplemental Onager® Miticide label for crop subgroup 13

- 07F commodities is acceptable.

### Hexythiazox Human Health Risk Assessment D404015

Page 16 of 36 The proposed supplemental Savey® 50 DF label for crop subgroup 13

- 07G commodities is acceptable.

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new and expanded uses of hexythiazox. Humans may be exposed to hexythiazox in food and drinking water, since hexythiazox may be applied directly to growing crops and application may result in hexythiazox reaching surface and ground water sources of drinking water. Additionall y humans may be exposed to hexythiazox in residential settings, since it may be applied to ornamental plantings in residences, public areas, and recreational sides, as well as on lawns and turf and to residential berries and fruit and nut trees. In an occ upational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application. There is a potential for post

- application exposure for workers re

- entering treated fields.

Risk assessments have been previo usly prepared for the existing uses of hexythiazox. This risk assessment considers all of the aforementioned exposure pathways based on the proposed new uses of hexythiazox, as well as the existing uses as well.

3.5 Consideration of Environmental Justi ce

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 an d Low

Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups ac cording to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that invo lve pesticide use in a residential setting. Extensive data on food consumpti on patterns are compiled by the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA ) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and catego rized by subgroups based on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessm ents are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

### Hexythiazox Human Health Risk Assessment D404015

Page 17 of 36 4.0 Hazard Characterization and Dose

- Response Assessment

4.1 Hazard Characterization

The toxicity datab ase for hexythiazox is complete and adequate for assessing risk

. The Hazard and Science Policy Council (HASPOC) concluded that an acute neurotoxicity study is not required at this time, and a new subchronic neurotoxicity study is not required, since the 28

- day neurotoxicity study is sufficient to assess subchronic
neurotox i city from hexythiazox exposure. The HASPOC also considered if an inhalation study was required for hexythiazox. B ased on a weight of evidence ( WOE) approach, the HASPOC concluded that a 28

- day inhalation toxicity study is not required for hexythiazox at this time. Th e committee’s deliberations considered all of the available hazard and exposure information for hexythiazox , as well as the following factors : (1) the physical/chemical properties and low volatility (1.0x10 - 8 

### mm Hg @ 25°C) of hexythiazox; (2) the low acute inhala tion toxicity of hexythiazox; (3 ) the primary target organ of hexythi a zox toxicity is the liver and adrenal glands following repeated hexythi azox exposure; and (4 ) the use of an oral POD results in occupational inhalation MOEs greater t han 1,400 ( HASPOC Memo, TXR No. 0056434, 9/18/12 )

.
Hexythiazox is associated with toxicity of the liver and adrenals following subchronic and chronic exposure to dogs, rats and mice, with the dog bei ng the most sensitive species. The prenatal developme ntal studies in rabbits and rats and the two

- generation reproduction study in rats showed no indication of increased susceptibility to in utero and/or postnatal exposure to hexythiazox. Reproductive toxicity was not observed. There is no concern for neuro toxicity following exposure to hexythiazox. The toxicology database for hexythiazox does not show any evidence of treatment

- related effects on the immune system. Hexythiazox is classified as “likely to be carcinogenic to humans”; however, s ince the effects seen in the study that serves as the basis for the chronic RfD occurred at doses substantially below the lowest dose that induced tumors, HED concluded that quantification of risk using a non

- linear approach; i.e., RfD, for hexythiazox will adequately acc ount for all chronic effects , including carcinogenicity, that could result from exposure to hexythiazox.

4.2 Hazard Profile

The hazard profiles for hexythiazox are contained in Appendix A of this memorandum.

4.3 Dose

- Response Assessment/Endpoint Select ion

No endpoint attributable to a single exposure was identified from the available oral toxicity database; therefore, an acute dietary risk assessment for hexythiazox is not required.

The chronic dietary endpoint was selected from a one

- year toxicity feeding study in the dog with a NOAEL of 2.5 mg/kg/day. At the study LOAEL of 12.5 mg/kg/day, increased absolute and relative adrenal weights and associated adrenal histopathology

### Hexythiazox Human Health Risk Assessment D404015

Page 18 of 36 were observed. A 100X uncertainty factor was applied to account for inter

- and intra

species variability resulting in a chronic reference dose (cRfD) of 0.025 mg/kg/day. Since the FQPA factor is reduced to 1X, the RfD is equivalent to the chronic population adjusted dose (cPAD).

Short

- term and intermediate

- term incidental oral and inhalation endpoints for risk assessment were selected from a two

- generation reproduction study conducted in the rat with a NOAEL of 30 mg/kg/day. At the study LOAEL of 180 mg/kg/day, decreased pup body weight during lactation and delayed hair growth and/or eye opening, and decreased parental body

- weight gain and increased absolute and relative liver, kidney, and adrenal weights were observed. In a co

- critical subchronic toxicity study in rats, increased liver and adrenal weights, as well as adrenal h istopathology (fatty degeneration of the adrenal zona fasciculata), were observed. Inhalation hazard is assumed to be equivalent to oral hazard.

For the short

- term and intermediate

- term dermal risk assessment s , no quantification of risk is required, ba sed on the fact that the dermal equivalent dose for this dermal exposure scenario is 1.5

- fold greater than the limit dose considering the NOAEL of 30 mg/kg/day from the oral reproduction study, and the estimated 2% dermal absorption for this compound

. EPA has classified hexythiazox as “likely to be carcinogenic to humans” based upon increased incidences of malignant and combined benign/malignant liver tumors in high

dose female B6C3F1 mice, and benign mammary gland tumors, observed in high dose male rats. There was no evidence of carcinogenicity in male mice and female rats. EPA concluded that the evidence as a whole was not strong enough to warrant quantitative estimation of carcinogenic risk to humans using a cancer slope factor. HED concluded th at quantification of risk using a non

- linear approach; i.e., RfD, for hexythiazox will adequately account for all chronic toxicity, including carcinogenicity, that could result from exposure to hexythiazox. That conclusion is based on the following conside rations: (1) the liver tumors found in the female mouse are common tumors; (2) the male mammary tumors were benign and of no biological significance; (3) hexythiazox is not mutagenic; (4) no carcinogenic response was seen in male mice or female rats

.

4 .4 FQPA Considerations

The Agency has determined that it is appropriate to reduce the FQPA safety factor to 1X for the following reasons:

The toxici ty database for hexythiazox is complete. There is no evidence of increased susceptibility or sensitivity in rats or rabbits to
pre

- and/or post

- natal exposure to hexythiazox. There is no evidence of neurotoxicity in the database. A developmental neurotoxicity (DNT) study is not required. The dietary risk assessment is highly conservative and not expected to

u nderestimate risk.

### Hexythiazox Human Health Risk Assessment D404015

Page 19 of 36 4.5 Summary of Toxicological Doses and Endpoints for Use in Human Risk Assessments and Levels

Table 4.5.1. Toxicological Doses and Endpoints for Hexythiazox for Use in Dietary and Non

Occupational Human Health Risk Assessments 1

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 risk is expected from this exposure scenario as no hazard was identified in any toxicity study for

this duration of exposure

Chronic Dietary All Populations NOAEL=2.5

mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Chronic RfD = 0.025

mg/kg/day

cPAD = 0.025 mg/kg/day One

- Year Toxicity Feeding Study

- Dog

LOAEL = 12.5 mg/kg/day based on increased absolute and relative adrenal weights and associated adrenal histopathology.

Short

- and Intermediate

Term Incidental oral NOAEL=30

mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Residential LOC for

MOE = 100 2

- Generation Reproduction Study

– Rat

LOAEL = 180 mg/kg/day, based on decreased pup body weight during lactation and delayed hair growth and/or eye opening, and decreased parental body

- weight gain and increased absolute and relative liver, kidney, and adrenal weights

.

Co

- Critical 13

- Week Oral Toxicity Study

– Rat NOAEL = 5.5 mg/kg/day LOAEL = 38 mg/kg/day, based on increased absolute and relative liver weights in both sexes, increased relative ovarian and kidney weights, and fatty degeneration of the adrenal zona fasc iculata.

@ 397.5/257.6 mg/kg/day, decreased body

- weight gain in females, slight swelling of hepatocytes in central zone (both sexes), increased incidence of glomerulonephrosis in males, increased adrenal weights

Cancer (oral, dermal, inhalation) Classification: “Likely to be Carcinogenic to Humans”. Insufficient evidence to warrant a

quantitative estimation of human risk using a cancer slope factor based on the common liver tumors (benign and malignant) observed only in high dose female mice, and benign mammary gland tumors of no biological significance, observed only in high dose male rats in the absence of mutagenic concerns. The chronic RfD is protective of all chronic effects including potential carcinogenicity of hexythiazox.

1 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. UF A = extrapolation from animal to human (intraspecies). UF H = potential variation in sensitivity among members of the human population (interspecies). UF L = use of a LOAEL to extrapolate a NOAEL. FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

### Hexythiazox Human Health Risk Assessment D404015

Page 20 of 36 Table 4.5.2 Summary of Toxicological Doses and Endpoints for Hexythiazox for Use in Occupational Human Health Risk Assessments

Exposure/ Scenario Point of

Departure Uncertainty

Factors Level of

Concern for Risk Assessment Study and Toxicological

Effects

Dermal S hort

- and intermediate

- Term N/A N / A N/A No dermal hazard identified

Inhalation Short

- and Intermediate

- Term Oral NOAEL = 30

mg/kg/day

Inhalation hazard assumed to be equivalent to oral hazard UF A =10x

UF H =10x Residential

LOC for MOE = 100

Occupational LOC for MOE = 100 2

- Generation Reproduction Study

–

Rat

LOAEL = 180 mg/kg/day, based on decreased pup body weight during lactation and delayed hair growth and/or eye opening, and decreased parental body

- weight gain and increased absolute and relative liver, k idney, and adrenal weights

Co

- critical 13

- Week Feeding Study

– Rat LOAEL = 38.1 mg/kg/day, based on increased absolute and relative liver weights in both sexes, increased relative ovarian and kidney weights, and fatty degeneration of the adrenal zona fasc iculate.

Cancer (oral, dermal, inhalation) Classification: “Likely to be Carcinogenic to Humans”. ”. Insufficient evidence to warrant a

quantitative estimation of human risk using a cancer slope factor based on the common liver tumors (benign and malignant) observed only in high dose female mice, and benign mammary gland tumors of no biological significance, observed only in h igh dose male rats in the absence of mutagenic concerns. The chronic RfD is protective of all chronic effects including potential carcinogenicity of hexythiazox.

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = un certainty factor. UF A = extrapolation from animal to human (intraspecies). UF H = potential variation in sensitivity among members of the human population (interspecies). UF L = use of a LOAEL to extrapolate a NOAEL. FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.



### 5 .0 Dietary Exposure/Risk Characterization

5.1 Residue Chemistry Summary Reside Chemistry Summary, D404573, D. Davis, 5/3/13



### The nature of the residue in plants, animals, and water has been adequately delineated. The residue s of concern for the tol erance e xpression and risk assessment are the parent compound and its metabolites which contain the (4

- chlorophenyl)

- 4

- methyl

- 2

- oxo

- 3

- thiazolidine moiety

.
The number and geographic representation of the submitted field sorghum samples are adequate to supp ort the requested geographically restricted use in Regions 6, 7, and 8.

### Hexythiazox Human Health Risk Assessment D404015

Page 21 of 36 Data were also provided on aspirated grain fractions. All residue data were generated by a validated data collection method, are supported by adequate storage stability data, and
sup port the requested use pattern. The available data are sufficient for establishing a tolerance of 1.5 ppm for the pepper/eggplant subgroup 8

- 10B. The data do not support the use of hexythiazox formulated as a dry flowable on this crop subgroup.

No new field trial data were submitted to support the requested expansion of the current use on the pome fruit crop group (CG) 11 to the pome fruit CG 11

- 10

, on the caneberry subgroup 13A to the caneberry subgroup 13

- 07A , on grapes to the small fruit vine climbing, except fuzzy kiwifruit subgroup 13

- 07F , and on strawberry to the low growing berry subgroup 13

- 07G. Since the original uses are already on the requested labels, and since the expansions are for the identical use pattern currently registered, no new data are required to support the requested expansions.

Updated maximum reasonably balanced diets (MRBD) for livestock have been calculated and indicated that the current livestock tolerances are adequate to cover secondary residues of hexythiazox. Ho wever, HED recommends increasing the ruminant meat by product tolerances to 0.05 ppm and the egg tolerance to 0.05 ppm to harmonize with Codex.

There are no processing commodities associated with sorghum and the pepper/eggplant subgroup 8

- 10B ; therefor e a discussion of residues in processed commodities is not relevant to this action.

The nature of the residue in rotational crops is not understood. However, HED previously concluded that, in consideration of the available confined and field rotational crop studies, a 120

- day plant back interval (PBI) for all crops not listed on the label is appropriate. This conclusion remains unchanged.

5.2 Drinking Water R esidue Profile
EFED Drinking Water Assessment, D401798, A. Shelby, 6/21/12 EFED Drinking Water Assessment, D404203, A. Shelby, 1/17/12



### Currently, the Agency does not have drinking water monitoring data for hexythiazox. Therefore, the potential for hexyth iazox residues in drinking water was evaluated through modeling.

Surface water residues are expected to exceed ground water residues; therefore, EFED provided estimated drinking water concentrations (EDWCs) for various scenarios from the Tier II PRZM/EX AMS surface water model assuming a 0.95 percent cropped area ( PCA ) adjustment. T he maximum estimated surface water concentrations for total residues of hexythiazox were f rom the MS soybean scenario. The 1

- in

- 10 year annual average value of 4.31 μg/L from this scenario was used in the chronic dietary risk
assessment.

### Hexythiazox Human Health Risk Assessment D404015

Page 22 of 36 5.3 Dietary Exposure and Risk Dietary Exposure and Risk Memorandum

, D 404574 , D. D avis, 5/3/13



### 5 .3.1 Acute Dietary Exposure/Risk

No toxic effects attributable to a single dose of hexythiazox were observed in the toxicology database; therefore, an acute dietary exposure and risk assessment for this chemical was not conducted.

5 .3.2 Chronic Dietary Exposure/Risk

The chronic dietary risk assessment used tolerance level residues, included modeled drinking water estimates, assumed 100% crop treated, and incorporated DEEM default
proc essing factors. The dietary assessment could be subs tantially refined using anticipated residues, percent crop treated information and empirical processing data; however these refinements were not conducted since risk estimates were not of concern. This highly conservative risk assessment showed no risks of concern (<100% of the chronic population adjusted dose (cPAD)) for the U.S. General P opulation or any subpopulation. The estimated exposure to the U.S. General P opulation res ulted in a risk equivalent to 17 % of the c PAD. The estimated exposure to chil dren 1

– 2 years of age, the most highly exposed subpopulation, res ulted in a risk equivalent to 82 % of the cPAD. Results for all subpopulat ions are summarized in Table 5 .3 .3, below.

5 .3.3 Cancer Dietary Risk

The HED Cancer Assessment Review Committee (CARC) has recently reconsidered hexythiazox and has classified the chemical as “Likely to be Carcinogenic to Humans”, but has determined that there is insufficient evidence to quantify risk using a cancer slope factor. Rather, the committee concluded tha t regulation based on the chronic reference dose will be protective for both chronic and carcinogenic risks. As noted above there are no chronic risks of concern.

Table 5.3. 3. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Hexythiazox

Population Subgroup Chronic Dietary Cancer

Dietary Exposure (mg/kg/day) % cPAD* Dietary Exposure (mg/kg/day) Risk

General U.S. Population 0.00 4356 1 7 No concern for risks associated with the carcinogenic potential of hexythiazox.

All Infants (< 1 year old) 0.00 8040 32

N/A N/A Children 1

- 2 years old 0.0 20483 82

Children 3

- 5 years old 0.01 3364 54

### Hexythiazox Human Health Risk Assessment D404015

Page 23 of 36 Table 5.3. 3. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Hexythiazox

Population Subgroup Chronic Dietary Cancer

Dietary Exposure (mg/kg/day) % cPAD* Dietary Exposure (mg/kg/day) Risk

Children 6

- 12 years old 0.00 6416 26

Youth 13

- 19 years old 0.00 3220 13

Adults 20

- 49 years old 0.00 2878 12

Adults 50+ years old 0.00 3229 13

Females 13

- 49 years old 0.00 3068 12

* Most highly exposed subpopulation is highlighted in bold.



### 5 .4 Anticipated Residue and Percent Crop Treated (%CT) Information

Anticipated residues and percent crop treated information were not used in the dietary exposure and risk assessment

.

6.0 Residential and Other Non

- Occupational Exposures/Risks Occupational and Residential Exposure and Risk Assessment , D404018 , A. LaMay

, 5/6/13



### There are no new residential uses proposed with th is action; however, there are registered

uses on residential sites, including (1) ornamental landscape plantings in residences, public areas, and recreational sites such as campgrounds, golf courses, parks and athletic fields, (2) ornamental lawns and turf (including residential), (3) residential pome fruit, stone fruit, and nut trees, and residential caneberries. The estimated exposure and risk assessments for the existing residential uses that have been revised to reflect updates to HED’s 2012 Residential SOPs as well as policy changes for body weight assumptions.

6 .1 Residential Handler Exposure and Risk

Since hexythiazox does not pose a dermal risk, only inhalation exposure assessments were conducted for residential handlers. Residential handler exposure i s expected to be short

- term in duration. Intermediate

- term exposures are not likely because of the intermittent nature of applications by residential applicators

. Residential handler inhalation margins of exposure ( MOEs ) significantly exceed 100 for all scenarios assessed and are not of concern. Residential estimated exposure and risks are shown in Table 6. 1, below.

### Hexythiazox Human Health Risk Assessment D404015

Page 24 of 36 Ta ble 6.1. Short

- term Residential Handler E xposure and Risk Estimates for Hexythiazox.

Exposure Scenario Target MOE Inhalation Unit Exposure (mg/lb ai) Maximum

Application Rate 1 Area Treated or

Amount Handled Daily 2 Inhalation

Dose (mg/kg/day) 3 MOE 4

Mixer/Loader/Applicator

Lawns/ Turf ; Gardens/Trees

, WDG/DF, Manually

- pressurized handwand / backpack 100 1.1 0.000625 lb ai/gallon 5 gallons 0.000043 700,000

Gardens/ Trees, WDG/DF, Hose

- end

sprayer 100 0.0014 4.375E

- 6 lb ai/ft 2 1200 ft 2 0.000000092 330,000,000

Gardens/ Trees, WDG/DF, Hose

- end

sprayer 100 0.0014 0.000625 lb ai/gallon 11 gallons 0.00000012 250,000,000

Lawns/ Turf, WDG/DF, Hose

- end

sprayer 100 0.022 0.1875 lb ai/acre 0.5 acres 0.000026 1,200,000

Gardens/Trees, WDG/DF, Manually

pressurized handwand / backpack 100 1.1 4.375E

- 6 lb ai/ft 2 1200 ft 2 0.000072 420,000

1 Based on registered or proposed label (Reg. No. # 10163

- 251 ).

2 Exposure Science Advisory Council Policy #9.1.

3 Inhalation Dose = Inhalation Unit Exposure ( mg/lb ai) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gallons/day) / BW ( 80 kg).

4 Inhalation MOE = Inhalation NOAEL ( 30 mg/kg/day) / Inhalation Dose (mg/kg/day).



### 6.2 Residential Post

- application Exposure

There is the potential for post

- application exposure for individuals exposed as a result of being in an environment that has been previously treated with hexythiazox

. The quantitative exposure/risk assessment for residential post

- application exposures is based

on incidental oral exposure to treated turf. As no dermal hazard was identified, a quantitative dermal post

- application assessment is not required. Short

- term exposure durations are anticipated for incidental oral exposures due to the intermittent nature of applications in residential environments. As the aerobic soil metabolism half life for hexythiazox is 145.2 days 1 

### , intermediate

- term exposure i s also possible for incidental soil ingestion exposure.

Child incidental oral exposure to treated turf was assessed for hexythiazox. Risk estimates greatly exceed the LOC of 100 for all scenarios associated with children’s exposure to treated turf and are not of concern. Post

- application exposure and ris k estimates are shown in Table 6 .2, below.

Table 6 .2. Residential Post

- application Non

- cancer Exposure and Risk Estimates for Hexythiazox (Short

- Term for Hand

- to

- Mouth and Object

- to

- Mouth Exposure; Sh ort

- and Intermediate

- Term for Incidental Soil Ingestion Exposure). Lifestage Post

- application Exposure Scenario App rate Dose MOEs

Child Turf

- sprays Hand to Mouth
0.1875 lb ai/acre 0.0029 11,000 Object to Mouth 0.00009 350,000
Incidental Soil Ingestion 0.0000063 4,700,000

1 Hexythiazox: Drinking Water Assessment for New Use on wheat, alfalfa, timothy, eggplant and peppers

. Andrew Shelby. DP Barcode: 396529 & 401798. 6/21/2012

.

### Hexythiazox Human Health Risk Assessment D404015

Page 25 of 36 6 .3 Other

6 .3.1. 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 metho d employed for hexythiazox . The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray D rift website for more information 2 

### . The Agency has completed its evaluation of the new database submitted 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 and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off

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

Although a quantitative residential post

- application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers. This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post

- application inhala tion exposure scenarios

.

It is noted that the 0.19 lb ai/acre application rate for turf was modeled to estimate post

application residential exposure of children. As this rate is equal to or higher than many of agricultural application rates, this sce nario is protective of any exposure of farm children via spray drift from agricultural hexythiazox applications.

6 .3.2. Residential Bystander Post

- Application Exposure

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

- application inhalation

e xposure assessment was not performed for hexythiazox at this time primarily because of the low acute inhalation tox icity (Toxicity Category IV) and low vapor pressure ( 2.3 x 10 - 8 

### mmHg ) . However, volatilization of pesticides may be a source of post

- applica tion 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, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 3 

### . 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

2 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm
3 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

### Hexythiazox Human Health Risk Assessment D404015

Page 26 of 36 procedures are developed, the Agency may revisit the need for a quantitative post

application inhalation exposure assessment for hexythiazox.

Although a quantita tive residential post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for handlers (i.e., groomers, treaters, etc). This exposure scenario is representative of a worse case inhalation exposure and should be considered protective of most post

- application inhalation exposure scenarios.

7.0 Aggregate Risk Assessments and Risk Characterization

7 .1 Acute Aggregate Risk

No toxic effects attributable to a single dose of hexythiazox were observed in the toxicology database; therefore, an acute aggregate risk assessment for this chemical is not required.

7 .2 Short

- and Intermediate

- Term Aggregate Risks

The s hort

- and int ermediate

- term aggregate risks combine residential handler (adult only) and post application exposures with ave rage food and water exposures. The residential estimated exposures used in the short

- and intermediate

- term aggregate risk assessments are shown in Table 7 .2.1, below.

Table 7 .2.1. Short

- and Intermediate

- Term Residential Exposure Values and Sources Used in the Hexythiazox Aggregate Risk Assessment

Population Handler Exposure (mg/kg/day) Postapplication Exposure (mg/kg/day) Residential Exposure (mg/kg/day) 1 

### Short

- Term

Adult Male 0.000072 Source: Table 6 .1 Gardens/Trees, handwand/backpack N/A ; no dermal endpoint 0.000072



### Adult Female 0.000072 Source: Table 6 .1 Gardens/Trees, handwand/backpack N/A ; no dermal endpoint 0.000072



### Child N/A ; only adults are assessed as handlers 3 0.0029 Source: Table 5.2 Hand

- to

- Mouth from Treated Turf 0.0029

### Hexythiazox Human Health Risk Assessment D404015

Page 27 of 36 Table 7 .2.1. Short

- and Intermediate

- Term Residential Exposure Values and Sources Used in the Hexythiazox Aggregate Risk Assessment

Population Handler Exposure (mg/kg/day) Postapplication Exposure (mg/kg/day) Residential Exposure (mg/kg/day) 1 

### Intermediate

- Term

Adult Male N/A ; intermediate term exposure not expected N/A ; no dermal endpoint

-



### Adult Female N/A ; intermediate term
exposure not expected N/A ; no dermal endpoint

-



### Child N/A ; only adults are assessed as handlers 0.0000063 Source: Table 5.2 Incidental Soil Ingestion 0.0000063

1 Residential exposure is the sum of the handler (adults only) and post application exposures.

2 N/A is not applicable
3 HED’s 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html )



### Short

- and intermediate

- term aggregate margins of exp osure for adults and children greatly exceed the LOC of 100 and are not of concern. Short

- and intermediate

- term estimated exposure s and risks are shown in Table 7 .2.2, below.

Table 7 .2.2. Short

- Term and/or Intermediate

- Term Aggregate Risk Calculations

Population Short

- Term Scenario

NOAEL mg/kg/day LOC 1 Max Allowable Exposure 2 mg/kg/day Average

Food & Water Exposure mg/kg/day Residential

Exposure 3 mg/kg/day Aggregate MOE

(food and residential) 4

Adult Male 30 100 0.3 0.003229 0.000072 9,100

Adult Female 30 100 0.3 0.00 3068 0.000072 9,600

Child 30 100 0.3 0.0 20483 0.0029 1, 300

Intermediate

- Term Scenario

Adult Male 30 100 0.3 0.003229 N/A 9,300

Adult Female 30 100 0.3 0.003068 N/A 9,800

Child 30 100 0.3 0.020483 0.0000063 1,500

1 The LOC of 100 is based on the standard inter

- and intra

- species extrapolation factors.
2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC = 30/100 = 0.3 mg/kg/day.
3 Residential Ex posure values taken from Table 7 .2.1.Average food & water exposure taken from Ta ble 5 .3.3.

4 Aggregate MOE = [NOAEL (Avg Food & Water Exposure + Residential Exposure)]

### Hexythiazox Human Health Risk Assessment D404015

Page 28 of 36 7 .3 Long

- Term (Chronic) Aggregate Risk

As there are no uses that are expected to result in long

- term residential exposure , l ong

term (chronic) aggregate risk includes only dietary ( food and water) exposure. As noted in Section 5 .3 .2 of this memorandum, there is no chronic dietary risk of concern.

8 .0 Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to hexythiazox and any other substances and hexythiazox 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 hexythiazox has a common mechanism of toxicity with other substances. For information regarding EPA’ s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and pro cedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposures and Risks Occupational and Residential Exposure and Risk Assessment , D404018 , A. LaMay

, 5/6/13



### An occupation exposure and risk assessment was conducted to support the new uses on alfalfa and timothy. Full details of that assessment are included in the memorandum cited above and the results are briefly summarized here.

9.1 Occupational Handler Risk

The occupational exposure and risk assessment addresses risks to workers exposed in an occupational setting via the dermal and inhalation routes of exposure. However, for hexythiazox a quantitative dermal risk assessment is not required; therefore risks were quantitatively assessed for inhalation exposure only. Based on the proposed uses, short

term exposures are anticipated as the proposed uses indicate the product is only to be
app lied once per year. As the inhalation point of departure is the same for both short

- and intermediate

- term exposure durations, the short

- term assessment is protective of possible longer

- term exposures (i.e., commercial applicators that may apply a product over a period of weeks).

All occupational handler scenarios assessed for the new and expanded uses of hexythiazox resulted in estimated inhalation margins of exposure (MOEs) which were significantly greater than 100 with baseline inhalation protection (n o respirator). Therefore, inhalation risks are not of concern and inhalation personal protective equipment (PPE, i.e., respirators) is not required.

### Hexythiazox Human Health Risk Assessment D404015

Page 29 of 36 Occupational handler risk estimates are shown in Table 9 .1.

1 Based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( [ March 2012 ] ); includes data from PHED/ORETF

/AHETF (level of mitigation: Baseline, PPE, Eng. Controls).

2 Based on register ed or proposed label

. 3 Exposure Science Advisory Council Policy #9.1. Table 9 .1.1. Short

- /Intermediate

- Term Occupational Exposure and Risk Estimates for Hexythiazox

. All estimates are at baseline mitigation (without respirator).

Exposure Scenario Crop or Target Inhalation Unit Exposure (ug/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
M/L, DF/WDG, Aerial, Broadcast Orchard, Field Crop

8.96 0.1875 lb ai/acre 350 acres 0.00735 4

, 100

M/L, DF/WDG, Airblast, Broadcast Orchard 40 acres 0.00084 36,000

M/L, DF/WDG, Chemigation,

Broadcast Orchard, Field Crop 350 acres 0.00735 4

, 100

Greenhouse 60 acres 0.00126 24,000

M/L, DF/WDG, Groundboom,

Broadcast Greenhouse 60 acres 0.00126 24,000
Field Crop 80 acres 0.00168 18,000

M/L, L/SC/EC, Aerial, Broadcast Orchard, Field Crop

0.219 0.1875 lb ai/acre 350 acres 0.00018 170,000

High

- acreage Field Crop 1200 acres 0.000616 49,000
M/L, L/SC/EC, Airblast, Broadcast Orchard 40 acres 0.0000205 1,500,000

M/L, L/SC/EC , Chemigation, Broadcast Orchard, Field Crops (all) 350 acres 0.00018 170,000

M/L, L/SC/EC, Groundboom,

Broadcast Field Crop 80 acres 0.0000411 730,000

High

- acreage Field Crop 200 acres 0.000103 290,000 Applicator
Applicator, Spray, Aerial, Broadcast Orchard, Field Crop Engineering Control: 0.0049

0.1875 lb ai/acre 350 acres 0.000004 7,400,000 High

- acreage Field Crop 1200 acres 0.000014 2,200,000 Applicator, Spray, Airblast, Broadcast Orchard 4.71 40 acres 0.000441 68,000

Applicator, Spray, Groundboom, Broadcast Greenhouse

0.34 60 acres 0.0000479 630,000 Field Crop 80 acres 0.0000638 470,000 High

- acreage Field Crop 200 acres 0.00016 190,000 Flagger Flagger, Spray, Aerial, Broadcast Orchard, Field Crop (all) 0.35 0.1875 lb ai/acre 350 acres 0.000288 100,000

Mixer/Loader/Applicator M/L/A, DF/WDG, Backpack, Broadcast Greenhouse 140 0.000625 lb ai/gallon 40 gallons 0.0000438 680,000

M/L/A, DF/WDG, Manually

pressurized Handwand, Broadcast Greenhouse 30 0.000625 lb ai/gallon 40 gallons 0.00000938 3,200,000

M/L/A, DF/ WDG, Mechanically

- pressurized Handgun , Broadcast Greenhouse 120 0.000625 lb ai/gallon 1000 gallons 0.000938 32,000

### Hexythiazox Human Health Risk Assessment D404015

Page 30 of 36 4 Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x Conversion Facto r (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled Daily (A or gal/day) /BW ( 80 kg).

5 Inhalation MOE = Inhalation NOAEL ( 30 mg/kg/day)/ Inhalation Dose (mg/kg/day).



### 9 .2 Occupational Post Application Risk

HED uses the term 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
tre ated 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 ta rget 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.

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

- application inhalation exposure assessment was not performed for hexythiazox at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV) and low vapor pressure ( 2.3 x 10 - 8 

### mmHg ) . 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 volatilization of pesticides and resuspens ion of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 4 

### . 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 proced ures, to identify the need for and, subsequently, the way to incorporate occupational post

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

- application inhalation exposure assessment for hexythiazox.

Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/com mercial handlers. Handler exposure 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

- application inhalation exposure scenarios.

The Worker Protection Standard for Agricultural Pesticides contains requirements for protecting workers from inhalation exposures during and after greenhouse applications through the use of ventilation requirements [40 CFR 170.110, (3) (Restrictions associated with pesticide applications)].

4 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

### Hexythiazox Human Health Risk Assessment D404015

Page 31 of 36 As no dermal hazard has been identified for hexythiazox, quantification of dermal post

application risk is not required. In accordance with the updated Part 158 data requirements (2007), one or more dislodgeable foliar residue (DFR) studies are required when a pesticide has residential or occupational uses that could result in postapplication dermal exposure. However, as quantification of dermal risk is not required for hexythiazox, a DFR study is not required for hexythiazox at this time.

The REI specified on the proposed label is based on the acute toxicity of hexythiazox. Hexythiazox is classified as Toxicity Category IV for acute dermal toxicity, T oxicity Category IV for acute dermal irritation, and Toxicity Category III for eye irritation. It is not a skin sensitizer. Under WPS for agricultural pesticides, ai’s classified as Acute III or IV for acute dermal, eye irritation and primary skin irrita tion are assigned a 12

- hour REI. Therefore, the WPS interim REI of 12 hours is adequate to protect agricultural workers from post

- application exposures to hexythiazox.

10 .0 Human Stu dies

This risk assessment relies in part on data from studies in whi ch adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from PHED 1.1; the AHETF database; the Outdoor Residential Exposure Task Force (ORETF) database; the ARTF database; and the Residential SOPs, are (1) subject 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. Des criptions of data sources, as well as guidance on their use, can be found at the Agency website 5



### .

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

- exposure

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

- app

- exposure

- data.html

### Hexythiazox Human Health Risk Assessment D404015

Page 32 of 36 Appendix A. Toxicology Assessment

A.1 Toxicity Profiles

Table A.1.1. Acute Toxicity Data on Hexythiazox Technical

Guideline No./ Study Type MRID No. Results Toxicity Category

870.1100 Acute oral toxicity 00146549 LD 50 = >5000 mg/kg IV

870.1200 Acute dermal toxicity 00146550 LD 50 = >5000 mg/kg IV

870.1300 Acute inhalation toxicity 00146554 LC 50 = >2.0 mg/L IV

870.2400 Primary eye irritation 00146551 Reddened conjunctiva III

870.2500 Acute dermal irritation 00146552 Non irritant IV

870.2600 Skin sensitization 00146553 Non sensitizer N/A



### Table A.1

. 2. Toxicity Profile of Hexythiazox

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3100 90

- Day oral toxicity rat 45067101 (1983) Acceptable/guideline 0, 10, 70, 500, or 3500
ppm M: 0, 1.2, 8.1, 58.6, or 397.5 mg/kg/day F: 0, 0.8, 5.4, 38.1 or 257.6 mg/kg/day NOAEL = 8.1/5.4 mg/kg/day, males/females LOAEL = 58.6/38.1 mg/kg/day, males/females, based on increased absolute and relative liver weights in both sexes, increased relative ovarian and kidney weights, and fatty degeneration of the adrenal zona fasciculata.

@ 397.5/257.6 mg/kg/day, decreased body

- weight gain in females, slight swelling of hepatocytes in central zone (both sexes), increased incidence of glomerulonephrosis in males, increased adrenal weights

870.3700a Prenatal developmental toxicity rat 44955711 (1984) Acceptable/guideline 0, 240, 720, or 2160 mg/kg/day Maternal NOAEL = 240 mg/kg/day LOAEL = 720 mg/kg/day based on decreased maternal body weight gain, and decreased food consumption. Developmental NOAEL = 240 mg/kg/day LOAEL = 720 mg/kg/day based on delayed ossification.

870.3700b Prenatal developmental toxicity rabbit 00146555 (1984) Acceptable/guideline 0, 120, 360, or 1080 mg/kg/day Materna l NOAEL 1080 mg/kg/day LOAEL >1080 mg/kg/day Developmenta l NOAEL 1080 mg/kg/day LOAEL >1080 mg/kg/day

870.3800 Two

- Generation reproduction and fertility effects rat 00147578 (1985) Acceptable/guideline 0, 60, 400, or 2400 ppm Average doses across generations: M: 0, 4.45, 29.73, or 180.67 mg/kg/day F: 0, 5.27, 34.77, or Parental/Systemic NOAEL = 29.73/34.77 mg/kg/day, males/females LOAEL = 180.67/207.67 mg/kg/day, males/females, based on decreased body weig ht gain and increased absolute and relative liver, kidney, and adrenal weights. Reproductive NOAEL 180.67/207.67 mg/kg/day, males/females LOAEL >180.67/207.67 mg/kg/day, males/females

### Hexythiazox Human Health Risk Assessment D404015

Page 33 of 36 Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

207.67 mg/kg/day Offspring NOAEL = 29.73/34.77 mg/kg/day, males/females LOAEL = 180.67/2 07.67 mg/kg/day, males/females, based on decreased pup body weight during lactation, and delayed hair growth and/or eye opening

.

870.4100b Chronic toxicity dog 00151359, 00146556, 00156895 (1984) Acceptable 0, 100, 500, or 5000 ppm (0, 2.5, 12.5, or 125 mg/kg/day) M: 0, 2.87, 13.1, or 153 mg/kg/day F: 0, 3.17, 13.9, or 148 mg/kg/day

4

- week: 0, 125, 500, 2000, 8000 ppm NOAEL = 2.5 mg/kg/day LOAEL = 12.5 mg/kg/day based on increased absolute and relative adrenal weights and associated adrenal histopat hology (adrenal cortex hypertrophy). @ 125 mg/kg/day, relative adrenal weights and associated adrenal cortex hypertrophy (more pronounced)

4

- week range

- finding: relative adrenal weight increased at 2000 ppm (50 mg/kg/day) and 8000 ppm (200 mg/kg/day)

870.4300 Chronic Toxicity/ Carcinogenicity rat 00146559 (1984) Acceptable/guideline 0, 60, 430, or 3,000 ppm M: 0, 3, 23, or 163 mg/kg/day F: 0, 4, 29, or 207 mg/kg/day NOAEL = 23/29 mg/kg/day, males/females LOAEL =163/207 mg/kg/day, males/females based on decreased body weight and body weight gain and increased absolute and relative liver weights in both sexes.

No evidence of carcinogenicity

870.4300 Carcinogenicity mice 00147577, 00156896 (1985) Acceptable/guideline 0, 40, 250, or 1500 ppm M: 0, 6.72, 41.6, or 267 mg/kg/day F: 0, 8.38, 51.2, or 318 mg/kg/day NOAEL = 41.6/51.2 mg/kg/day, males/females LOAEL = 267/318 mg/kg/day, males/females) based on decreased male body weight and body weight gain, and increased absolute and relative liver weigh ts in both sexes.

Evidence of carcinogenicity (causes liver tumors in females).

Gene Mutation 870.5100 (Salmonella typhimurium and Escherichia coli reverse gene mutation assay) 44955710 (1983) Acceptable The test was negative up to the highest dose tested (6400 μg/plate +/

- S9.

Gene Mutation 870.5300 ( In vitro mammalian cell forward gene mutation assay in CHO cells) 00155154 (1985) Acceptable Independently performed trials were negative up to precipitating doses ( 60 μg/mL) and severely cytotoxic concentrations (200 μg/mL

- S9; 400 μg/mL +S9).

Cytogenetics 870.5375 In vitro mammalian cell cytogenetic assay in 00156894 (1986) Acceptable The test was negative up to precipitating doses accompanied by severe cytotoxicity ( 167 μg/mL +/

- S9).

### Hexythiazox Human Health Risk Assessment D404015

Page 34 of 36 Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

CHO cells

Cytogenetics 870.5395 In vivo mouse micronucleus assay 44955708 Unacceptable

There’s an update The results were inconclusive because a positive response, which was within the wide range of historical background data, was recorded for female mice at the mid

- and high

doses (500 and 1000 mg/kg). The assay should be repeated to confirm or refute the eq uivocal results.

Other Effects 870.5550 In vitro UDS assay in primary rat hepatocytes 00156893 (1985) Acceptable The test was negative up to a lethal dose (250 μg/mL).

870.6200b Subchronic neurotoxicity Crj:CD(SD)IGS(SPF)
rats 48657401 (2004) Acceptable/nonguideline 0, 100, 1000, or 10000
ppm Males: 0, 8.8, 88.7, or 868.2 mg/kg/day Females: 0, 9.5, 90.1, or 892.7 mg/kg/day (28 days) NOAEL = 1000 ppm (males 88 mg/kg/day; females 90 mg/kg/day). LOAEL = 10000 ppm (males 868 mg/kg/day; females 892 mg/kg/day), based on decreased motor activity in both sexes, decreased body weight in males, increased adrenal weight in females, and increased liver weight in both sexes.

HASPOC (D0056434): 28

- day duration is sufficient to

assess subchronic neurotoxicity from hexythiazox exposure

870.7485 Metabolism and pharmacokinetics 00146558 (1985) Acceptable/guideline

Single oral dose at 10 mg/kg (Group B); 14 daily oral doses (10 mg/kg) of unlabeled material followed by one dose (10 mg/kg) of [ 14 C] test material (Group C); and a single oral dose of 880 mg/kg (Group D). Absorption and distribution of dosed radioactivity were rapid. The radioactive material was rapidly eliminated in the urine and feces; the majority of the radioactivi ty was eliminated within 24 hours. There were no observable differences in the total elimination of NA

- 73 between male and female rats. The major route of elimination in both the male and female rats was by fecal excretion. The major metabolite found, P T

- 1

- 8 (cis), accounted for 8

- 12% of the administered radioactivity in the low dose groups. Approximately 11

- 20% and 65

- 69% of the dosed radioactivity was identified as unchanged NA

- 73 in the low

dose and high

- dose groups, respectively. All other metaboli tes were present at low concentrations (<2%). There was no apparent sex difference in metabolite formation. Significant levels of NA

- 73 equivalent [ 14 C]

- residues were detected in the fat, liver, and adrenals. A sex

related difference in the residue leve ls of all tissues was observed, with residues in female tissues being two

- fold higher than those found in male tissues.

870.7485 Metabolism and pharmacokinetics 0146557 (1983) Acceptable/non

- guideline

Single low dose (10 mg/kg/day) Total recovery of radioactivity 72 hours after treatment accounted for 101.9

- 103% of the dose. The distribution of radioactivity 72 hours after dosing was as follows: 1) 30% (male and female) was excreted in the urine, 2) 60% (female) to 67% (male) was ex creted in the feces, and 3) about 4% (male) to 10% (female) of the administered radioactivity remained in the tissues, with the highest concentration in the fat (2.3 ppm, males; 5.4 ppm, females). Significant sex differences existed for the pharmacokineti cs of NA

- 73 in these rats, with females exhibiting slower elimination rats and higher tissue residues (about double)

### Hexythiazox Human Health Risk Assessment D404015

Page 35 of 36 Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

than males. NA

- 73 was metabolized to a large number of metabolites that were excreted both in the urine and feces. Seven metabolites were structurally identified in addition to the parent compound in both excreta of both sexes, with the major fecal metabolite, PT

- 1

- 8 (cis) accounting for 10% of the dosed radioactivity. The others were all minor metabolites accounting for less than 1.4%. A bout 20% of the dose was excreted as unchanged NA

- 73 (97% of which was in the feces). No significant sex difference was apparent with respect to metabolite formation.

870.7600 Dermal penetration 40608402, 40787901 (1985) Unacceptable The total percent of dose absorbed averaged 2%, 1%, and 1.1% for cannulated rats (10

- hour sacrifice) and 0.8%, 0.2%, and 0.2% for non

- cannulated rats (1

- hour sacrifice) at the low, medium, and high dose levels, respectively. The amount of radioactivity in the blood, carcass, urine and other organs totaled <2% of the applied dose. The results of this study (2% dermal absorption) can be used for risk assessment purposes.
870.7800 Immunotoxicity 48685201 (2012) Acceptable/Guideline Immunotoxicity NOAEL is 4500 ppm (equivalent to 904 mg/kg/day). A LOAEL was not established.

### Hexythiazox Human Health Risk Assessment D404015

Page 36 of 36 Appendix B : Toxicology Data Requirements

The toxicology data requirements (40 CFR 158.340) for the food uses of hexythiazox 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 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 (nonrodent)

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

- Day Dermal

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

- Day Dermal

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

- Day Inhalation

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

no CR yes

yes D

no C

no

no A

870.3700a Developmental Toxicity (rodent)

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

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

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

yes yes 870.4100a Chronic Toxicity (rodent)

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

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

.................... 870.5375 Mutagenicity

— Structural Chromosomal Aberrations

... 870.5550 Mutagenicity

— Other Genotoxic Effects

....................... yes yes yes y es

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 Develop. Neurotoxicity

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

no

yes yes CR -

-

no A

yes B

no

870.7485 General Metabolism

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

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

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

no

yes yes

yes

yes Special Studies

A HASPOC (D0056434): not required at this time; B HASPOC (D0056434): 28

- day study is sufficient to assess subchronic neurotoxicity from hexythiazox exposure ; C dermal equivalent dose is 1.5

- fold greater than the limit dose considering the NOAEL of 30 mg/kg/day from the oral reproduction study and the estimated 2% dermal absorption for this compound ; D not required since there is a 4

- week study and a 1

- year study available