### Hexythiazox Human Health Risk Assessment for New Uses on Alfalfa and Timothy

Page 3 of 30 1.0 Executive Summary

Gowan Company is proposing amended registration of its hexythiazox formulation, Onager ® Miticide, to add regionally restricted new uses on alfalfa and timothy. In support of the proposed amendment, Gowan Company, under PP# 1F7934 , is proposing

tolerances for alfalfa forage and hay , and t imothy forage and hay

.

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 immunotoxicity or neurotoxicity following exposure to hexythiazox. The toxicology database for hexythiazox does not show any evidence of treatment

- related effects on the immune system. Hexythiazox is clas sified as “likely to be carcinogenic to humans”; however, the evidence as a whole is not strong enough to warrant a quantitative estimation of human risk. Since the effects seen in the study that serves as the basis for

the chronic RfD occurred at doses su bstantially below the lowest dose that induced tumors, the chronic RfD is considered protective of all chronic effects including potential carcinogenicity.

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

- year dog feeding study. Short

- term and intermediate

- term incident al 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 nature and magnitude of the residue in plants, animals and wat er has been adequately delineated to support the proposed amended use on alfalfa and timothy. The submitted labels are adequate to support the proposed uses. An adequate high performance liquid chromatography method with UV detection ( HPLC/UV ) exists to enforce th e required crop and livestock tolerances. The analytical reference standard at the EPA Repository for hexythiazox has expire d . An updated certificate of analysis or a new analytical reference standard must be provided to the EPA National Pestic ide Standards Repository

. The submitted field trial data were generated using adequate data collection methods, are supported by adequate storage stability data, and support tolerances of 15 ppm for alfalfa forage, 30 ppm for alfalfa hay, and 40 ppm fo r b oth timothy forage and hay. Revised tolerances for ruminant fat at 0.05 ppm and ruminant meat

- by

- products at 0.2 ppm, as

well as new tolerances of 0.01 ppm in egg and 0.05 ppm for fat and poultry meat by

products are required. There are no processed comm odities associated with alfalfa and timothy. The nature of the residue in rotational crops in not adequately understood, however, based on the available confined and limited rotational crop data, HED

### Hexythiazox Human Health Risk Assessment for New Uses on Alfalfa and Timothy

Page 4 of 30 concludes that

, in light of the 120 day plant

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

No Canadian or Mexican MRLs have been established for residues of this active ingredient in plants or livestock. There are no codex MRLs established f or alfalfa or

t imothy; however, there are Codex MRLs for livestock at 0.05 ppm in/on the following: edible offal (mammalian); mammalian fats (except milk fats); milks; milk fats; poultry, edible offal; poultry meat (fat). The U.S. and Code x residue defini tions in both plants

and livestock are harmonized. There is no issue of international harmonization with respect to the recommended alfalfa

, timothy , and egg tolerances since there are no

established international tolerances for these commodities . Due to the increased livestock dietary burden expected with the new uses on alfalfa and timothy, revised U.S. livestock

tolerances in fat and meat byproducts of ruminants are required. HED is recommending

an increase in the ruminant fat and milk tolerance s to 0 .05 ppm in order to account for the increased dietary burden to livestock and to be harmonized with Codex. Additionally new tolerances for poultry fat and meat byproducts are recommended at 0.05 ppm to be

harmonized with Codex. However, the recommended t olerance increase for livestock meat byproducts will not be harmonized with Codex as the potential hexythiazox residue level in meat byproducts may exceed the current Codex MRL.

An acute endpoint was not selected for hexythiazox; therefore, the Agency c onducted 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 processing factors, and modeled water values . This unrefined assessment resulted in estimated chronic dietary (food and water) risks of 13% of the chronic population adjusted dose (cPAD) for the U.S. population an d 63 % of the cPAD

for children 1

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

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 settings. These uses were reassessed to reflec t 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; significantly exceed ing the level of concern (L OC) of 100 and are not of

concern . The MOEs for children’s incidental oral exposure to treated turf ranged 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 c oncern, 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

- term aggregate MOEs ranged from 1,600 to 14,000; 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. Chronic dietary risk is not of concern.

### Hexythiazox Human Health Risk Assessment for New Uses on Alfalfa and Timothy

Page 5 of 30 A quantitative dermal risk assessment is not required for hexythiazox. Occupational

handler inhalation MOEs significantly exceed 100 for all scenarios assessed associated

with the alfalfa and timothy 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 hours is appropriate and in complia nce 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 Envir onmental Justice in Minority Populations and Low

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

Regulatory Recommendation

Provide d the registrant submits a revised Section F (see Table 10 .2) and updated certificate(s) of analysis or new analytical reference standard

, there are no human health risks of concern that would preclude the establishment /revision of tolerances for the

combi ned residues of hexythiazox and its metabolites containing the (4

- chlorophenyl)

- 4

- methyl

- 2

- oxo

- 3

- thiazolidine moiety calculated as the stoichiometric equivalent of hexythiazox as follows:

U nder 40 CFR 180.448 (a) Cattle, fat.....................

... 0.05 ppm Cattle, meat byproducts......

.. 0.2 ppm Goat, fat.........................

. 0.05 ppm Goat, meat byproducts......

... 0. 2 ppm Horse, fat........................ 0.05 ppm Horse, meat byproducts......

. 0. 2 ppm Sheep, fat.....................

... 0.05 ppm Sheep, meat byproducts......

.. 0. 2 ppm
Milk...........................

... 0.05 ppm Poultry, fat.....................

. 0.05 ppm Poultry, meat byproducts...

... 0.05 ppm Egg..............................

. 0.01 ppm

U nder 40 CFR 180.448 (c ) Alfalfa, Forage..................15 ppm Alfalfa, Hay..................... 30 ppm Timothy, Forage................ 40 ppm Timothy, Hay................... 40 ppm

### Hexythiazox Human Health Risk Assessment for New Uses on Alfalfa and Timothy

Page 6 of 30 The current tolerance expression listed in the 40CFR 180.448 is in compliance with the HED Interim Guidance on Tolerance Expressions (S. Knizner, 5/27/09).

2.0 Ingredient Profile

Residue Che mistry Summary Document, D39686 2, D. Drew

, 6/18 /1 2



### 2.1 Summary of Registered/Proposed Uses

Gowan Company is proposing amended registration of the 1 lb ai/gal emulsifiable concentrate (EC) formulation of hexythiazox (Onager ® Miticide, EPA Reg. No. 10163

- 277) to add regionally restricted n ew uses on alfalfa and timothy. A summary of the use directions are provided in Table 2.1, below.

Table 2.1. Summary of 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

Alfalfa

Foliar, Broadcast, Ground (15

- 20 gal/A) or Aerial (min. 5 gal/A) Onager

1 lb ai/gal EC [10163

- 277] 0.0781

-

0.1875 1 0.1875 14 Use limited to alfalfa grown west of the

Rockies. Apply prior to

adult mite build

- up.

Timothy

Foliar, Broadcast, Ground (15

- 20 gal/A) or Aerial (min. 5 gal/A) Onager

1 lb ai/gal EC [10163

- 277] 0.0781

-

0.1875 1 0.1875 0 (forage)

14 (hay) Use limited to timothy grown west of the Rockies. Apply prior to

adult mite build

- up. Animals may graze treated fields on the day of application.



### Conclusions

. The label directions for alfalfa and timothy are adequate to allow

evaluation of the residue data relative to those proposed uses. T he proposed labels for use of Onager Miticide on alfalfa and timothy are acceptable and are supported by the

submitted data.

### Hexythiazox Human Health Risk Assessment for New Uses on Alfalfa and Timothy

Page 7 of 30 2.2 Structure and Nomenclature

Table 2.2 Structure and Nomenclature of Hexythiaz ox.
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® 1E Ovicide/Miticide)

(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



### 2.3 Physical and Chemical Properties

Table 2 .3

. Physicochemical Properties of Hexythiazox.

Parameter Value Reference 1

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

1 References and values as cited in the petition materials for PP#9F7556.

### Hexythiazox Human Health Risk Assessment for New Uses on Alfalfa and Timothy

Page 8 of 30 3. 0 Hazard Characterization/Assessment

3.1 Hazard Characterization

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

. HED previously required acute neurotoxicity, subchronic neurotoxicity , and immunotoxicity

stud ies as condition s of registration (D383744, Davis

, 6/22/11) . An immunotoxicity study and a 28

- day neurotoxicity study have been received and reviewed by the Agency, and they have been found acceptable. 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 icity from hexythiazox exposure. The HASPOC also considered if an inhalation study was required for hexythiazox. B ased on

a we ight 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 we ll 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 than 1,400 ( HASPOC Memo, TXR No. 0056434, 9/18/12 )

.

Hexythiazox is associated with toxicity of the liver and adrenals follow ing 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 susceptibi lity to in utero and/or postnatal exposure to hexythiazox. Reproductive toxicity was not observed. There is no concern for immunotoxicity or neurotoxicity following exposure to hexythiazox. The toxicology database for hexythiazox does not show any evidenc e of treatment

- related effects on the immune system. Hexythiazox is classified as “likely to be carcinogenic to humans”; however, the evidence as a whole is not strong enough to warrant a quantitative estimation of human risk. Since 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, the chronic RfD is considered protective of all chronic effects including potential carcinogenicity of hexythiazox.

3.2 Hazard Profile

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

3.3 Dose

- Response Assessment/Endpoint Se lection

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.

### Hexythiazox Human Health Risk Assessment for New Uses on Alfalfa and Timothy

Page 9 of 30 The chronic dietary endpoint was selected from a one

- year toxic ity 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 were observed. A 100X uncertainty factor was applied to account for in ter

- 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 histopathology (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 assess ment s , no quantification of risk is required, based 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 estima ted 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 mamma ry 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 us ing a cancer slope factor.

3.4 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 s usceptibility 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

underestimate risk.

### Hexythiazox Human Health Risk Assessment for New Uses on Alfalfa and Timothy

Page 10 of 30 3.5 Summary of Toxicological Doses and Endpoints for Use in Human Risk

Assessments and Levels

Table 3.5.1 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, an d 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

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

### Hexythiazox Human Health Risk Assessment for New Uses on Alfalfa and Timothy

Page 11 of 30 Table 3.5.1 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

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 fema le 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

o bserved 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.



### Table 3.5.2 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, kidney, 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 sexe s, increased relative ovarian and kidney weights, and fatty degeneration of the

adrenal zona fasciculate.

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.

### Hexythiazox Human Health Risk Assessment for New Uses on Alfalfa and Timothy

Page 12 of 30 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.



### 4.0 Dietary Exposure/Risk Characterization

4.1 Food Residue Profile

Residue Che mistry Summary Document, D396862, D. Drew

, 6/18 /1 2



### The nature of the residue in plants, animals, and water has been adequately delineated.

The residue s of concern for the tolerance e xpression and risk assessment are the parent compound and its metabolites which contain the (4

- chlorophenyl)

- 4

- methyl

- 2

- oxo

- 3

- thiazolidine moiety

.

An ad equate high performance liquid chromatography method with UV detection (HPLC/UV) exists to enforce the recommended revised and new plant and livestock

tolerance s

. This method is listed in the U.S. EPA Index of Residue Analytical Methods under hexythiazox as method AMR

- 985

- 87. Residues are expressed in terms of hexythiazox using a molecular weight conversion factor of 1.55. The method LOQ is 0.02 ppm.

Acceptable multi

- residue methods data have been submitted reflecting testing of hexythiazox and its metabolites through FDA Multi

- residue Protocols C through E. Acceptable recoveries were obtained for hexythiazox on pears using Protocol D; however, hexythiazox was n ot recovered from fortified hops samples. Hexythiazox metabolites were not recovered through Protocols C through E.

The requested new regional uses on alfalfa and timothy are supported by adequate, geographically representative residue data. The numbe r and locations of field trials are in accordance with OCSPP 860.1500 harmonized test guidelines, for geographically restricted use on alfalfa and timothy. The field trial data reflect the proposed use pattern, were generated using validated data collecti on methods, and are supported by adequate storage stability data. The available data are sufficient for establishing tolerances of 15 and 30 ppm for alfalfa forage and hay, respectively, and 40 ppm each for timothy forage and hay.

Updated maximum reasonably balanced diets (MRBD) for ruminants have been calculated and an increase in the meat byproduct tolerances to 0.2 ppm and the fat tolerances to 0.05 ppm for cattle, goat, horse and sheep is required. HED ha d previously

concluded that there was n o reasonable expectation of quantifiable residues of hexythiazox in poultry commodities [40 CFR §180.6(a)(3)] resulting from the established

uses of hexythiazox. However, because of the potential increase of hexythiazox in the poultry diet, largely due t o alfalfa use, the need for hexythiazox tolerances on poultry

### Hexythiazox Human Health Risk Assessment for New Uses on Alfalfa and Timothy

Page 13 of 30 commodities has been revisited. Based on an updated MRBD for poultry, hexythiazox tolerances for eggs at 0.01 ppm, poultry fat at 0.05 ppm, and meat byproducts at 0.05 ppm are required. There is no reasonable expectation of quantifiable residues of hexythiazox in poultry meat (muscle) at this time; therefore, a tolerance is not required for this livestock commodity.

There are no processing commodities associated with alfalfa and timothy; th erefore 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 rota tional crop studies, a 120

- day plantback interval for all crops not listed on the label is appropriate. This conclusion remains unchanged.

No Canadian or Mexican MRLs have been established for residues of this active ingredient in plants or livestock. T here are no codex MRLs established for alfalfa or timothy; however, there are Codes MRLS for livestock at 0.05 ppm in/on the following: edible offal (mammalian); mammalian fats (except milk fats); milks; milk fats; poultry, edible offal; poultry meat (fat) . The U.S. and Codes residue definitions in both plants and livestock are harmonized. There is no issue of international harmonization with respect

to the recommended alfalfa

, timothy , and egg tolerances since there are no established

international toler ances for these commodities . Due to the increased livestock dietary burden expected with the new uses on alfalfa and timothy, revised U.S. livestock

tolerances in fat and meat byproducts of ruminants are required. HED is recommending

an increase in the r uminant fat and milk tolerance s to 0.05 ppm in order to account for the increased dietary burden to livestock and to be harmonized with Codex. Additionally new tolerances for poultry fat and meat byproducts are recommended at 0.05 ppm to be

harmonized wit h Codex. However, the recommended tolerance increase for livestock meat byproducts will not be harmonized with Codex as the potential hexythiazox residue level in meat byproducts may exceed the current Codex MRL.

4.2 Drinking Water Residue Profile

EFED Drinking Water Assessment, D401798, A. Shelby, 6/21/12



### The drinking water residues used in the dietary risk assessment were provided by the

Environmental Fate and Effects Division (EFED) in the following memorandum: “Hexythiazox: Drinking Water Assessment for New Use on wheat, alfalfa, timothy, eggplant and peppers”

.

T he Agency does not have monitoring data available to perform a quantitative drinking water risk assessment for hexythiazox. Therefore, the potential for hexythiazox residues in drinking water was evaluated through modeling. Since no environmental fate data has

been submitted for the degradates of concern, EFED conducted the assessment for total

residues. S urface water residue values greatly exceed groundwater estimated drinking

water co ncentrations , so surface water residues were included in HED’s dietary risk

assessment.

### Hexythiazox Human Health Risk Assessment for New Uses on Alfalfa and Timothy

Page 14 of 30 Based on PRIZM/EXAMS modeling results and a 0.95 percent cropped area ( PCA ) adjustment, the maximum estimated surface water exposure concentrations for total

residue s of hexythiazox were from the MS soybean scenario . For the chronic dietary risk assessment, the 1 in 10 year annual average surface water concentration of 4.3 μg/L was

used.

4.3 Dietary Exposure and Risk
Dietary Exposure and Risk Memorandum

, D 396863, D. Drew, 8/16 /12



### 4.3.1 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.

4.3 .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 essin g factors. The dietary assessment could be substantially 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 highl y 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 13 % of the c PAD. The estimated exposure to children 1

– 2 years of age, the most highly exposed subpopulation, res ulted in a risk equivalent to 63 % of the cPAD. Results for all subpopulat ions are summarized in Table 4.3 .3, below.

4.3.3 Cancer Dietary R isk

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 sl ope factor. Rather, the committee concluded that 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.

### Hexythiazox Human Health Risk Assessment for New Uses on Alfalfa and Timothy

Page 15 of 30 Table 4.3.3

. 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 0.003273 13 No concern for risks associated

with the carcinogenic potential of hexythiazox.

All Infants (< 1 year old) 0.006107 24

N/A N/A Children 1

- 2 years old 0.015729 63

Children 3

- 5 years old 0.010453 42

Children 6

- 12 years old 0.004861 19

Youth 13

- 19 years old 0.002351 9.4

Adults 20

- 49 years old 0.002128 8.5

Adults 50+ years old 0.002395 9.6

Females 13

- 49 years old 0.002221 8.9

* Most highly exposed subpopulation is highlighted in bold.



### 4.4 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 conducted to support the amended and ne w use s of hexythiazox on alfalfa and timothy

.

5.0 Residential and Other Non

- Occupational Exposures/Risks
D396864, A. LaMay , 9 / 25 /12

, Occupational and Residential Exposure and Risk Assessment



### There are no new residential uses proposed with the new use on alfalfa and timothy. 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 tr ees, 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.

### Hexythiazox Human Health Risk Assessment for New Uses on Alfalfa and Timothy

Page 16 of 30 5.1 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 is expected to be

short

- term in duration. Intermediate

- term e xposures 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 estim ated exposure and risks are shown in Table 5.1, below.

Table 5.1.. 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).



### 5.2 Residential P ost

- 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 expo sures 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 is also possible for incidental soil ingestion exposure.

Child inciden tal oral exposure to treated turf was assessed for hexythiazox. Risk estimates greatly exceed the LOC of 100 for all scenarios associated with children’s

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 for New Uses on Alfalfa and Timothy

Page 17 of 30 exposure to treated turf and are not of concern. Post

- application exposure and risk

estimates are sh own in Table 5.2, below.

Table 5.2. Residential Post

- application Non

- cancer Exposure and Risk Estimates for Hexythiazox (Short

- Term for Hand

- to

- Mouth and Object

- to

- Mouth Exposure; Short

- 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



### 5.3 Other

5.3.1. 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 groundboom application metho ds. 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. The Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new data base submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy o n 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 dr ift management practices to reduce off

- target drift and risks associated with aerial as well as other application types where appropriate.

Although a quantitative residential post

- application inhalation exposure assessment was not performed as a result o f 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 out door agricultural and commercial post

- application inhalation exposure scenarios. Additionally, the 0.1875 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 t han many of agricultural application rates, this scenario is protective of any exposure of farm children via spray drift from agricultural hexythiazox applications.

5.3.2. Residential Bystander 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

### Hexythiazox Human Health Risk Assessment for New Uses on Alfalfa and Timothy

Page 18 of 30 10 - 8 

### mmHg 2 

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

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov /scipoly/SAP/meetings/2009/120109meeting.html ). 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 inhalati on exposure into the Agency's risk assessments. If new policies or procedures are developed, the Agency may revisit the need for a quantitative post

application inhalation exposure assessment for hexythiazox

.

6.0 Aggregate Risk Assessments and Risk Characte rization

6.1 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.

6 .2 Short

- and Intermediate

- Term Aggregate Risks

The s hort

- and intermediate

- 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 6.2.1, below.

Table 6.2.1. 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 5.1 Gardens/Trees, handwand/backpack N/A 2 ; no dermal endpoint 0.000072



### Adult Female 0.000072

Source: Table 5.1 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

2 Hexythiazox: HED Registration Review Scoping Document. DP Barcode: D335052. 12/19/06.

### Hexythiazox Human Health Risk Assessment for New Uses on Alfalfa and Timothy

Page 19 of 30 Table 6.2.1. 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 exposure for adults and children greatly exceed the LOC of 100 and are not of concern. Short

- and intermediate

- term estimated exposures and risks are shown in Table 6.2.2, below.

Table 6.2.2. 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 0.002395 0.000072 12,000

Adult Female 30 100 0.3 0.00 2221 0.000072 13,000

Child 30 100 0.3 0.0 15729 0.0029 1,600

Intermediate

- Term Scenario

Adult Male 30 100 0.3 0.002395 N/A 12,000

Adult Female 30 100 0.3 0.002221 N/A 14,000

Child 30 100 0.3 0.015729 0.0000063 1,900

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 Exposure values taken from Table 6.2.1.Average food & water exposure taken from Table

4.3.3.

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

### Hexythiazox Human Health Risk Assessment for New Uses on Alfalfa and Timothy

Page 20 of 30 6.3 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 4.3 .2 of this memorandum, there is no chronic dieta ry risk of concern.

7.0 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 st atements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s

website at http://www.epa.gov/pesticides/cumulative/.

8.0 Occupational Exposures and Risks
D396864, A. LaMay , 9/ 25 /12, Occupational and Residential Exposure and Risk Assessment



### 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.

8.1 Occupational Handler Risk

The occupational exposure and risk assessment addresses risks to worke rs 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 th e proposed uses, short

term exposures are anticipated as the proposed uses indicate the product is only to be applied 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 amended field corn and new greenhouse tomato uses resulted in es timated inhalation margins of exposure (MOEs) which were significantly greater than 100 with baseline inhalation protection (no respirator). Therefore, inhalation risks are not of concern and inhalation personal protective equipment (PPE, i.e., respirator s) is not required.

### Hexythiazox Human Health Risk Assessment for New Uses on Alfalfa and Timothy

Page 21 of 30 Occupational handler risk estimates for alfalfa and timothy are shown in Table 8.1.

Table 8. 1. Short

- /Intermediate

- Term Occupational Exposure and Risk Estimates for Hexythiazox

.

All estimates are at baseline mitigation (without respirator) except aerial applicator

.

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, L/SC/EC, Aerial,

Broadcast High

- acreage Field Crop

0.219 0.1875 lb

ai/acre 1200 acres 0.000616 49,000

M/L, L/SC/EC

, Chemigation, Broadcast Field Crops (all) 350 acres 0.00018 170,000

M/L, L/SC/EC, Groundboom, Broadcast High

- acreage Field Crop 200 acres 0.000103 290,000

Applicator

Applicator, Spray, Aerial,

Broadcast High

- acreage Field Crop Engineering Control:

0.068 0.1875 lb

ai/acre 1200 acres 0.000191 160,000

Applicator, Spray, Groundboom, Broadcast High

- acreage Field Crop 0.34 200 acres 0.00016 190,000

Flagger

Flagger, Spray, Aerial,

Broadcast Field Crop (all) 0.35 0.1875 lb

ai/acre 350 acres 0.000288 100,000

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.

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).



### 8.2 Occupational Post Application Risk

HED uses the term postapplication 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 previo usly treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting.

For the occupational dermal exposure pathway, short

- and intermediate

- term quantitative

risks assessment were not co nducted since quantification of dermal risk is not required for hexythiazox. Therefore no occupational dermal risks of concern have been identified for hexythiazox.

Based on the Agency's current practices, a quantitative occupational postapplication inhalation exposure assessment was not performed for hexythiazox at this time. However, there are multiple potential sources of postapplication inhalation exposure to

ind ividuals performing postapplication activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or

### Hexythiazox Human Health Risk Assessment for New Uses on Alfalfa and Timothy

Page 22 of 30 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. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meeti ngs/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available postapplication inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures , to identify the need for and, subsequently, the way to incorporate occupational postapplication inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational postapplication 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/commercia l 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 o ccupational post

- application inhalation exposure scenarios.

T he label Restricted Entry Interval (REI) of 12 hours is appropriate and in compliance Worker Protection Standard requirements

.

9.0 Human Stu dies

This risk assessment relies in part on data fr om studies in which adult human subjects were intentionally exposed to a pesticide or o ther 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 HED’s 2012 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. Descripti ons of data sources, as well as guidance on their use, can be found at http://www.epa.gov/pesticides/science/handler

- exposure

- data.html

, http://www.epa.gov/pesticides/science/re sidential

- exposure

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

- app

- exposure

- data.html

.

10 .0 Data Needs and Label Recommendations

10 .1 Toxicology

No toxicity data for hexythiazox are required at this time.

### Hexythiazox Human Health Risk Assessment for New Uses on Alfalfa and Timothy

Page 23 of 30 10 .2 Residue Chemistry

The following residue chemistry deficiencies have been identified.

860.1550 Proposed Tolerances

A revised Section F reflecting the recommended tolerances and commodity definitions presented in Table 10 .2 , below.

Table 1 0.2. Tolerance Summary for Hexythiazox

Commodity 1 Tolerance (ppm) Comments; Correct Commodity Definition Established Proposed Recommended

40 CFR §180.448( a )

Cattle, fat 0.02

- 0.0 5 An increase is required based on updated MRBD calculations and to

harmonize with Codex MRL.

Cattle, meat byproducts 0.05

- 0.20 An increase is required based on updated MRBD calculations.

Goat, fat 0.02

- 0.0 5 An increase is required based on updated MRBD calculations and to

harmonize with Codex MRL.

Goat, meat byproducts 0.05

- 0.20 An increase is required based on updated MRBD calculations.

Horse, fat 0.02

- 0.0 5 An increase is required based on updated MRBD calculations and to

harmonize with Codex MRL.

Horse, meat byproducts 0.05

- 0.20 An increase is required based on updated MRBD calculations.

Sheep, fat 0.02

- 0.0 5 An increase is required based on updated MRBD calculations and to

harmonize with Codex MRL.

Sheep, meat byproducts 0.05

- 0.20 An increase is required based on updated MRBD calculations.

Milk 0.02

- 0.05 An increase is recommended in order to

harmonize with Codex MRL.

Poultry, fat

-- - 0.05 Recommended tolerance based on updated MRBD calculations and to

harmonize with Codex MRL.

Poultry, meat byproducts

-- - 0.05 Recommended tolerance based on updated MRBD calculations and to

harmonize with Codex MRL.

Egg

-- - 0.01 Recommended tolerance based on updated MRBD calculations.

40 CFR §180.448( c )

Alfalfa, Forage

-- 7 15 Alfalfa, forage (EPA Zones 9

- 11 only)

Recommended tolerance based on

outcome of OECD MRL calculation procedure.

### Hexythiazox Human Health Risk Assessment for New Uses on Alfalfa and Timothy

Page 24 of 30 Table 1 0.2. Tolerance Summary for Hexythiazox

Commodity 1 Tolerance (ppm) Comments; Correct Commodity Definition Established Proposed Recommended

Alfalfa, Hay

-- 14 30 Alfalfa, h ay (EPA Zones 9

- 11 only)

Recommended tolerance based on

outcome of OECD MRL calculation procedure.

Timothy, Forage

-- 35 40 Timothy, f orage (EPA Zone 11 only)

Recommended tolerance based on

outcome of OECD MRL calculation procedure.

Timothy, Hay

-- 17 40 Timothy, h ay (EPA Zone 11 only)

Recommended tolerance based on

outcome of OECD MRL calculation procedure.

1 Includes only commodities of interest for this action : does not include all currently established tolerances for hexythiazox.



### The standard for hexythiazox expire d on 4/14/2012. An updated certificate of analysis or a new analytical reference standard must be provided to the EPA National Pesticide Standards Repository

.

10 .3 Occupational/Residential Exposure

There are no data gaps with respect to occupational/residential exposure and risk assessment required to support the requested new use.

In accordance with the updated Part 158 data requirements (2007), a turf transferable residue (TTR) study is required for all occupational (e.g., sod farms, g olf courses, parks, and recreational areas) or residential turf uses. However, the requirement for a TTR study is waived for hexythiazox since the hand

- to

- mouth MOE for children is >1,000 based on default values for the fraction of application rate availa ble for transfer after a turf application. ( Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) Studies . 6/7/2012, Exposure Science Advisory Council). Further, 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 post

- application dermal exposure. However, as quantification of dermal risk is not required for hexythiazox, a DFR study is not required for hexythiazox

.

11.0 Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Execu tive 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 for New Uses on Alfalfa and Timothy

Page 25 of 30 As a p art of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on

patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by In dividuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and

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

12 .0 Human Studies

This risk assessment relies in part on data from studies in which adult human s ubjects were intentionally exposed to a pesticide or o ther 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 HED’s 2012 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. Descriptions of data sources, as well as guidance on their use, can be found at http://www.epa.gov/pesticides/science/handler

- exposure

- data.html

, http://www.epa.gov/pesticides/science/resid ential

- exposure

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

- app

- exposure

- data.html

.

### Hexythiazox Human Health Risk Assessment for New Uses on Alfalfa and Timothy

Page 26 of 30 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 relati ve 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

se xes), 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, bas ed on decreased body weight 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 for New Uses on Alfalfa and Timothy

Page 27 of 30 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 = 180.67/207.67 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 histopathology (adrenal cortex hypertrophy).

@ 125 mg/kg/day, relative adrenal weights and associated adrenal cortex hypertrophy (more pronounced)

4

- w eek 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 weights 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 for New Uses on Alfalfa and Timothy

Page 28 of 30 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 for New Uses on Alfalfa and Timothy

Page 29 of 30 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 for New Uses on Alfalfa and Timothy

Page 30 of 30 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