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

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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 timothy 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 being 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 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. 

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 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 parental 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 water 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 the required

crop and livestock tolerances. The analytical reference standard at the EPA Repository 

for hexythiazox has expired. An updated certificate of analysis or a new analytical 

reference standard must be provided to the EPA National Pesticide 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 for both 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 byproducts are required. There are no processed commodities 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

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concludes that, in light of the 120 day plant-back interval (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 for alfalfa or 

timothy; 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 Codex 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 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 tolerances 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 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. 

An acute endpoint was not selected 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 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 and 63% of the cPAD 

for children 1 – 2 years of age, the most highly exposed population subgroup. 

This 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 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; significantly exceeding the level of concern (LOC) of 100 and are not of 

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

scenarios 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 long-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 scenarios. Chronic 

dietary risk is not of concern. 
Hexythiazox Human Health Risk Assessment for New Uses on Alfalfa and Timothy

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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. The label restricted entry 

interval (REI) of 12 hours is appropriate and in compliance Worker Protection 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 LowIncome Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).

Regulatory Recommendation

Provided 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 

combined 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:

Under 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

Under 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

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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 Chemistry Summary Document, D396862, D. Drew, 6/18/12

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 new 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. The 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

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2.2 Structure and Nomenclature

Table 2.2 Structure and Nomenclature of Hexythiazox.

Compound

Common name Hexythiazox

Company experimental names DPX-Y5893, NA-73

IUPAC name (4RS,5RS)-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 Reference1

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, pKa Not applicable

Octanol/water partition coefficient 

Log(POW)

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.

N

S

H3C

O

Cl

N

H

O

S

N

H

O

H3C

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

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3.0 Hazard Characterization/Assessment

3.1 Hazard Characterization

The toxicity database for hexythiazox is complete and adequate for assessing risk. HED 

previously required acute neurotoxicity, subchronic neurotoxicity, and immunotoxicity

studies as conditions 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 neurotoxicity from hexythiazox exposure. The 

HASPOC also considered if an inhalation study was required for hexythiazox. Based 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. The 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 inhalation toxicity of hexythiazox; (3) 

the primary target organ of hexythiazox toxicity is the liver and adrenal glands following 

repeated hexythiazox 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 following subchronic 

and chronic exposure to dogs, rats and mice, with the dog being 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 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 Selection

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

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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 

were observed. A 100X uncertainty factor was applied to account for inter- and intraspecies 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 assessments, 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 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 highdose 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. 

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 toxicity 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 

underestimate risk.
Hexythiazox Human Health Risk Assessment for New Uses on Alfalfa and Timothy

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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

UFA = 10x

UFH = 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 

IntermediateTerm 

Incidental 

oral

NOAEL=30 

mg/kg/day

UFA = 10x

UFH = 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 

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

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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 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 

observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from 

animal to human (intraspecies). UFH = potential variation in sensitivity among members of the human population (interspecies). UFL

= 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

Short- and 

intermediateTerm 

N/A N/A N/A No dermal hazard identified

Inhalation

Short- and 

IntermediateTerm 

Oral NOAEL = 30 

mg/kg/day

Inhalation hazard 

assumed to be 

equivalent to oral 

hazard

UFA=10x

UFH=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 sexes, 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 high 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

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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 = 

uncertainty factor. UFA = extrapolation from animal to human (intraspecies). UFH = potential variation in sensitivity 

among members of the human population (interspecies). UFL = 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 Chemistry Summary Document, D396862, D. Drew, 6/18/12

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

The residues of concern for the tolerance expression and risk assessment are the parent 

compound and its metabolites which contain the (4-chlorophenyl)-4-methyl-2-oxo-3-

thiazolidine moiety.

An adequate high performance liquid chromatography method with UV detection 

(HPLC/UV) exists to enforce the recommended revised and new plant and livestock

tolerances. 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 not 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 number 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 collection 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 had previously 

concluded that there was no 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 to 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; therefore 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 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. There 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 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 tolerances 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 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”. 

The 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. Surface water residue values greatly exceed groundwater estimated drinking 

water concentrations, 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 

residues 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, D396863, 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 

processing 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 highly conservative risk assessment showed no risks of concern (<100% of the 

chronic population adjusted dose (cPAD)) for the U.S. General Population or any 

subpopulation. The estimated exposure to the U.S. General Population resulted in a risk 

equivalent to 13% of the cPAD. The estimated exposure to children 1 – 2 years of age, 

the most highly exposed subpopulation, resulted in a risk equivalent to 63% of the cPAD. 

Results for all subpopulations are summarized in Table 4.3.3, below.

4.3.3 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 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

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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 new uses 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 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.
Hexythiazox Human Health Risk Assessment for New Uses on Alfalfa and Timothy

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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 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 5.1, below. 

Table 5.1.. Short-term Residential Handler Exposure and Risk Estimates for Hexythiazox.

Exposure Scenario Target MOE

Inhalation 

Unit 

Exposure

(mg/lb ai)

Maximum 

Application 

Rate1

Area Treated or 

Amount 

Handled Daily2

Inhalation

Dose

(mg/kg/day)3 MOE4

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/ft2 1200 ft2

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, Manuallypressurized handwand / backpack 100 1.1 4.375E-6 lb 

ai/ft2 1200 ft2

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 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 days1, intermediate-term exposure is 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 

 

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 shown 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 methods. 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 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 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 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 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 than 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 postapplication inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are developed, the Agency may revisit the need for a quantitative postapplication inhalation exposure assessment for hexythiazox.

6.0 Aggregate Risk Assessments and Risk Characterization

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 short- and intermediate-term aggregate risks combine residential handler (adult only)

and post application exposures with average 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/A2; 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 handlers3

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.
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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 LOC1

Max 

Allowable

Exposure2

mg/kg/day

Average

Food & 

Water

Exposure

mg/kg/day

Residential 

Exposure3

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 0.002221 0.000072 13,000

Child 30 100 0.3 0.015729 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)]
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6.3 Long-Term (Chronic) Aggregate Risk

As there are no uses that are expected to result in long-term residential exposure, longterm (chronic) aggregate risk includes only dietary (food and water) exposure. As noted 

in Section 4.3.2 of this memorandum, there is no chronic dietary 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 statements released by EPA’s Office 

of Pesticide Programs concerning common mechanism determinations and procedures for 

cumulating effects from substances found to have a common mechanism on EPA’s 

website at http://www.epa.gov/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 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, shortterm 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 estimated 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., respirators) 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 

Rate2

Area Treated or 

Amount Handled 

Daily3

Inhalation

Mitigation Level Dose 

(mg/kg/day)4 MOE5

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 registered or proposed label.

3 Exposure Science Advisory Council Policy #9.1.

4

Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x Conversion Factor (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 previously 

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 conducted 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 

individuals 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/meetings/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/commercial 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 label Restricted Entry Interval (REI) of 12 hours is appropriate and in compliance 

Worker Protection Standard requirements.

9.0 Human Studies

This risk assessment relies in part on data from studies in which adult human subjects 

were intentionally exposed to a pesticide or other chemical. These data, which include 

studies from 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/residential-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

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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 10.2. Tolerance Summary for Hexythiazox

Commodity1 Tolerance (ppm) Comments; Correct Commodity 

Definition Established Proposed Recommended 

40 CFR §180.448(a)

Cattle, fat 0.02 - 0.05 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 - 0.05 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 - 0.05 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 - 0.05 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.
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Table 10.2. Tolerance Summary for Hexythiazox

Commodity1 Tolerance (ppm) Comments; Correct Commodity 

Definition Established Proposed Recommended 

Alfalfa, Hay -- 14 30 Alfalfa, hay (EPA Zones 9-11 only)

Recommended tolerance based on 

outcome of OECD MRL calculation 

procedure.

Timothy, Forage -- 35 40 Timothy, forage (EPA Zone 11 only)

Recommended tolerance based on 

outcome of OECD MRL calculation 

procedure.

Timothy, Hay -- 17 40 Timothy, hay (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 expired 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, golf 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 available 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. Executive Order 12898, 

"Federal Actions to Address Environmental Justice in Minority Populations and LowIncome 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 part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED 

estimates risks to population subgroups from pesticide exposures that are based on 

patterns of that subgroup’s food and water 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 Individuals (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 for adult applicators and for toddlers, youths, and adults entering or 

playing on treated areas postapplication are evaluated. Further considerations are 

currently in development as OPP has committed resources and expertise to the 

development of specialized software and models that consider exposure to bystanders and 

farm workers as well as lifestyle and traditional dietary patterns among specific 

subgroups.

12.0 Human Studies

This risk assessment relies in part on data from studies in which adult human subjects 

were intentionally exposed to a pesticide or other chemical. These data, which include 

studies from 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/residential-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

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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 LD50 = >5000 mg/kg IV

870.1200 Acute dermal toxicity 00146550 LD50 = >5000 mg/kg IV

870.1300 Acute inhalation toxicity 00146554 LC50 = >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

Maternal NOAEL 1080 mg/kg/day 

LOAEL >1080 mg/kg/day 

Developmental 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 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
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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-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 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).
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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 highdoses (500 and 1000 mg/kg). The assay should be repeated 

to confirm or refute the equivocal 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 [14C] 

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 radioactivity 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, PT-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 lowdose and high-dose groups, respectively. All other 

metabolites were present at low concentrations (<2%). 

There was no apparent sex difference in metabolite 

formation. Significant levels of NA-73 equivalent [14C]-

residues were detected in the fat, liver, and adrenals. A sexrelated difference in the residue levels 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 excreted 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 pharmacokinetics 

of NA-73 in these rats, with females exhibiting slower 

elimination rats and higher tissue residues (about double) 
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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%. About 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. 
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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

yesD

noC

no

noA

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

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)...............................

870.6100b 90-Day Neurotoxicity (hen) ..........................................

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

870.6200b 90-Day Neurotoxicity Screening Battery (rat) ..............

870.6300 Develop. Neurotoxicity .................................................

no

no

yes

yes

CR

-

-

noA

yesB

no

870.7485 General Metabolism ......................................................

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

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

yes

no

yes

yes

yes

yes

Special Studies 

AHASPOC (D0056434): not required at this time; BHASPOC (D0056434): 28-day study is sufficient to assess 

subchronic neurotoxicity from hexythiazox exposure; Cdermal 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; Dnot required since there is a 4-week study and a 1-year study available