Document ID: EPA-HQ-OPP-2007-0330-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-05-09T04:00Z

FILE NAME:    Hexythiazox Potato NOF 061129

Template Number P25	

EPA Registration Division contact: Shaja Brothers, (703) 308-3194	

PP#7E7182

 by establishing  tolerances for residues of

hexythiazox
(trans-5-(4-chlorophenyl)-N-cyclohexyl-4-methyl-2-oxothiazolidine-3-carb
oxamide) and its metabolites containing the
(4-chlorophenyl)-4-methyl-2-oxo-3-thiazolidine moiety in or on the raw
agricultural commodity potato at 0.02 part per million (ppm) (regional
tolerance).  EPA has determined that the petition contains data or
information regarding the elements set forth in section 408(d)(2) of the
FFDCA; however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data supports granting of the
petition.  Additional data may be needed before EPA rules on the
petition.

                                      

. A practical analytical method, high pressure liquid chromatography
with an ultraviolet detector, which detects and measures residues of
hexythiazox and its metabolites as a common moiety, is available for
enforcement purposes with a limit of detection that allows monitoring of
food with residues at or above the levels set in these tolerances.

.  Seven field trials were conducted in Idaho and Washington.  These
trials are sufficient to support a regional tolerance for potatoes in
the Pacific Northwest (EPA climate region 11).  Residues of hexythiazox
and its metabolites were below 0.02 ppm in all cases.  A processing
study was not conducted because residues were not detected  in potatoes 
from plots treated at 5 times the proposed application rate. 

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.  In a developmental toxicity study in rats, the maternal
No-Observed-Adverse-Effect-Level (NOAEL) was 240 mg/kg/day and the
maternal Lowest-Observed-Adverse-Effect-Level (LOAEL) was 720 mg/kg/day
based on increased ovarian weights and decreased bone ossification.

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. In a 1-year feeding study in dogs, the NOAEL was 2.5 mg/kg/day and the
LOAEL was 12.5 mg/kg/day, based on increased alkaline phosphatase,
increased adrenal and liver weights, and liver and adrenal lesions.  In
a carcinogenicity study in mice, the NOAEL was 36 mg/kg/day and the
LOAEL was 215 mg/kg/day.  Effects were decreased bwt in males and
increased hepatocellular carcinomas and combined adenoma/carcinomas.

In a chronic feeding/carcinogenicity study in rats, the NOAEL (systemic)
was 26 mg/kg/day and the LOAEL (systemic) was 180 mg/kg/day based on
decreased bwt gain and increased liver weights in both sexes.

The chronic reference dose (RfD) for hexythiazox is based on the 1-year
dog feeding study with a NOAEL of 2.5 mg/kg/day and an uncertainty
factor of 100.  The Agency has classified hexythiazox as a category C
(possible human) carcinogen based on an increased incidence of
hepatocellular carcinomas (p = 0.028) and combined adenomas/carcinomas
(p = 0.024) in female mice at the highest dose tested (1,500 ppm) when
compared to the controls as well as a significantly increased (p<0.001)
incidence of pre-neoplastic hepatic nodules in both males and females at
the highest dose tested.  The decision supporting a category C
classification was based primarily on the fact that only one species was
affected and mutagenicity studies were negative.  In classifying
hexythiazox as a category C carcinogen, the Agency concluded that a
quantitative estimate of the carcinogenic potential for humans should be
calculated because of the increased incidence of liver tumors in the
female mouse.  A Q1* of 0.022 mg/kg/day-1 in human equivalents was
published in the Federal Register of October 16, 1998 (63 FR 55430)
(FRL-6035-2).

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. Tolerances have been established (40 CFR 180.448) for residues of
hexythiazox and its metabolites containing the
(4-chlorophenyl)-4-methyl-2-oxo-3-thiazolidine moiety in or on almond
hulls, wet apple pomace, the caneberry crop subgroup, the citrus crop
group, cotton, date, hop, the pome fruit crop group, the stone fruit
crop group, the tree nut crop group, peppermint, pistachios, spearmint,
strawberries, milk and the meat, fat and meat byproducts of cattle,
goat, horse, sheep and swine. 

EPA has estimated the following dietary exposures from hexythiazox in
food  (Federal Register of September 29, 2000 (65 FR 58437)
(FRL-6746-5).

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.

i. Acute exposure.  For acute dietary exposure of the general population
including infants and children, a dose and endpoint attributable to a
single exposure were not identified by the Agency from the available
oral toxicity studies.  An acute RfD of 2.4 mg/kg/day for females 13-50
years of age was identified from the rat developmental toxicology based
on delayed ossification.  A conservative analysis was performed by the
Agency using existing and  recommended tolerance level residues and 100%
crop treated (CT) information for all commodities.  The acute dietary
exposure estimate for the female 13-50 year-old subgroup was 0.002617
mg/kg/day at the 95th percentile.  The registrant has concluded that the
proposed use on potatoes will not contribute to a significant
incremental increase to this dietary exposure.

ii. Chronic exposure.  A partially refined deterministic analysis was
performed by the Agency using anticipated residue (AR) levels for mos
crops and %CT or anticipated market share information for all crops. 
Dietary exposure estimates for the U.S. population were and other
representative subgroups were <0.00003 mg/kg/day.  The registrant has
concluded that the proposed use on potatoes will not contribute to a
significant incremental increase to this dietary exposure.

iii. Cancer.  A partially refined deterministic analysis was performed
by the Agency using AR levels and %CT or anticipated market share
information for all crops.  The chronic dietary exposure estimate for
the U.S. population was 0.000011 mg/kg/day.  The registrant has
concluded that the proposed use on potatoes will not contribute to a
significant incremental increase in oncogenic risk.

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. Using the Generic Expected Environmental Concentration (GENEEC) and
Screening Concentration in Ground Water (SCI-GROW) models, the Agency
has calculated the estimated environmental concentrations (EECs) of
hexythiazox to be 910.32 nanograms per liter (ng/L) for surface water
and 1.47 ng/L for ground water.  These estimates are based on a maximum
application rate of 0.1875 lb active ingredient per acre. 

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. The term “residential exposure” is used by the Agency to refer to
non-occupational, non-dietary exposure; e.g., for lawn and garden pest
control, indoor pest control, termiticides, and flea and tick control on
pets.  Hexythiazox is not registered for use on any sites that would
result in residential exposure.

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	.EPA has not determined whether hexythiazox has a common mechanism of
toxicity with other substances or how to include this pesticide in a
cumulative risk assessment.  Unlike other pesticides for which EPA has
followed a cumulative risk approach based on a common mechanism of
toxicity, hexythiazox does not share a toxic metabolite with other
substances.  For the purposes of this tolerance action, therefore, the
registrant has not assumed that hexythiazox has a common mechanism of
toxicity with other substances.  For purposes of this petition the
potential risks of hexythiazox in its aggregate exposure only will be
considered.

EPA evaluated aggregate risks and made a determination of safety in Unit
IV.D. of the Federal Register of November 10, 2004 (69 FR 65073).  The
registrant has concluded that the proposed use on potatoes will not
contribute to significant incremental acute, chronic or oncogenic
dietary exposure. 

.

i. Acute risk.  Aggregate exposure risk includes exposure from food and
water.  For acute dietary exposure of the general population, a dose and
endpoint attributable to a single exposure were not identified by the
Agency from the available oral toxicity studies.  For the relevant
population subgroup of females 13+ years, the risk from acute “food
only” exposure is less than 1% of the RfD, which is less than EPA’s
level of concern.  The acute drinking water level of comparison (DWLOC)
calculated for the relevant population subgroup of females 13+ years is
72,000 parts per billion (ppb).  The calculated DWLOC is significantly
higher than the drinking water EECs for ground water (0.0015 ppb) and
surface water (0.910 ppb).  EPA has concluded with reasonable certainty
that residues of hexythiazox in drinking water do not contribute to the
acute aggregate health risk.

ii. Short- and intermediate-term risk.  Hexythiazox is not registered
for use on any sites that would result in residential exposure. 
Therefore the aggregate risk is the sum of the risk from food and water,
which do not exceed the Agency’s level of concern.

iii. Chronic risk.  Aggregate chronic risk (non-cancer) exposure from
“food only” exposure utilizes less than 1% of the RfD for all
population subgroups.  The chronic DWLOC for hexythiazox exposure in
drinking water is 870 ppb for the U.S. population and 250 ppb for
infants and children.  The calculated DWLOCs are significantly higher
than the drinking water EECs for ground water (0.0015 ppb) and surface
water (0.910 ppb).  EPA has concluded with reasonable certainty that
residues of hexythiazox in drinking water do not contribute to the
chronic (non-cancer) aggregate health risk.

iv. Cancer risk.  The carcinogenic risk estimate (food only) for the
general U.S. population is <5 x 10-7.  Thus the carcinogenic dietary
risk associated with the existing and proposed uses of hexythiazox does
not exceed the level of concern for excess lifetime cancer risk (1 x
10-6).  The surface water and ground water EECs were used to compare
against the back-calculated DWLOC for aggregate risk assessments.  For
the carcinogenic risk scenario, EPA calculated a DWLOC of 1.2 ppb for
the U.S. population.  The EECs for ground water and surface water
(0.0015 ppb and 0.910 ppb respectively) are less than EPA’s calculated
DWLOC.  Therefore, EPA concluded that residues of hexythiazox in
drinking water do not contribute significantly to the carcinogenic
aggregate human health risk.

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	There are no international maximum residue limits for hexythiazox on
potato.

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