FILE NAME:    Hexythiazox NOF 100812

Template Number P25	

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GOWAN COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE

(August 12, 2010)

EPA Registration Division contact: Mark Suarez, PM #13, telephone (703)
305-0120	

TEMPLATE:

 

by amending the existing 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 to remove the
geographical restriction for existing field corn tolerances and
establish a new tolerance for aspirated grain fractions. 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.

    

                               

Plant metabolism. The nature of the residues in plants is adequately
understood for purposes of this tolerance.  Metabolism studies in fruit
crops, radish and tea have been previously reviewed by the Agency.  The
Agency has determined that the residues of concern are hexythiazox and
its metabolites containing the
(4-chlorophenyl)-4-methyl-2-oxo-3-thiazolidine moiety.  The results of a
new corn metabolism study (MRID   48081501, currently in review) are
consistent with the other plant metabolism data.

Analytical method. A practical analytical method, high pressure liquid
chromatography with a UV 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 this tolerance. 

Magnitude of residues. Twenty new field trials were conducted by Gowan
Company in support of the proposed label amendments for field corn.  The
amendments include 1) removing the regional use restriction and 2)
reducing the pre-harvest interval to 30 days.  The results of these new
trials support the currently established tolerance levels of 0.02 ppm
for field corn grain and 6.0 ppm for field corn forage.  We propose to
increase the tolerance for field corn stover to 6.0 ppm.

Magnitude of the Residue in Processed Food/Feed.  Data on field corn
processed commodities support the establishment of a new tolerance of
0.5 ppm for aspirated grain fractions.

Acute toxicity. A battery of acute toxicity studies places technical
grade hexythiazox in Toxicity Category IV for acute oral LD50 (LD50 >
5,000 milligram/kilograms (mg/kg)), Category III for dermal LD50 (LD50
>5,000 mg/kg), Category III for inhalation LC50 (LC50 >2.0 mg/L),
Category III for primary eye irritation (showed mild irritation
(reddened conjunctiva)), Category IV for dermal irritation (non
irritant). Hexythiazox is a non-sensitizer.  Acute toxicological studies
place technical grade hexythiazox in Toxicology Category III.  

Genotoxicty. The following genotoxicity studies were all negative: Ames
gene mutation, CHO gene mutation, CHO chromosome aberration, mouse
micronucleus and rat hepatocyte unscheduled DNA synthesis.

Reproductive and developmental toxicity.  In a developmental toxicity
study in rats, the maternal No-Adverse-Effect-Level (NOAEL) was 240
mg/kg/day and the maternal Lowest-Adverse-Effect-Level (LOAEL) was 720
mg/kg/day based on increased ovarian weights and decreased bone
ossification. In a developmental toxicity study in rabbits, the maternal
NOAEL was 1,080 mg/kg/day (HDT); the maternal LOAEL was not determined.
The developmental NOAEL was 1,080 mg/kg/day (HDT); the developmental
LOAEL was not determined.  In a 2-generation reproduction study in rats,
the parental NOAEL was 35 mg/kg/day and the parental LOAEL was 200
mg/kg/day based on decreased body weight gain, decreased food
consumption and efficiency, and increased liver, kidney and ovarian
weights. The reproductive NOAEL was 35 mg/kg/day and the reproductive
LOAEL was 200 mg/kg/day based on decreased pup bwt during lactation,
delayed hair growth and eye opening. 

Subchronic toxicity. In a 1-month feeding study in dogs, the NOAEL was
1.75 mg/kg/day and the LOAEL was 12.5 mg/kg/day, based on increased
liver and adrenal weights.

Chronic toxicity. 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
bodyweight 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 body weight gain and increased liver weights in both sexes.

A 2009 report from the Cancer Assessment Review Committee (CARC)
(September 02,2009,PC Code 128849, TXR 0055255) noted that the NOAEL of
2.5 mg/kg/day, from the one year toxicity study in dogs, used in
establishing the chronic reference dose (RfD) is approximately 65-fold
lower than the lowest dose (163 mg/kg/day) that induced tumors. Thus,
the chronic RfD of 0.025 mg/kg/day would be protective of all chronic
effects including potential carcinogenicity of hexythiazox.  The CARC
concluded that the evidence as a whole was not strong enough to warrant
the use of a linear low dose extrapolation model applied to the animal
data (Q1*) for a quantitative estimation of human risk, as had been
previously assessed in October 16, 1998, [63.FR55540].

Animal metabolism. The metabolism of hexythiazox has been studied in
goats, hens and rats. Metabolic pathways in the animal are similar to
those in plants.

Metabolic toxicology.  There are no metabolites of toxicological concern
based on a differential metabolism between plants and animals.

Endocrine disruptions.  No specific test have been conducted with
hexythiazox to determine whether the chemical may have any effect in
humans that is similar to an effect produced by a naturally ocurring
estrogen or other endocrine effects.  However, there were no significant
findings in other relevant toxicity tests, i.e., teratology and
multi-generational reproduction studies, which would suggest that
hexythiazox produces effects characteristic of the disruptions of
hormones.

	

Dietary Exposure from food. A dietary risk assessment for all registered
crops has been recently completed by the Agency ( March 17, 2010,
75FR12691.)

Acute Exposure.  No acute endpoint has been identified in the
toxicological studies for hexythiazox; therefore, a quantitative acute
dietary exposure assessment is unnecessary.

Chronic Exposure. A tier 1 chronic risk assessment indicates that the
proposed use results in an incremental additional dietary risk of not
more than 0.3% of the chronic Population Adjusted Dose (cPAD) for any
population The registrant has concluded that hexythiazox use in field
corn will not significantly contribute to this dietary exposure.

Cancer.   The Agency has previously determined that the chronic
reference dose is sufficient to evaluate all chronic risk of
hexythiazox, including carcinogenic potential.

Dietary Exposure from drinking water. The Agency used screening level
water exposure models in the dietary exposure analysis and risk
assessment for hexythiazox in drinking water.  Based on the Pesticide
Root Zone Model /Exposure Analysis Modeling System (PRZM/EXAMS) the
estimated drinking water concentration (EDWC) of hexythiazox for chronic
exposures for non-cancer and cancer assessments is estimated to be 4.1
parts per billion (ppb) for surface water. Since surface water residue
values greatly exceed groundwater EDWCs, surface water residues were
used in the dietary risk assessment (July 14, 2010 75FR40741).

From non-dietary exposure. HED has conducted a residential risk
assessment to support recently approved uses on turf, ornamental
landscape plantings, ornamental plants, orchids and residential fruit
trees, nut trees and caneberries. The Agency concludes that there are no
residential risks of concern associated with these uses (January 28,
2010 EPA Memo. PR Code: 128849, DP Barcode D372889.)

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.

1. US population

Acute risk.  No adverse effect resulting from a single oral exposure to
hexythiazox has been identified, thus hexythiazox is not expected to
pose an acute risk.

Short-and intermediate term risk. EPA has concluded the combined
short-term food, water, and residential exposures result in aggregate
MOEs of 16,000 for adults and 2,000 for children. Because EPA's level of
concern for hexythiazox is a MOE of 100 or below, these MOEs are not of
concern.

Chronic risk.  EPA previously concluded that chronic exposure to
hexythiazox from food and water will utilize no more than 49% of the
cPAD for (children 1-2 years old) the population group receiving the
greatest exposure.   This assessment utilized existing tolerance values,
assumed 100% crop treated and utilized default processing factors.  The
incremental additional potential dietary exposure associated with the
proposed use will utilize no greater than 0.3%  of the cPAD.  Chronic
residential exposure to residues of hexythiazox is not expected.

Cancer risk  As discussed in the Federal Register of March 17, 2010, (75
FR 12691), EPA concluded that regulation based on the chronic reference
dose will be protective for both chronic and carcinogenic risks. There
are no chronic risks of concern.

Infants and Children Based on these risk assessments, it can be
concluded that there is a reasonable certainty that no harm will result
to the general population, or to infants and children from aggregate
exposure to hexythiazox residues.

No national or transnational maximum residue levels for hexythiazox on
field corn exist apart from those in the United States.

 

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