Document ID: EPA-HQ-OPP-2010-0916-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-12-15T05:00Z

Docket ID #:  EPA-HQ-OPP-2010-0916

COMPANY NOTICE OF FILING FOR HEXYTHIAZOX TOLERANCE PETITION 

EPA Registration Division contact: Sidney Jackson, 703-305-7610 

Interregional Research Project Number 4 (IR-4) and Gowan Company

PP# 0E7787

.448, by establishing a tolerance 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 tomato at
0.50 parts per million (ppm). 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. Five new greenhouse trials were conducted by IR4
in support of the proposal to add greenhouse tomatoes to the label.  
The results of these new trials support the proposed tolerance levels of
0.50 ppm.

Magnitude of the Residue in Processed Food/Feed.  Tomatoes grown in
greenhouses are intended for the fresh market, not for processing
commodities.  Processing studies are not required. Greenhouse tomatoes
are not rotated to other crops.

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 EPA 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.  EPA has previously determined that the residues
of concern in plant and animal commodities are hexythiazox and its
metabolite containing the (4 chlorophenyl)-4-methyl-2oxo-3-thiazolidine
moiety. 

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 (July 14, 2010,
75FR40741).

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 8% of the chronic Population Adjusted Dose (cPAD) for any
population subgroup. The registrant has concluded that hexythiazox use
in greenhouse tomatoes will not significantly contribute to 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. EPA 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 in the July 14, 2010, 75FR40741 
that chronic exposure to hexythiazox from food and water will utilize no
more than 49% of the cPAD for  the population group receiving the
greatest exposure (children 1-2 years old).   The current assessment
evaluated all registered crops, pending tolerance actions and the
proposed new tolerance for tomatoes. This assessment utilized the
proposed tolerance value for tomatoes, assumed 100% crop treated and
utilized default processing factors.  The additional potential dietary
exposure associated with the proposed use, using a conservative Tier 1
assessment for all tomatoes, not just limited to greenhouse grown
tomatoes, will now utilize 57% of the cPAD.  Actual exposure will be
considerably less. 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.

According to the Codex alimentarius website
(http://www.codexalimentarius.net/mrls/) a 0.1 ppm MRL has been
established by Codex.

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