hexythiazox (Savey) Pesticide Petition Filing 8/98
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ENVIRONMENTAL PROTECTION AGENCY
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
SUMMARY: This notice announces the initial filing of pesticide
petitions proposing the establishment of regulations for residues of
certain pesticide chemicals in or on various food commodities.
DATES: Comments, identified by the docket control number PF-826, must
be received on or before September 25, 1998.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Division
(7502C), Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 119, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically to: opp-
email@example.com. Follow the instructions under ``SUPPLEMENTARY
INFORMATION.'' No confidential business information should be submitted
Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment that does not contain CBI must be submitted
for inclusion in the public record. Information not marked confidential
may be disclosed publicly by EPA without prior notice. All written
comments will be available for public inspection in Rm. 1132 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: The product manager listed in the
Product Manager telephone number Address
Beth Edwards (PM 3)........... Rm. 206, CM #2, 703- 1921 Jefferson
305-5400, e- Davis Hwy,
mail:edwards.beth@epa Arlington, VA
Sidney Jackson (PM 22)........ Rm. 233, CM #2, 703- Do.
SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as
follows proposing the establishment and/or amendment of regulations for
residues of certain pesticide chemicals in or on various food
commodities under section 408 of the Federal Food, Drug, and Comestic
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these petitions
contain data or information regarding the elements set forth in section
408(d)(2); 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
The official record for this notice of filing, as well as the
public version, has been established for this notice of filing under
docket control number [PF-826] (including comments and data submitted
electronically as described below). A public version of this record,
including printed, paper versions of electronic comments, which does
not include any information claimed as CBI, is available for inspection
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal
holidays. The official record is located at the address in
``ADDRESSES'' at the beginning of this document.
Electronic comments can be sent directly to EPA at:
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comments and data
will also be accepted on disks in Wordperfect 5.1 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket number (insert docket number) and appropriate
petition number. Electronic comments on notice may be filed online at
many Federal Depository Libraries.
List of Subjects
Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping
Dated: August 13, 1998.
Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Petitioner summaries of the pesticide petitions are printed below
as required by section 408(d)(3) of the FFDCA. The summaries of the
petitions were prepared by the petitioners and represent the views of
the petitioners. EPA is publishing the petition summaries verbatim
without editing them in any way. The petition summary announces the
availability of a description of the analytical methods available to
EPA for the detection and measurement of the pesticide chemical
residues or an explanation of why no such method is needed.
2. Gowan Company
EPA has received a pesticide petition (PP 8F4985) from Gowan
Company, P.O. Box 5569, Yuma, AZ 85366-5569 proposing pursuant to
section 408(d) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C.
346a(d), to amend 40 CFR part 180 by establishing a tolerance for
residues of the acaricide hexythiazox in or on strawberries, apples,
wet apple pomace, cottonseed and cotton gin byproducts. The chemical
name of hexythiazox is trans-5-(4-chlorophenyl)-N-cyclohexyl-4-methyl-
2-oxothiazolidine-3-carboxamide. Metabolites containing the (4-
chlorophenyl)-4-methyl-2-oxo-3-thiazolidine moiety are included in the
tolerance expression. Time-limited tolerances for strawberries, cotton
seed and cotton gin byproducts are currently in effect. Gowan Company
has proposed that the tolerances for cotton seed and cotton gin
byproducts be geographically limited to California only. A permanent
tolerance exists for apples, but Gowan Company proposes to increase the
tolerance level in connection with a proposed change in the use
pattern. A tolerance for residues in wet apple pomace has not been
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 support granting of the petition.
Additional data may be needed before EPA rules on the petition. The
proposed analytical method is high performance liquid chromatography
with an ultraviolet detector. As required by section 408(d) of the
FFDCA, as recently amended by the Food Quality Protection Act (FQPA)
Pub. L. 104-170, Gowan Company included in the petition a summary of
the petition and authorization for the summary to be published in the
Federal Register in a notice of receipt of the petition. The summary
represents the views of Gowan Company; EPA, as mentioned above, is in
the process of evaluating the petition. As required by section
408(d)(3) of the FFDCA, EPA is including the summary as a part of this
notice of filing.
A. Residue Chemistry
1. Plant metabolism. The metabolism of hexythiazox in apples,
pears, grapes, and citrus has been studied. The major portion of the
residue is parent compound. The metabolites are hydroxycyclohexyl and
ketocyclohexyl analogs of hexythiazox and the amide formed by loss of
the cyclohexyl ring.
2. Animal metabolism. The metabolism of hexythiazox in goats, hens
and rats has been studied. Metabolic pathways in animals are similar to
those in plants.
3. Analytical method. An adequate analytical method (HPLC with UV
detection) is available for enforcement purposes. Parent compound and
all of its metabolites are converted to a common moiety before
4. Magnitude of residues--i. Strawberries. Seventy samples of
treated strawberries were analyzed. The maximum residue observed (MRO)
at a preharvest interval of 3-days was 2.06 ppm and the average residue
was 0.67 ppm. A tolerance of 3 ppm was proposed.
ii. Cotton. Twenty residue studies were conducted in the U.S.,
Brazil, and Spain. Four additional studies, including a processing
study, were conducted in California. The MRO in cotton seed was 0.097
ppm and the average residue was 0.065 ppm. A tolerance of 0.2 ppm was
proposed. The maximum residue observed in cotton gin byproducts was
2.29 ppm and the average residue was 1.07 ppm. A tolerance of 3 ppm was
proposed. The proposed tolerances are geographically limited to
California only. A field crop rotation study indicated that residues
would not be present in crops planted 4-months after application of
iii. Apples--a total of 20 trials were conducted. The maximum
residue in apples having a preharvest interval of 1-month was 0.38 ppm
and the average residue was 0.14 ppm. A tolerance of 0.4 ppm was
proposed. Processing studies indicated that hexythiazox residues
concentrate by a factor of 1.7 in wet apple pomace, and a tolerance of
0.7 ppm was proposed.
B. Toxicological Profile
1. Acute toxicity. The acute oral and dermal LD<INF>50</INF> of
technical hexythiazox is > 5,000 mg/kg, and the 4-hour acute inhalation
LC<INF>50</INF> is > 2 mg/L. It is not a dermal irritant or sensitizer
and is a mild eye irritant.
2. Genotoxicity. The following genotoxicity tests were all
negative: Ames gene mutation, CHO gene mutation, CHO chromosome
aberration, mouse micronucleus and rat hepatocyte unscheduled DNA
3. Reproductive and developmental toxicity. Hexythiazox has not
been observed to induce developmental or reproductive effects. The
lowest reproductive or developmental no-observed effected level (NOEL)
was 200 milligram/kilogram/day (mg/kg/day), the highest dose tested
(HDT), in a 2-generation rat reproduction study.
4. Chronic toxicity. The Office of Pesticide Programs has
established the Reference Dose (RfD) for hexythiazox at 0.025 mg/kg/
day. The RfD for hexythiazox is based on a 1-year dog feeding study
with a NOEL of 2.5 mg/kg/day and an uncertainty factor of 100. The
endpoint effect of concern was hypertrophy of the adrenal cortex in
both sexes, decreased red blood cell counts, hemoglobin content and
hematocrit in males.
5. Carcinogenicity. 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 HDT (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 HDT. 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 0.039 (mg/kg/day)-1 in human equivalents was calculated.
C. Aggregate Exposure
Tolerances have been established (40 CFR 180.448) for combined
residues of hexythiazox [trans-5-(4-chlorophenyl)-N-cyclohexyl-4-
methyl-2-oxothiazolidine-3-carboxamide] and its metabolites containing
the (4-chlorophenyl)-4-methyl-2-oxo-3-thiazolidine moiety in or on
apples at 0.02 ppm and pears at 0.3 ppm. Use on several other crops had
been previously proposed [PP 6F4738], and an aggregate exposure
analysis has taken into consideration all current and proposed uses.
The nature and metabolism of
hexythiazox in plants and animals is adequately understood.
Hexythiazox is also registered for use on outdoor ornamental plants
by commercial applicators only. It is believed that non-occupational
exposure from this use is very low. Hexythiazox is not registered for
greenhouse, lawn, garden, or residential use. The environmental fate of
hexythiazox has been evaluated, and the compound is not expected to
contaminate groundwater or surface water to any measurable extent.
1. Chronic exposure. A chronic dietary exposure analysis was
conducted for the general U.S. population and 26 population subgroups.
In this analysis it was assumed that 100% of crops were treated. A
chronic exposure of 0.000172 mg/kg/day was calculated for the average
U.S. population. Non-nursing infants, the most heavily exposed
subgroup, had a calculated exposure of 0.000972 mg/kg/day. Actual
exposure would be much lower, however, because far less than 100% of
crops would be treated.
The Agency has not conducted a detailed analysis of potential
exposure to hexythiazox via drinking water or outdoor ornamental
plants. However, it is believed that chronic exposure from these
sources is very small.
2. Acute exposure. No developmental, reproductive or mutagenic
effects have been observed with hexythiazox. Therefore, an analysis of
acute exposure has not been conducted.
D. Cumulative Effects
At this time the Agency has not reviewed available information
concerning the potentially cumulative effects of hexythiazox and other
substances that may have a common mechanism of toxicity. For purposes
of this petition only, the Agency is considering only the potential
risks of hexythiazox in its aggregate exposure.
E. Safety Determination
1. U.S. population--i. Chronic risk. Chronic risk was calculated
using anticipated residue concentrations from all current and proposed
uses of hexythiazox and assuming that 100% of each crop is treated.
Dietary exposure of the general U.S. population was equivalent to 0.7%
of the RfD. Exposure of the most heavily exposed subgroup, non-nursing
infants, was equivalent to 3.9% of the RfD.
ii. Oncogenic risk. Oncogenic risk was evaluated using anticipated
residue concentrations and taking into account the percent of crop
known or expected to be treated. Lifetime oncogenic risk for the U.S.
population was calculated to be 4.5 x 10-7.
iii. Acute risk. An estimate of acute risk with this compound has
not been conducted since no acute reproductive or developmental effects
have been observed.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of hexythiazox, EPA
considered data from developmental toxicity studies in the rat and
rabbit and a 2-generation study in the rat. The developmental toxicity
studies are designed to evaluate adverse effects on the developing
organism resulting from pesticide exposure during prenatal development
to one or both parents. Reproduction studies provide information
relating to effects from exposure to the pesticide on the reproductive
capability of mating animals and data on systemic toxicity.
No developmental or reproductive effects have been observed in any
study with hexythiazox. The lowest acute NOEL was 2,400 ppm in the diet
(200 mg/kg/day), the HDT, in the 2-generation rat reproduction study.
In the rat developmental study, the maternal and fetotoxic NOEL was 240
mg/kg/day and the developmental NOEL was 2,160 mg/kg/day, the HDT. In
the rabbit developmental study, the maternal and developmental NOEL was
1,080 mg/kg/day, the HDT.
Taking into account current toxicological data requirements, the
database for hexythiazox relative to prenatal and postnatal effects is
complete. In the rat developmental study, the NOELs for maternal
toxicity and fetotoxicity were the same, which suggests that there is
no special prenatal sensitivity in the absence of maternal toxicity.
Furthermore, the lowest developmental or reproductive NOEL is two
orders of magnitude higher than the chronic NOEL on which the RfD is
based. It is concluded that there is a reasonable certainty of no harm
to infants and children from aggregate exposure to hexythiazox
F. International Tolerances
Codex MRLs of 0.5 mg/kg for residues of hexythiazox in strawberries
and apples have been established. The U.S. tolerance proposals are
somewhat at variance with the Codex MRLs because they are based upon
different preharvest intervals. Also, it is believed that the U.S.
proposed tolerance levels allow for a greater margin of safety than the
Codex MRLs. There are no Codex MRLs for the other commodities in this
petition. There are no Canadian or Mexican MRLs for hexythiazox. (Beth
[FR Doc. 98-22430 Filed 8-25-98; 8:45 am]
BILLING CODE 6560-50-F