hexythiazox (Savey) Pesticide Petition Filing 1/98
[Federal Register: January 28, 1998 (Volume 63, Number 18)]
>From the Federal Register Online via GPO Access [wais.access.gpo.gov]
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-787, must
be received on or before February 27, 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. 1132, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically to: opp-
firstname.lastname@example.org. 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
Amelia M. Acierto............. Rm. 4W60, 4th. floor, 2800 Crystal
CSI #2, 703-308-8377, Drive,
e- Arlington, VA
Adam Heyward.................. Rm. 206, CM #2, 703- 1921 Jefferson
305-5518, e-mail: Davis Hwy.,
heyward. Arlington, VA
Joseph Tavano................. Rm. 214, 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-787] (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. Comment 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 [PF-787] and appropriate petition
number. Electronic comments on notice may be filed online at many
Federal Depository Libraries.
List of Subjects
Environmental protection, Agricultural commodities, Feed additives,
Food additives, Pesticides and pests, Reporting and recordkeeping
Dated:January 20, 1998
Acting 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.
1. Gowan Company
In May, 1996, EPA received a pesticide petition (PP 6F4738) from
Gowan Company, P. O. Box 5569, Yuma, AZ 85366-5569. The petition
proposed, pursuant to section 408 of the Federal Food, Drug, and
Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 to
establish tolerances for the acaricide hexythiazox and its metabolites
in or on the raw agricultural commodities stone fruits (except plums)
at 1 part per million (ppm), almonds at 0.2 ppm and almond hulls at 10
ppm, and also in milk, cattle meat and cattle fat at 0.05 ppm, and
cattle meat byproducts at 0.1 ppm (April 30, 1997, 62 FR 23455-23457)
(FRL-5600-8). In April 1997, the registrant amended the tolerance
petition by proposing to establish a tolerance for stone fruits
including plums at 1 ppm, a tolerance for prunes at 5 ppm, and a
tolerance for all tree nuts at 0.2 ppm. The proposed tolerances for
animal products were unchanged. 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.
A. Residue Chemistry
1. Plant metabolism. The metabolism of hexythiazox in apples,
citrus, grapes and pears 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. 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
3. Magnitude of residues. Twenty-four stone fruit residue trials
were conducted over 3-years. The geographic distribution of the trials
agrees with the recommendation given in the ``EPA Residue Chemistry
Guidance''(1994). In these trials, the maximum combined residues of
hexythiazox and its metabolites were 0.52 ppm. Twelve tree nut residue
trials were conducted over 4 years. In these trials, the maximum
combined residues of hexythiazox and its metabolites were 0.17 ppm in
almond nutmeat and 7.5 ppm in the raw agricultural commodity almond
B. Toxicological Profile
1. Acute toxicity. The acute oral and dermal LD<INF>50</INF> of
technical hexythiazox is greater than 5,000 milligram/kilograms (mg/
kg), and the 4-hour acute inhalation LC<INF>50</INF> is greater than 2
mg/L. It is not a dermal irritant or sensitizer and is a mild eye
2. Genotoxicity. The following genotoxicity tests were all
Ames gene mutation, CHO gene mutation, CHO chromosome aberration,
mouse micronucleus and rat hepatocyte unscheduled DNA synthesis.
3. Reproductive and developmental toxicity. Hexythiazox has not
been observed to induce developmental or reproductive effects. The
lowest reproductive or developmental no-observed-effect-level (NOEL)
observed was 200 milligram/kilograms/day (mg/kg/day), the highest dose
tested, in a 2-generation rat reproduction study.
4. Subchronic toxicity. The Office of Pesticide Programs has
established the 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. Chronic toxicity. 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 Q<SUP>1*</SUP> of 0.039 (mg/kg/
day)<SUP>-1</SUP> in human equivalents was calculated.
C. Aggregate Exposure
Tolerances have been established (40 CFR 180.448) for the 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. 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. Dietary exposure. The Agency has calculated in the Federal
Register of February 21, 1996 (61 FR 6152-6154) (FRL-5350-6), that
current uses on apples and pears would result in an exposure of
0.000051 mg/kg/day for the U.S. population, assuming that all residues
are at tolerance levels and 100% of the crops are treated. Non-nursing
infants, the subgroup having the highest exposure, would have an
exposure of 0.000600 mg/kg/day. Using the same conservative
assumptions, it is calculated that the current and proposed uses
together would result in an exposure of 0.001133 mg/kg for the U.S.
population and 0.007256 mg/kg/day for non-nursing infants, which
remains the most highly exposed subgroup.
Actual exposure will be much lower, however. Only a small fraction
of these crops will be treated with hexythiazox, and average residues
are far below the tolerance levels. For example, residues in apples
treated at 10 times the currently approved application rate remained
below the limit of quantitation, 0.01 ppm. Also, residues in apple
juice are expected to be less than 50% of the residue level in the
whole fruit. Average residues in stone fruits except cherries are
expected to be 7% of the proposed tolerance level, average residues in
cherries are expected to be 11% of the tolerance level and average
residues in almond nutmeat are expected to be below 20% of the proposed
tolerance level. Furthermore, only a very small percentage of crops
(less than 1% up to 5%, depending on the crop) are expected to be
treated with hexythiazox. When actual residues rather than tolerance
levels and the percentage of treated crop are taken into account, then
the actual exposure is estimated to be 0.0000069 mg/kg/day for the U.S.
2. Drinking water. 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.
3. Non-dietary 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. Determination of Safety for U.S. Population
1. Chronic risk. The Agency has calculated (FR 61 6152-6154),
assuming that residues are at tolerance levels and 100% of crops are
treated, that the current use on apples and pears utilizes 0.2% of the
reference dose (RfD) for the U.S. population and 2.4% of the RfD for
non-nursing infants. Using these same assumptions, it is calculated
that all current and proposed uses would result in TMRCs equivalent to
4.5% of the RfD for the U.S. population and 29.0% of the RfD for non-
nursing infants. However, when actual residues rather than tolerance
levels and the percent of crop treated are taken into account, actual
chronic risk for the U.S. population is expected to be only 0.43% of
The actual dietary carcinogenic risk to the U.S. population is
calculated to be 2.7 x 10<SUP>-7</SUP>, which is below the Agency's
criterion of 1 x 10<SUP>-6</SUP>.
2. Acute risk. An estimate of acute risk with this compound has not
been conducted since no acute reproductive or developmental effects
have been observed.
F. Determination of Safety for 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 pre-natal 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 highest dose tested, 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 highest dose tested. In the rabbit
developmental study, the maternal and developmental NOEL was 1,080 mg/
kg/day, the highest dose tested.
Taking into account current toxicological data requirements, the
database for hexythiazox relative to pre-natal and post-natal 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 pre-natal 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
G. International Tolerances
Codex maximum residue levels (MRLs) of 1 mg/kg (1 ppm) have been
established for residues of hexythiazox in cherries and peaches. The
U.S. tolerance proposal for stone fruits is in harmony with these MRLs.
There are no Codex MRLs for the other commodities in this petition.
There are no Canadian or Mexican MRLs for hexythiazox. (Adam Heyward)
[FR Doc. 98-2088 Filed 1-27-98; 8:45 am]
BILLING CODE 6560-50-F