hexythiazox (Savey) Pesticide Petition Filing 7/98
[Federal Register: July 17, 1998 (Volume 63, Number 137)]
>From the Federal Register Online via GPO Access [wais.access.gpo.gov]
ENVIRONMENTAL PROTECTION AGENCY
BASF Corporation; Pesticide Tolerance Petition Filing
AGENCY: Environmental Protection Agency (EPA).
SUMMARY: This notice announces the initial filing of a pesticide
petition proposing the establishment of regulations for residues of a
certain pesticide chemical in or on various food commodities.
DATES: Comments, identified by the docket control number PF-820, must
be received on or before August 17, 1998.
ADDRESSES: By mail submit written comments to: Information and Records
Integrity Branch, Public Information and Services Divison (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 by following
the instructions under ``SUPPLEMENTARY INFORMATION.'' No confidential
business information should be submitted through e-mail.
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. 119 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: Beth Edwards, Insecticide Branch,
Registration Division (7505C), Office of Pesticide Programs,
Environmental Protection Agency, 401 M St., SW., Washington, DC 20460.
Office location, telephone number, and e-mail address: Rm. 206, Crystal
Mall #2, 1921 Jefferson Davis Highway, Arlington, VA 22202, (703) 305-
5400; e-mail: firstname.lastname@example.org.
SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition as
follows proposing the establishment and/or amendment of regulations for
residues of certain pesticide chemical 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 this petition
contains 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 petition.
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-820] (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 5.1/6.1 file format or
ASCII file format. All comments and data in electronic form must be
identified by the docket control number (PF-820) and appropriate
petition number. Electronic comments on this 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: July 13, 1998.
Director, Registration Division, Office of Pesticide Programs.
Summary of Petition
The petitioner summary of the pesticide petition is printed below
as required by section 408(d)(3) of the FFDCA. The summary of the
petition was prepared by the petitioner and represents the views of the
petitioner. EPA is publishing the petition summary 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.
EPA has received a pesticide petition (PP 4E4411) from BASF
Corporation, Agricultural Products, P.O. Box 13528, Research Triangle
Park, NC 27709 proposing pursuant to section 408(d) of the Federal
Food, Drug, and Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR
180.448 by establishing a tolerance for residues of hexythiazox [trans-
carboxamide] and its metabolites containing the (4-chlorophenyl)-4-
thiazolidine moiety (expressed as parts per million (ppm) of the parent
compound), in or on the raw agricultural commodity dried hops. The
proposed analytical method is gas chromatography using Nitrogen
Phosphorous detection. 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. Residue Chemistry
1. Plant and animal metabolism. BASF Corporation notes that
metabolism in plants and animals is understood.
2. Analytical method. The proposed analytical method involves
methanol extraction, clean-up by partition, and detection of residues
by gc with npd.
3. Magnitude of residues. Nine residue trials were conducted in
Bavaria Germany. The method of detection had a limit of detection of
0.05 ppm. After kiln drying, hops residues ranged from 0.61 to 1.53 ppm
and averaged approximately 0.9 ppm.
B. Toxicological Profile
1. Acute toxicity. For the technical grade active ingredient:
Acute oral toxicity--Rat. LD<INF>50</INF> >5,000 milligram/
killograms (mg/kg) (Tox Category IV); Acute Dermal Toxicity (rat)
LD<INF>50</INF> > 5,000 mg/kg (Tox Category III); Acute Inhalation
Toxicity (rat) LC<INF>50</INF> > 2.0 mg/l (4 hrs) (Tox Category IV);
Primary Eye Irritation (rabbit) - Hexythiazox is a mild ocular irritant
(Tox Category III); Primary Dermal irritation (rabbit) - Hexythiazox is
not a dermal irritant (Tox Category IV); Dermal Sensitization (guinea
pig) - Hexythiazox is not a dermal sensitizer.
2. Genotoxicty. All mutagenicity tests were negative. Ames Testing.
Negative (Accession No. 072941). In vitro cytogenicity (Chinese hamster
ovary cells): Negative (MRID 00156894). Rat primary hepatocyte
unscheduled DNA synthesis assay (MRID 00156893). Mammalian cell forward
gene mutation assay (MRID 00155154).
3. Reproductive and developmental toxicity--i. Developmental
toxicity--Rat. The maternal toxicity NOEL was determined to be 240 mg/
kg/day. The fetotoxicity NOEL was 240 mg/kg/day, and the compound was
not embryotoxic at the highest dose tested (HDT), 2,160 mg/kg/day (MRID
ii. Developmental toxicity-- Rabbit. No development or maternal
toxicity was observed at the HDT, 1,080 mg/kg/day (MRID 00146555).
iii. Multi-generation reproduction-- Rat. The parental toxicity
NOEL was determined to be 20 mg/kg/day. No reproductive effects were
observed at 2,400 ppm (200 mg/kg/day), the HDT.
4. Chronic toxicity. The data submitted in support of this
tolerance and other relevant material have been reviewed. The
toxicological and metabolism data considered in support of this
tolerance are discussed in detail in related documents published in the
Federal Registers of April 26, 1989 (54 FR 17947), and February 21,
1996 (61 FR 6552) (FRL-5350-6) .
5. Chronic toxicity non-rodent--Dog and rodent--Rat. The NOEL for
chronic effects for hexythiazox is 2.5 mg/kg/day, based upon a 1-year
dog study, and the RfD is 0.025 mg/kg/day (MRID 00146556, 00151359, and
00156895). A 2-year rat study showed a systemic NOEL of 430 ppm (21.5
mg/kg/day, MRID 00146559). No evidence of oncogenicity was observed in
6. Oncogenicity in the rodent-- Mouse. Hexythiazox produced an
oncogenic effect in the livers of female mice (MRID 00147577, 00156896,
40328701, and 40328702) with a systemic NOEL of 250 ppm (37.5 mg/kg/
day). The Agency has calculated an oncogenic potential of Q* = 0.039
7. Hormonal effects. No specific hormonal effects testing has been
conducted with hexythiazox, however, the compound was tested in two
developmental bioassays and a multi-generation reproduction bioassay.
No hormonal effects were noted in these relevant tests.
8. Threshold effects. A chronic dietary exposure/risk assessment
has been performed for hexythiazox using the established reference dose
(RfD) of 0.025 mg/kg-bwt/day. The RfD was based on a NOEL of 2.5 mg/kg/
day from a 1-year dog feeding study.
9. Non-threshold effects. The Agency has classified hexythiazox as
a class C (possible human) carcinogen based on a significantly
increased incidence of hepatocellular carcinomas (p=0.028), and
adenomas/carcinomas combined (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 preneo-plastic hepatic nodules in both males
and females at the HDT (1,500 ppm). The decision supporting a Category
C classification (rather than a Category B) was based primarily on the
fact that only one species was affected (mouse), mutagenicity assays
did not support upgrading to a B classification, and structure-activity
relationship of hexythiazox to other compounds supported a C
classification. 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 malignant liver tumors in the female mouse.
Thus, a Q* of 3.9 x 10<SUP>-2</SUP> (mg/kg/day)-1 in human
equivalents has been calculated. A full review of the data indicates
that although hexythiazox is a carcinogen in mice, the risks would be
extremely small from the proposed use on hops. Estimated dietary
carcinogenic risk to the general population based on the highly
conservative assumptions that all imported hops are treated with
hexythiazox and would bear residues at the proposed tolerance level is
estimated to be approximately 3 x10<SUP>-7</SUP>. In fact, the Agency
estimated in 1993, that the most conservative estimate of the
percentage of beer containing foreign grown hops (including imported
beer and domestic beer brewed with imported hops) to be approximately
49%. In addition, the average residue seen in the residue studies
supporting this tolerance was approximately 0.9 ppm. Incorporating this
information into the risk calculation the estimated oncogenic risk from
the proposed use is reduced to approximately 7 x 10<SUP>-8</SUP>. Even
this is an overestimation, as the calculations assume that the level of
hexythiazox in finished beer is the same as the level in the dried
hops. BASF has supplied information which demonstrates that finished
beer brewed with hops containing an average level of 1.16 ppm results
in hexythiazox levels of <0.05 ppm in the finished beer. Assuming a
level of 0.05 ppm in beer produced from hops would further reduce the
theoretical risk to approximately 4 x 10<SUP>-9</SUP>.
A chronic dietary exposure/risk assessment has been performed for
hexythiazox using a RfD of 0.025 mg/kg-bwt/day. The RfD was based on a
NOEL of 2.5 mg/kg/day from a 1-year dog feeding study and a safety
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. The analysis was performed
using tolerance level residues and 100% crop treated information. The
exposure for established tolerances and the current proposal utilizes
<1% of the RfD for the U.S.population.
C. Aggregate Exposure
1. Dietary exposure. The exposure for established tolerances and
proposal utilizes <1% of the RfD for the U.S. population. Non-nursing
infants <l represent the most exposed sub-population and the percent of
the RfD consumed by this group is <3%. BASF has estimated the
theoretical oncogenic risk for the currently registered uses of
hexythiazox (apples and pears) to be approximately 1.5 x
10<SUP>-6</SUP>. This risk number includes the very conservative
assumptions that all apples and pears are treated with hexythiazox and
that all resulting residues are at the tolerance level. In its recent
FR Notice establishing the tolerance in apples the Agency recognized
these conservative overestimations and concluded ``in reality, the
Agency knows that all apples would not be treated with this pesticide
and expect that even apples receiving maximum treatment will have
residues far below tolerance level. For example, in field trials
conducted using application rates 10 times the label amount, residues
in apples still did not exceed the tolerance level. Further, the
maximum residue level (MRL) in apple juice would be expected to be less
than 50% of the residue level in whole fruit. Based on an assessment of
the cancer risks of the proposed use of hexythiazox, the Agency
believes that the proposed use of hexythiazox on apples will pose an
extremely small risk to humans.'' The current proposal will not
increase the theoretical oncogenic risk significantly.
In addition, the Agency has concluded that based on the residue and
feeding levels of spent hops ``meat and milk tolerances are not
required for this petition.''
2. ``Other'' exposure. Other potential sources of exposure of the
general population to residues of pesticides are residues in drinking
water and exposure from non-occupational sources. Since this tolerance
is for an ``imported use,'' BASF does not anticipate exposure to
residues of hexythiazox in drinking water. BASF has not estimated non-
occupational exposure for hexythiazox. Since the current registrations
for hexythiazox in the United States are limited to commercial apple/
pear production, the potential for non-occupational exposure to the
general population is considered to be insignificant.
D. Cumulative Effects
BASF also considered the potential for cumulative effects of
hexythiazox and other substances that have a common mechanism of
toxicity. BASF is unaware of any conclusive data regarding the
potential for hexythiazox to share a common mechanism for toxic effects
with any other compound. In dietary assessment, the food factor for
hops is only 0.03%. Therefore, BASF concluded that any concern
regarding a common mechanism of toxicity would be insignificant.
E. Safety Determination
1. U.S. population. Using the exposure assumptions described above,
BASF concludes that aggregate exposure to hexythiazox will utilize
approximately <1% of the RfD for the U.S. population. EPA generally has
no concern for exposures below 100% of the RfD. In addition the
calculated theoretical oncogenic risk associated with this use is more
than 100 times less than the Agency's general level of concern (1 x
Therefore, based on the completeness and reliability of the
toxicity data and the conservative exposure assessment, BASF concludes
that there is a reasonable certainty that no harm will result from
aggregate exposure to residues of hexythiazox, including all
anticipated dietary exposure and all other non-occupational exposures.
2. Infants and children. The toxicity database includes both
developmental and reproductive testing in which no significant concerns
were identified. BASF therefore believes the established RfD of 0.025
mg/kg/day is the appropriate approach for assessing risk in children.
Based on the completeness and reliability of the toxicity data and the
conservative exposure assessment, BASF concludes that there is a
reasonable certainty that no harm will result to infants and children
from aggregate exposure to the residues of hexythiazox, including all
anticipated dietary exposure and all other non-occupational exposures.
F. Other Considerations
The qualitative nature of the residues in plants and animals is
adequately understood. There is a practical analytical method for
detecting and measuring levels of hexythiazox in or on food with a
limit of detection that allows monitoring of food with residues at or
above the levels set in these tolerances.
G. International Tolerances
A maximum residue level has not been established for hexythiazox by
the Codex Alimentarius Commission.
[FR Doc. 98-19247 Filed 7-16-98; 8:45 am]
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