fenhexamid Pesticide Petition Filing 11/98
[Federal Register: November 20, 1998 (Volume 63, Number 224)]
>From the Federal Register Online via GPO Access [wais.access.gpo.gov]
ENVIRONMENTAL PROTECTION AGENCY
Notice of Filing of Pesticide Tolerance 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-842, must
be received on or before December 21, 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: Mary L. Waller, Registration Support
Branch, Registration Division (7505W), Office of Pesticide Programs,
Environmental Protection Agency, 401 M St., SW, Washington, DC 20460.
Office location, telephone number, and e-mail address: Rm. 247, Crystal
Mall #2, 1921 Jefferson Davis Highway, Arlington, VA 22202, (703) 308-
9354; e-mail: email@example.com.
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 Cosmetic
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-842] (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-842) 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, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping
Dated: November 10, 1998.
Director, Registration Division, Office of Pesticide Programs.
Summary of Petition
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 summaries announce 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. Tomen Agro, Inc. and Bayer Corporation, Agriculture Division
EPA has received a pesticide petition (PP 7F4890) from the TM-402
Fungicide Task Force comprised of Tomen Agro, Inc., 100 First Street,
Suite 1610, San Francisco, CA 94105 and Bayer Corporation, Agriculture
Division, 8400 Hawthorn Road, P.O. Box 4913, Kansas City, MO 64120-
0013, 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 N-(2,3-dichloro-4-
methyl-cyclohexanecarboxamide (TM-402 or Fenhexamid) in or on the raw
agricultural commodities grapes and strawberries at 3.0 parts per
million (ppm) and in raisens at 6.0 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.
A. Residue Chemistry
1. Analytical method. An adequate method for purposes of
enforcement of the proposed TM-402 tolerances in plant commodities is
available. Bayer AG Analytical Method No. 00362 was used by Bayer AG to
determine magnitude of TM-402 residues in fresh and processed grapes.
This method has been independently validated. The limits of
quantitation (LOQ) were determined to be 0.02 ppm for grapes, wine, and
juice, and 0.05 ppm for strawberries, and raisins.
2. Magnitude of residues. The maximum TM-402 residues in fresh
grapes, grape juice, raisins or wine permitted by the proposed label is
2.9 ppm. The maximum TM-402 calculated residue for grape juice is 1.7
ppm. For raisins the calculated residue value is 5.2 ppm, and for wine
the value is 1.2 ppm. The maximum TM-402 residue for fresh strawberries
permitted by the proposed label is 2.3 ppm. The average TM-402 residues
for fresh grapes, grape juice, raisins and wine resulting from the
treatment of grapes permitted by the proposed label are 1.3 ppm. The
average TM-402 calculated residue for grape juice is 0.8 ppm. For
raisins the average calculated residue value was 2.3 ppm, and for wine
the values are 0.52 ppm. The average TM-402 residue for fresh
strawberries permitted by the proposed label is 1.2 ppm. Since
strawberries, grapes and processed grape commodities are not
significant livestock feeds, a nature-of-the-residue discussion in
livestock is not required. Additionally, since no aquatic uses are
proposed, magnitude of the residue data in fish and irrigated crops are
B. Toxicological Profile
1. Acute toxicity. Data from a complete battery of acute toxicity
studies for TM-402 technical are available. The acute oral toxicity
study resulted in an LD<INF>50</INF> of >5,000 milligrams/kilogram (mg/
kg) for both sexes. The acute dermal toxicity in rats resulted in an
LD<INF>50</INF> of > 5,000 mg/kg for both sexes. The acute inhalation
was investigated in two studies in rats. Inhalation by aerosol at the
maximum technically possible concentration of 0.322 mg/l resulted in no
deaths or symptoms (LC<INF>50</INF> >0.322 mg/l). A dust inhalation
study resulted in an LC<INF>50</INF> >5.057 mg/l. TM-402 was not
irritating to the skin or eyes after a 4 hour exposure period. The
Buehler dermal sensitization study in guinea pigs indicated that TM-402
is not a sensitizer. Based on these results TM-402 technical is placed
in toxicity Category IV and does not pose any acute dietary risks.
2. Genotoxicty. The potential for genetic toxicity of TM-402 was
evaluated in six assays including two Ames tests, an HGPRT forward
mutation assay, a UDS assay, an in vitro chromosomal aberration assay
in CHO cells, and a micronucleus test in mice. The compound was found
to be devoid of any mutagenic activity in each of these assays
including those tests that investigated the absence or presence of
metabolic activating systems. The weight of evidence indicates that TM-
402 technical does not pose a risk of mutagenicity or genotoxicity.
3. Reproductive and developmental toxicity. TM-402 has been tested
for reproductive toxicity in rats and developmental toxicity in both
rats and rabbits.
i. In a 2-generation reproduction study (one mating per
generation), 30 Sprague-Dawley rats per sex per dose were administered
0, 100, 500, 5,000, or 20,000 ppm of TM-402 in the diet. The
reproductive toxicity no observed adverse effect level (NOAEL) was
20,000 ppm. The neonatal NOAEL was 500 ppm, and the lowest abserved
effect level (LOAEL) was 5,000 ppm based on decreased pup body weight.
The parental toxicity NOAEL was 500 ppm based on lower adult pre-mating
body weights at 5,000 and 20,000 ppm, lower gestation body weights at
20,000 ppm, lower lactation body weights at 5,000 and 20,000 ppm, and
statistically significant changes in clinical chemistry parameters,
terminal body weights, and organ weights at 5,000 and 20,000 ppm. Based
on this study, it is clear that the only toxic effects in the neonates
occurred at parentally toxic doses.
ii. In rats. TM-402 was administered by gavage at doses of 0 or
1,000 mg/kg for gestation days 6-15. No maternal toxicity,
embryotoxicity, fetotoxicity, or teratogenic effects were observed at
the limit dose of 1,000 mg/kg/day. Therefore, the NOAEL for maternal
and developmental toxicity was 1,000 mg/kg/day.
iii. In rabbits. TM-402 was administered by gavage at doses of 0,
100, 300, and 1,000 mg/kg for gestation days 6-18. Body weight gain and
feed consumption of the dams were reduced at the two top doses. One
abortion occurred in each of the top two dose groups and two total
resorptions occurred in the top dose group. The placental weights were
slightly decreased at 300 mg/kg/day and above. In the 1,000 mg/kg/day
group slightly decreased fetal weights and a slightly retarded skeletal
ossification were observed. All other parameters investigated in the
study were unaffected. Therefore, the NOAELs for maternal and
developmental toxicity were 100 mg/kg/day in this study.
Based on the 2-generation reproduction study in rats, TM-402 is not
considered a reproductive toxicant and shows no evidence of endocrine
effects. The data from the developmental toxicity studies on TM-402
show no evidence of a potential for developmental effects
(malformations or variations) at doses that are not maternally toxic.
The NOAEL for both maternal and developmental toxicity in rats was
1,000 mg/kg/day and for rabbits the NOAEL for both maternal and
developmental toxicity was 100 mg/kg/day.
4. Subchronic toxicity. The subchronic toxicity of TM-402 has been
evaluated in rats, mice, and dogs.
i. TM-402 was administered in the diet to rats for 13 weeks at
doses of 0, 2,500, 5,000, 10,000 and 20,000 ppm. The NOAEL was 5,000
ppm (415 mg/kg/day in males and 549 mg/kg/day in females). Reversible
liver effects were observed at 10,000 ppm.
ii. TM-402 was administered in the diet to mice for approximately
14 weeks at doses of 0, 100, 1,000 and 10,000 ppm. The NOAEL was 1,000
ppm (266.6 mg/kg/day in males and 453.9 mg/kg/day in females).
Increased feed and water consumption and kidney and liver effects were
observed at 10,000 ppm.
iii. TM-402 was administered in the diet to beagle dogs for 13
weeks at doses of 0, 1,000, 7,000 and 50,000 ppm. The NOAEL was 1,000
ppm (33.9 mg/kg/day in males and 37.0 mg/kg/day in females. Increased
Heinz bodies were observed at 7,000 ppm.
5. Chronic toxicity. The chronic toxicity of TM-402 has been
evaluated in a 1 year dog study and a 2 year chronic toxicity/
oncogenicity study in rats.
i. TM-402 was administered in the feed at doses of 0, 500, 3,500,
or 25,000 ppm to 4 male and 4 female beagle dogs per group for 52
weeks. A systemic
NOAEL of 500 ppm (an average dose of 17.4 mg/kg/day over the course of
the study) was observed based on decreased food consumption and
decreased body weight gain at 25,000 ppm, decreased erythrocyte,
hemoglobin and hematocrit values at 25,000 ppm, increased Heinz bodies
at 3,500 ppm and above, and a dose-dependent increase of alkaline
phosphatase at 3,500 ppm and above. There were no treatment related
effects on either macroscopic or histologic pathology.
ii. A combined chronic/oncogenicity study was performed in Wistar
rats. Fifty animals/sex/dose were administered doses of 0, 500, 5,000,
or 20,000 ppm for 24 months in the feed. A further 10 animals/sex/group
received the same doses and were sacrificed after 52 weeks. The doses
administered relative to body weight were 0, 28, 292, or 1,280 mg/kg/
day for males and 0, 40, 415, or 2067 mg/kg/day for females. The NOAEL
in the study was 500 ppm (28 mg/kg/day for males and 40 mg/kg/day for
females) based on body weight decreases in females at 5,000 ppm and
above, changes in biochemical liver parameters in the absence of
morphological changes in both sexes at 5,000 ppm and above, and caecal
mucosal hyperplasia evident at 5,000 ppm and above.
The NOAEL in the chronic dog study was 17.4 mg/kg/day based on body
weight, hematology and clinical chemistry effects. The lowest NOAEL in
the 2 year rat study was determined to be 28 mg/kg/day based on body
weight, clinical chemistry parameters in the liver, and caecal mucosal
6. Oncogenicity. The oncogenic potential of TM-402 has been in a 2
year oncogenicity study in mice and a 2 year chronic toxicity/
oncogenicity study in rats.
i. Mouse. TM-402 was administered to 50 B6C3F1 mice/sex/group in
their feed at concentrations of 0, 800 ,2,400 , or 7,000 ppm for 24
months. These concentrations resulted in a compound intake of
247.4,807.4 or 2354.8 mg,kg,day in males and 364.5, 1054.5 and 3178.2
mg/kg/day in females. A further 10 mice/sex/group received the same
concentrations and were sacrificed after 12 months. There was no
treatment effect on mortality, feed consumption,the hematological
system or on the liver. Water consumption was increased in both sexes,
and body weights were 8% lower in males at the highest dose of 7,000
ppm. At 7,000 ppm, elevated plasma creatinine concentrations, decreased
kidney weights, and an increased occurrence of morphological lesions
indicated a nephrotoxic effect of the compound. There was no shift in
the tumor spectrum with treatment, and therefore, TM-402 was not
oncogenic in this study.
ii. Rat. In the 2 year rat chronic/oncogenicity study described
above, there was no indication of an oncogenic response. There was no
indication of an oncogenic response in the 2 year rat and mouse studies
7. Neurotoxicity. The possibility for acute neurotoxicity of TM-402
was investigated. TM-402 was administered by gavage ina single dose to
12 Wistar rats/sex/group at doses of 0, 200, 630, 2,000 mg/kg. There
was no evidence of neurotoxicity at any level tested.
8. Endocrine disruption. TM-402 has no endocrine-modulation
characteristics as demonstrated by the lack of endocrine effects in
developmental, reproductive, subchronic, and chronic studies.
C. Aggregate Exposure
1. Dietary exposure. Sources of dietary exposure to TM-402 are
limited to the crops in the current submission. The following are the
proposed tolerances: grapes - 3.0 ppm and strawberries - 3.0 ppm. A
food additive tolerance of 6.0 ppm in raisins is also being proposed.
2. Drinking water. Review of the environmental fate data indicates
the TM-402 is relatively immobile and rapidly degrades in the soil and
water. TM-402 dissipates in the environment via several processes.
Therefore, a significant contribution to aggregate risk from drinking
water is unlikely.
3. Non-dietary exposure. There is no significant potential for non-
occupational exposure to the general public. The proposed uses are
limited to agricultural and horticultural use.
D. Cumulative Effects
Consideration of a common mechanism of toxicity is not appropriate
at this time since there is no significant toxicity observed for TM-
402. Even at toxicology limit doses, only minimal toxicity is observed
for TM-402. Therefore, only the potential risks of TM-402 are
considered in the exposure assessment.
E. Safety Determination
1. U.S. population. Based on the most sensitive species, Tomen Agro
has calculated an appropriate Reference Dose (RfD) for TM-402. Using
the NOAEL of 17.4 mg/kg/day in the 1 year dog study and an uncertainty
factor (UF) of 100 to account for inter- and intra-species variability,
an RfD of 0.177 mg/kg/day is recommended.
A chronic dietary risk assessment which included all proposed
tolerances was conducted on TM-402 using U.S. EPA's Dietary Risk
Evaluation System (DRES). The theoretical maximum residue contribution
(TMRC) for the U.S. population (48 States) is 0.00125 mg/kg/day and
this represents 0.71% of the propoed RfD. The most highly exposed
subgroup was children (1- 6 years old) where the TMRC was 0.00382 mg/
kg/day, representing only 2.15% of the proposed RfD. For non-nursing
infants (>1 year old) the TMRC was 0.00101 mg/kg/day (0.57% of the RfD)
and for children 7-12 years old the TMRC is 0.00156 mg/kg/day (0.88% of
the RfD). If these calculations consider the average of anticipated
residue values instead of assuming ``tolerance level'' residues, the
values are reduced to approximately one-third of those listed above.
Even under the most conservative assumptions, the estimates of dietary
exposure clearly demonstrate adequate safety margins of all segments of
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of TM-402, the
available developmental toxicity and reproductive toxicity studies and
the potential for endocrine modulation by TM-402 were considered.
Developmental toxicity studies in two species indicate that TM-402 does
not impose additional risks to developing fetuses and is not a
teratogen. The 2-generation reproduction study in rats demonstrated
that there were no adverse effects on reproductive performance,
fertility, fecundity, pup survival, or pup development at non-
maternally toxic levels. Maternal and developmental NOAELs and LOAELs
were comparable, indicating no increase in susceptibility of developing
organisms. No evidence of endocrine effects were noted in any study. It
is therefore concluded that TM-402 poses no additional risk for infants
and children and no additional uncertainty factor is warranted.
[FR Doc. 98-31069 Filed 11-19-98; 8:45 am]
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