[Federal Register Volume 63, Number 234 (Monday, December 7, 1998)]
[Notices]
[Pages 67476-67483]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-32426]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-848; FRL-6047-2]
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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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-848, must
be received on or before January 6, 1999.
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 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. 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
table below:
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Office location/
Product Manager telephone number Address
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Mary Waller (PM 21)........... Rm. 247, CM #2, 703- 1921 Jefferson
308-9354, e- Davis Hwy,
mail:[email protected] Arlington, VA
ail.epa.gov.
Cynthia Giles-Parker (PM 22).. Rm. 247, CM #2, 703- Do.
305-7740, e-mail:
parker.cynthia@epamai.
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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
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-848] (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
[[Page 67477]]
record is located at the address in ``ADDRESSES'' at the beginning of
this document.
Electronic comments can be sent directly to EPA at:
opp-docket@epamail.epa.gov
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 (insert docket number) 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
requirements.
Dated: November 24, 1998.
James Jones,
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. BASF Corporation, Agricultural Products
PP 7E4874
EPA has received a pesticide petition (PP 7E4874) 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 part
180 by establishing an import tolerance for residues of the fungicide
fenpropimorph, (+)-cis-4-(3-(4-tert-butylphenyl)-2-methylpropyl)-2,6-
dimethylmorpholine in or on the raw agricultural commodity bananas at
1.5 parts per million (ppm) of which no more than 0.3 ppm is found in
the pulp. 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 method of analysis includes extraction,
liquid/liquid partition, column clean-up, and quantitation by gas
chromatography/nitrogen-phosphorus detector. The overall fortification
recoveries from the unpeeled, whole banana, and the peeled (pulp)
samples together averaged 87.1% 9.3% (N=76).
3. Magnitude of residues. Fifteen crop residue trials were
conducted in the banana growing regions of Mexico, South, and Central
America including three sites in Colombia, four sites in Costa Rica,
four sites in Ecuador, one site in Guatemala, two sites in Honduras,
and one site in Mexico. Four sequential applications were made at the
target rate of 545 g/ha to both bagged and unbagged bananas at each
site. Fruit from both the bagged and unbagged treatments were harvested
at 0 days following the last application.
Whole fruit (peel and pulp) samples and pulp only samples were
analyzed for all treatments at all sites. Under typical practices
(bagged bananas) residue in the whole fruit ranged from < the="" limit="" of="" quantitation="" (loq)="" (0.050="" milligrams/kilogram="" (mg/kg))="" to="" a="" maximum="" of="" 0.4="" mg/kg.="" banana="" pulp="" residues="" from="" bagged="" bananas="" ranged="" from="">< the="" loq="" (0.050="" mg/kg="" to="" 0.20="" mg/kg="" and="" averaged="" 0.0518="" mg/kg.="" the="" average="" value="" was="" calculated="" by="" assuming="" all="" values="" below="" the="" loq="" were="" equal="" to="" one-half="" the="" loq="" or="" 0.025="" mg/kg.="" under="" worst-case="" practices="" (unbagged="" bananas)="" residue="" in="" the="" whole="" fruit="" ranged="" from="">< the="" loq="" (0.050="" mg/kg="" to="" a="" maximum="" of="" 1.4="" mg/kg.="" banana="" pulp="" residues="" from="" unbagged="" bananas="" ranged="" from="">< the="" loq="" (0.050="" mg/kg="" to="" 0.43="" mg/kg="" and="" averaged="" 0.1149="" mg/kg.="" the="" average="" value="" was="" calculated="" by="" assuming="" all="" values="" below="" the="" loq="" were="" equal="" to="" one-half="" the="" loq="" or="" 0.025="" mg/kg.="" b.="" toxicological="" profile="" 1.="" acute="" toxicity.="" based="" on="" available="" acute="" toxicity="" data="" fenpropimorph="" does="" not="" pose="" any="" acute="" toxicity="" risks.="" these="" studies="" are="" not="" required="" for="" an="" import="" tolerance,="" but="" we="" have="" provided="" the="" following="" paragraph="" to="" demonstrate="" that="" fenpropimorph="" is="" not="" an="" acute="" toxicant.="" the="" acute="" toxicity="" studies="" place="" technical="" fenpropimorph="" in="" acute="" toxicity="" category="" iii="" for="" acute="" oral,="" dermal,="" inhalation,="" and="" skin="" irritation;="" and="" in="" acute="" toxicity="" category="" iv="" for="" eye="" irritation="" and="" the="" technical="" material="" is="" not="" a="" skin="" sensitizer.="" additionally,="" results="" of="" an="" acute="" oral="" neurotoxicity="" and="" a="" subchronic="" oral="" feeding="" neurotoxicity="" study="" demonstrated="" that="" fenpropimorph="" was="" not="" a="" neurotoxic="" compound.="" 2.="" genotoxicity.="" a="" modified="" ames="" test="" (1="" study;="" point="" mutation):="" negative;="" in="" vitro="" cytogenetics-human="" lymphocytes="" (1="" study;="" chromosome="" aberrations):="" negative;="" mouse="" micronucleus="" assay="" (1="" study;="" chromosome="" aberrations):="" negative;="" in="" vitro="" uds="" test="" using="" rat="" hepatocytes="" (1="" study;="" dna="" damage="" and="" repair):="" negative;="" fenpropimorph="" has="" been="" tested="" in="" a="" total="" of="" 4="" genetic="" toxicology="" assays.="" these="" assays="" were="" performed="" both="" in="" vitro="" and="" in="" vivo="" and="" multiple="" assays="" were="" conducted="" for="" each="" of="" the="" three="" epa="" guideline="" requirement="" categories.="" based="" on="" the="" data="" presented="" in="" this="" petition,="" fenpropimorph="" does="" not="" induce="" gene="" mutations="" and="" does="" not="" induce="" other="" effects="" indicative="" of="" genotoxicity.="" fenpropimorph="" does="" not="" pose="" a="" mutagenic="" hazard="" to="" humans.="" 3.="" reproductive="" and="" developmental="" toxicity.="" a="" 2-generation="" reproduction="" study="" with="" rats="" fed="" dosages="" of="" 0,="" 0.625,="" 1.25,="" and="" 2.5="" milligrams/kilogram/day="" (mg/kg/day)="" (average="" mg/kg/day="" dose="" levels="" for="" both="" male="" and="" female="" rats)="" with="" a="" reproductive="" no="" observed="" adverse="" effect="" level="" (noael)="" of="" 2.5="" mg/kg/day="" and="" with="" a="" parental="" noael="" of="" 2.5="" mg/kg/day="" based="" on;="" (i)="" no="" treatment-related="" clinical="" signs,="" significant="" body="" weight="" changes,="" parameters="" of="" fertility="" and="" gestation,="" or="" macro-="" or="" histopathological="" changes="" were="" observed="" for="" the="" parental="" f0="" and="" f1="" at="" all="" dose="" levels="" tested;="" (ii)="" in="" the="" f1="" litters,="" a="" slight="" increased="" incidence="" of="" stillborn="" pups,="" unfolding="" of="" the="" ear,="" and="" slight="" reduced="" body="" weight="" development="" during="" lactation="" were="" observed="" in="" the="" 2.5="" mg/kg/day="" dose="" level="" group;="" and="" (iii)="" in="" the="" f2="" litters,="" no="" treatment-related="" effects="" were="" observed="" at="" all="" dose="" levels="" tested.="" a="" developmental="" prenatal="" study="" was="" conducted="" via="" oral="" gavage="" in="" rats="" resulted="" in="" dosages="" of="" 0,2.5,="" 10,="" 40,="" and="" 160="" highest="" dose="" tested="" (hdt)="" mg/kg/day="" from="" day="" 6="" to="" 15="" of="" gestation="" with="" a="" development="" toxicity="" noael="" of="" 40="" mg/kg/day="" and="" a="" maternal="" toxicity="" of="" 10="" mg/kg/day="" based="" on="" the="" following:="" (i)="" signs="" of="" maternal="" toxicity,="" in="" the="" form="" of="" [[page="" 67478]]="" decreased="" body="" weights="" and/or="" clinical="" signs="" observed="" at="" dose="" levels="">
40 mg/kg/day; (ii) maternal animals in the 160 mg/kg/day dose group
showed an increased incidence of vaginal bleeding from day 10 to 19 of
gestation and increased placental weight; (iii) maternal animals in the
160 mg/kg/day dose group showed an increase in the number of
resorptions as compared to controls; (iv) decreases in fetal body
weights and size and number of viable fetus were observed at the HDT;
(v) a significant number of fetuses had a finding of cleft palate in
the high dose group tested were observed; and (vi) litters from animals
treated at the lower doses remained entirely unaffected.
A second developmental perinatal study was conducted via oral
gavage in rats resulted in dosages of 0, 2.5, 10, 40, and 160 HDT mg/
kg/day from day 15 to 21 of gestation with a development toxicity NOAEL
of 40 mg/kg/day and a maternal toxicity of 40 mg/kg/day based on the
following: (i) four animals died on days 1 to 6 after delivery; (ii)
signs of maternal toxicity, in the form of decreased body weights and/
or clinical signs observed at the top dose level; (iii) at birth, body
weight was significantly reduced in the pups of the top dose group;
(iv) the brood care at the top dose group animals was generally
unsatisfactory and led to a high perinatal mortality of the fetuses
with only 30 viable fetuses left on day 1 post partum, the dead fetuses
showed no increased incidence of malformations; (v) the few surviving
pups of the dams at the 160 mg/kg/day dose group showed decreases in
fetal body weights and size was retarded, no disturbances were found in
the functional and behavioral tests that were conducted on the
surviving pups; (vi) at necropsy, all dams showed comparable number of
implantations and the animals scarified as scheduled revealed no
treatment-related changes and also the mean organ weights were similar
in treated and untreated groups; and (vii) litters from animals treated
at the lower doses remained entirely unaffected and no pathological
findings were also noted in these pups.
A series of two developmental study, Study A dose levels were 0,
2.4, 12, 36, and 60 mg/kg/day and, Study B dose levels were 0, 7.5, 15,
and 30 mg/kg/day were conducted via oral gavage in rabbits resulted in
dosages of 0, 2.4, 7.5, 12, 15, 30, 36, and 60 HDT mg/kg/day with a
development toxicity NOAEL of 15 mg/kg/day and a maternal toxicity of
15 mg/kg/day based on the following: (i) Severe clinical signs and/or
mortality were observed at dose levels > 30 mg/kg/day; (ii) decreased
body weight, food consumption, and absorption/premature delivery in the
36 and 60 mg/kg/day dose groups which survived to the end of the
studies; (iii) fetal effects consisted of high number of dead fetuses
and several gross malformations (pseudo ancylosis, syndactylia,
micromelia, aplasia of the twelveth rib) at the HDT; and (iv) pseudo
ancylosis was also seen in 1 fetus from the 12 mg/kg/day dose group and
in 6 fetuses in the 36 mg/kg/day dose level, but this finding is known
to occur spontaneously in rabbits of this strain used and the
contractures usually normalize during early stages of life. Due to the
severe effect at the high dose level (HDL), these effects may be
considered to represent a specific teratogenic effect of the treatment.
4. Chronic toxicity. Based on review of the available data, BASF
believes the Reference Dose (RfD) for fenpropimorph will be based on a
2-year feeding study in rats with a threshold NOAEL of 0.3 mg/kg/day.
Using an uncertainty factor of 100, the RfD is calculated to be 0.003
mg/kg/day. The following are summaries of the pertinent toxicity data
supporting fenpropimorph tolerances. Additionally, these are summaries
of EPA reviewed Phase III Toxicology Summaries prepared by BASF
Corporation for EPA.
A 1 year feeding study in dogs fed dosages of 0, 0.8, 3.2, or 12.7
mg/kg/day with a NOAEL of 3.2 mg/kg/day based on the following effects:
(i) no changes in body weights nor food consumption for both the high
dose male and female dogs were observed at all tested dose levels as
compared to controls; (ii) blood biochemistry values were slightly
increased in high dose males (alkaline phosphatase) and females
(alanine aminotransferase); (iii) the cholininesterase from plasma, red
blood cells, and brain showed comparable activities in treated and
untreated dogs; and (iv) neither organ weight analyses nor macro- and
histopathological examinations demonstrated any treatment related
effects as compared to controls.
A combined chronic feeding/oncogenicity study was performed in rats
being fed dosages of 0, 0.2, 0.3, 1.7 and 8.8 mg/kg/day (males) and 0,
0.2, 0.4, 2.1, and 11.2 mg/kg/day (females) with a NOAEL of 0.3 mg/kg/
day (males) and 0.4 mg/kg/day (females) based on the following effects:
(i) decreased in body weights were observed in both males and female
rat at dose levels > 1.7 mg/kg/day with a very slight progression of
severity to the upper level; (ii) decreased food consumption in female
rats at the HDT; (iii) significantly lower activities of plasma
cholinesterase were noted in male and female rats in the HDT where as
no effect was found for red blood cell cholinesterase values; (iv) at
terminal sacrifice, reduced activities of brain cholinesterase were
detected in males, only, at the 1.7 and 8.8 mg/kg/day dose levels
groups tested; (v) increased liver weights for females at dose levels >
2.1 mg/kg/day and in males of the top dose group; (vi) microscopic
findings were observed in the liver of male and female rats in the
HDLs, only; and (vii) no increased incidence of neoplasms occurred at
any dose levels tested in this study.
A carcinogenicity study in mice fed dosages of 0, 0.5, 3.0, 16, and
106 HDT mg/kg/day (males) and 0, 0.5, 3.5, 17, and 118 HDT mg/kg/day
(females) with a NOAEL of 3.0 and 3.5 mg/kg/day for male and female
mice, respectively, based on the following effects: (i) decreased body
weights and slight inferior food conversion ratio were observed in both
male and female mice at the HDT; (ii) decreased cholinesterase
activities were observed in red blood cells for female mice in the 17
and 118 mg/kg/day dose level tested at terminal sacrifice; (iii) at the
HDT increased liver weights were observed for female mice at terminal
sacrifice and in males at interim sacrifice after 52 weeks; and (iv) no
increased incidence of neoplasms occurred at any dose levels tested in
this study.
5. Endocrine disruption. No specific tests have been performed with
fenpropimorph to determine whether the chemical may have an effect in
humans that is similar to an effect produced by naturally occurring
estrogen or other endocrine effects. However, there are significant
findings in other relevant toxicity studies, i.e. teratology and multi-
generation reproductive studies, that would suggest fenpropimorph
produces endocrine related effects.
C. Aggregate Exposure
Based on the information above it is concluded that the RfD used to
assess safety to children should be 0.003 mg/kg/day dose level
established in the 2- year rat oral feeding study. Using the assumption
stated for the general population, BASF concluded that the most
sensitive child population group is that of children > 1 year. Using
the same RfD and the same conservative exposure assumptions employed in
the dietary risk analysis for the general population. It was calculated
that the exposure to this group to be approximately > 11% of the RfD
for all uses proposed in this document. Therefore, based on the
completeness and reliability of the
[[Page 67479]]
toxicity data, and the exposure assessment discussed above, BASF
concludes that there is a reasonable certainty that no harm will result
to infants and children from aggregate exposure to residues of
fenpropimorph, including all anticipated dietary exposure.
1. Dietary exposure. For the purpose of assessing the potential
chronic dietary exposure, BASF has estimated aggregate exposure based
on Theoretical Maximum Residue Contribution (TMRC) from the tolerance
of fenpropimorph on bananas at 0.3 ppm the maximum residue found in
bananas. The TMRC is a ``worse case'' estimate of dietary exposure
since it is assumed that 100% of all crops for which the tolerances are
established are treated and that pesticide residues are always found at
tolerance levels. Based on the expected RfD of 0.003 mg/kg/day (from
the NOAEL determined in the 2-year feeding study in rats and a 100 fold
safety factor) and the tolerance level residue chronic dietary exposure
of the general population is less than 2.5% of the RfD. Therefore,
based on the completeness and reliability of the toxicity data, and the
exposure assessment discussed above, BASF concludes that there is a
reasonable certainty that no harm will result from aggregate exposure
to residues of fenpropimorph, including all anticipated dietary
exposure.
2. Food. BASF has reviewed the available toxicology database to
determine the endpoints of concern. For Fenpropimorph BASF believes
there is no concern regarding an acute dietary risk since the available
data do not indicate any evidence of significant toxicity from a 1-day
or single, event exposure by the oral route.
3. Drinking water/Non-dietary exposure. There are no other
potential sources (such as in drinking water and exposure from non-
occupational sources) of exposure to fenpropimorph for the general
population to residues of fenpropimorph due to the fact the action
being requested is to establish an import tolerance, only.
4. Threshold and non-threshold effects. The proposed RfD for
fenpropimorph is based on a 2-year feeding study in rats with a
threshold NOAEL of 0.3 mg/kg/day. Using an uncertainty factor of 100,
the RfD is calculated to be 0.003 mg/kg/day. Fenpropimorph is
considered not to be a carcinogenic material. Therefore, it should be
regulated by the traditional RfD approach to quantify human risk.
D. Cumulative Effects
BASF has considered the potential for cumulative effects of
fenpropimorph and other substances that have a common mechanism of
toxicity. BASF is not aware of any other active ingredients which is
structurally similar to fenpropimorph that are registered on bananas.
Therefore, BASF has considered only the potential risks of
fenpropimorph in its exposure assessment.
E. Safety Determination
1. U.S. population. Using the exposure assumptions described above,
based on the completeness and there liability of the toxicity data,
BASF has estimated that aggregate exposure to fenpropimorph will
utilize > 2.5% of the RfD for the U.S. population. EPA generally has no
concern for exposure below 100% of the RfD. Therefore, based on the
completeness and reliability of the toxicity data, and the exposure
assessment discussed above, BASF concludes that there is a reasonable
certainty that no harm will result from aggregate exposure to residues
of fenpropimorph, including all anticipated dietary exposure.
2. Infants and children. The findings in the rat and rabbit are
most likely as a result of excessive maternal toxicity, treatment of
pregnant rats and rabbits with fenpropimorph induced embryotoxic
effects which manifested themselves in the form of early resorptions
and structural anomalies in the offspring. In both the rat and rabbit,
the dose-effect relationship was rather steep and showed clear
threshold levels. At dose levels below the threshold of maternal
toxicity, reproductive parameters as well as the offsprings remained
entirely unaffected. This data demonstrates that the rat and rabbit are
similarly sensitive to fenpropimorph. Additionally, the NOAEL of 0.3
mg/kg/day from the chronic rat study used to set the RfD is 33x to 50x
lower than the maternal NOAELs established in the rat and rabbit
teratology studies, respectively. The developmental effects observed in
either the rat or rabbit occurred only at maternally toxic doses.
Therefore, no additional safety factor is needed for children.
A 2-generation reproduction study with rats fed dosages of 0,
0.625, 1.25, and 2.5 mg/kg/day (average mg/kg/day dose levels for both
male and female rats) with a reproductive NOAEL of 2.5 mg/kg/day and
with a parental NOAEL of 2.5 mg/kg/day based on: (i) no treatment-
related clinical signs, significant body weight changes, parameters of
fertility and gestation, or macro-or histopathological changes were
observed for the parental F0 and F1 at all dose levels tested; and (ii)
in the F1 litters, a slight increased incidence of stillborn pups,
unfolding of the ear, and slight reduced body weight development during
lactation were observed in the 2.5 mg/kg/day doselevel group; (iii) in
the F2 litters, no treatment-related effects were observed at all dose
levels tested. As stated above, the NOAEL of 0.3 mg/kg/day from the
chronic rat study used to set the RfD is approximately 8x lower than
the maternal NOAEL established in the rat reproduction study.
Therefore, no additional safety factor is needed for children.
F. International Tolerances
A maximum residue level has not been established under Codex
Alimentarius Commission for fenpropimorph in any of the crops
petitioned: bananas.
2. Rohm and Haas Company
PP 1F3995, 1F3989 and 2F4154
EPA has received data intended to satisfy the conditions which
caused time-limits to be placed on the tolerances proposed by the three
pesticide petitions PP 1F3995, 1F3989, and 2F4154 from Rohm and Haas
Company, 100 Independence Mall West, Philadelphia, PA 19106-2399,
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 extending
until December 31, 2001 the time-limited tolerances for residues of
fenbuconazole (alpha-(2-(4-chlorophenyl)-ethyl)-alpha-phenyl-3-(1H-
1,2,4-triazole)-1-propanenitrile) in or on the raw agricultural
commodities bananas at 0.3 parts per million (ppm), banana pulp at 0.05
ppm, stone fruits (except plums and prunes) at 2.0 ppm, and pecans at
0.1 ppm. EPA has determined that the submissions concern the additional
data requirements as elements set forth in section 408(f)(1) of the
FFDCA; however, EPA has not fully evaluated the sufficiency of the
submitted data at this time.
A summary of the data that support the tolerances, and of exposure
to and risks from the use of fenbuconazole, is printed below. This
summary of the petitions was prepared by the registrant and represents
the views of the registrant. EPA is publishing the petition summary
with only minor editing changes. The petition summary includes an
announcement of the availability of the analytical methods available to
EPA for the detection and
[[Page 67480]]
measurement of the pesticide chemical residues.
A. Residue Chemistry
The tolerance expression for fenbuconazole residues in or on
bananas, banana pulp, pecans, and stone fruit (except plums and prunes)
is the combined residues of fenbuconazole (alpha-(2-(4-chlorophenyl)-
ethyl)-alpha-phenyl-3-(1H-1,2,4-triazole)-1-propanenitrile) and its
metabolites cis-5-(4-chlorophenyl)-dihydro-3-phenyl-3-(1H-1,2,4-
triazole-1-ylmethyl)-2-3H-furanone and trans-5-(4-chlorophenyl)-
dihydro-3-phenyl-3-(1H-1,2,4-triazole-1-ylmethyl)-2-3H-furanone.
Residues of these compounds are combined and expressed as parent
compound to determine the total residue in or on bananas, banana pulp,
pecans, and stone fruit (except plums and prunes). No changes in the
tolerances of fenbuconazole or in the tolerance expression (parent plus
lactone metabolites) for pecans, bananas, or stone fruit from that
indicated in 40 CFR 180.480 will be necessary for the tolerance
extensions. Current tolerances for fenbuconazole are 0.3 ppm for banana
whole fruit, 0.05 ppm for banana pulp, 0.1 ppm for pecans, and 2.0 ppm
for the stone fruit crop group (except plums and prunes). There is also
a current time-limited (Section 18) tolerance for fenbuconazole on
blueberries of 1.0 ppm.
1. Analytical method. Fenbuconazole residues (parent plus lactones)
are measured in pecans, stone fruit, and bananas at an analytical
sensitivity of 0.01 milligrams/kilogram (mg/kg) by soxhlet extraction
of samples in methanol, partitioning into methylene chloride,
redissolving in toluene, clean up on silica gel, and gas liquid
chromatography using nitrogen specific thermionic detection.
2. Magnitude of residues--i. Pecans. Four field trials were
conducted in pecans. Eight to ten applications were made at the maximum
use rate of 0.125 lb a.i./A, and nuts were harvested 28 days after the
last application. Field residue values in nutmeat for the four trials
were 0.004, 0.004, <0.01, and=""><0.01 ppm.="" ii.="" bananas.="" fourteen="" field="" trials="" were="" conducted="" on="" pulp="" from="" bagged="" bananas,="" and="" nine="" field="" trials="" were="" conducted="" on="" whole="" fruit="" from="" bagged="" bananas.="" bagged="" bananas="" are="" typically="" used="" in="" commerce.="" eight="" applications="" (5="" and="" 7="" applications="" in="" two="" trials)="" were="" made="" at="" the="" maximum="" use="" rate="" of="" 0.09="" lb="" a.i./a="" and="" bananas="" were="" harvested="" on="" the="" last="" day="" of="" application.="" the="" highest="" field="" residue="" values="" were="" 0.019="" ppm="" in="" pulp="" and="" 0.0589="" ppm="" in="" whole="" fruit.="" the="" average="" field="" residue="" values="" were="" 0.004="" ppm="" in="" pulp="" and="" 0.010="" ppm="" in="" whole="" fruit.="" iii.="" stone="" fruit--a.="" peaches.="" ten="" field="" trials="" were="" conducted="" on="" peaches.="" seven="" to="" ten="" applications="" were="" made="" at="" the="" maximum="" use="" rate="" of="" 0.1="" lb="" a.i./a="" and="" fruit="" were="" harvested="" on="" the="" last="" day="" of="" application.="" the="" highest="" field="" residue="" value="" was="" 0.5096="" ppm,="" and="" the="" average="" field="" residue="" value="" was="" 0.351="" ppm.="" b.="" cherries.="" eleven="" field="" trials="" were="" conducted="" on="" cherries.="" five="" to="" six="" applications="" were="" made="" at="" the="" maximum="" use="" rate="" of="" 0.1="" lb="" a.i./a="" and="" fruit="" were="" harvested="" on="" the="" last="" day="" of="" application.="" the="" highest="" field="" residue="" value="" was="" 0.641="" ppm,="" and="" the="" average="" field="" residue="" value="" was="" 0.434="" ppm.="" c.="" apricots.="" two="" field="" trials="" were="" conducted="" on="" apricots.="" six="" applications="" were="" made="" at="" the="" maximum="" use="" rate="" of="" 0.125="" lb="" a.i./a="" and="" fruit="" was="" harvested="" on="" the="" last="" day="" of="" application.="" the="" field="" residue="" values="" in="" four="" samples="" measured="" were="" 0.168,="" 0.226,="" 0.268,="" and="" 0.279="" ppm.="" b.="" toxicological="" profile="" the="" toxicology="" of="" fenbuconazole="" is="" summarized="" in="" the="" following="" sections.="" there="" is="" no="" evidence="" to="" suggest="" that="" human="" infants="" and="" children="" will="" be="" more="" sensitive="" than="" adults,="" that="" fenbuconazole="" will="" modulate="" human="" endocrine="" systems="" at="" anticipated="" dietary="" exposures,="" or="" cause="" cancer="" in="" humans="" at="" the="" dietary="" exposures="" anticipated="" for="" this="" fungicide.="" while="" the="" biochemical="" target="" for="" the="" fungicidal="" activity="" of="" members="" of="" the="" dmi="" class="" is="" shared,="" it="" cannot="" be="" concluded="" that="" the="" mode="" of="" action="" of="" fenbuconazole="" which="" produces="" phytotoxic="" effects="" in="" plants="" or="" toxic="" effects="" in="" animals="" is="" also="" common="" to="" a="" single="" class="" of="" chemicals.="" 1.="" acute="" toxicity.="" fenbuconazole="" is="" practically="" nontoxic="" after="" administration="" by="" the="" oral,="" dermal="" andrespiratory="" routes.="" the="" acute="" oral="">50 in mice and rats is >2,000 mg/kg. The acute dermal
LD50 in rats is >5,000 mg/kg. Fenbuconazole was not
significantly toxic to rats after a 4 hour inhalation exposure, with an
LD50 value of > 2.1 mg/L. Fenbuconazole is classified as not
irritating to skin (Draize score = 0), in consequentially irritating to
the eyes (mean irritation score= 0), and it is not a sensitizer. No
evidence exists regarding differential sensitivity of children and
adults to acute exposure.
2. Genotoxicity. Fenbuconazole has been adequately tested in a
variety of in vitro and in vivo mutagenicity tests. It is negative in
the Ames test, negative in in vitro and in vivo somatic and germcell
tests, and did not induce unscheduled in DNA synthesis (UDS).
Fenbuconazole is not genotoxic.
3. Reproductive and developmental toxicity. These conclusions were
extracted from 60 FR 27419, May 24, 1995. Fenbuconazole is not
teratogenic. The maternal no observed adverse effect level (NOAEL) in
rabbits was 10 mg/kg/day and 30 mg/kg/day in rats. The fetal NOAEL was
30 mg/kg/day in both species. The parental NOAEL was 4.0 mg/kg/day (80
ppm) in a 2-generation reproduction study in rats. The reproductive
NOAEL in this study was greater than 40.0 mg/kg/day (800 ppm; highest
dose tested (HDT)). Fenbuconazole had no effect on male reproductive
organs or reproductive performance at any dose. The adult lowest
observed adverse effect level (LOAEL) was 40.0 mg/kg/day (800 ppm;
HDT). Systemic effects of decreased body weight gain; maternal deaths;
and hepatocellular, adrenal, and thyroid follicular cell hypertrophy
were observed. No effects on neonatal survival or growth occurred below
the adult toxic levels. Fenbuconazole does not produce birth defects
and is not toxic to the developing fetus at doses below those which are
toxic to the mother.
4. Subchronic toxicity. In a 21 day dermal toxicity study in the
rat, the NOAEL was greater than 1,000 mg/kg/day, with no effects seen
at this limit dose.
5. Chronic toxicity. In 2 year combined chronic toxicity/
oncogenicity studies in rats, the NOAEL was 80 ppm (3.03 mg/kg/day for
males and 4.02 mg/kg/day for females) based on decreased body weight,
and liver and thyroid hypertrophy. In a 1 year chronic toxicity study
in dogs, the NOAEL was 150 ppm (3.75 mg/kg/day) based on decreased body
weight, and increased liver weight. The LOAEL was 1,200 ppm (30 mg/kg/
day). In a 78 week oncogenicity study in mice, the NOAEL was 10 ppm
(1.43 mg/kg/day). The LOAEL was 200 ppm (26.3 mg/kg/day, males) and 650
ppm (104.6mg/kg/day, females) based on increased liver weights and
histopathological effects on the liver. These effects were consistent
with chronic enzyme induction from high dose dietary exposure.
A Reference Dose (RfD) for systemic effects at 0.03 mg/kg/day was
established by EPA in 1995 based on the NOAEL of 3.0 mg/kg/day from the
rat chronic study. This RfD adequately protects both adults and
children.
Twenty-four month rat chronic feeding/carcinogenicity studies with
fenbuconazole showed effects at 800 and 1,600 ppm. Fenbuconazole
produced a minimal, but statistically
[[Page 67481]]
significant increase in the incidence of combined thyroid follicular
cell benign and malignant tumors. These findings occurred only in male
rats following life-time ingestion of very high levels (800 and 1,600
ppm in the diet) fenbuconazole. Ancillary mode-of-action studies
demonstrated that the increased incidence of thyroid tumors was
secondary to increased liver metabolism and biliary excretion of
thyroid hormone in the rat. This mode of action is a nonlinear
phenomenon in that thyroid tumors occur only at high doses where there
is an increase in liver mass and metabolic capacity of the liver. At
lower doses of fenbuconazole in rats, the liver is unaffected and there
is no occurrence of the secondary thyroid tumors. Worst-case estimates
of dietary intake of fenbuconazole in human adults and children
indicate effects on the liver or thyroid, including thyroid tumors,
will not occur, and there is a reasonable certainty of no harm.
In support of the findings above, EPA's Science Advisory Board has
approved a final thyroid tumor policy, confirming that it is reasonable
to regulate chemicals on the basis that there exists a threshold level
for thyroid tumor formation, conditional upon providing plausible
evidence that a secondary mode of action is operative. This decision
supports a widely-held and internationally respected scientific
position.
In a 78 week oncogenicity study in mice there was no statistically
significant increase of any tumor type in males. There were no liver
tumors in the control females and liver tumor incidences in treated
females just exceeded the historical control range. However, there was
a statistically significant increase in combined liver adenomas and
carcinomas in females at the high dose only (1,300 ppm; 208.8 mg/kg/
day). In ancillary mode-of-action studies in female mice, the increased
tumor incidence was associated with changes in several parameters in
mouse liver following high doses of fenbuconazole including: an
increase in P450 enzymes (predominately of the CYP 2B type), an
increase in cell proliferation, an increase in hepatocyte hypertrophy,
and an increase in liver mass (or weight). Changes in these liver
parameters as well as the occurrence of the low incidence of liver
tumors were nonlinear with respect to dose (i.e., were observed only at
high dietary doses of fenbuconazole). Similar findings have been shown
with several pharmaceuticals, including phenobarbital, which is not
carcinogenic in man. The nonlinear relationship observed with respect
to liver changes (including the low incidence of tumors) and dose in
the mouse indicates that these findings should be carefully considered
in deciding the relevance of high-dose animal tumors to human dietary
exposure.
The Carcinogenicity Peer Review Committee (PRC) of the Health
Effects Division (HED) classified fenbuconazole as a Group C tumorigen
(possible human carcinogen with limited evidence of carcinogenicity in
animals). The PRC used a low-dose extrapolation model. The
Q1* risk factor applied (1.06 x 10-2 (mg/kg/
day)-1) was based on the rat oncogenicity study and surface
area was estimated by (body weight)3/4.
Since the PRC published the above estimate they have agreed that
low-dose extrapolation for fenbuconazole, based on rat thyroid tumors,
is inappropriate given the EPA's policy regarding thyroid tumors and
the data which exist for fenbuconazole. The PRC agrees that the more
appropriate data set for the low-dose extrapolation and risk factor
estimate is the mouse. From these data a Q1* of (0.36 x
10-2(mg/kg/day)-1) is calculated when surface
area is estimated by (bodyweight)3/4. All estimates of
dietary oncogenic risk are based on this risk factor.
Since fenbuconazole will not leach into groundwater (see below)
there is no increased cancer risk from this source. Neither is
fenbuconazole registered for residential use, so there is no risk from
non-occupational residential exposure either. All estimates of excess
risk to cancer are from dietary sources.
6. Endocrine disruption. The mammalian endocrine system includes
estrogen and androgens as well as several other hormone systems.
Fenbuconazole does not interfere with the reproductive hormones. Thus,
fenbuconazole is not estrogenic or androgenic.
While fenbuconazole interferes with thyroid hormones in rats by
increasing thyroid hormone excretion, it does so only secondarily and
only above those dietary levels which induce metabolism in the liver.
These effects are reversible in rats, and humans are far less sensitive
to these effects than rats. The RfD protects against liver induction
because it is substantially below the animal NOAEL. As noted
previously, maximal human exposures are far below the RfD level, and
effects on human thyroid will not occur at anticipated dietary levels.
We know of no instances of proven or alleged adverse reproductive
or developmental effects to domestic animals or wildlife as a result of
exposure to fenbuconazole or its residues. In fact, no effects should
be seen because fenbuconazole has low octanol/water partition
coefficients and is known not to bioaccumulate. Fenbuconazole is
excreted within 48 hours after dosing in mammalian studies.
C. Aggregate Exposure and Risk
1. Dietary exposure--Chronic exposure and risk. Risk associated
with chronic dietary exposure from fenbuconazole was assessed on two
level using two dietary exposure models. In the first assessment,
tolerance level residues were assumed and in the second assessment
average field trial residues were used. Both assessments assumed 100%
of crop treated, except for stone fruit in which 12.8% of crop treated
was assumed 63 FR 31636, June 10, 1998, (FRL 5791-9). Residues in pulp
from bagged bananas were used in the assessments, since only bagged
bananas are used in commerce. The Anticipated Residue Contribution
(ARC) from all existing food uses of fenbuconazole was assessed; these
foods included stone fruit (except plums, and prunes), bananas, pecans,
and blueberries).
The RfD used for the chronic dietary analysis is 0.03 mg/kg/day.
Potential chronic exposures were estimated using NOVIGEN's Dietary
Exposure Evaluation Model (DEEM Version 5.31), which uses USDA food
consumption data from the 1989-1992 survey, and the EPA's Dietary Risk
Evaluation System (DRES), which uses USDA food consumption data from
1977-1978. The existing fenbuconazole tolerances and average
fenbuconazole residues result in ARCs that are equivalent to the
following percentages of the RfD.:
----------------------------------------------------------------------------------------------------------------
Population Subgroup DEEM\1\ %RfD DEEM\2\ %RfD DRES\1\ %RfD DRES\2\ %RfD
----------------------------------------------------------------------------------------------------------------
U. S. Population (48 States).... 0.2% <0.01% 0.31%="" 0.06%="" nursing="" infants=""><1 year="" old)...="" 0.4%="" 0.1%="" 1.47%="" 0.27%="" non-nursing="" infants=""><1year old)="" 1.3%="" 0.2%="" 2.46%="" 0.45%="" [[page="" 67482]]="" children="" (1-6="" years="" old)........="" 0.5%="" 0.1%="" 0.74%="" 0.14%="" children="" (7-12="" years="" old).......="" 0.3%=""><0.01% 0.44%="" 0.08%="" females="" (13+/nursing)...........="" 0.3%=""><0.01% 0.28%="" 0.05%="" ----------------------------------------------------------------------------------------------------------------="" \1\="" assumes="" residues="" are="" present="" at="" tolerance="" levels="" and="" 100%="" of="" crop="" treated="" except="" stone="" fruit="" (12.8%="" of="" crop="" treated).="" \2\="" assumes="" residues="" are="" present="" at="" their="" average="" field="" residue="" levels="" and="" 100%="" of="" crop="" treated="" except="" stone="" fruit="" (12.8%="" of="" crop="" treated).="" d.="" aggregate="" cancer="" risk="" for="" u.s.="" population="" fenbuconazole="" has="" been="" classified="" as="" a="" group="" c="" carcinogen="" with="" a="">* value of 0.00359 mg/kg/day-1. Assuming
fenbuconazole residues are present at tolerance levels and assuming
100% crop treated, except stone fruit (12.8% of crop treated assumed),
give a cancer risk assessment for existing food uses for the U.S.
population of 3.31 x 10-7 for the DRES and DEEM analyses,
respectively. Assuming fenbuconazole residues are present at average
field residue levels and assuming 100% of crop treated, except stone
fruit (12.8% of crop treated assumed), gives a cancer risk assessment
for existing food uses for the U.S. population of 6.34 x
10-8 and 4.94 x 10-8 for the DRES and DEEM
analyses, respectively.
The individual crop cancer risk assessments for bananas, stone
fruit, pecans, and blueberries were 4.11 x 10-8, 2.78 x
10-7, 1.73 x 10-9, and 9.74 x 10-9,
respectively (DRES analysis), and were 5.11 x 10-8, 1.67 x
10-7, 7.37 x 10-10, and 1.38 x 10-8,
respectively (DEEM analysis).
1. Drinking water. Fenbuconazole has minimal tendency to
contaminate groundwater or drinking water because of its adsorptive
properties on soil, solubility in water, and degradation rate. Data
from laboratory studies and field dissipation studies have been used in
the USDA PRZM/GLEAMS computer model to predict the movement of
fenbuconazole. The model predicts that fenbuconazole will not leach
into groundwater, even if heavy rainfall is simulated. The modeling
predictions are consistent with the data from environmental studies in
the laboratory and the results of actual field dissipation studies.
There are no data on passage of fenbuconazole through water treatment
facilities and there are no State water monitoring programs which
target fenbuconazole.
2. Non-dietary exposure. Fenbuconazole has no veterinary
applications and is not approved for use in swimming pools. It is not
labeled for application to residential lawns or for use on ornamentals,
nor is fenbuconazole applied to golf courses or other recreational
areas. Therefore, there are no data to suggest that these exposures
could occur. Any acute exposures to children would come from dietary
exposure or inadvertent dermal contact . As previously discussed,
fenbuconazole is neither orally or dermally acutely toxic. Thus, there
is a reasonable certainty that no exposure would occur to adults,
infants or children from these sources.
E. Cumulative Effects
The toxicological effects of fenbuconazole are related to its
effects on rodent liver. These are manifested in rats and mice
differently. Fenbuconazole causes liver toxicity in rats and mice in
the form of hepatocyte enlargement and enzyme induction. In rats the
liver enzyme induction causes increased biliary removal of thyroxin and
the hepatotoxicity leads to elevated thyroid stimulating hormone levels
with subsequent development of thyroid gland hyperplasia and tumors.
This process is reversible and demonstrates a dose level below which no
thyroid gland stimulation can be demonstrated in rats. Liver toxicity
in the mouse is manifest by hepatocyte enlargement, enzyme induction,
and hepatocellular hyperplasia (cell proliferation). These processes
are associated with the appearance of a small number of liver tumors.
In both cases, rats and mice, the initiating event(s) do not occur
below a given dose, i.e., the effects are nonlinear, and the processes
are reversible. Therefore, since the tumors do not occur at doses below
which hepatocyte enlargement and enzyme induction occur, the RfD
protects against tumors because it is substantially below the NOAEL for
liver effects and maximal human exposures are below the RfD. Effects on
human thyroid will not occur at anticipated dietary levels. The mode of
action data should be carefully considered in deciding the relevance of
these high-dose animal tumors to human dietary exposure.
Extensive data are available on the biochemical mode of action by
which fenbuconazole produces animal tumors in both rats and mice.
However, there are no data which suggest that the mode of action by
which fenbuconazole produces these animal tumors or any other
toxicological effect is common to all fungicides of this class. In
fact, the closest structural analog to fenbuconazole among registered
fungicides of this class is not tumorigenic in animals even at
maximally tolerated doses and has a different spectrum of toxicological
effects.
F. Safety Determination.
1. All crops (current food uses). The exposure to fenbuconazole
from all current food uses will utilize 1.3% (non-nursing infants < 1="" year="" old)="" and="" 0.4%="" (nursing="" infants="">< 1="" year="" old)="" of="" the="" rfd="" (deem="" analysis),="" and="" will="" utilize="" 2.46%="" (non-nursing="" infants="">< 1="" year="" old)="" and="" 1.47%="" (nursing="" infants="">< 1="" year="" old)="" of="" the="" rfd="" (dres="" analysis),="" assuming="" residues="" are="" present="" at="" tolerance="" levels="" and="" assuming="" 100%="" of="" crop="" treated,="" except="" stone="" fruit="" (12.8%="" of="" crop="" treated="" assumed).="" the="" percent="" of="" the="" rfd="" that="" will="" be="" utilized="" by="" children="" 1-6="" years="" old="" and="" 7-12="" years="" old="" is="" 0.5="" and="" 0.3%,="" respectively="" (deem="" analysis),="" and="" 0.74="" and="" 0.44%,="" respectively="" (dres="" analysis),="" assuming="" residues="" are="" present="" at="" tolerance="" levels="" and="" assuming="" 100%="" crop="" treated,="" except="" stone="" fruit.="" 2.="" stone="" fruit="" (except="" plums="" and="" prunes).="" the="" exposure="" to="" fenbuconazole="" from="" stone="" fruit="" (excluding="" plums="" and="" prunes)="" will="" utilize="" 1.1%="" of="" the="" rfd="" for="" non-nursing="" infants="">< 1="" year="" old,="" 0.3%="" of="" the="" rfd="" for="" nursing="" infants="">< 1="" year="" old,="" 0.4%="" of="" the="" rfd="" for="" children="" 1-6="" years="" old,="" and="" 0.2%="" of="" the="" rfd="" for="" children="" 7-12="" years="" old="" (deem="" analysis)="" assuming="" residues="" are="" present="" at="" tolerance="" levels="" and="" assuming="" 100%="" of="" crop="" treated,="" except="" stone="" fruit="" (12.8%="" of="" crop="" treated="" assumed).="" 3.="" bananas.="" the="" exposure="" to="" fenbuconazole="" from="" bananas="" will="" utilize="" 0.2%="" of="" the="" rfd="" for="" non-nursing="" infants="">< 1="" year="" old,="" 0.1%="" of="" the="" rfd="" for="" nursing="" infants="">< 1="" year="" old,="" 0.1%="" of="" the="" rfd="" for="" children="" 1-6="" years="" old,="" and="" 0.1%="" of="" the="" rfd="" for="" children="" 7-12="" years="" old="" (deem="" analysis)="" assuming="" residues="" are="" present="" at="" tolerance="" levels="" and="" assuming="" 100%="" of="" crop="" treated,="" except="" stone="" fruit="" (12.8%="" of="" crop="" treated="" assumed).="" 4.="" pecans.="" the="" exposure="" to="" fenbuconazole="" from="" pecans="" will="" utilize="" [[page="" 67483]]=""><0.01% of="" the="" rfd="" for="" each="" of="" the="" population="" subgroups:="" non-nursing="" infants="">< 1="" year="" old,="" nursing="" infants="">< 1="" year="" old,="" children="" 1-6="" years="" old,="" and="" children="" 7-12="" years="" old="" (deem="" analysis)="" assuming="" residues="" are="" present="" at="" tolerance="" levels="" and="" assuming="" 100%="" of="" crop="" treated,="" except="" stone="" fruit="" (12.8%="" of="" crop="" treated="" assumed).="" 5.="" blueberries.="" the="" exposure="" to="" fenbuconazole="" from="" blueberries,="" will="" utilize="">< 0.01%="" of="" the="" rfd="" for="" each="" of="" the="" population="" subgroups,="" non-nursing="" infants="">< 1="" year="" old,="" nursing="" infants="">< 1="" year="" old,="" children="" 1-6="" years="" old,="" and="" children="" 7-12="" years="" old="" (deem="" analysis)="" assuming="" residues="" are="" present="" at="" tolerance="" levels="" and="" assuming="" 100%="" of="" crop="" treated,="" except="" stone="" fruit="" (12.8%="" of="" crop="" treated="" assumed).="" section="" 408="" of="" the="" ffdca="" provides="" that="" epa="" shall="" apply="" an="" additional="" tenfold="" margin="" of="" safety="" for="" infants="" and="" children="" in="" the="" case="" of="" threshold="" effects="" to="" account="" for="" pre-="" and="" post-natal="" toxicity="" and="" the="" completeness="" of="" the="" database="" unless="" epa="" determines="" that="" a="" different="" margin="" of="" safety="" will="" be="" safe="" for="" infants="" and="" children.="" margins="" of="" safety="" are="" incorporated="" into="" epa="" risk="" assessments="" either="" directly="" through="" use="" of="" a="" margin="" of="" exposure="" (moe)="" analysis="" or="" through="" using="" uncertainty="" (safety)="" factors="" in="" calculating="" a="" dose="" level="" that="" poses="" no="" appreciable="" risk="" to="" humans.="" in="" either="" case,="" epa="" generally="" defines="" the="" level="" of="" appreciable="" risk="" as="" exposure="" that="" is="" greater="" than="" 1/100="" of="" the="" noael="" in="" the="" animal="" study="" appropriate="" to="" the="" particular="" risk="" assessment.="" this="" hundredfold="" uncertainty="" (safety)="" factor/moe="" exposure="" (safety)="" is="" designed="" to="" account="" for="" combined="" inter-="" and="" intra-="" species="" variability.="" epa="" believes="" that="" reliable="" data="" support="" using="" the="" standard="" hundredfold="" margin/factor="" but="" not="" the="" additional="" tenfold="" margin/factor="" when="" epa="" has="" a="" complete="" data="" base="" under="" existing="" guidelines="" and="" when="" the="" severity="" of="" the="" effect="" in="" infants="" or="" children="" or="" the="" potency="" or="" unusual="" toxic="" properties="" of="" a="" compound="" do="" not="" raise="" concerns="" regarding="" the="" adequacy="" of="" the="" standard="" margin/factor.="" the="" agency="" fqpa="" safety="" factor="" committee="" removed="" the="" additional="" 10x="" safety="" factor="" to="" account="" for="" sensitivity="" of="" infants="" and="" children.="" rohm="" and="" haas="" company="" concludes="" that="" there="" is="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" from="" exposure="" to="" fenbuconazole="" residues="" to="" the="" u.s.="" population="" or="" to="" infants="" and="" children.="" g.="" international="" tolerances="" there="" are="" no="" codex="" maximum="" residue="" limits="" (mrls)="" for="" fenbuconazole,="" but="" the="" fenbuconazole="" database="" was="" evaluated="" by="" the="" who="" and="" fao="" expert="" panels="" at="" the="" joint="" meeting="" on="" pesticide="" residues="" (jmpr)="" in="" september,="" 1997.="" an="" adi="" (rfd)="" of="" 0.03="" mg/kg/day="" was="" proposed="" and="" accepted="" (pesticide="" residues="" in="" food--who/fao="" report="" 1997;="" no.="" 145),="" and="" a="" total="" of="" 36="" codex="" mrls,="" including="" mrls="" for="" pecans,="" stone="" fruit,="" and="" bananas,="" have="" been="" submitted="" for="" review.="" [fr="" doc.="" 98-32426="" filed="" 12-4-98;="" 8:45="" am]="" billing="" code="" 6560-50-f="">