[Federal Register Volume 63, Number 20 (Friday, January 30, 1998)]
[Notices]
[Pages 4631-4640]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-2363]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-788; FRL-5766-2]
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-788, must
be received on or before March 2, 1998.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch (7502C), Information Resources and Services
Division, Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 119, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically to: docket@epamail.epa.gov. Follow 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: The product manager listed in the
table below:
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Office location/
Product Manager telephone number Address
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Joanne Miller (PM 23)......... Rm. 237, CM #2, 703- 1921 Jefferson
305-6224, e-mail: Davis Hwy,
[email protected] Arlington, VA
l.epa.gov.
Cynthia Giles-Parker (PM 22).. Rm. 229, 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-788] (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:
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 5.1/6.1 or ASCII file
format. All comments and data in electronic form must be identified by
[[Page 4632]]
the docket control number [PF-788] 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: January 22, 1998.
James Jones,
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. FMC Corporation
PP 7F4795
EPA has received a pesticide petition (PP 7F4795) from FMC
Corporation, 1735 Market Street, Philadelphia, PA 19103, 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 carfentrazone-ethyl in or on the raw agricultural
commodities (RAC) cereal grain at 0.1 parts per million (ppm), 0.3 ppm
in or on hay; 0.2 ppm in or on straw; 1.0 ppm in or on forage; 0.15 ppm
in or on stover and 0.1 ppm in or on sweet corn, K + CWHR (kernels plus
cob with husk removed) and in or on the RACs soybeans and soybean seed
at 0.1 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. Plant metabolism. The metabolism of carfentrazone-ethyl in
plants is adequately understood. Corn, wheat, and soybean metabolism
studies with carfentrazone-ethyl have shown uptake of material into
plant tissue with no significant movement into grain or seeds. All
three plants extensively metabolized carfentrazone-ethyl and exhibited
a similar metabolic pathway. The residues of concern are the combined
residues of carfentrazone-ethyl and carfentrazone-ethyl-chloropropionic
acid.
2. Analytical method. There is a practical analytical method for
detecting and measuring levels of carfentrazone and its metabolites in
or on food with a limit of quantitation (LOQ) that allows monitoring of
food with residues at or above the levels set in the tolerances. The
analytical method for carfentrazone-ethyl involves separate analyses
for parent and its metabolites. The parent is analyzed by GC/ECD. The
metabolites are derivatized with boron trifluoride and acetic anhydride
for analysis by GC/MSD using selective ion monitoring.
3. Magnitude of residues. Carfentrazone-ethyl 50DF was applied
postemergent to 28 wheat trials, 24 corn trials, and 22 soybean trials
in the appropriate EPA regions. The RACs were harvested at the
appropriate growth stages and subsequent analyses determined that the
residues of carfentrazone-ethyl and its metabolites will not exceed the
proposed tolerances of 1.0, 0.3, 0.2, and 0.1 ppm for wheat forage,
hay, straw, and grain, respectively; 0.1 ppm each for corn forage,
fodder, and grain; and 0.1 ppm for soybean seed. Residue data from a
cow feeding study demonstrated that no accumulation of carfentrazone-
ethyl or its metabolites occurred in milk or tissues.
B. Toxicological Profile
1. Acute toxicity. Carfentrazone-ethyl demonstrates low oral,
dermal and inhalation toxicity. The acute oral LD50 value in
the rat was greater than 5,000 milligram/kilograms (mg/kg), the acute
dermal LD50 value in the rat was greater than 4,000 mg/kg
and the acute inhalation LC50 value in the rat was greater
than 5.09 mg/L/4h. Carfentrazone-ethyl is non-irritating to rabbit skin
and minimally irritating to rabbit eyes. It did not cause skin
sensitization in guinea pigs. An acute neurotoxicity study in the rat
had a systemic No observed adverse effect level (NOAEL) of 500 mg/kg
based on clinical signs and decreased motor activity levels; the NOAEL
for neurotoxicity was greater than 2,000 mg/kg (highest dose tested);
(HDT) based on the lack of neurotoxic clinical signs or effects on
neuropathology.
2. Genotoxicity. Carfentrazone-ethyl did not cause mutations in the
Ames assay with or without metabolic activation. There was a positive
response in the Chromosome Aberration assay without activation but a
negative response with activation. The Mouse Micronucleus assay (an in
vivo test which also measures chromosome damage), the CHO/HGPRT forward
mutation assay and the Unscheduled DNA Synthesis assay were negative.
The overwhelming weight of the evidence supports the conclusion that
Carfentrazone-ethyl is not genotoxic.
3. Reproductive and developmental toxicity. Carfentrazone-ethyl is
not considered to be a reproductive or a developmental toxin. In the 2-
generation reproduction study, the No observed effect level (NOEL) for
reproductive toxicity was greater than 4,000 ppm (greater than 323 to
greater than 409 mg/kg/day). In the developmental toxicity studies, the
rat and rabbit maternal NOELs were 100 mg/kg/day and 150 mg/kg/day,
respectively. The developmental NOEL for the rabbit was greater than
300 mg/kg/day which was the highest dose tested and for the rat the
NOEL was 600 mg/kg/day based on increased litter incidences of
thickened and wavy ribs at 1,250 mg/kg/day. These two findings
(thickened and wavy ribs) are not considered adverse effects of
treatment but related delays in rib development which are generally
believed to be reversible.
4. Subchronic toxicity. Ninety-day feeding studies were conducted
in mice, rats and dogs with Carfentrazone-ethyl. The NOEL for the mouse
study was 4,000 ppm (571 mg/kg/day), for the rat study was 1,000 ppm
(57.9 mg/kg/day for males; 72.4 mg/kg/day for females) and for dogs was
150 mg/kg/day. A 90-day subchronic neurotoxicity study in the rat had a
systemic NOEL of 1,000 ppm (59.0 mg/kg/day for males; 70.7 mg/kg/day
for females) based on decreases in body weights, body weight gains and
food consumption at 10,000 ppm; the neurotoxicity NOEL was greater than
20,000 ppm (1,178.3 mg/kg/day for males; 1,433.5 mg/kg/day for females)
which was the highest dose tested.
5. Chronic toxicity. Carfentrazone-ethyl is not carcinogenic to
rats or mice. A 2-Year Combined Chronic Toxicity/Oncogenicity study in
the rat was negative for carcinogenicity and had a chronic toxicity
NOEL of 200 ppm (9 mg/kg/day) for males and 50 ppm (3 mg/kg/day) for
females based on red fluorescent granules consistent with porphyrin
deposits in the liver at the 500 and 200 ppm levels, respectively.
[[Page 4633]]
An 18 Month Oncogenicity study in the mouse had a carcinogenic NOEL
that was greater than 7,000 ppm (>1,090 mg/kg/day for males; >1,296 mg/
kg/day for females) based on no evidence of carcinogenicity at the
highest dose tested. A 1-Year Oral Toxicity study in the dog had a NOEL
of 50 mg/kg/day based on isolated increases in urine porphyrins in the
150 mg/kg/day group (this finding was not considered adverse).
Using the Guidelines for Carcinogen Risk Assessment, carfentrazone-
ethyl should be classified as Group ``E'' for carcinogenicity -- no
evidence of carcinogenicity -- based on the results of carcinogenicity
studies in two species. There was no evidence of carcinogenicity in an
18-month feeding study in mice and a 2-year feeding study in rats at
the dosage levels tested. The doses tested are adequate for identifying
a cancer risk. Thus, a cancer risk assessment is not necessary.
6. Animal metabolism. The metabolism of carfentrazone-ethyl in
animals is adequately understood. Carfentrazone-ethyl was extensively
metabolized and readily eliminated following oral administration to
rats, goats, and poultry via excreta. All three animals exhibited a
similar metabolic pathway. As in plants, the parent chemical was
metabolized by hydrolytic mechanisms to predominantly form
carfentrazone-ethyl-chloropropionic acid which was readily excreted.
7. Endocrine disruption. An evaluation of the potential effects on
the endocrine systems of mammals has not been determined; however, no
evidence of such effects were reported in the chronic or reproductive
toxicology studies described above. There was no observed pathology of
the endocrine organs in these studies. There is no evidence at this
time that carfentrazone-ethyl causes endocrine effects.
C. Aggregate Exposure
1. Dietary exposure-- i. Acute dietary. The Agency has determine
that there is no concern for an acute dietary risk assessment since the
available data do not indicate any evidence of significant toxicity
from a 1-day or single event exposure by the oral route (Federal
Register: September 30, 1997, 62 FR 51032-51038). Thus an acute dietary
risk assessment is not necessary.
ii. Chronic dietary. Based on the available toxicity data, the EPA
has established a provisional Reference Dose (RfD) for carfentrazone-
ethyl of 0.06 mg/kg/day. The RfD for carfentrazone-ethyl is based on a
90-day feeding study in rats with a threshold NOEL of 57.9 mg/kg/day
and an uncertainty factor of 100, with an additional modifying factor
of 10 to account for the fact that the chronic studies have not yet
been reviewed by the EPA. For purposes of assessing the potential
chronic dietary exposure, a Tier 1 dietary risk assessment was
conducted based on the Theoretical Maximum Residue Contribution (TMRC)
from the proposed tolerances for carfentrazone-ethyl on soybeans at 0.1
ppm, wheat at 0.2 ppm and corn (field) at 0.15 ppm. (The TMRC is a
``worse case'' estimate of dietary exposure since it is assumed that
100% of all crops for which tolerances are established are treated and
that pesticide residues are present at the tolerance levels.) At this
time the dietary exposure to residues of carfentrazone-ethyl in or on
food will be limited to residues on soybeans, wheat and corn. There are
no other established U.S. tolerances for carfentrazone-ethyl, and there
are no registered uses for carfentrazone-ethyl on food or feed crops in
the U.S. In conducting this exposure assessment, the following very
conservative assumptions were made--100% of soybeans, wheat and corn
will contain carfentrazone-ethyl residues and those residues would be
at the level of the tolerance which result in an overestimate of human
exposure.
2. Food. Dietary exposure from the proposed uses would account for
1.3% or less of the RfD in subpopulations (including infants and
children).
3. Drinking water. Studies have indicated that carfentrazone-ethyl
will not move into groundwater, therefore water has not been included
in the dietary risk assessment.
4. Non-dietary exposure. No specific worker exposure tests have
been conducted with carfentrazone-ethyl. The potential for non-
occupational exposure to the general population has not been fully
assessed. No specific worker exposure tests have been conducted with
carfentrazone-ethyl.
D. Cumulative Effects
EPA is also required to consider the potential for cumulative
effects of carfentrazone-ethyl and other substances that have a common
mechanism of toxicity. EPA consideration of a common mechanism of
toxicity is not appropriate at this time since EPA does not have
information to indicate that toxic effects produced by carfentrazone-
ethyl would be cumulative with those of any other chemical compounds;
thus only the potential risks of carfentrazone-ethyl are considered in
this exposure assessment.
E. Safety Determination
1. U.S. population. Using the conservative exposure assumptions
described and based on the completeness and reliability of the toxicity
data, the aggregate exposure to carfentrazone-ethyl will utilize 0.61%
of the RfD for the U.S. population. EPA generally has no concern for
exposures below 100% of the RfD. Therefore, based on the completeness
and reliability of the toxicity data and the conservative exposure
assessment, there is a reasonable certainty that no harm will result
from aggregate exposure to residues of carfentrazone-ethyl, including
all anticipated dietary exposure and all other non-occupational
exposures.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of carfentrazone-ethyl,
EPA considers data from developmental toxicity studies in the rat and
rabbit and the 2-generation reproduction study in the rat. The
developmental toxicity studies are designed to evaluate adverse effects
on the developing organism resulting from pesticide exposure during
prenatal development. Reproduction studies provide information relating
to effects on the reproductive capacity of males and females exposed to
the pesticide. Developmental toxicity was not observed in developmental
toxicity studies using rats and rabbits. In these studies, the rat and
rabbit maternal NOELs were 100 mg/kg/day and 150 mg/kg/day,
respectively. The developmental NOEL for the rabbit was greater than
300 mg/kg/day which was the highest dose tested and for the rat was 600
mg/kg/day based on increased litter incidences of thickened and wavy
ribs. These two findings are not considered adverse effects of
treatment but related delays in rib development which are generally
believed to be reversible.
In a 2-generation reproduction study in rats, no reproductive
toxicity was observed under the conditions of the study at 4,000 ppm
which was the highest dose tested.
FFDCA section 408 provides that EPA may apply an additional safety
factor for infants and children in the case of threshold effects to
account for pre- and post-natal toxicity and the completeness of the
database. Based on the current toxicological data requirements, the
database relative to pre- and post-natal effects for children is
complete and an additional uncertainty factor is not warranted.
Therefore at this time, the provisional RfD of 0.06 mg/kg/day is
[[Page 4634]]
appropriate for assessing aggregate risk to infants and children.
3. Reference dose (RfD). Using the conservative exposure
assumptions described above, the percent of the RfD that will be
utilized by aggregate exposure to residues of carfentrazone-ethyl for
non-nursing infants (<1 year="" old)="" would="" be="" 0.28%="" and="" for="" children="" 1-6="" years="" of="" age="" would="" be="" 1.37%="" (the="" most="" highly="" exposed.="" f.="" international="" tolerances="" there="" are="" no="" codex="" alimentarius="" commission="" (codex)="" maximum="" residue="" levels="" (mrls)="" for="" carfentrazone-ethyl="" on="" any="" crops="" at="" this="" time.="" however,="" mrls="" for="" small="" grains="" in="" europe="" have="" been="" proposed="" which="" consist="" of="" carfentrazone-ethyl="" and="" carfentrazone-ethyl-chloropropionic="" acid.="" (pm="" 23)="" 2.="" rohm="" and="" haas="" company="" pp="" 2f4127="" 2f4135,="" 3f4194,="" 3h5663,="" 7f4887,="" and="" 7f4900="" epa="" has="" received="" six="" pesticide="" petitions="" (pp="" 2f4127,="" 2f4135,="" 3f4194,="" 3h5663,="" 7f4887,="" and="" 7f4900)="" 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="" (ffdca),="" 21="" u.s.c.="" 346a(d),="" to="" amend="" 40="" cfr="" part="" 180="" by="" establishing="" permanent="" tolerances="" for="" almond,="" apple,="" and="" grapefruit="" and="" time-limited="" tolerances="" for="" wheat="" and="" animal="" commodities="" for="" residues="" of="" [alpha-(2-="" (4-chlorophenyl)-ethyl)-alpha-phenyl-3-(1h-1,2,4-triazole)-1-="" propanenitrile="" (fenbuconazole)="" in="" or="" on="" the="" raw="" agricultural="" commodities="" (rac)="" almond="" nuts="" at="" 0.05="" parts="" per="" million="" (ppm);="" almond="" hulls="" at="" 3.0="" ppm;="" apples="" at="" 0.4="" ppm;="" apple="" pomace,="" wet="" at="" 1.0="" ppm;="" grapefruit="" at="" 1.0="" ppm;="" citrus="" oil="" (grapefruit)="" at="" 35.0="" ppm;="" grapefruit="" pulp,="" dried="" at="" 4.0="" ppm;="" sugar="" beet="" root="" at="" 0.2="" ppm;="" sugar="" beet="" top="" at="" 9.0="" ppm;="" sugar="" beet="" pulp,="" dried="" at="" 1.0="" ppm;="" sugar="" beet="" molasses="" at="" 0.4="" ppm;="" wheat="" grain="" at="" 0.05="" ppm;="" wheat="" straw="" at="" 10.0="" ppm;="" fat="" of="" cattle,="" hogs,="" horses,="" goats,="" and="" sheep="" at="" 0.05="" ppm;="" and="" liver="" of="" cattle,="" hogs,="" horses,="" goats,="" and="" sheep="" at="" 0.3="" ppm.="" the="" analytical="" method="" involves="" soxhlet="" extraction,="" partitioning,="" redissolving,="" clean-up,="" and="" analysis="" by="" gas-liquid="" chromatography="" using="" nitrogen="" specific="" thermionic="" detection.="" epa="" has="" determined="" that="" the="" petitions="" contain="" 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="" petitions.="" additional="" data="" may="" be="" needed="" before="" epa="" rules="" on="" the="" petitions.="" a.="" residue="" chemistry="" the="" tolerance="" expression="" for="" fenbuconazole="" residues="" in="" or="" on="" almond="" nuts="" or="" hulls,="" apples="" or="" apple="" process="" fractions,="" grapefruit="" and="" all="" related="" commodities,="" sugar="" beets,="" and="" wheat="" grain="" or="" straw="" is="">-(2-(4-chlorophenyl)-ethyl)--phenyl-(1H-1,2,4-
triazole-1-propanenitrile, plus cis-5-(4-chlorophenyl) dihydro-3-
phenyl-3-(1H-1,2,4-triazole-1-ylmethyl-)-2(3H)-furanone, plus 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 almond nuts
or hulls, apples or apple process fractions, grapefruit and all related
commodities, sugar beets and all related commodities, and wheat grain
or straw.
The tolerance expression for fenbuconazole residues in or on animal
fat is -(2-(4-chlorophenyl)-ethyl)--phenyl-(1H-1,2,4-
triazole-1-propanenitrile, plus 4-chloro--(hydroxymethyl)-
-phenyl-benzenebutanenitrile. Residues of these compounds are
combined and expressed as parent compound to determine the total
residue.
The tolerance expression for fenbuconazole residues in or on animal
liver is -(2-(4-chlorophenyl)-ethyl)--phenyl-(1H-
1,2,4-triazole-1-propanenitrile, plus cis-5-(4-chlorophenyl) dihydro-3-
phenyl-3-(1H-1,2,4-triazole-1-ylmethyl-)-2(3H)-furanone, plus trans-5-
(4-chlorophenyl) dihydro-3-phenyl-3-(1H-1,2,4-triazole-1-ylmethyl-)-
2(3H)-furanone, plus 4-chloro--(hydroxymethyl)--
phenyl-benzenebutanenitrile. Residues of these compounds are combined
and expressed as parent compound to determine the total residue.
Analytical methods to measure the components of the residue in or
on almond nuts and almond hulls, apples, apple process fractions,
grapefruit, sugar beets, wheat grain and wheat straw, and animal
commodities have been validated and accurately quantify residues of
fenbuconazole. The residues of fenbuconazole will not exceed the
proposed Permanent Tolerances in/on apples or apple process fractions,
in/on almonds or related commodities, in/on grapefruit or related
commodities following foliar treatment, on sugar beets or related
commodities, or in/on wheat or related commodities following foliar or
seed treatment.
1. Analytical method. Fenbuconazole residues (parent plus lactones)
are measured at an analytical sensitivity of 0.01 mg/kg in apples, and
wheat grain and straw by soxhlet extraction of samples in methanol,
partitioning into methylene chloride, redissolving in toluene, clean-up
on silica gel, and gas-liquid chromatography (GLC) analysis using
nitrogen specific thermionic detection. Fenbuconazole residues are
measured at an analytical sensitivity of 0.01 mg/kg in fat and liver in
essentially the same manner except that one of the analytes in these
matrices, 4-chloro--(hydroxymethyl)--phenyl-
benzenebutanenitrile, is measured at a sensitivity of 0.05 ppm.
2. Magnitude of residues-- i. Wheat. Residue studies have been
conducted in accordance with the geographic distribution mandated by
the EPA for wheat. In the wheat grain, the raw agricultural commodity,
the fenbuconazole residues ranged from no detectable residue (NDR < loq="0.01" mg/kg)="" to="" approximately="" 0.01="" ppm.="" in="" wheat="" straw="" the="" fenbuconazole="" residues="" ranged="" from="" approximately="" 0.05="" ppm="" to="" approximately="" 4.5="" ppm.="" residues="" were="" measured="" in="" processed="" fractions="" of="" wheat="" including="" cleaned="" grain,="" bread,="" patent="" flour,="" flour,="" red="" dog,="" bran,="" shorts/germ,="" and="" middlings.="" the="" epa="" concluded="" that="" no="" concentration="" above="" the="" residue="" levels="" in="" the="" rac="" occurred="" so="" no="" tolerances="" for="" any="" of="" these="" commodities="" were="" required.="" tolerances="" of="" 0.05="" ppm="" in="" wheat="" grain="" and="" 10="" ppm="" in="" wheat="" straw="" are="" proposed="" based="" on="" these="" data.="" feeding="" studies="" in="" the="" cow,="" goat,="" and="" hen="" indicated="" that="" the="" only="" animal="" commodities="" which="" require="" tolerances="" are="" fat="" and="" liver.="" there="" were="" no="" significant="" residues="" in="" eggs="" or="" milk="" at="" any="" dose="" level.="" in="" cows="" there="" were="" residues="" in="" fat="" only="" at="" the="" 10x="" level="" in="" one="" animal="" at="" 0.06="" mg/kg.="" liver="" contained="" quantifiable="" residues="" in="" all="" dose="" groups="" and="" the="" magnitude="" of="" the="" residue="" correlated="" closely="" with="" the="" dose="" level.="" at="" study="" day="" 28="" the="" 1="" x="" livers="" averaged="" 0.08="" mg/kg.="" residues="" declined="" significantly="" during="" the="" depuration="" period.="" in="" the="" fat="" and="" liver="" one="" of="" the="" components="" of="" the="" fenbuconazole="" tolerance="" expression="" has="" a="" loq="0.05" mg/kg.="" because="" there="" were="" detectable="" residues="" only="" in="" liver,="" not="" fat,="" at="" the="" 1x="" level,="" the="" loq="" of="" the="" least="" sensitive="" component="" drives="" the="" fat="" tolerance.="" tolerances="" of="" 0.05="" ppm="" in="" fat="" and="" 0.3="" ppm="" in="" liver="" are="" proposed="" based="" on="" the="" animal="" data.="" tolerances="" for="" wheat="" process="" fractions="" and="" wheat="" rotation="" crops="" are="" not="" required="" because="" no="" concentration="" of="" residues="" occurs="" in="" process="" fractions="" of="" wheat="" and="" no="" residues="" occur="" in="" rotation="" crops.="" [[page="" 4635]]="" ii.="" apples.="" residue="" studies="" have="" been="" conducted="" in="" accordance="" with="" the="" geographic="" distribution="" mandated="" by="" the="" epa="" for="" apples.="" in="" the="" apples,="" the="" raw="" agricultural="" commodity="" (rac),="" the="" fenbuconazole="" residues="" ranged="" from="" approximately="" 0.1="" mg/kg="" to="" approximately="" 0.3="" mg/="" kg.="" residues="" were="" measured="" in="" process="" fractions="" of="" apples,="" apple="" juice,="" and="" apple="" pomace.="" concentration="" above="" the="" residue="" levels="" in="" the="" rac="" occurred="" only="" in="" the="" pomace="" at="" approximately="" two-fold.="" thus,="" no="" tolerance="" for="" juice="" is="" required,="" but="" a="" tolerance="" for="" pomace="" is="" required.="" seven="" field="" trials="" on="" apples="" were="" carried="" out="" in="" 1990="" in="" six="" states:="" pennsylvania,="" washington,="" north="" carolina,="" michigan,="" virginia,="" and="" west="" virginia.="" two="" application="" rates="" were="" used="" in="" each="" of="" the="" studies,="" the="" anticipated="" maximum="" application="" rate="" of="" 0.14="" kg="" ai/ha="" and="" a="" 2x="" exaggerated="" rate="" of="" 0.28="" kg="" ai/ha.="" a="" total="" of="" eight="" to="" ten="" applications="" were="" made="" at="" the="" normal="" timing="" in="" each="" trial,="" and="" the="" fruit="" was="" harvested="" at="" 0,="" 7,="" and="" 13="" or="" 14="" days="" after="" the="" final="" application.="" all="" samples="" were="" frozen="" immediately="" after="" they="" were="" harvested="" and="" were="" kept="" frozen="" until="" analysis,="" or="" shipped="" fresh="" immediately="" after="" harvest="" and="" processed="" and="" frozen="" immediately="" upon="" receipt="" and="" kept="" frozen="" until="" analysis.="" samples="" were="" analyzed="" using="" the="" residue="" analytical="" method="" for="" rh-7592="" parent="" and="" metabolites="" in="" stone="" fruit,="" and="" residues="" were="" corrected="" for="" average="" fortification="" recoveries.="" as="" would="" be="" expected,="" the="" residue="" levels="" were="" seen="" to="" increase="" with="" decreased="" phi="" and="" increased="" application="" rate.="" the="" average="" half-life="" of="" residue="" decline="" for="" six="" studies="" was="" 11.9="" days.="" the="" average="" parent="" residue="" at="" 13-14="" phi="" at="" the="" 0.14="" kg="" ai/ha="" rate="" was="" 0.086="" mg/kg.="" formulation="" bridging="" studies="" were="" conducted="" on="" apples="" in="" 1993.="" apples="" grown="" in="" washington="" and="" pennsylvania="" were="" treated,="" in="" separate="" plots,="" with="" the="" 2f="" and="" 75="" wp="" formulations="" of="" fenbuconazole="" at="" a="" rate="" of="" 0.14="" kg="" ai/ha/application.="" a="" total="" of="" ten="" or="" twelve="" applications="" were="" made="" using="" an="" airblast="" sprayer="" at="" the="" normal="" timing="" of="" each="" trial,="" and="" the="" fruit="" was="" harvested="" at="" 14="" days="" after="" the="" final="" application="" (14="" day="" pre-harvest="" interval="" or="" phi).="" samples="" were="" shipped="" fresh="" immediately="" after="" harvest="" and="" frozen="" immediately="" upon="" receipt="" and="" kept="" frozen="" until="" processing="" and="" subsequent="" analysis.="" samples="" were="" analyzed="" using="" the="" residue="" analytical="" method="" for="" rh-7592="" parent="" and="" metabolites="" in="" stone="" fruit,="" but="" residues="" were="" not="" corrected="" for="" average="" fortification="" recoveries.="" total="" residues="" from="" the="" two="" trials="" were="" 0.226="" and="" 0.135="" mg/="" kg="" in="" the="" 2f="" formulation,="" and="" 0.184="" and="" 0.162="" mg/kg="" in="" the="" 75wp="" formulation.="" there="" were="" no="" significant="" differences="" in="" apparent="" residues="" found="" from="" the="" use="" of="" the="" two="" formulations,="" and="" residues="" due="" to="" parent="" compound="" constituted="" greater="" than="" 85%="" of="" the="" total="" residues="" found="" on="" the="" fruit.="" seven="" field="" residue="" trials="" were="" conducted="" on="" apples="" in="" 1995,="" in="" california,="" colorado,="" michigan,="" new="" york,="" ohio,="" oregon,="" and="" washington.="" apples="" were="" treated="" with="" dilute="" (0.014="" kg="" ai/hl)="" and="" concentrate="" (0.035="" kg="" ai/hl)="" sprays="" of="" the="" 2f="" formulation="" of="" fenbuconazole="" at="" a="" 0.14="" kg="" ai/ha.="" a="" total="" of="" eight="" to="" ten="" applications="" were="" made="" using="" airblast="" sprayers,="" with="" first="" application="" at="" early="" bud="" break="" and="" subsequent="" applications="" on="" a="" 10-14="" day="" schedule="" through="" bloom="" and="" a="" 14="" to="" 21="" day="" schedule="" in="" the="" cover="" sprays="" until="" harvest.="" the="" apples="" were="" harvested="" by="" hand="" at="" a="" phi="" of="" 14="" days.="" residue="" samples="" were="" analyzed="" using="" the="" residue="" analytical="" method="" for="" rh-7592="" parent="" and="" metabolites="" in="" stone="" fruit,="" but="" residues="" were="" not="" corrected="" for="" average="" fortification="" recoveries.="" samples="" from="" three="" sites="" were="" also="" analyzed="" using="" the="" residue="" analytical="" method="" for="" metabolite="" rh-7905.="" metabolite="" rh-7905="" was="" not="" detected="" in="" any="" of="" the="" samples.="" the="" total="" residues="" from="" the="" concentrate="" sprays="" ranged="" from="" 0.015="" to="" 0.274="" mg/kg="" and="" averaged="" 0.137="" mg/kg.="" the="" total="" residues="" from="" the="" dilute="" sprays="" ranged="" from="" 0.019="" to="" 0.295="" mg/kg="" and="" averaged="" 0.139="" mg/kg.="" there="" is="" not="" a="" significant="" difference="" in="" the="" magnitude="" of="" the="" residues="" between="" dilute="" and="" concentrate="" spray="" volumes="" of="" the="" 2f="" formulation="" of="" fenbuconazole.="" an="" additional="" residue="" study="" was="" conducted="" on="" apples="" grown="" in="" pennsylvania="" in="" 1994="" and="" the="" fruit="" was="" used="" for="" a="" processing="" study.="" the="" apples="" received="" nine="" foliar="" applications="" of="" the="" 2f="" formulation="" of="" fenbuconazole="" at="" the="" normal="" timing="" at="" a="" rate="" of="" 0.14="" kg="" ai/ha/="" application.="" the="" fruit="" was="" harvested="" 14="" days="" after="" the="" last="" treatment.="" the="" rac="" samples="" were="" shipped="" fresh="" and="" either="" immediately="" processed="" or="" frozen="" for="" storage.="" all="" rac="" and="" processed="" samples="" were="" analyzed="" within="" a="" less="" than="" 30="" day="" period,="" eliminating="" the="" need="" for="" generation="" of="" storage="" stability="" data.="" the="" apples="" were="" processed="" at="" the="" food="" research="" laboratory="" of="" cornell="" university="" using="" methodology="" simulating="" commercial="" apple="" processing.="" briefly,="" the="" processing="" consisted="" of="" washing="" the="" apples="" in="" water,="" grinding="" in="" a="" hammer="" mill="" to="" apple="" mash,="" and="" pressing="" of="" the="" mash="" to="" form="" both="" fresh="" apple="" juice="" and="" wet="" pomace.="" the="" juice="" was="" either="" canned="" (sampled="" as="" unpasteurized="" juice)="" or="" canned="" and="" pasteurized="" (sampled="" as="" pasteurized="" juice).="" the="" wet="" pomace="" (moisture="" content="" 69%)="" was="" also="" sampled.="" all="" samples="" were="" frozen="" on="" generation="" and="" stored="" frozen="" until="" analysis.="" samples="" were="" analyzed="" using="" the="" residue="" analytical="" method="" for="" rh-7592="" and="" metabolites="" in="" stone="" fruit,="" and="" residues="" were="" not="" corrected="" for="" average="" fortification="" recovery.="" the="" average="" total="" residues="" for="" each="" component,="" and="" its="" concentration="" factor,="" were="" as="" follows:="" unwashed="" fruit="" 0.065="" mg/kg="" na,="" washed="" fruit="" 0.070="" mg/kg="" na,="" wet="" pomace="" 0.159="" mg/kg="" 2.46,="" unpasteurized="" juice="" 0.004="" mg/kg="" 0.06,="" pasteurized="" juice="" 0="" mg/kg="" 0.00.="" no="" concentration="" of="" residues="" was="" seen="" in="" the="" human="" diet="" component,="" i.e.="" apple="" juice.="" concentration="" of="" residues="" of="" approximately="" 2-fold="" was="" seen="" in="" wet="" pomace,="" which="" is="" not="" a="" component="" of="" the="" human="" diet.="" feeding="" studies="" in="" the="" cow,="" goat,="" and="" hen="" indicated="" that="" the="" only="" animal="" commodities="" which="" require="" tolerances="" are="" fat="" and="" liver.="" there="" were="" no="" significant="" residues="" in="" eggs="" or="" milk="" at="" any="" dose="" level.="" residues="" in="" animals="" declined="" significantly="" during="" the="" depuration="" period.="" in="" the="" fat="" and="" liver="" one="" of="" the="" components="" of="" the="" fenbuconazole="" tolerance="" expression="" has="" a="" loq="0.05" mg/kg.="" because="" there="" were="" detectable="" residues="" only="" in="" liver,="" not="" fat,="" the="" loq="" of="" the="" least="" sensitive="" component="" drives="" the="" fat="" tolerance.="" tolerances="" of="" 0.05="" ppm="" in="" fat="" and="" 0.3="" ppm="" in="" liver="" were="" proposed="" based="" on="" the="" animal="" data.="" tolerances="" for="" other="" apple="" process="" fractions="" and="" for="" rotation="" crops="" are="" not="" required="" because="" no="" concentration="" of="" residues="" occurs="" in="" other="" process="" fractions="" of="" apples="" and="" rotation="" crops="" are="" not="" a="" concern="" for="" perennial="" crops.="" iii.="" almonds.="" residue="" studies="" have="" been="" conducted="" in="" accordance="" with="" the="" geographic="" distribution="" mandated="" by="" the="" epa="" for="" almonds.="" there="" are="" no="" process="" fractions="" of="" almonds.="" six="" field="" trials="" in="" almonds="" were="" carried="" out="" at="" five="" sites="" in="" california="" in="" 1987.="" in="" all="" of="" the="" studies,="" the="" anticipated="" maximum="" application="" rate="" of="" 0.11="" kg="" ai/ha="" and="" a="" 2x="" exaggerated="" rate="" of="" 0.22="" kg="" ai/ha.="" a="" total="" of="" three="" applications="" were="" made="" at="" the="" normal="" timing="" in="" all="" trials,="" and="" the="" almonds="" were="" harvested="" at="" maturity,="" 127-200="" days="" after="" the="" final="" application.="" samples="" were="" shipped="" fresh="" or="" frozen.="" hulls="" were="" separated="" from="" the="" nuts="" and="" processed="" in="" a="" hobart="" food="" processor="" with="" dry="" ice="" or="" in="" a="" wiley="" mill="" without="" dry="" ice.="" nuts="" were="" shelled="" and="" the="" nutmeat="" homogenized="" in="" a="" waring="" food="" processor="" with="" dry="" ice.="" the="" processed="" samples="" were="" stored="" frozen="" until="" analysis.="" samples="" were="" analyzed="" using="" the="" residue="" analytical="" method="" for="" rh-="" [[page="" 4636]]="" 7592="" and="" metabolites.="" no="" residue="" in="" any="" nutmeat="" sample="" at="" the="" 1x="" application="" rate="" reached="" 0.01="" mg/kg.="" residues="" in="" the="" hull="" at="" the="" 1x="" rate="" ranged="" from="" 0.1="" to="" 1.5="" mg/kg.="" one="" nutmeat="" sample="" treated="" at="" the="" 2x="" rate="" had="" a="" quantifiable="" residue="" of="" 0.027="" mg/kg.="" the="" remainder="" had="" no="" detectable="" residue.="" hull="" sample="" residues="" from="" the="" 2x="" rate="" ranged="" from="" 0.5="" to="" 6.6="" mg/kg.="" feeding="" studies="" in="" the="" cow,="" goat,="" and="" hen="" indicated="" that="" the="" only="" animal="" commodities="" which="" require="" tolerances="" are="" fat="" and="" liver.="" there="" were="" no="" significant="" residues="" in="" eggs="" or="" milk="" at="" any="" dose="" level.="" residues="" in="" animals="" declined="" significantly="" during="" the="" depuration="" period.="" in="" the="" fat="" and="" liver="" one="" of="" the="" components="" of="" the="" fenbuconazole="" tolerance="" expression="" has="" a="" loq="0.05" mg/kg.="" because="" there="" were="" detectable="" residues="" only="" in="" liver,="" not="" fat,="" the="" loq="" of="" the="" least="" sensitive="" component="" drives="" the="" fat="" tolerance.="" tolerances="" of="" 0.05="" ppm="" in="" fat="" and="" 0.3="" ppm="" in="" liver="" were="" proposed="" based="" on="" the="" animal="" data.="" tolerances="" for="" almond="" process="" fractions="" and="" rotational="" crops="" are="" not="" required="" because="" there="" are="" no="" process="" fractions="" of="" almonds="" and="" rotational="" crops="" are="" not="" a="" concern="" for="" perennial="" crops.="" iv.="" grapefruit.="" trials="" included="" both="" grapefruit="" and="" orange,="" so="" the="" following="" text="" covers="" the="" residue="" results="" for="" both.="" six="" residue="" trials="" were="" conducted="" in="" 1993="" on="" grapefruit="" and="" oranges="" grown="" in="" texas,="" florida="" and="" california="" (one="" grapefruit="" and="" one="" orange="" trial="" at="" each="" site).="" three="" airblast="" sprayer="" applications="" of="" the="" 2f="" formulation="" of="" fenbuconazole="" at="" the="" rate="" of="" 0.28="" kg="" ai/ha/application="" were="" made="" at="" the="" normal="" timing,="" and="" the="" fruit="" was="" harvested="" by="" hand="" at="" pre-harvest="" intervals="" (phis)="" of="" 0="" days="" (all="" trials),="" and="" approximately="" 15,="" 30="" and="" 60="" days="" (three="" trials).="" the="" whole="" fruit="" was="" analyzed="" using="" the="" residue="" analytical="" method="" for="" rh-7592="" parent="" and="" metabolites="" in="" stone="" fruit="" and="" residues="" were="" not="" corrected="" for="" average="" fortification="" recoveries.="" the="" average="" total="" residue="" in="" whole="" grapefruit="" at="" 0="" day="" phi="" was="" 0.344="" mg/kg,="" with="" a="" range="" of="" 0.190="" -="" 0.499="" mg/kg.="" the="" average="" total="" residue="" in="" whole="" oranges="" at="" 0="" day="" phi="" was="" 0.438="" mg/kg,="" with="" a="" range="" of="" 0.339="" -="" 0.528="" mg/="" kg.="" for="" both="" fruits,="" the="" 0="" day="" phi="" residues="" were="">97% parent. In the
three trials which measured residue decline, the average total residue
value had decreased to about 40% of the original value by 60 PHI.
Residue trials were conducted in 1993 and 1994 on grapefruit and
oranges grown in seven different locations. Sites with both grapefruit
and orange trials were in Texas (2) and Florida (3), and in California
there was one site for oranges and another for grapefruit. Three
airblast sprayer applications of the 2F formulation of fenbuconazole at
the rate of 0.28 kg ai/ha/application were made at the normal timing,
and the fruit was harvested by hand on the day of the final application
(for a 0 day Pre-Harvest Interval). The fruit was processed in two
different ways: as whole fruit, or as pulp only with the peel
discarded. Samples were analyzed using the residue analytical method
for RH-7592 parent and metabolites in stone fruit, and residues were
not corrected for average fortification recoveries. Six of the RAC
samples were also analyzed using the residue analytical method for
metabolite RH-7905 (the glucoside conjugate). No detectable residues of
RH-7905 were found in any sample. Average total residue for whole
oranges was 0.238 mg/kg, and 0.0082 mg/kg for orange pulp. Average
total residue for whole grapefruit was 0.141 mg/kg, and 0.0078 mg/kg
for grapefruit pulp. Nearly all of the fenbuconazole residues lie on
the peel, and [NDR] no detectable residue to LOQ levels are seen in the
edible portion of the fruit, i.e. the pulp.
Feeding studies in the cow, goat, and hen indicated that the only
animal commodities which require tolerances are fat and liver. There
were no significant residues in eggs or milk at any dose level.
Residues in animals declined significantly during the depuration
period. In the fat and liver one of the components of the fenbuconazole
tolerance expression has a LOQ = 0.05 mg/kg. Because there were
detectable residues only in liver, not fat, the LOQ of the least
sensitive component drives the fat tolerance. Tolerances of 0.05 ppm in
fat and 0.3 ppm in liver were proposed based on the animal data.
Tolerances for rotational crops are not required for tree fruits.
v. Sugar beets. Residue studies have been conducted in accordance
with the geographic distribution mandated by the EPA for sugar beets.
Following full season foliar treatment, the residues of fenbuconazole
were higher in the sugar beet tops than in the root. Combined residues
in root averaged 0.415 mg/kg. Residues in tops were more variable, and
ranged from 0.56-8.89 mg/kg. In a formulation bridging study the
residues were higher in the sugar beet tops compared to the root. Total
root residues in the 75WP formulation ranged from 0.0061 to 0.268 mg/kg
and averaged 0.0616 mg/kg. Total root residues in the 2F formulation
ranged from 0.0223 to 0.0523 mg/kg and averaged 0.0328 mg/kg. Total top
residues averaged 2.15 mg/kg in the 75WP formulation, and 2.69 mg/kg in
the 2F formulation. There was no significant difference in residues
between formulations of fenbuconazole. In a processing study the
concentration factor for each component was: root - 1.0X, dry pulp -
5.39X, molasses - 1.82X, and refined sugar - 0.1X. Compared to raw
roots, a reduction of residues was seen in the human diet component,
sugar. Concentration of residues was seen in molasses and dry pulp,
neither of which is a component of the human diet.
Tolerances for rotational crops are not required because EPA
determined under the wheat petition that rotational crops are not a
concern for fenbuconazole.
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 and respiratory routes. The acute
oral LD50 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), inconsequentially 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. Mutagenicity. 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 germ cell
tests, and did not induce unscheduled DNA synthesis (UDS).
Fenbuconazole is not genotoxic.
3. Reproductive and developmental toxicity. These conclusions were
extracted from the Federal Register of May 24, 1995 (60 FR 27419).
Fenbuconazole is not teratogenic. The maternal no observable effect
level (NOEL) in rabbits was 10 mg/kg/day and
[[Page 4637]]
30 mg/kg/day in rats. The fetal NOEL was 30 mg/kg/day in both species.
The parental NOEL was 4.0 mg/kg/day (80 ppm) in a 2-generation
reproduction study in rats. The reproductive NOEL in this study was
greater than 40.0 mg/kg/day (800 ppm; highest dose tested).
Fenbuconazole had no effect on male reproductive organs or reproductive
performance at any dose. The adult lowest observed effect level (LOEL)
was 40.0 mg/kg/day (800 ppm; highest dose tested). 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 NOEL 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 NOEL 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 NOEL was 150 ppm (3.75 mg/kg/day) based on decreased body
weight, and increased liver weight. The LOEL was 1,200 ppm (30 mg/kg/
day). In a 78-week oncogenicity study in mice, the NOEL was 10 ppm
(1.43 mg/kg/day). The LOEL was 200 ppm (26.3 mg/kg/day, males) and 650
ppm (104.6 mg/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 NOEL of 3.0 mg/kg/day from the
rat chronic study. This RfD adequately protects both adults and
children.
6. Carcinogenicity. Twenty-four-month rat chronic feeding/
carcinogenicity studies with fenbuconazole showed effects at 800 and
1,600 ppm. Fenbuconazole produced a minimal, but statistically
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 dataset 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 (body weight) 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.
7. Endocrine effects. 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 NOEL. 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.
[[Page 4638]]
C. Aggregate Exposure
1. Dietary exposure-- Food. i. Wheat. For wheat, children 1 to 6
years old, not infants, are the highest consumers (g/kg bw/d basis).
For children 1-6 the dietary TMRC for existing tolerances utilizes only
5% of the RfD. The dietary TMRC for wheat in this group is estimated to
be 0.00016 mg/kg/day and uses 0.52% of the RfD. Additional dietary
exposure (TMRC) to fenbuconazole from residues which might be
transferred to animal fat and liver from treated wheat is estimated to
be 0.00006 mg/kg/day and uses 0.22% of the RfD. No residues occur in
animal meats, milk, or eggs. Thus, the TMRC, the worst-case exposure,
in the two most sensitive subpopulations of consumers, non-nursing
infants less than one year old and children 1 to 6 years old, still
utilizes less than 18% and less than 6%, respectively, of the
fenbuconazole RfD. The dietary TMRCs for other children and for adults
utilize less than this.
The calculated additional cancer risk for wheat (Q1* =
0.36 x 10-2 (mg/kg/day)-1) has an upper-bound of
0.2 x 10-6. The calculated additional cancer risk for animal
fat and liver has an upper-bound of 0.1 x 10-6. The upper
bound estimate on excess cancer risk for all uses including wheat is
0.7 x 10-6. The estimate shows that the TMRC, the worst-case
exposure, for consumers to fenbuconazole presents a reasonable
certainty of no harm. The actual residue contribution is anticipated to
be significantly less than this estimate.
ii. Apples. The EPA used the DRES model to estimate consumer
dietary exposure to fenbuconazole residues for the most recently
approved tolerance in bananas (memorandum of E.A. Doyle, February 8,
1995). (memorandum of E.A. Doyle, 8 February 1995). The EPA used the
Theoretical Maximum Residue Contribution (TMRC) for pecans and bananas,
and adjusted the TMRC for the stone fruit crop group by excluding
plums/prunes and limiting sales volume to 12.8% of the available stone
fruit market. From this EPA calculated an upper-bound risk of 0.9 x 10-
6 for additional cancer risk (Q1* = 1.06 x 10-2
(mg/kg/day)-1). (Federal Register of May 24, 1995 (60 FR 27419)). This
estimate does not reflect the change in Q1*, the use of the
DEEM database, the percent crop treated for all crops, or average
residues. When these factors are included the aggregate lifetime
exposure for consumers to fenbuconazole has an upper bound risk
estimate of 0.18 x 10-6 for apples and 0.28 x
10-6 for all pending and approved uses combined. The
theoretical maximum estimated exposure to the most sensitive
subpopulation, non-nursing infants less than one year old, for this
same scenario utilizes no more than 0.89% of the RfD. Thus, the
addition of fenbuconazole use on apples meets the EPA criterion of
reasonable certainty of no harm.
iii. Almonds. The consumer dietary exposure to fenbuconazole
residues was estimated for the most recently approved tolerance in
bananas (memorandum of E.A. Doyle, 8 February 1995). The EPA used the
Theoretical Maximum Residue Contribution (TMRC) for pecans and bananas,
and adjusted the TMRC for the stone fruit crop group by excluding
plums/prunes and limiting sales volume to 12.8% of the available stone
fruit market. From this EPA calculated an upper-bound risk of 0.9 x
10-6 for additional cancer risk (Q1* = 1.06 x
10-2 (mg/kg/day)-1). (Federal Register of May 24,
1995 (60 FR 27419)). This estimate does not reflect the change in
Q1*, the use of the DEEM database, the percent crop treated
for all crops, or average residues. When these factors are included the
aggregate lifetime exposure for consumers to fenbuconazole has an upper
bound cancer risk estimate of 7.5 x 10-11 for almonds and
0.28 x 10-6 for all pending and approved uses combined. The
theoretical maximum estimated exposure to the most sensitive
subpopulation, non-nursing infants less than one year old, for this
same scenario utilizes no more than 0.89% of the RfD. Thus, the
addition of fenbuconazole use on almonds meets the EPA criterion of
reasonable certainty of no harm.
This estimate shows that the estimated exposure for consumers to
fenbuconazole presents a reasonable certainty of no harm. The actual
dietary residue contribution will likely be less than this estimate.
iv. Grapefruit. The consumer dietary exposure to fenbuconazole
residues was estimated for the most recently approved tolerance in
bananas (memorandum of E.A. Doyle, 8 February 1995). The EPA used the
Theoretical Maximum Residue Contribution (TMRC) for pecans and bananas,
and adjusted the TMRC for the stone fruit crop group by excluding
plums/prunes and limiting sales volume to 12.8% of the available stone
fruit market. From this EPA calculated an upper-bound risk of 0.9 x
10-6 for additional cancer risk (Q1* = 1.06 x
10-2 (mg/kg/day)-1). (Federal Register of May 24,
1995 (60 FR 27419)). This estimate does not reflect the change in
Q1*, the use of the DEEM database, the percent crop treated
for all crops, or average residues. When the new Q1* of
(0.36 x 10-2 (mg/kg/day)-1) and surface area
estimated by (body weight)3/4 plus the other factors are
included, the aggregate lifetime exposure to consumers to fenbuconazole
has an upper bound risk estimate of 7.0 x 10-8 for
grapefruit and 0.17 x 10-6 for all pending and approved uses
combined. The theoretical maximum estimated exposure to the most
sensitive subpopulation, non-nursing infants less than one year old,
for this same scenario utilizes no more than 0.39% of the RfD. Thus,
the addition of fenbuconazole use on grapefruit meets the EPA criterion
of reasonable certainty of no harm.
This estimate shows that the estimated exposure for consumers to
fenbuconazole presents a reasonable certainty of no harm. The actual
dietary residue contribution will likely be less than this estimate.
v. Sugar beets. The consumer dietary exposure to fenbuconazole
residues was estimated for the most recently approved tolerance in
bananas (memorandum of E.A. Doyle, 8 February 1995). The EPA used the
TMRC for pecans and bananas, and adjusted the TMRC for the stone fruit
crop group by excluding plums/prunes and limiting sales volume to 12.8%
of the available stone fruit market. From this EPA calculated an upper-
bound risk of 0.9 x 10-6 for additional cancer risk
(Q1* = 1.06 x 10-2 (mg/kg/day)-1).
(Federal Register of May 24, 1995 (60 FR 27419)). This estimate does
not reflect the change in Q1*, the use of the DEEM database,
the percent crop treated for all crops, or average residues. When the
new Q1* of (0.36 x 10-2 (mg/kg/
day)-1)) and surface area estimated by (body
weight)3/4 plus the other factors are included the aggregate
lifetime exposure for consumers to fenbuconazole has an upper bound
cancer risk estimate of 1.0 x 10-8 for sugar beets and 0.17
x 10-6 for all pending and approved uses combined. The
theoretical maximum estimated exposure to the most sensitive
subpopulation, non-nursing infants less than one year old, for this
same scenario utilizes no more than 0.01% of the RfD for sugar beets
and 0.39% of the RfD for all crops combined. Thus, the addition of
fenbuconazole use on sugar beets meets the EPA criterion of reasonable
certainty of no harm.
2. 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
[[Page 4639]]
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.
3. 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.
D. Cumulative Effects
The toxicological effects of fenbuconazole are related to the
effects on rodent liver. These are manifest 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 NOEL 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.
E. Safety Determination
1. U.S. population-- i. Wheat. The Rohm and Haas Company estimates
the risk to the U.S. adult population from use of fenbuconazole on
wheat as utilizing approximately 0.36% of the RfD. Using the EPA low
dose extrapolation model and the risk factor based on the mouse data
(0.36 x 10-6 (mg/kg/day)-1) the excess cancer risk from
dietary sources for fenbuconazole use on wheat and the associated
animal commodities is estimated at 0.3 x 10-6. The upper
bound estimate on excess cancer risk for all uses including wheat is
0.7 x 10-6.
This assumes that all of the wheat consumed in the U.S. will
contain residues of fenbuconazole (in actuality a small fraction of the
total crop is likely to be treated). The combined risk for wheat plus
registered uses will not exceed either the dietary risk standard
established by the Food Quality Protection Act (FQPA) for the US
population, (one x 10-6), or the RfD.
The sole acute risk would be for women of childbearing age. The
EPA/OREB calculated that the worst-case Margin of Exposure (MOE) for
fenbuconazole measured against the developmental LOEL would be greater
than 30,000. This is clearly adequate. The MOE would be even higher for
consumer dietary exposure from any source. Thus, there is adequate
safety for this group and there is a reasonable certainty that no harm
will result from fenbuconazole use on wheat.
ii. Apples. When the DEEM database is used and the assumptions in
the above calculations the Rohm and Haas Company estimates the risk to
the U.S. adult population from use of fenbuconazole on apples as
utilizing approximately 0.17% of the RfD. The calculated upper bound
estimate on excess cancer risk for all uses (apples, apricots, almonds,
bananas, cherries, nectarines, peaches, pecans, and wheat, plus the
associated processing and animal commodities) is 0.28 x
10-6.
The combined risk for apples plus registered uses plus almonds and
wheat will not exceed the dietary risk standards established by the
FQPA for the US population (one x 10-6 excess cancer risk,
or the RfD).
The sole acute risk would be for women of childbearing age. The
EPA/OREB calculated that the worst-case Margin of Exposure (MOE) for
fenbuconazole measured against the developmental LOEL would be greater
than 30,000. This is clearly adequate. The MOE would be even higher for
consumer dietary exposure from any source. Thus, there is adequate
safety for this group and there is a reasonable certainty that no harm
will result from fenbuconazole use on apples.
iii. Almonds. When the DEEM database is used and the assumptions in
the above calculations the Rohm and Haas Company estimates the risk to
the U.S. adult population from use of fenbuconazole on almonds as
utilizing approximately 0.00007% of the RfD. The calculated upper bound
estimate on excess cancer risk for all uses (apples, apricots, almonds,
bananas, cherries, nectarines, peaches, pecans, and wheat, plus the
associated processing and animal commodities) is 0.28 x
10-6.
The combined risk for almonds plus registered uses plus apples and
wheat will not exceed the dietary risk standards established by the
FQPA for the US population (one x 10-6 excess cancer risk,
or the RfD).
The sole acute risk would be for women of childbearing age. The
EPA/OREB calculated that the worst-case Margin of Exposure (MOE) for
fenbuconazole measured against the developmental LOEL would be greater
than 30,000. This is clearly adequate. The MOE would be even higher for
consumer dietary exposure from any source. Thus, there is adequate
safety for this group and there is a reasonable certainty that no harm
will result from fenbuconazole use on almonds.
iv. Grapefruit. When the DEEM database is used and the assumptions
in the above calculations the Rohm and Haas Company estimates the risk
to the U.S. adult population from use of fenbuconazole on grapefruit as
utilizing approximately 0.06% of the RfD. The calculated upper bound
estimate on excess cancer risk for all uses (apples, apricots, almonds,
bananas, cherries, grapefruit, nectarines, peaches, pecans, sugar
beets, and wheat, plus the associated processing and animal
commodities) is 0.17 x 10-6.
The combined risk for grapefruit plus registered and pending uses
will not exceed the dietary risk standards established by the FQPA for
the U.S.
[[Page 4640]]
population (one x 10-6 excess cancer risk, or the RfD).
The sole acute risk would be for women of childbearing age. The
EPA/OREB calculated that the worst-case Margin of Exposure (MOE) for
fenbuconazole measured against the developmental LOEL would be greater
than 30,000. This is clearly adequate. The MOE would be even higher for
consumer dietary exposure from any source. Thus, there is adequate
safety for this group and there is a reasonable certainty that no harm
will result from fenbuconazole use on grapefruit.
v. Sugar beets. When the DEEM database is used and the assumptions
in the above calculations the Rohm and Haas Company estimates the risk
to the U.S. adult population from use of fenbuconazole on sugar beets
as utilizing approximately 0.009% of the RfD. The calculated upper
bound estimate on excess cancer risk for all uses (apples, apricots,
almonds, bananas, cherries, grapefruit, nectarines, peaches, pecans,
sugar beets, and wheat, plus the associated processing and animal
commodities) is 0.17 x 10-6. Therefore, the combined risk
for sugar beets plus registered and pending uses will not exceed the
dietary risk standards established by the FQPA for the U.S. population
(one x 10-6 excess cancer risk, or the RfD).
The sole acute risk would be for women of childbearing age. The
EPA/OREB calculated that the worst-case Margin of Exposure (MOE) for
fenbuconazole measured against the developmental LOEL would be greater
than 30,000. This is clearly adequate. The MOE would be even higher for
consumer dietary exposure from any source. Thus, there is adequate
safety for this group and there is a reasonable certainty that no harm
will result from fenbuconazole use on sugar beets.
2. Infants and children-- i. Wheat. The reproductive and
developmental toxicity data base for fenbuconazole is complete. There
is no selective increase in toxicity to developing animals. Thus, there
is no evidence that prenatal and postnatal exposure would present
unusual or disproportionate hazard to infants or children. Therefore,
there is no need to impose an additional uncertainty factor to protect
infants and children.
The EPA calculated the dietary risk to infants and children for
existing tolerances. The estimated dietary exposure (TMRC) for this
subpopulation is 0.00522 mg/kg/day which represents only 17% of the
RfD; no other subgroup used in excess of 17% of the RfD. The EPA
estimated lifetime oncogenic risk in the range of one in a million at
0.9 x 10-6, using (Q1* = 1.06 x 10-2
(mg/kg/day)-1). (Federal Register of May 24, 1995 (60 FR
27419)).
For the wheat use the most sensitive subgroup is children 1 to 6
years old and the estimated risk to this subgroup is less than 18% of
the RfD. Utilizing the risk factor (Q1* = 0.36 x
10-2 (mg/kg/day)-1), the estimated excess cancer
risk for the U.S. population is less than 1 x 10-6.
Therefore the wheat use is safe within the meaning of the FQPA and
there is a reasonable certainty that no harm will result to infants or
children from the approval of fenbuconazole use on wheat.
ii. Apples and almonds. The reproductive and developmental toxicity
data base for fenbuconazole is complete. There is no selective increase
in toxicity to developing animals. Thus, there is no evidence that
prenatal and postnatal exposure would present unusual or
disproportionate hazard to infants or children. Therefore, there is no
need to impose an additional uncertainty factor to protect infants and
children. The dietary exposure estimate for children utilizes only
0.89% of the RfD.
iii. Grapefruit and sugar beets. The reproductive and developmental
toxicity data base for fenbuconazole is complete. There is no selective
increase in toxicity to developing animals. Thus, there is no evidence
that prenatal and postnatal exposure would present unusual or
disproportionate hazard to infants or children. Therefore, there is no
need to impose an additional uncertainty factor to protect infants and
children. The dietary exposure estimate for children utilizes only
0.39% of the RfD.
F. Environmental Fate
Fenbuconazole has little to no mobility in soil (Koc = 4425). It is
stable to hydrolysis and aqueous photolysis in buffered solutions, but
does degrade photolytically in natural waters and soil (half-life 87
and 79 days, respectively). Laboratory soil metabolism half-lives or
DT50 values for fenbuconazole range from 29 to 532 days under
terrestrial conditions and from 442 to 906 days in soil exposed to
aquatic conditions. Field-trial soil dissipation studies had half-lives
ranging from 157 to 407 days and indicated no significant downward
movement of residues. These field trials show fenbuconazole degrades
more rapidly outdoors than in laboratory metabolism studies. When
material was applied in a single application, fenbuconazole degraded to
about 50% of the applied material in less than 60 days. In wheat the
DT50 in green heads was measured as 18 days and in green wheat stalks
the DT50 was 84.4 days. These results only reflect foliar dissipation
in wheat at the particular growth stage(s) during the study and not at
all stages of wheat. The results of residue decline analyses in a
number of environmental media support the EPA conclusion that there is
no environmental hazard associated with the proposed agricultural use
of this chemical.
G. International Tolerances
There are no Codex Maximum Residue Levels (MRLs) for fenbuconazole,
but the fenbuconazole database will be evaluated by the WHO and the FAO
Expert Panels at the Joint Meeting on Pesticide Residues (JMPR) in
September 1997. An Allowable Daily Intake (ADI (RfD)) of 0.03 mg/kg/day
is proposed and a total of 36 Codex MRLs are proposed in the data
submission. (PM 22)
[FR Doc. 98-2363 Filed 1-29-98; 8:45 am]
BILLING CODE 6560-50-F
