[Federal Register Volume 64, Number 122 (Friday, June 25, 1999)]
[Notices]
[Pages 34237-34243]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-16238]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-788A and PF-848A; FRL-6076-9]
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces the amendment of pesticide petitions
1F3989, and 7F4900, proposing the
[[Page 34238]]
establishment of regulations for residues of certain pesticide
chemicals in or on various food commodities.
DATES: Comments, identified by the docket control number PF-788A, and
PF-848A, must be received on or before July 26, 1999.
ADDRESSES: By mail submit written comments to: Information and Records
Integrity Branch, Public Information and Services Divison (7502C),
Office of Pesticides Programs, Environmental Protection Agency, 401 M
St., SW., Washington, DC 20460. In person bring comments to: Rm. 119,
CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically by following
the instructions under ``SUPPLEMENTARY INFORMATION.'' No confidential
business information should be submitted through e-mail.
Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment that does not contain CBI must be submitted
for inclusion in the public record. Information not marked confidential
may be disclosed publicly by EPA without prior notice. All written
comments will be available for public inspection in Rm. 119 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: Cynthia Giles-Parker, Registration
Support Branch, Registration Division (7505C), Office of Pesticide
Programs, Environmental Protection Agency, 401 M St., SW., Washington,
DC 20460. Office location, telephone number, and e-mail address: Rm.
247, Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA
22202, (703) 305-7740; e-mail: giles-parker.cynthia@epamail.epa.gov.
SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition as
follows proposing the establishment and/or amendment of regulations for
residues of certain pesticide chemical in or on various food
commodities under section 408 of the Federal Food, Drug, and Comestic
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that this petition
contains data or information regarding the elements set forth in
section 408(d)(2); however, EPA has not fully evaluated the sufficiency
of the submitted data at this time or whether the data supports
granting of the petition. Additional data may be needed before EPA
rules on the petition.
The official record for this notice of filing, as well as the
public version, has been established for this notice of filing under
docket control number [PF-788A], and [PF-848A] (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 file format or
ASCII file format. All comments and data in electronic form must be
identified by the docket control number (PF-788A), and (PF-848A) 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: June 9, 1999.
James Jones,
Director, Registration Division, Office of Pesticide Programs.
Summary of Petition
The petitioner summary of the pesticide petition is printed below
as required by section 408(d)(3) of the FFDCA. The summary of the
petition was prepared by the petitioner and represents the views of the
petitioner. EPA is publishing the petition 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.
Rohm and Haas Company
PP 1F3989 and 7F4900
Amended Petitions
In the Federal Registers of January 30, 1998 (63 FR 4631) (FRL-
5766-2), and December 7, 1998 (63 FR 67476) (FRL-6047-2), EPA issued a
notice of filing announcing that it had received pesticide petitions
(PP) 1F3989, and 7F4900 from Rohm and Haas Company, 100 Independence
Mall West, Philadelphia, PA 19106-2399, pursuant to section 408(d) of
the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d)
proposing to amend 40 CFR part 180. In petition 1F3989, Rohm and Haas
Company proposed among other things, to establish a time-limited
tolerance for residues of fenbuconazole (-(2-[4-chlorophenyl]-
ethyl)--phenyl-3-(1H-1,2,4-triazole)-1-propanenitrile] in or
on stone fruits (except plums and prunes) at 2.0 ppm. In petition
7F4900, Rohm and Haas Company proposed, among other things, to
establish permanent tolerances for fenbuconazole in or on grapefruit at
1.0 ppm, citrus oil (grapefruit) at 35.0 ppm, and grapefruit pulp,
dried at 4.0 ppm.
Today's notice of filing announces the receipt of pesticide
petitions from Rohm and Haas Company proposing to amend PP 1F3989 and
7F4900 by establishing tolerances for residues of fenbuconazole
(-(2-[4-chlorophenyl]-ethyl)--phenyl-3-(1H-1,2,4-
triazole)-1-propanenitrile] plus RH-9129 and RH-9130, the
diastereomeric lactone metabolites of fenbuconazole [5-(4-
chlorophenyl)-dihydro-3-phenyl-3-(methyl-1H-1,2,4-triazole-1-yl)-2-3H-
furanone) in or on the raw agricultural commodities plums at 2.0 parts
per million (ppm), plums, dried (prunes) at 7.0 ppm (PP 1F3989), and
for oranges at 1.0 ppm, orange, dry pulp at 4.0 ppm, and orange, citrus
oil at 16 ppm (7F4900). EPA has determined that the petition contains
data or information regarding the elements set forth in section
408(d)(2) of the FFDCA; however, EPA has not fully evaluated the
sufficiency of the submitted data at this time or whether the data
support granting of the petition. Additional data may be needed before
EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The metabolism of fenbuconazole in plants
(wheat, peaches, and sugar beets) is adequately understood for the
purpose of these tolerances. The metabolism of fenbuconazole in all
crops was similar and involves oxidation of the benzylic position alpha
to the chlorophenyl ring. The metabolites which result from this
[[Page 34239]]
path are the benzylic alcohols and their conjugates, including sulfates
and glucuronides, the iminolactones, the lactones, and the ketoacid,
all resulting from intramolecular cyclization. A second pathway is
oxidation of the unchlorinated ring to produce the 3- and 4-phenols and
their conjugates. Combinations of the above two pathways produce
phenol-lactones and their conjugates. A third pathway is cleavage of
the triazole moiety, which produces free triazole and its conjugates.
2. Analytical method. An adequate enforcement method is available
to enforce the established and proposed tolerances. Quantitation of
fenbuconazole residues (parent plus lactones) at an analytical
sensitivity of 0.01 milligrams/kilogram (mg/kg) is accomplished 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.
3. Magnitude of residues. Field residue trials were conducted with
an aqueous flowable formulation of fenbuconazole in geographically
representative regions of the United States. The results from these
studies support the proposed tolerances, and clearly indicate that the
lactone metabolites (RH-9129 and RH-9130) are minor contributors to the
total residue.
i. Oranges. A total of 16 field residue trials were conducted in
oranges. Three applications were made at 0.25 pounds active ingredient/
acre (lb ai/A), twice the maximum use rate of 0.125 lb ai/A, and whole
fruit was harvested on the same day as the last application. The
highest field residue value in whole fruit was 0.752 ppm. The average
field residue value in whole fruit was 0.276 ppm. The highest field
residue value in the edible pulp from five field trials was 0.0104 ppm.
The average field residue value in pulp was 0.005 ppm. Residues were
measured in orange process fractions including, juice, dried pulp, and
cold press (citrus) oil. In the processing study, three applications
were made at 0.25 lb ai/A, twice the maximum use rate of 0.125 lb ai/A,
and the fruit were harvested seven days after the last application.
Fruit was processed into multiple components. No residues (<0.01 ppm)="" were="" detected="" in="" juice,="" thus="" were="" was="" no="" concentration="" of="" residues="" in="" fresh="" juice.="" the="" average="" residues="" in="" dried="" pulp="" (cattle="" feed)="" and="" citrus="" oil="" (defined="" as="" a="" non-ready-to-eat="" processed="" commodity)="" were="" 4.1-="" and="" 32.1-times="" the="" amount="" of="" residues="" in="" fresh="" oranges,="" respectively.="" ii.="" plums.="" a="" total="" of="" 10="" field="" residue="" trials="" were="" conducted="" in="" plums.="" six="" to="" nine="" applications="" were="" made="" at="" the="" maximum="" use="" rate="" of="" 0.1="" lb="" ai/a,="" and="" whole="" fruit="" was="" harvested="" on="" the="" same="" day="" as="" the="" last="" application.="" the="" highest="" field="" residue="" value="" in="" whole="" fruit="" was="" 0.315="" ppm;="" the="" next="" highest="" field="" residue="" value="" was="" 0.071="" ppm.="" the="" average="" field="" residue="" value="" in="" whole="" fruit="" was="" 0.062="" ppm.="" residues="" were="" measured="" in="" dried="" plums="" (prunes)="" in="" three="" residue="" trials.="" six="" applications="" were="" made="" at="" the="" maximum="" use="" rate="" of="" 0.1="" lb="" ai/a,="" and="" whole="" fruit="" was="" harvested="" on="" the="" same="" day="" as="" the="" last="" application.="" dried="" plums="" contained="" residues="" of="" 0.0244,="" 0.04,="" and="" 0.139="" ppm.="" b.="" toxicological="" profile="" 1.="" acute="" toxicity.="" fenbuconazole="" is="" practically="" non-toxic="" after="" administration="" by="" the="" oral="" and="" dermal="" routes,="" and="" was="" not="" significantly="" toxic="" to="" rats="" after="" a="" 4-hour="" inhalation="" exposure.="" fenbuconazole="" is="" classified="" as="" not="" irritating="" to="" skin="" and="" inconsequentially="" irritating="" to="" the="" eyes.="" it="" is="" not="" a="" skin="" sensitizer.="" 2.="" genotoxicity.="" fenbuconazole="" was="" negative="" (non-mutagenic)="" in="" an="" ames="" assay="" with="" and="" without="" hepatic="" enzyme="" activation.="" fenbuconazole="" was="" negative="" in="" a="" hypoxanthine="" guanine="" phosphoribosyl="" transferase="" (hgprt)="" gene="" mutation="" assay="" using="" chinese="" hamster="" ovary="" (cho)="" cells="" in="" culture="" when="" tested="" with="" and="" without="" hepatic="" enzyme="" activation.="" in="" isolated="" rat="" hepatocytes,="" fenbuconazole="" did="" not="" induce="" unscheduled="" dna="" synthesis="" (uds)="" or="" repair.="" fenbuconazole="" did="" not="" produce="" chromosome="" effects="" in="" rats="" in="" vivo.="" on="" the="" basis="" of="" the="" results="" from="" this="" battery="" of="" tests,="" it="" is="" concluded="" that="" fenbuconazole="" is="" not="" mutagenic="" or="" genotoxic.="" 3.="" reproductive="" and="" developmental="" toxicity--i.="" rat="" developmental="" toxicity.="" in="" the="" developmental="" study="" in="" rats,="" the="" maternal="" (systemic)="" no-observed="" adverse="" effect="" level="" (noael)="" was="" 30="" mg/kg/day="" based="" on="" decreases="" in="" body="" weight="" (bwt)="" and="" body="" weight="" gain="" at="" the="" lowest-="" observed="" adverse="" effect="" level="" (loael)="" of="" 75="" mg/kg/day.="" the="" developmental="" (fetal)="" noael="" was="" 30="" mg/kg/day="" based="" on="" an="" increase="" in="" post="" implantation="" loss="" and="" a="" significant="" decrease="" in="" the="" number="" of="" live="" fetuses="" per="" dam="" at="" the="" loael="" of="" 75="" mg/kg/day.="" ii.="" rabbit="" developmental="" toxicity.="" in="" the="" developmental="" study="" in="" rabbits,="" the="" maternal="" (systemic)="" noael="" was="" 10="" mg/kg/day="" based="" on="" decreased="" bwt="" gain="" at="" the="" loael="" of="" 30="" mg/kg/day.="" the="" developmental="" (fetal)="" noael="" was="" 30="" mg/kg/day="" based="" on="" increased="" resorptions="" at="" the="" loael="" of="" 60="" mg/kg/day.="" iii.="" rat="" reproduction.="" in="" the="" 2-generation="" reproduction="" toxicity="" study="" in="" rats,="" the="" maternal="" (systemic)="" noael="" was="" 4="" mg/kg/day="" based="" on="" decreased="" bwt="" and="" food="" consumption,="" increased="" number="" of="" dams="" delivering="" nonviable="" offspring,="" and="" increases="" in="" adrenal="" and="" thyroid="" weights="" at="" the="" loael="" of="" 40="" mg/kg/day.="" the="" reproductive="" (pup)="" noael="" was="" 40="" mg/kg/="" day,="" the="" highest="" dose="" tested="" (hdt).="" 4.="" subchronic="" toxicity--i.="" rat="" 90-day="" oral="" study.="" a="" subchronic="" feeding="" study="" in="" rats="" conducted="" for="" 13-weeks="" resulted="" in="" a="" noael="" of="" 20="" ppm="" (1.3="" and="" 1.5="" mg/kg/day="" in="" males="" and="" females,="" respectively).="" minimal="" liver="" hypertrophy="" was="" observed="" in="" males="" at="" the="" loael="" of="" 80="" ppm.="" increased="" liver="" weight,="" hepatic="" hypertrophy,="" thyroid="" hypertrophy,="" and="" decreased="" bwt="" were="" observed="" at="" the="" higher="" doses="" (400="" and="" 1,600="" ppm).="" ii.="" mouse="" 90-day="" oral="" study.="" a="" subchronic="" feeding="" study="" in="" mice="" conducted="" for="" 13-weeks="" resulted="" in="" a="" noael="" of="" 60="" ppm="" (11.1="" and="" 17.6="" mg/="" kg/day="" in="" males="" and="" females,="" respectively).="" increased="" liver="" weight,="" hypertrophy="" in="" the="" liver="" (males),="" and="" increases="" in="" clinical="" chemistry="" parameters="" (males)="" were="" observed="" at="" the="" loael="" of="" 180="" ppm.="" these="" effects="" were="" all="" observed="" in="" females="" at="" 540="" ppm="" in="" addition="" to="" males.="" iii.="" dog="" 90-day="" oral="" study.="" a="" subchronic="" feeding="" study="" in="" dogs="" conducted="" for="" 13-weeks="" resulted="" in="" a="" noael="" of="" 100="" ppm="" (3.3="" and="" 3.5="" mg/="" kg/day="" in="" males="" and="" females,="" respectively).="" at="" the="" loael="" of="" 400="" ppm,="" increased="" liver="" weight,="" clinical="" chemistry="" parameters,="" and="" liver="" hypertrophy="" (males)="" were="" observed.="" iv.="" rat="" 4-week="" dermal="" study.="" 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--i.="" dog.="" a="" 1-year="" feeding="" study="" in="" dogs="" resulted="" in="" a="" noael="" of="" 15="" ppm="" (0.62="" mg/kg/day)="" for="" females="" and="" 150="" ppm="" (5.2="" mg/kg/day)="" for="" males.="" decreased="" bwt,="" increased="" liver="" weight,="" liver="" hypertrophy,="" and="" pigment="" in="" the="" liver="" were="" observed="" at="" the="" loael="" of="" 150="" and="" 1,200="" ppm="" in="" females="" and="" males,="" respectively.="" ii.="" mouse.="" a="" 78-week="" chronic/oncogenicity="" study="" was="" conducted="" in="" male="" and="" female="" mice="" at="" 0,="" 10,="" 200="" (males="" only),="" 650,="" and="" 1,300="" ppm="" (females="" only).="" the="" noael="" was="" 10="" ppm="" (1.4="" mg/kg/day),="" and="" the="" loael="" was="" 200="" ppm="" (26.3="" mg/kg/day)="" for="" males="" and="" 650="" ppm="" (104.6="" mg/kg/day)="" for="" females="" based="" on="" increased="" liver="" weight="" and="" [[page="" 34240]]="" histopathological="" effects="" on="" the="" liver,="" which="" were="" consistent="" with="" chronic="" enzyme="" induction.="" there="" was="" no="" statistically="" significant="" increase="" of="" any="" tumor="" type="" in="" males,="" 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).="" there="" were="" no="" liver="" tumors="" in="" the="" control="" females,="" and="" liver="" tumor="" incidences="" in="" treated="" females="" just="" exceeded="" the="" historical="" control="" range.="" 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="" weight.="" changes="" in="" these="" liver="" parameters="" as="" well="" as="" the="" occurrence="" of="" the="" low="" incidence="" of="" liver="" tumors="" were="" non-linear="" 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="" humans.="" the="" non-linear="" dose="" response="" relationship="" observed="" with="" respect="" to="" liver="" changes="" (including="" the="" low="" incidence="" of="" tumors)="" in="" the="" mouse="" indicates="" that="" these="" findings="" should="" be="" carefully="" considered="" in="" deciding="" the="" relevance="" of="" high-dose="" animal="" tumors="" to="" human="" dietary="" exposure.="" iii.="" rat.="" a="" 24-month="" chronic/oncogenicity="" study="" in="" male="" and="" female="" rats="" was="" conducted="" at="" 0,="" 8,="" 80,="" and="" 800="" ppm="" fenbuconazole,="" and="" a="" second="" 24-month="" chronic/oncogenicity="" was="" conducted="" in="" male="" rats="" at="" 0,="" 800,="" and="" 1,600="" ppm.="" the="" noael="" was="" 80="" ppm="" (3="" and="" 4="" mg/kg/day="" in="" males="" and="" females,="" respectively),="" and="" the="" loael="" was="" 800="" ppm="" (31="" and="" 43="" mg/kg/day="" in="" males="" and="" females,="" respectively)="" based="" on="" decreased="" bwt,="" increased="" liver="" and="" thyroid="" weights,="" and="" liver="" and="" thyroid="" hypertrophy.="" 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)="" of="" 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="" non-linear="" phenomenon="" in="" that="" thyroid="" tumors="" occur="" only="" at="" high="" doses="" where="" there="" is="" an="" increase="" in="" liver="" weight="" 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="" that="" 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.="" the="" reference="" dose="" (rfd)="" of="" 0.03="" mg/kg/day="" was="" established="" by="" the="" agency="" based="" on="" the="" noael="" of="" 3.0="" mg/kg/day="" in="" the="" chronic="" rat="" feeding="" study="" and="" an="" uncertainty="" factor="" of="" 100.="" the="" carcinogenicity="" peer="" review="" committee="" (cprc)="" of="" the="" health="" effects="" division="" (hed)="" of="" epa="" has="" classified="" fenbuconazole="" as="" a="" group="" c="" tumorigen="" (possible="" human="" carcinogen="" with="" limited="" evidence="" of="" carcinogenicity="" in="" animals).="" the="" committee="" has="" decided="" that="" it="" is="" appropriate="" to="" use="" a="" low-dose="" extrapolation="" model="" based="" on="" the="" mouse="" data="" with="" the="">1* of 0.359 x 10-2 (mg/kg/
day)-1 and surface area estimated by (bwt)3/4.
All estimates of dietary oncogenic risk are based on this risk factor.
6. Animal metabolism. The absorption, distribution, excretion, and
metabolism of fenbuconazole in rats, goats, and hens were investigated.
Following oral administration, fenbuconazole was completely and rapidly
absorbed, extensively metabolized by oxidation/hydroxylation and
conjugation, and rapidly and essentially completely excreted
predominately in the feces. Fenbuconazole did not accumulate in
tissues.
7. Metabolite toxicology. Common metabolic pathways for
fenbuconazole have been identified in both plants (wheat, peaches, and
sugar beets) and animals (rat, goat, and hen). The metabolic pathway
common to both plants and animals involves oxidation of the benzylic
position alpha to the chlorophenyl ring. The metabolites which result
from this path are the benzylic alcohols and their conjugates,
including sulfates and glucuronides, the iminolactones, the lactones,
and the ketoacid, all resulting from intramolecular cyclization. A
second pathway is oxidation of the unchlorinated ring to produce the 3-
and 4-phenols and their conjugates. Combinations of the above two
pathways produce phenol-lactones and their conjugates. A third pathway
is cleavage of the triazole moiety, which produces free triazole and
its conjugates. Extensive degradation and elimination of polar
metabolites occurs in animals such that residues are unlikely to
accumulate in humans or animals exposed to these residues through the
diet.
8. Endocrine disruption. The mammalian endocrine system includes
estrogen and androgens as well as other hormonal systems. Fenbuconazole
is not known to interfere with reproductive hormones; thus,
fenbuconazole should not be considered to be estrogenic or androgenic.
There are no known instances of proven or alleged adverse reproductive
or developmental effects to people, domestic animals, or wildlife as a
result of exposure to fenbuconazole or its residues.
C. Aggregate Exposure
1. Dietary exposure--i. Food. Permanent tolerances have been
established (40 CFR 180.480) or proposed for the residues of
fenbuconazole in or on a variety of raw agricultural commodities:
------------------------------------------------------------------------
Commodity Tolerance (ppm)
------------------------------------------------------------------------
Almond nutmeat...................... 0.05 (P)\1\
Almond hulls........................ 3.0 (P)
Apples.............................. 0.4 (P)
Apple pomace, wet................... 1.0 (P)
Banana (whole fruit)................ 4.0
Banana (pulp)....................... 0.05
[[Page 34241]]
Blueberry........................... 0.3 (P)
Cattle, fat......................... 0.05 (P)\3\
Cattle, liver....................... 0.1 (P)\4\
Citrus oil (grapefruit)............. 35.0 (P)
Grapefruit.......................... 1.0 (P)
Grapefruit juice.................... N/R2
Molasses (beet)..................... 0.4\5\
Pecans.............................. 0.1
Pulp, dried (beet).................. 1.0
Pulp, dry (grapefruit).............. 4.0 (P)
Refined sugar....................... N/R2
Stone Fruit (except plum/prune)..... 2.0
Sugar beet (root)................... 0.2 (P)
Sugar beet (top).................... 9.0 (P)
Wheat (grain)....................... 0.05 (P)
Wheat (straw)....................... 10.0 (P)
------------------------------------------------------------------------
\1\ (P): Proposed tolerance;
\2\ Tolerance not required because concentration factor is < 1="" in="" processing="" study;="" \3\="" an="" identical="" tolerance="" is="" pending="" for="" fat="" in="" poultry,="" hogs,="" horses,="" sheep,="" and="" goats;="" \4\="" an="" identical="" tolerance="" is="" pending="" for="" liver="" in="" poultry,="" hogs,="" horses,="" sheep,="" and="" goats;="" \5\="" for="" livestock="" feed;="" not="" a="" human="" dietary="" component.="" risk="" assessments="" were="" conducted="" by="" rohm="" and="" haas="" to="" assess="" dietary="" exposures="" and="" risks="" from="" fenbuconazole="" as="" follows:="" a.="" acute="" exposure="" and="" risk.="" no="" acute="" endpoint="" was="" identified="" for="" fenbuconazole,="" and="" no="" acute="" risk="" assessment="" is="" required.="" b.="" chronic="" exposure="" and="" risk.="" risk="" associated="" with="" chronic="" dietary="" exposure="" from="" fenbuconazole="" was="" assessed="" on="" four="" levels.="" in="" the="" first="" assessment,="" tolerance="" level="" residues="" and="" 100%="" crop="" treated="" were="" assumed.="" in="" the="" second="" assessment,="" tolerance="" level="" residues="" and="" rohm="" and="" haas="" company's="" conservative="" estimates="" of="" the="" highest="" achievable="" percent="" crop="" treated="" refinements="" were="" assumed.="" rohm="" and="" haas="" company's="" percent="" of="" crop="" treated="" estimates="" used="" in="" the="" assessments="" are="" almonds="50%," blueberry="30%," grapefruit="30%," bananas="20%," apples="15%," oranges="15%," pecans="11%," sugar="" beets="3%," and="" wheat="0.3%." in="" the="" third="" assessment,="" average="" field="" trial="" (anticipated)="" residues="" and="" 100%="" crop="" treated="" were="" assumed.="" in="" the="" fourth="" assessment,="" average="" field="" trial="" residues="" and="" rohm="" and="" haas="" company's="" percent="" of="" crop="" treated="" estimates="" indicated="" above="" were="" assumed.="" rohm="" and="" haas="" company's="" processing="" factors="" for="" apple,="" orange,="" and="" grapefruit="" juice="" were="" assumed="" in="" all="" four="" assessments.="" one="" hundred="" percent="" crop="" treated="" was="" assumed="" when="" calculating="" the="" dietary="" burden="" from="" which="" secondary="" residue="" tolerances="" in="" meat="" and="" fat="" were="" derived.="" a="" 12.8%="" crop="" treated="" refinement="" was="" used="" for="" stone="" fruit="" in="" all="" four="" assessments="" june="" 10,="" 1998="" (fr="" 63="" 31636)="" (frl="" 5791-5).="" the="" anticipated="" residue="" contribution="" (arc)="" from="" all="" proposed="" and="" existing="" food="" uses="" of="" fenbuconazole="" was="" assessed.="" 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="">TM, Version 5.31), which uses
USDA food consumption data from the 1989-1992 survey. The existing and
proposed fenbuconazole tolerances, and average fenbuconazole residues
result in ARCs that are equivalent to the following percentages of the
RfD:
----------------------------------------------------------------------------------------------------------------
DEEM\1\ DEEM\2\ DEEM\3\ DEEM\4\
Population Subgroup %RfD %RfD %RfD %RfD
----------------------------------------------------------------------------------------------------------------
U.S. Population (48 States)................................. 2.7 0.9 0.4 0.1
Non-Hispanic Other than Black or White...................... 3.5 1.0 0.5 0.2
All Infants (< 1-year="" old)..................................="" 6.1="" 3.5="" 1.0="" 0.4="" nursing="" infants="">< 1-year="" old)..............................="" 2.2="" 0.8="" 0.5="" 0.1="" non-nursing="" infants="">< 1-year="" old)..........................="" 7.7="" 4.7="" 1.3="" 0.5="" children="" (1-6="" years="" old)....................................="" 6.4="" 1.8="" 1.1="" 0.3="" children="" (7-12="" years="" old)...................................="" 4.2="" 1.2="" 0.7="" 0.2="" females="" (13+="" nursing).....................................="" 3.2="" 0.8="" 0.5="" 0.1="" ----------------------------------------------------------------------------------------------------------------="" \1\="" assumes="" residues="" are="" present="" at="" tolerance="" levels="" and="" 100%="" crop="" treated="" (12.8%="" stone="" fruit);="" \2\="" assumes="" residues="" are="" present="" at="" tolerance="" levels="" and="" includes="" percent="" crop="" treated="" refinements;="" \3\="" assumes="" residues="" are="" present="" at="" their="" average="" field="" trial="" residue="" levels="" and="" 100%="" crop="" treated="" (12.8%="" stone="" fruit);="" and="" \4\="" assumes="" residues="" are="" present="" at="" their="" average="" field="" trial="" residue="" levels,="" and="" includes="" percent="" crop="" treated="" refinements.="" c.="" aggregate="" cancer="" risk="" for="" u.s.="" population.="" fenbuconazole="" has="" been="" classified="" as="" a="" group="" c="" carcinogen="" with="" a="">1* value of
0.00359 mg/kg/day-1. Cancer risk assessments for all
existing and proposed food uses for the U.S. population are as follows:
[[Page 34242]]
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Assumptions/Refinements All Crops Orange & Proc. Frac. Plums/Prunes
----------------------------------------------------------------------------------------------------------------
Tolerance residue levels and 100% 2.90E-06 1.05E-06 1.46E-07
crop treated (12.8% stone fruit)
assumed:............................
Tolerance residue levels and percent 9.24E-07 1.57E-07 1.46E-07
crop treated refinements assumed:...
Anticipated residue levels and 100% 4.65E-07 1.6E-08 3E-09
crop treated (12.8% stone fruit)
assumed:............................
Anticipated residue levels and 1.44E-07 2E-09 3E-09
percent crop treated refinements
assumed:............................
----------------------------------------------------------------------------------------------------------------
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. Computer
modeling of laboratory and field dissipation data using EPA's Pesticide
Root Zone Model (PRZM) and USDA's Groundwater Loading Effects of
Agricultural Management Systems (GLEAMS) models predict 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 is no established Maximum
Concentration Level (MCL) for residues of fenbuconazole in drinking
water. No drinking water health advisory levels have been established
for fenbuconazole. There is no entry for fenbuconazole in the
``Pesticides in Groundwater Database'' (EPA 734-12-92-001; September,
1992).
3. Non-dietary exposure. Fenbuconazole is not currently registered
for any indoor or outdoor residential uses; therefore, no non-dietary
residential exposure is anticipated.
D. Cumulative Effects
The potential for cumulative effects of fenbuconazole with other
substances that have a common mechanism of toxicity was considered.
Fenbuconazole belongs to the class of fungicide chemicals known as
triazoles, which have demethylase inhibition capability. The
toxicological effects of fenbuconazole are related to its effects on
rodent thyroid and liver. Extensive data are available on the
biochemical mode of action by which fenbuconazole produces animal
tumors in rats and mice. These data indicate that the initiating events
do not occur below a given dose, and that the processes are reversible.
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. Acute exposure and risk. Since no acute
endpoint was identified for fenbuconazole, no acute risk assessment is
required.
ii. Chronic exposure and risk. Using the conservative exposure
assumptions described above and taking into account the completeness
and reliability of the toxicity data, the percentage of the RfD that
will be utilized by dietary (food only) exposure to residues of
fenbuconazole from existing, pending, and proposed tolerances is 2.7%
for the U.S. population, assuming residues are present at their
tolerance levels and 100% crop treated (12.8% for stone fruit).
Aggregate exposure is not expected to exceed 100%. EPA generally has no
concern for exposures below 100% of the RfD because the RfD represents
the level at or below which daily aggregate dietary exposure over a
lifetime will not pose appreciable risks to human health. Rohm and Haas
concludes that there is a reasonable certainty that no harm will result
from aggregate exposure to fenbuconazole residues to the U.S.
population.
2. Infants and children--Safety factor for Infants and children--i.
General. In assessing the potential for additional sensitivity of
infants and children to residues of fenbuconazole, data from
developmental toxicity studies in the rat and rabbit, and 2-generation
reproduction studies in the rat are considered. The developmental
toxicity studies are designed to evaluate adverse effects on the
developing organism resulting from maternal pesticide exposure during
gestation. Reproduction studies provide information relating to effects
from exposure to the pesticide on the reproductive capability of mating
animals and data on systemic toxicity.
ii. Developmental toxicity studies--a. Rat. In the developmental
study in rats, the maternal (systemic) NOAEL was 30 mg/kg/day based on
decreases in bwt and bwt gain at the LOAEL of 75 mg/kg/day. The
developmental (fetal) NOAEL was 30 mg/kg/day based on an increase in
post implantation loss and a significant decrease in the number of live
fetuses per dam at the LOAEL of 75 mg/kg/day.
b. Rabbit. In the developmental study in rabbits, the maternal
(systemic) NOAEL was 10 mg/kg/day based on decreased bwt gain at the
LOAEL of 30 mg/kg/day. The developmental (fetal) NOAEL was 30 mg/kg/day
based on increased resorptions at the LOAEL of 60 mg/kg/day.
iii. Reproductive toxicity study. In the 2-generation reproduction
toxicity study in rats, the maternal (systemic) NOAEL was 4 mg/kg/day
based on decreased bwt and food consumption, increased number of dams
delivering nonviable offspring, and increases in adrenal and thyroid
weights at the LOAEL of 40 mg/kg/day. The reproductive (pup) NOAEL was
40 mg/kg/day, the highest dose tested (HDT).
iv. Pre- and Post-Natal sensitivity. The pre- and post-natal
toxicology database for fenbuconazole is complete with respect to
current toxicological data requirements. There is a 10-fold difference
between the developmental NOAEL of 30 mg/kg/day from the rat and rabbit
developmental toxicity studies and the NOAEL of 3 mg/kg/day from the
chronic rat feeding study which is the basis of the RfD. It is further
noted that in the rabbit and rat developmental toxicity studies, the
developmental NOAELs are similar to or greater than the respective
maternal NOAELs. In the rat reproduction study, the maternal NOAEL (4
mg/kg/day) was ten times lower than the developmental (pup) and
reproductive NOAEL (40 mg/kg/day, the HDT). These studies indicate that
there is no additional sensitivity for infants and children in the
absence of maternal toxicity for fenbuconazole.
v. Acute risk. No acute dietary risk has been identified for
fenbuconazole.
vi. Chronic risk. Using the exposure assumptions described above,
the exposure to fenbuconazole from food will utilize 7.7% (non-nursing
infants < [[page="" 34243]]="" 1-year="" old)="" and="" 2.2%="" (nursing="" infants="">< 1-year="" old)="" of="" the="" rfd="" assuming="" residues="" are="" present="" at="" tolerance="" levels="" and="" 100%="" crop="" treated="" (12.8%="" for="" stone="" fruit),="" and="" will="" utilize="" 1.3%="" (non-nursing="" infants="">< 1-year="" old)="" and="" 0.5%="" (nursing="" infants="">< 1-year="" old)="" of="" the="" rfd="" assuming="" residues="" are="" present="" at="" their="" average="" field="" residue="" levels="" and="" 100%="" crop="" treated="" (12.8%="" for="" stone="" fruit).="" the="" percent="" of="" the="" rfd="" that="" will="" be="" used="" by="" the="" food="" exposure="" for="" children="" 1-6="" years="" old="" is="" 6.4="" and="" 1.1%="" assuming="" residues="" are="" present="" at="" tolerance="" and="" average="" field="" residue="" levels,="" respectively,="" and="" 100%="" crop="" treated="" (12.8%="" for="" stone="" fruit).="" the="" percent="" of="" the="" rfd="" that="" will="" be="" used="" by="" the="" food="" exposure="" for="" children="" 7-12="" years="" old="" is="" 4.2="" and="" 0.7%="" assuming="" residues="" are="" present="" at="" tolerance="" and="" average="" field="" residue="" levels,="" respectively,="" and="" 100%="" crop="" treated="" (12.8%="" for="" stone="" fruit).="" epa="" generally="" has="" no="" concern="" for="" exposures="" below="" 100%="" of="" the="" rfd="" because="" the="" rfd="" represents="" the="" level="" at="" or="" below="" which="" daily="" aggregate="" dietary="" exposure="" over="" a="" lifetime="" will="" not="" pose="" appreciable="" risks="" to="" human="" health.="" vii.="" conclusion.="" it="" is="" concluded="" that="" reliable="" and="" complete="" data="" support="" the="" use="" of="" the="" 100-fold="" uncertainty="" factor,="" and="" that="" an="" additional="" 10-fold="" factor="" is="" not="" needed="" to="" ensure="" the="" safety="" of="" infants="" and="" children="" from="" dietary="" exposure.="" f.="" international="" tolerances="" there="" are="" no="" codex="" maximum="" residue="" levels="" (mrls)="" for="" fenbuconazole,="" but="" the="" fenbuconazole="" database="" was="" evaluated="" by="" the="" world="" health="" organization="" (who)="" and="" the="" food="" and="" agriculture="" organization="" (fao)="" expert="" panels="" at="" the="" joint="" meeting="" on="" pesticide="" residues="" (jmpr)="" in="" september="" 1997.="" an="" allowable="" daily="" intake="" (adi="" (same="" as="" the="" rfd)="" of="" 0.03="" mg/kg/day="" and="" a="" total="" of="" 32="" codex="" mrls="" were="" proposed="" in="" the="" jmpr="" report.="" [fr="" doc.="" 99-16238="" filed="" 6-24-99;="" 8:45="" am]="" billing="" code="" 6560-50-f="">