64FR34237A Notice of Filing of Pesticide Petitions
robop...@us.govnews.org
Posting-number: Volume 64, Issue 122, Page 34237A
[Federal Register: June 25, 1999 (Volume 64, Number 122)]
[Notices]
[Page 34237-34243]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr25jn99-59]
-----------------------------------------------------------------------
ENVIRONMENTAL PROTECTION AGENCY
[PF-788A and PF-848A; FRL-6076-9]
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
-----------------------------------------------------------------------
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-park...@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-d...@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 (<greek-a>-(2-[4-chlorophenyl]-
ethyl)-<greek-a>-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
(<greek-a>-(2-[4-chlorophenyl]-ethyl)-<greek-a>-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 Q<INF>1*</INF> of 0.359 x 10<SUP>-2</SUP> (mg/kg/
day)<SUP>-1</SUP> and surface area estimated by (bwt)<SUP>3/4</SUP>.
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/R<SUP>2</SUP>
Molasses (beet)..................... 0.4\5\
Pecans.............................. 0.1
Pulp, dried (beet).................. 1.0
Pulp, dry (grapefruit).............. 4.0 (P)
Refined sugar....................... N/R<SUP>2</SUP>
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 (DEEM<SUP>TM</SUP>, 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 Q<SUP>1*</SUP> value of
0.00359 mg/kg/day<SUP>-1</SUP>. Cancer risk assessments for all
existing and proposed food uses for the U.S. population are as follows:
[[Page 34242]]
----------------------------------------------------------------------------------------------------------------
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