[Federal Register Volume 63, Number 234 (Monday, December 7, 1998)]
[Notices]
[Pages 67476-67483]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-32426]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-848; FRL-6047-2]


Notice of Filing of Pesticide Petitions

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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SUMMARY: This notice announces the initial filing of pesticide 
petitions proposing the establishment of regulations for residues of 
certain pesticide chemicals in or on various food commodities.
DATES: Comments, identified by the docket control number PF-848, must 
be received on or before January 6, 1999.
ADDRESSES: By mail submit written comments to: Public Information and 
Records Integrity Branch, Information Resources and Services Division 
(7502C), Office of Pesticides Programs, Environmental Protection 
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments 
to: Rm. 1132, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
    Comments and data may also be submitted electronically by following 
the instructions under ``SUPPLEMENTARY INFORMATION.'' No confidential 
business information should be submitted through e-mail.
    Information submitted as a comment concerning this document may be 
claimed confidential by marking any part or all of that information as 
``Confidential Business Information'' (CBI). CBI should not be 
submitted through e-mail. Information marked as CBI will not be 
disclosed except in accordance with procedures set forth in 40 CFR part 
2. A copy of the comment that does not contain CBI must be submitted 
for inclusion in the public record. Information not marked confidential 
may be disclosed publicly by EPA without prior notice. All written 
comments will be available for public inspection in Rm. 1132 at the 
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday, 
excluding legal holidays.

FOR FURTHER INFORMATION CONTACT: The product manager listed in the 
table below:

------------------------------------------------------------------------
                                   Office location/
        Product Manager            telephone number          Address
------------------------------------------------------------------------
Mary Waller (PM 21)...........  Rm. 247, CM #2, 703-    1921 Jefferson
                                 308-9354, e-            Davis Hwy,
                                 mail:waller.mary@epam   Arlington, VA
                                 ail.epa.gov.
Cynthia Giles-Parker (PM 22)..  Rm. 247, CM #2, 703-    Do.
                                 305-7740, e-mail:
                                 giles-
parker.cynthia@epamai
l.epa.gov.
------------------------------------------------------------------------

SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as 
follows proposing the establishment and/or amendment of regulations for 
residues of certain pesticide chemicals in or on various food 
commodities under section 408 of the Federal Food, Drug, and Comestic 
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these petitions 
contain data or information regarding the elements set forth in section 
408(d)(2); however, EPA has not fully evaluated the sufficiency of the 
submitted data at this time or whether the data supports granting of 
the petition. Additional data may be needed before EPA rules on the 
petition.
    The official record for this notice of filing, as well as the 
public version, has been established for this notice of filing under 
docket control number [PF-848] (including comments and data submitted 
electronically as described below). A public version of this record, 
including printed, paper versions of electronic comments, which does 
not include any information claimed as CBI, is available for inspection 
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal 
holidays. The official

[[Page 67477]]

record is located at the address in ``ADDRESSES'' at the beginning of 
this document.
    Electronic comments can be sent directly to EPA at:
    [email protected]


    Electronic comments must be submitted as an ASCII file avoiding the 
use of special characters and any form of encryption. Comment and data 
will also be accepted on disks in Wordperfect 5.1 file format or ASCII 
file format. All comments and data in electronic form must be 
identified by the docket number (insert docket number) and appropriate 
petition number. Electronic comments on this notice may be filed online 
at many Federal Depository Libraries.

List of Subjects

    Environmental protection, Agricultural commodities, Food additives, 
Feed additives, Pesticides and pests, Reporting and recordkeeping 
requirements.

    Dated: November 24, 1998.

James Jones,

Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

    Petitioner summaries of the pesticide petitions are printed below 
as required by section 408(d)(3) of the FFDCA. The summaries of the 
petitions were prepared by the petitioners and represent the views of 
the petitioners. EPA is publishing the petition summaries verbatim 
without editing them in any way. The petition summary announces the 
availability of a description of the analytical methods available to 
EPA for the detection and measurement of the pesticide chemical 
residues or an explanation of why no such method is needed.

1. BASF Corporation, Agricultural Products

PP 7E4874

    EPA has received a pesticide petition (PP 7E4874) from BASF 
Corporation, Agricultural Products, P.O. Box 13528, Research Triangle 
Park, NC 27709, proposing pursuant to section 408(d) of the Federal 
Food, Drug, and Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR part 
180 by establishing an import tolerance for residues of the fungicide 
fenpropimorph, (+)-cis-4-(3-(4-tert-butylphenyl)-2-methylpropyl)-2,6-
dimethylmorpholine in or on the raw agricultural commodity bananas at 
1.5 parts per million (ppm) of which no more than 0.3 ppm is found in 
the pulp. EPA has determined that the petition contains data or 
information regarding the elements set forth in section 408(d)(2) of 
the FFDCA; however, EPA has not fully evaluated the sufficiency of the 
submitted data at this time or whether the data supports granting of 
the petition. Additional data may be needed before EPA rules on the 
petition.

A. Residue Chemistry

    1. Plant and animal metabolism. BASF Corporation notes that 
metabolism in plants and animals is understood.
    2. Analytical method. The method of analysis includes extraction, 
liquid/liquid partition, column clean-up, and quantitation by gas 
chromatography/nitrogen-phosphorus detector. The overall fortification 
recoveries from the unpeeled, whole banana, and the peeled (pulp) 
samples together averaged 87.1%  9.3% (N=76).
    3. Magnitude of residues. Fifteen crop residue trials were 
conducted in the banana growing regions of Mexico, South, and Central 
America including three sites in Colombia, four sites in Costa Rica, 
four sites in Ecuador, one site in Guatemala, two sites in Honduras, 
and one site in Mexico. Four sequential applications were made at the 
target rate of 545 g/ha to both bagged and unbagged bananas at each 
site. Fruit from both the bagged and unbagged treatments were harvested 
at 0 days following the last application.
    Whole fruit (peel and pulp) samples and pulp only samples were 
analyzed for all treatments at all sites. Under typical practices 
(bagged bananas) residue in the whole fruit ranged from < the limit of 
quantitation (LOQ) (0.050 milligrams/kilogram (mg/kg)) to a maximum of 
0.4 mg/kg. Banana pulp residues from bagged bananas ranged from < the 
LOQ (0.050 mg/kg to 0.20 mg/kg and averaged 0.0518 mg/kg. The average 
value was calculated by assuming all values below the LOQ were equal to 
one-half the LOQ or 0.025 mg/kg.
    Under worst-case practices (unbagged bananas) residue in the whole 
fruit ranged from < the LOQ (0.050 mg/kg to a maximum of 1.4 mg/kg. 
Banana pulp residues from unbagged bananas ranged from < the LOQ (0.050 
mg/kg to 0.43 mg/kg and averaged 0.1149 mg/kg. The average value was 
calculated by assuming all values below the LOQ were equal to one-half 
the LOQ or 0.025 mg/kg.

B. Toxicological Profile

    1. Acute toxicity. Based on available acute toxicity data 
fenpropimorph does not pose any acute toxicity risks. These studies are 
not required for an import tolerance, but we have provided the 
following paragraph to demonstrate that fenpropimorph is not an acute 
toxicant. The acute toxicity studies place technical fenpropimorph in 
acute toxicity category III for acute oral, dermal, inhalation, and 
skin irritation; and in acute toxicity category IV for eye irritation 
and the technical material is not a skin sensitizer. Additionally, 
results of an acute oral neurotoxicity and a subchronic oral feeding 
neurotoxicity study demonstrated that fenpropimorph was not a 
neurotoxic compound.
    2. Genotoxicity. A Modified Ames Test (1 Study; point mutation): 
Negative; In Vitro Cytogenetics-Human lymphocytes (1 Study; Chromosome 
Aberrations): Negative; Mouse Micronucleus Assay (1 Study; Chromosome 
Aberrations): Negative; In Vitro UDS Test Using Rat Hepatocytes (1 
Study; DNA damage and repair): Negative; fenpropimorph has been tested 
in a total of 4 genetic toxicology assays. These assays were performed 
both in vitro and in vivo and multiple assays were conducted for each 
of the three EPA Guideline requirement categories. Based on the data 
presented in this petition, fenpropimorph does not induce gene 
mutations and does not induce other effects indicative of genotoxicity. 
Fenpropimorph does not pose a mutagenic hazard to humans.
    3. Reproductive and developmental toxicity. A 2-generation 
reproduction study with rats fed dosages of 0, 0.625, 1.25, and 2.5 
milligrams/kilogram/day (mg/kg/day) (average mg/kg/day dose levels for 
both male and female rats) with a reproductive no observed adverse 
effect level (NOAEL) of 2.5 mg/kg/day and with a parental NOAEL of 2.5 
mg/kg/day based on; (i) no treatment-related clinical signs, 
significant body weight changes, parameters of fertility and gestation, 
or macro- or histopathological changes were observed for the parental 
F0 and F1 at all dose levels tested; (ii) in the F1 litters, a slight 
increased incidence of stillborn pups, unfolding of the ear, and slight 
reduced body weight development during lactation were observed in the 
2.5 mg/kg/day dose level group; and (iii) in the F2 litters, no 
treatment-related effects were observed at all dose levels tested.
    A developmental prenatal study was conducted via oral gavage in 
rats resulted in dosages of 0,2.5, 10, 40, and 160 highest dose tested 
(HDT) mg/kg/day from day 6 to 15 of gestation with a development 
toxicity NOAEL of 40 mg/kg/day and a maternal toxicity of 10 mg/kg/day 
based on the following: (i) signs of maternal toxicity, in the form of

[[Page 67478]]

decreased body weights and/or clinical signs observed at dose levels > 
40 mg/kg/day; (ii) maternal animals in the 160 mg/kg/day dose group 
showed an increased incidence of vaginal bleeding from day 10 to 19 of 
gestation and increased placental weight; (iii) maternal animals in the 
160 mg/kg/day dose group showed an increase in the number of 
resorptions as compared to controls; (iv) decreases in fetal body 
weights and size and number of viable fetus were observed at the HDT; 
(v) a significant number of fetuses had a finding of cleft palate in 
the high dose group tested were observed; and (vi) litters from animals 
treated at the lower doses remained entirely unaffected.
    A second developmental perinatal study was conducted via oral 
gavage in rats resulted in dosages of 0, 2.5, 10, 40, and 160 HDT mg/
kg/day from day 15 to 21 of gestation with a development toxicity NOAEL 
of 40 mg/kg/day and a maternal toxicity of 40 mg/kg/day based on the 
following: (i) four animals died on days 1 to 6 after delivery; (ii) 
signs of maternal toxicity, in the form of decreased body weights and/
or clinical signs observed at the top dose level; (iii) at birth, body 
weight was significantly reduced in the pups of the top dose group; 
(iv) the brood care at the top dose group animals was generally 
unsatisfactory and led to a high perinatal mortality of the fetuses 
with only 30 viable fetuses left on day 1 post partum, the dead fetuses 
showed no increased incidence of malformations; (v) the few surviving 
pups of the dams at the 160 mg/kg/day dose group showed decreases in 
fetal body weights and size was retarded, no disturbances were found in 
the functional and behavioral tests that were conducted on the 
surviving pups; (vi) at necropsy, all dams showed comparable number of 
implantations and the animals scarified as scheduled revealed no 
treatment-related changes and also the mean organ weights were similar 
in treated and untreated groups; and (vii) litters from animals treated 
at the lower doses remained entirely unaffected and no pathological 
findings were also noted in these pups.
    A series of two developmental study, Study A dose levels were 0, 
2.4, 12, 36, and 60 mg/kg/day and, Study B dose levels were 0, 7.5, 15, 
and 30 mg/kg/day were conducted via oral gavage in rabbits resulted in 
dosages of 0, 2.4, 7.5, 12, 15, 30, 36, and 60 HDT mg/kg/day with a 
development toxicity NOAEL of 15 mg/kg/day and a maternal toxicity of 
15 mg/kg/day based on the following: (i) Severe clinical signs and/or 
mortality were observed at dose levels > 30 mg/kg/day; (ii) decreased 
body weight, food consumption, and absorption/premature delivery in the 
36 and 60 mg/kg/day dose groups which survived to the end of the 
studies; (iii) fetal effects consisted of high number of dead fetuses 
and several gross malformations (pseudo ancylosis, syndactylia, 
micromelia, aplasia of the twelveth rib) at the HDT; and (iv) pseudo 
ancylosis was also seen in 1 fetus from the 12 mg/kg/day dose group and 
in 6 fetuses in the 36 mg/kg/day dose level, but this finding is known 
to occur spontaneously in rabbits of this strain used and the 
contractures usually normalize during early stages of life. Due to the 
severe effect at the high dose level (HDL), these effects may be 
considered to represent a specific teratogenic effect of the treatment.
    4. Chronic toxicity. Based on review of the available data, BASF 
believes the Reference Dose (RfD) for fenpropimorph will be based on a 
2-year feeding study in rats with a threshold NOAEL of 0.3 mg/kg/day. 
Using an uncertainty factor of 100, the RfD is calculated to be 0.003 
mg/kg/day. The following are summaries of the pertinent toxicity data 
supporting fenpropimorph tolerances. Additionally, these are summaries 
of EPA reviewed Phase III Toxicology Summaries prepared by BASF 
Corporation for EPA.
    A 1 year feeding study in dogs fed dosages of 0, 0.8, 3.2, or 12.7 
mg/kg/day with a NOAEL of 3.2 mg/kg/day based on the following effects: 
(i) no changes in body weights nor food consumption for both the high 
dose male and female dogs were observed at all tested dose levels as 
compared to controls; (ii) blood biochemistry values were slightly 
increased in high dose males (alkaline phosphatase) and females 
(alanine aminotransferase); (iii) the cholininesterase from plasma, red 
blood cells, and brain showed comparable activities in treated and 
untreated dogs; and (iv) neither organ weight analyses nor macro- and 
histopathological examinations demonstrated any treatment related 
effects as compared to controls.
    A combined chronic feeding/oncogenicity study was performed in rats 
being fed dosages of 0, 0.2, 0.3, 1.7 and 8.8 mg/kg/day (males) and 0, 
0.2, 0.4, 2.1, and 11.2 mg/kg/day (females) with a NOAEL of 0.3 mg/kg/
day (males) and 0.4 mg/kg/day (females) based on the following effects: 
(i) decreased in body weights were observed in both males and female 
rat at dose levels > 1.7 mg/kg/day with a very slight progression of 
severity to the upper level; (ii) decreased food consumption in female 
rats at the HDT; (iii) significantly lower activities of plasma 
cholinesterase were noted in male and female rats in the HDT where as 
no effect was found for red blood cell cholinesterase values; (iv) at 
terminal sacrifice, reduced activities of brain cholinesterase were 
detected in males, only, at the 1.7 and 8.8 mg/kg/day dose levels 
groups tested; (v) increased liver weights for females at dose levels > 
2.1 mg/kg/day and in males of the top dose group; (vi) microscopic 
findings were observed in the liver of male and female rats in the 
HDLs, only; and (vii) no increased incidence of neoplasms occurred at 
any dose levels tested in this study.
    A carcinogenicity study in mice fed dosages of 0, 0.5, 3.0, 16, and 
106 HDT mg/kg/day (males) and 0, 0.5, 3.5, 17, and 118 HDT mg/kg/day 
(females) with a NOAEL of 3.0 and 3.5 mg/kg/day for male and female 
mice, respectively, based on the following effects: (i) decreased body 
weights and slight inferior food conversion ratio were observed in both 
male and female mice at the HDT; (ii) decreased cholinesterase 
activities were observed in red blood cells for female mice in the 17 
and 118 mg/kg/day dose level tested at terminal sacrifice; (iii) at the 
HDT increased liver weights were observed for female mice at terminal 
sacrifice and in males at interim sacrifice after 52 weeks; and (iv) no 
increased incidence of neoplasms occurred at any dose levels tested in 
this study.
    5. Endocrine disruption. No specific tests have been performed with 
fenpropimorph to determine whether the chemical may have an effect in 
humans that is similar to an effect produced by naturally occurring 
estrogen or other endocrine effects. However, there are significant 
findings in other relevant toxicity studies, i.e. teratology and multi-
generation reproductive studies, that would suggest fenpropimorph 
produces endocrine related effects.

C. Aggregate Exposure

    Based on the information above it is concluded that the RfD used to 
assess safety to children should be 0.003 mg/kg/day dose level 
established in the 2- year rat oral feeding study. Using the assumption 
stated for the general population, BASF concluded that the most 
sensitive child population group is that of children > 1 year. Using 
the same RfD and the same conservative exposure assumptions employed in 
the dietary risk analysis for the general population. It was calculated 
that the exposure to this group to be approximately > 11% of the RfD 
for all uses proposed in this document. Therefore, based on the 
completeness and reliability of the

[[Page 67479]]

toxicity data, and the exposure assessment discussed above, BASF 
concludes that there is a reasonable certainty that no harm will result 
to infants and children from aggregate exposure to residues of 
fenpropimorph, including all anticipated dietary exposure.
    1. Dietary exposure. For the purpose of assessing the potential 
chronic dietary exposure, BASF has estimated aggregate exposure based 
on Theoretical Maximum Residue Contribution (TMRC) from the tolerance 
of fenpropimorph on bananas at 0.3 ppm the maximum residue found in 
bananas. The TMRC is a ``worse case'' estimate of dietary exposure 
since it is assumed that 100% of all crops for which the tolerances are 
established are treated and that pesticide residues are always found at 
tolerance levels. Based on the expected RfD of 0.003 mg/kg/day (from 
the NOAEL determined in the 2-year feeding study in rats and a 100 fold 
safety factor) and the tolerance level residue chronic dietary exposure 
of the general population is less than 2.5% of the RfD. Therefore, 
based on the completeness and reliability of the toxicity data, and the 
exposure assessment discussed above, BASF concludes that there is a 
reasonable certainty that no harm will result from aggregate exposure 
to residues of fenpropimorph, including all anticipated dietary 
exposure.
    2. Food. BASF has reviewed the available toxicology database to 
determine the endpoints of concern. For Fenpropimorph BASF believes 
there is no concern regarding an acute dietary risk since the available 
data do not indicate any evidence of significant toxicity from a 1-day 
or single, event exposure by the oral route.
    3. Drinking water/Non-dietary exposure. There are no other 
potential sources (such as in drinking water and exposure from non-
occupational sources) of exposure to fenpropimorph for the general 
population to residues of fenpropimorph due to the fact the action 
being requested is to establish an import tolerance, only.
    4. Threshold and non-threshold effects. The proposed RfD for 
fenpropimorph is based on a 2-year feeding study in rats with a 
threshold NOAEL of 0.3 mg/kg/day. Using an uncertainty factor of 100, 
the RfD is calculated to be 0.003 mg/kg/day. Fenpropimorph is 
considered not to be a carcinogenic material. Therefore, it should be 
regulated by the traditional RfD approach to quantify human risk.

D. Cumulative Effects

    BASF has considered the potential for cumulative effects of 
fenpropimorph and other substances that have a common mechanism of 
toxicity. BASF is not aware of any other active ingredients which is 
structurally similar to fenpropimorph that are registered on bananas. 
Therefore, BASF has considered only the potential risks of 
fenpropimorph in its exposure assessment.

E. Safety Determination

    1. U.S. population. Using the exposure assumptions described above, 
based on the completeness and there liability of the toxicity data, 
BASF has estimated that aggregate exposure to fenpropimorph will 
utilize > 2.5% of the RfD for the U.S. population. EPA generally has no 
concern for exposure below 100% of the RfD. Therefore, based on the 
completeness and reliability of the toxicity data, and the exposure 
assessment discussed above, BASF concludes that there is a reasonable 
certainty that no harm will result from aggregate exposure to residues 
of fenpropimorph, including all anticipated dietary exposure.
    2. Infants and children. The findings in the rat and rabbit are 
most likely as a result of excessive maternal toxicity, treatment of 
pregnant rats and rabbits with fenpropimorph induced embryotoxic 
effects which manifested themselves in the form of early resorptions 
and structural anomalies in the offspring. In both the rat and rabbit, 
the dose-effect relationship was rather steep and showed clear 
threshold levels. At dose levels below the threshold of maternal 
toxicity, reproductive parameters as well as the offsprings remained 
entirely unaffected. This data demonstrates that the rat and rabbit are 
similarly sensitive to fenpropimorph. Additionally, the NOAEL of 0.3 
mg/kg/day from the chronic rat study used to set the RfD is 33x to 50x 
lower than the maternal NOAELs established in the rat and rabbit 
teratology studies, respectively. The developmental effects observed in 
either the rat or rabbit occurred only at maternally toxic doses. 
Therefore, no additional safety factor is needed for children.
    A 2-generation reproduction study with rats fed dosages of 0, 
0.625, 1.25, and 2.5 mg/kg/day (average mg/kg/day dose levels for both 
male and female rats) with a reproductive NOAEL of 2.5 mg/kg/day and 
with a parental NOAEL of 2.5 mg/kg/day based on: (i) no treatment-
related clinical signs, significant body weight changes, parameters of 
fertility and gestation, or macro-or histopathological changes were 
observed for the parental F0 and F1 at all dose levels tested; and (ii) 
in the F1 litters, a slight increased incidence of stillborn pups, 
unfolding of the ear, and slight reduced body weight development during 
lactation were observed in the 2.5 mg/kg/day doselevel group; (iii) in 
the F2 litters, no treatment-related effects were observed at all dose 
levels tested. As stated above, the NOAEL of 0.3 mg/kg/day from the 
chronic rat study used to set the RfD is approximately 8x lower than 
the maternal NOAEL established in the rat reproduction study. 
Therefore, no additional safety factor is needed for children.

F. International Tolerances

    A maximum residue level has not been established under Codex 
Alimentarius Commission for fenpropimorph in any of the crops 
petitioned: bananas.

2. Rohm and Haas Company

PP 1F3995, 1F3989 and 2F4154

    EPA has received data intended to satisfy the conditions which 
caused time-limits to be placed on the tolerances proposed by the three 
pesticide petitions PP 1F3995, 1F3989, and 2F4154 from Rohm and Haas 
Company, 100 Independence Mall West, Philadelphia, PA 19106-2399, 
proposing pursuant to section 408(d) of the Federal Food, Drug, and 
Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR part 180 by extending 
until December 31, 2001 the time-limited tolerances for residues of 
fenbuconazole (alpha-(2-(4-chlorophenyl)-ethyl)-alpha-phenyl-3-(1H-
1,2,4-triazole)-1-propanenitrile) in or on the raw agricultural 
commodities bananas at 0.3 parts per million (ppm), banana pulp at 0.05 
ppm, stone fruits (except plums and prunes) at 2.0 ppm, and pecans at 
0.1 ppm. EPA has determined that the submissions concern the additional 
data requirements as elements set forth in section 408(f)(1) of the 
FFDCA; however, EPA has not fully evaluated the sufficiency of the 
submitted data at this time.
    A summary of the data that support the tolerances, and of exposure 
to and risks from the use of fenbuconazole, is printed below. This 
summary of the petitions was prepared by the registrant and represents 
the views of the registrant. EPA is publishing the petition summary 
with only minor editing changes. The petition summary includes an 
announcement of the availability of the analytical methods available to 
EPA for the detection and

[[Page 67480]]

measurement of the pesticide chemical residues.

A. Residue Chemistry

    The tolerance expression for fenbuconazole residues in or on 
bananas, banana pulp, pecans, and stone fruit (except plums and prunes) 
is the combined residues of fenbuconazole (alpha-(2-(4-chlorophenyl)-
ethyl)-alpha-phenyl-3-(1H-1,2,4-triazole)-1-propanenitrile) and its 
metabolites cis-5-(4-chlorophenyl)-dihydro-3-phenyl-3-(1H-1,2,4-
triazole-1-ylmethyl)-2-3H-furanone and trans-5-(4-chlorophenyl)-
dihydro-3-phenyl-3-(1H-1,2,4-triazole-1-ylmethyl)-2-3H-furanone. 
Residues of these compounds are combined and expressed as parent 
compound to determine the total residue in or on bananas, banana pulp, 
pecans, and stone fruit (except plums and prunes). No changes in the 
tolerances of fenbuconazole or in the tolerance expression (parent plus 
lactone metabolites) for pecans, bananas, or stone fruit from that 
indicated in 40 CFR 180.480 will be necessary for the tolerance 
extensions. Current tolerances for fenbuconazole are 0.3 ppm for banana 
whole fruit, 0.05 ppm for banana pulp, 0.1 ppm for pecans, and 2.0 ppm 
for the stone fruit crop group (except plums and prunes). There is also 
a current time-limited (Section 18) tolerance for fenbuconazole on 
blueberries of 1.0 ppm.
    1. Analytical method. Fenbuconazole residues (parent plus lactones) 
are measured in pecans, stone fruit, and bananas at an analytical 
sensitivity of 0.01 milligrams/kilogram (mg/kg) by soxhlet extraction 
of samples in methanol, partitioning into methylene chloride, 
redissolving in toluene, clean up on silica gel, and gas liquid 
chromatography using nitrogen specific thermionic detection.
    2. Magnitude of residues--i. Pecans. Four field trials were 
conducted in pecans. Eight to ten applications were made at the maximum 
use rate of 0.125 lb a.i./A, and nuts were harvested 28 days after the 
last application. Field residue values in nutmeat for the four trials 
were 0.004, 0.004, <0.01, and <0.01 ppm.
    ii. Bananas. Fourteen field trials were conducted on pulp from 
bagged bananas, and nine field trials were conducted on whole fruit 
from bagged bananas. Bagged bananas are typically used in commerce. 
Eight applications (5 and 7 applications in two trials) were made at 
the maximum use rate of 0.09 lb a.i./A and bananas were harvested on 
the last day of application. The highest field residue values were 
0.019 ppm in pulp and 0.0589 ppm in whole fruit. The average field 
residue values were 0.004 ppm in pulp and 0.010 ppm in whole fruit.
    iii. Stone fruit--a. Peaches. Ten field trials were conducted on 
peaches. Seven to ten applications were made at the maximum use rate of 
0.1 lb a.i./A and fruit were harvested on the last day of application. 
The highest field residue value was 0.5096 ppm, and the average field 
residue value was 0.351 ppm.
    b. Cherries. Eleven field trials were conducted on cherries. Five 
to six applications were made at the maximum use rate of 0.1 lb a.i./A 
and fruit were harvested on the last day of application. The highest 
field residue value was 0.641 ppm, and the average field residue value 
was 0.434 ppm.
    c. Apricots. Two field trials were conducted on apricots. Six 
applications were made at the maximum use rate of 0.125 lb a.i./A and 
fruit was harvested on the last day of application. The field residue 
values in four samples measured were 0.168, 0.226, 0.268, and 0.279 
ppm.

B. Toxicological Profile

    The toxicology of fenbuconazole is summarized in the following 
sections. There is no evidence to suggest that human infants and 
children will be more sensitive than adults, that fenbuconazole will 
modulate human endocrine systems at anticipated dietary exposures, or 
cause cancer in humans at the dietary exposures anticipated for this 
fungicide. While the biochemical target for the fungicidal activity of 
members of the DMI class is shared, it cannot be concluded that the 
mode of action of fenbuconazole which produces phytotoxic effects in 
plants or toxic effects in animals is also common to a single class of 
chemicals.
    1. Acute toxicity. Fenbuconazole is practically nontoxic after 
administration by the oral, dermal andrespiratory routes. The acute 
oral 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), in consequentially irritating to 
the eyes (mean irritation score= 0), and it is not a sensitizer. No 
evidence exists regarding differential sensitivity of children and 
adults to acute exposure.
    2. Genotoxicity. Fenbuconazole has been adequately tested in a 
variety of in vitro and in vivo mutagenicity tests. It is negative in 
the Ames test, negative in in vitro and in vivo somatic and germcell 
tests, and did not induce unscheduled in DNA synthesis (UDS). 
Fenbuconazole is not genotoxic.
    3. Reproductive and developmental toxicity. These conclusions were 
extracted from 60 FR 27419, May 24, 1995. Fenbuconazole is not 
teratogenic. The maternal no observed adverse effect level (NOAEL) in 
rabbits was 10 mg/kg/day and 30 mg/kg/day in rats. The fetal NOAEL was 
30 mg/kg/day in both species. The parental NOAEL was 4.0 mg/kg/day (80 
ppm) in a 2-generation reproduction study in rats. The reproductive 
NOAEL in this study was greater than 40.0 mg/kg/day (800 ppm; highest 
dose tested (HDT)). Fenbuconazole had no effect on male reproductive 
organs or reproductive performance at any dose. The adult lowest 
observed adverse effect level (LOAEL) was 40.0 mg/kg/day (800 ppm; 
HDT). Systemic effects of decreased body weight gain; maternal deaths; 
and hepatocellular, adrenal, and thyroid follicular cell hypertrophy 
were observed. No effects on neonatal survival or growth occurred below 
the adult toxic levels. Fenbuconazole does not produce birth defects 
and is not toxic to the developing fetus at doses below those which are 
toxic to the mother.
    4. Subchronic toxicity. In a 21 day dermal toxicity study in the 
rat, the NOAEL was greater than 1,000 mg/kg/day, with no effects seen 
at this limit dose.
    5. Chronic toxicity. In 2 year combined chronic toxicity/ 
oncogenicity studies in rats, the NOAEL was 80 ppm (3.03 mg/kg/day for 
males and 4.02 mg/kg/day for females) based on decreased body weight, 
and liver and thyroid hypertrophy. In a 1 year chronic toxicity study 
in dogs, the NOAEL was 150 ppm (3.75 mg/kg/day) based on decreased body 
weight, and increased liver weight. The LOAEL was 1,200 ppm (30 mg/kg/
day). In a 78 week oncogenicity study in mice, the NOAEL was 10 ppm 
(1.43 mg/kg/day). The LOAEL was 200 ppm (26.3 mg/kg/day, males) and 650 
ppm (104.6mg/kg/day, females) based on increased liver weights and 
histopathological effects on the liver. These effects were consistent 
with chronic enzyme induction from high dose dietary exposure.
    A Reference Dose (RfD) for systemic effects at 0.03 mg/kg/day was 
established by EPA in 1995 based on the NOAEL of 3.0 mg/kg/day from the 
rat chronic study. This RfD adequately protects both adults and 
children.
    Twenty-four month rat chronic feeding/carcinogenicity studies with 
fenbuconazole showed effects at 800 and 1,600 ppm. Fenbuconazole 
produced a minimal, but statistically

[[Page 67481]]

significant increase in the incidence of combined thyroid follicular 
cell benign and malignant tumors. These findings occurred only in male 
rats following life-time ingestion of very high levels (800 and 1,600 
ppm in the diet) fenbuconazole. Ancillary mode-of-action studies 
demonstrated that the increased incidence of thyroid tumors was 
secondary to increased liver metabolism and biliary excretion of 
thyroid hormone in the rat. This mode of action is a nonlinear 
phenomenon in that thyroid tumors occur only at high doses where there 
is an increase in liver mass and metabolic capacity of the liver. At 
lower doses of fenbuconazole in rats, the liver is unaffected and there 
is no occurrence of the secondary thyroid tumors. Worst-case estimates 
of dietary intake of fenbuconazole in human adults and children 
indicate effects on the liver or thyroid, including thyroid tumors, 
will not occur, and there is a reasonable certainty of no harm.
    In support of the findings above, EPA's Science Advisory Board has 
approved a final thyroid tumor policy, confirming that it is reasonable 
to regulate chemicals on the basis that there exists a threshold level 
for thyroid tumor formation, conditional upon providing plausible 
evidence that a secondary mode of action is operative. This decision 
supports a widely-held and internationally respected scientific 
position.
    In a 78 week oncogenicity study in mice there was no statistically 
significant increase of any tumor type in males. There were no liver 
tumors in the control females and liver tumor incidences in treated 
females just exceeded the historical control range. However, there was 
a statistically significant increase in combined liver adenomas and 
carcinomas in females at the high dose only (1,300 ppm; 208.8 mg/kg/
day). In ancillary mode-of-action studies in female mice, the increased 
tumor incidence was associated with changes in several parameters in 
mouse liver following high doses of fenbuconazole including: an 
increase in P450 enzymes (predominately of the CYP 2B type), an 
increase in cell proliferation, an increase in hepatocyte hypertrophy, 
and an increase in liver mass (or weight). Changes in these liver 
parameters as well as the occurrence of the low incidence of liver 
tumors were nonlinear with respect to dose (i.e., were observed only at 
high dietary doses of fenbuconazole). Similar findings have been shown 
with several pharmaceuticals, including phenobarbital, which is not 
carcinogenic in man. The nonlinear relationship observed with respect 
to liver changes (including the low incidence of tumors) and dose in 
the mouse indicates that these findings should be carefully considered 
in deciding the relevance of high-dose animal tumors to human dietary 
exposure.
    The Carcinogenicity Peer Review Committee (PRC) of the Health 
Effects Division (HED) classified fenbuconazole as a Group C tumorigen 
(possible human carcinogen with limited evidence of carcinogenicity in 
animals). The PRC used a low-dose extrapolation model. The 
Q1* risk factor applied (1.06 x 10-2 (mg/kg/
day)-1) was based on the rat oncogenicity study and surface 
area was estimated by (body weight)3/4.
    Since the PRC published the above estimate they have agreed that 
low-dose extrapolation for fenbuconazole, based on rat thyroid tumors, 
is inappropriate given the EPA's policy regarding thyroid tumors and 
the data which exist for fenbuconazole. The PRC agrees that the more 
appropriate data set for the low-dose extrapolation and risk factor 
estimate is the mouse. From these data a Q1* of (0.36 x 
10-2(mg/kg/day)-1) is calculated when surface 
area is estimated by (bodyweight)3/4. All estimates of 
dietary oncogenic risk are based on this risk factor.
    Since fenbuconazole will not leach into groundwater (see below) 
there is no increased cancer risk from this source. Neither is 
fenbuconazole registered for residential use, so there is no risk from 
non-occupational residential exposure either. All estimates of excess 
risk to cancer are from dietary sources.
    6. Endocrine disruption. The mammalian endocrine system includes 
estrogen and androgens as well as several other hormone systems. 
Fenbuconazole does not interfere with the reproductive hormones. Thus, 
fenbuconazole is not estrogenic or androgenic.
    While fenbuconazole interferes with thyroid hormones in rats by 
increasing thyroid hormone excretion, it does so only secondarily and 
only above those dietary levels which induce metabolism in the liver. 
These effects are reversible in rats, and humans are far less sensitive 
to these effects than rats. The RfD protects against liver induction 
because it is substantially below the animal NOAEL. As noted 
previously, maximal human exposures are far below the RfD level, and 
effects on human thyroid will not occur at anticipated dietary levels.
    We know of no instances of proven or alleged adverse reproductive 
or developmental effects to domestic animals or wildlife as a result of 
exposure to fenbuconazole or its residues. In fact, no effects should 
be seen because fenbuconazole has low octanol/water partition 
coefficients and is known not to bioaccumulate. Fenbuconazole is 
excreted within 48 hours after dosing in mammalian studies.

C. Aggregate Exposure and Risk

    1. Dietary exposure--Chronic exposure and risk. Risk associated 
with chronic dietary exposure from fenbuconazole was assessed on two 
level using two dietary exposure models. In the first assessment, 
tolerance level residues were assumed and in the second assessment 
average field trial residues were used. Both assessments assumed 100% 
of crop treated, except for stone fruit in which 12.8% of crop treated 
was assumed 63 FR 31636, June 10, 1998, (FRL 5791-9). Residues in pulp 
from bagged bananas were used in the assessments, since only bagged 
bananas are used in commerce. The Anticipated Residue Contribution 
(ARC) from all existing food uses of fenbuconazole was assessed; these 
foods included stone fruit (except plums, and prunes), bananas, pecans, 
and blueberries).
    The RfD used for the chronic dietary analysis is 0.03 mg/kg/day. 
Potential chronic exposures were estimated using NOVIGEN's Dietary 
Exposure Evaluation Model (DEEM Version 5.31), which uses USDA food 
consumption data from the 1989-1992 survey, and the EPA's Dietary Risk 
Evaluation System (DRES), which uses USDA food consumption data from 
1977-1978. The existing fenbuconazole tolerances and average 
fenbuconazole residues result in ARCs that are equivalent to the 
following percentages of the RfD.:

 
----------------------------------------------------------------------------------------------------------------
       Population Subgroup           DEEM\1\ %RfD        DEEM\2\ %RfD        DRES\1\ %RfD        DRES\2\ %RfD
----------------------------------------------------------------------------------------------------------------
U. S. Population (48 States)....  0.2%                <0.01%              0.31%               0.06%
Nursing Infants (<1 year old)...  0.4%                0.1%                1.47%               0.27%
Non-Nursing Infants (<1year old)  1.3%                0.2%                2.46%               0.45%

[[Page 67482]]

 
Children (1-6 years old)........  0.5%                0.1%                0.74%               0.14%
Children (7-12 years old).......  0.3%                <0.01%              0.44%               0.08%
Females (13+/nursing)...........  0.3%                <0.01%              0.28%               0.05%
----------------------------------------------------------------------------------------------------------------
\1\ Assumes residues are present at tolerance levels and 100% of crop treated except stone fruit (12.8% of crop
  treated).
\2\ Assumes residues are present at their average field residue levels and 100% of crop treated except stone
  fruit (12.8% of crop treated).

D. Aggregate Cancer Risk for U.S. Population

    Fenbuconazole has been classified as a Group C Carcinogen with a 
Q,* value of 0.00359 mg/kg/day-1. Assuming 
fenbuconazole residues are present at tolerance levels and assuming 
100% crop treated, except stone fruit (12.8% of crop treated assumed), 
give a cancer risk assessment for existing food uses for the U.S. 
population of 3.31 x 10-7 for the DRES and DEEM analyses, 
respectively. Assuming fenbuconazole residues are present at average 
field residue levels and assuming 100% of crop treated, except stone 
fruit (12.8% of crop treated assumed), gives a cancer risk assessment 
for existing food uses for the U.S. population of 6.34 x 
10-8 and 4.94 x 10-8 for the DRES and DEEM 
analyses, respectively.
    The individual crop cancer risk assessments for bananas, stone 
fruit, pecans, and blueberries were 4.11 x 10-8, 2.78 x 
10-7, 1.73 x 10-9, and 9.74 x 10-9, 
respectively (DRES analysis), and were 5.11 x 10-8, 1.67 x 
10-7, 7.37 x 10-10, and 1.38 x 10-8, 
respectively (DEEM analysis).
    1. Drinking water. Fenbuconazole has minimal tendency to 
contaminate groundwater or drinking water because of its adsorptive 
properties on soil, solubility in water, and degradation rate. Data 
from laboratory studies and field dissipation studies have been used in 
the USDA PRZM/GLEAMS computer model to predict the movement of 
fenbuconazole. The model predicts that fenbuconazole will not leach 
into groundwater, even if heavy rainfall is simulated. The modeling 
predictions are consistent with the data from environmental studies in 
the laboratory and the results of actual field dissipation studies. 
There are no data on passage of fenbuconazole through water treatment 
facilities and there are no State water monitoring programs which 
target fenbuconazole.
    2. Non-dietary exposure. Fenbuconazole has no veterinary 
applications and is not approved for use in swimming pools. It is not 
labeled for application to residential lawns or for use on ornamentals, 
nor is fenbuconazole applied to golf courses or other recreational 
areas. Therefore, there are no data to suggest that these exposures 
could occur. Any acute exposures to children would come from dietary 
exposure or inadvertent dermal contact . As previously discussed, 
fenbuconazole is neither orally or dermally acutely toxic. Thus, there 
is a reasonable certainty that no exposure would occur to adults, 
infants or children from these sources.

E. Cumulative Effects

    The toxicological effects of fenbuconazole are related to its 
effects on rodent liver. These are manifested in rats and mice 
differently. Fenbuconazole causes liver toxicity in rats and mice in 
the form of hepatocyte enlargement and enzyme induction. In rats the 
liver enzyme induction causes increased biliary removal of thyroxin and 
the hepatotoxicity leads to elevated thyroid stimulating hormone levels 
with subsequent development of thyroid gland hyperplasia and tumors. 
This process is reversible and demonstrates a dose level below which no 
thyroid gland stimulation can be demonstrated in rats. Liver toxicity 
in the mouse is manifest by hepatocyte enlargement, enzyme induction, 
and hepatocellular hyperplasia (cell proliferation). These processes 
are associated with the appearance of a small number of liver tumors. 
In both cases, rats and mice, the initiating event(s) do not occur 
below a given dose, i.e., the effects are nonlinear, and the processes 
are reversible. Therefore, since the tumors do not occur at doses below 
which hepatocyte enlargement and enzyme induction occur, the RfD 
protects against tumors because it is substantially below the NOAEL for 
liver effects and maximal human exposures are below the RfD. Effects on 
human thyroid will not occur at anticipated dietary levels. The mode of 
action data should be carefully considered in deciding the relevance of 
these high-dose animal tumors to human dietary exposure.
    Extensive data are available on the biochemical mode of action by 
which fenbuconazole produces animal tumors in both rats and mice. 
However, there are no data which suggest that the mode of action by 
which fenbuconazole produces these animal tumors or any other 
toxicological effect is common to all fungicides of this class. In 
fact, the closest structural analog to fenbuconazole among registered 
fungicides of this class is not tumorigenic in animals even at 
maximally tolerated doses and has a different spectrum of toxicological 
effects.

F. Safety Determination.

    1. All crops (current food uses). The exposure to fenbuconazole 
from all current food uses will utilize 1.3% (non-nursing infants < 1 
year old) and 0.4% (nursing infants < 1 year old) of the RfD (DEEM 
analysis), and will utilize 2.46% (non-nursing infants < 1 year old) 
and 1.47% (nursing infants < 1 year old) of the RfD (DRES analysis), 
assuming residues are present at tolerance levels and assuming 100% of 
crop treated, except stone fruit (12.8% of crop treated assumed). The 
percent of the RfD that will be utilized by children 1-6 years old and 
7-12 years old is 0.5 and 0.3%, respectively (DEEM analysis), and 0.74 
and 0.44%, respectively (DRES analysis), assuming residues are present 
at tolerance levels and assuming 100% crop treated, except stone fruit.
    2. Stone Fruit (except plums and prunes). The exposure to 
fenbuconazole from stone fruit (excluding plums and prunes) will 
utilize 1.1% of the RfD for non-nursing infants < 1 year old, 0.3% of 
the RfD for nursing infants < 1 year old, 0.4% of the RfD for children 
1-6 years old, and 0.2% of the RfD for children 7-12 years old (DEEM 
analysis) assuming residues are present at tolerance levels and 
assuming 100% of crop treated, except stone fruit (12.8% of crop 
treated assumed).
    3. Bananas. The exposure to fenbuconazole from bananas will utilize 
0.2% of the RfD for non-nursing infants < 1 year old, 0.1% of the RfD 
for nursing infants < 1 year old, 0.1% of the RfD for children 1-6 
years old, and 0.1% of the RfD for children 7-12 years old (DEEM 
analysis) assuming residues are present at tolerance levels and 
assuming 100% of crop treated, except stone fruit (12.8% of crop 
treated assumed).
    4. Pecans. The exposure to fenbuconazole from pecans will utilize

[[Page 67483]]

<0.01% of the RfD for each of the population subgroups: non-nursing 
infants < 1 year old, nursing infants < 1 year old, children 1-6 years 
old, and children 7-12 years old (DEEM analysis) assuming residues are 
present at tolerance levels and assuming 100% of crop treated, except 
stone fruit (12.8% of crop treated assumed).
    5. Blueberries. The exposure to fenbuconazole from blueberries, 
will utilize < 0.01% of the RfD for each of the population subgroups, 
non-nursing infants < 1 year old, nursing infants < 1 year old, 
children 1-6 years old, and children 7-12 years old (DEEM analysis) 
assuming residues are present at tolerance levels and assuming 100% of 
crop treated, except stone fruit (12.8% of crop treated assumed).
    Section 408 of the FFDCA provides that EPA shall apply an 
additional tenfold margin of safety for infants and children in the 
case of threshold effects to account for pre- and post-natal toxicity 
and the completeness of the database unless EPA determines that a 
different margin of safety will be safe for infants and children. 
Margins of safety are incorporated into EPA risk assessments either 
directly through use of a margin of exposure (MOE) analysis or through 
using uncertainty (safety) factors in calculating a dose level that 
poses no appreciable risk to humans. In either case, EPA generally 
defines the level of appreciable risk as exposure that is greater than 
1/100 of the NOAEL in the animal study appropriate to the particular 
risk assessment. This hundredfold uncertainty (safety) factor/MOE 
exposure (safety) is designed to account for combined inter- and intra-
species variability. EPA believes that reliable data support using the 
standard hundredfold margin/factor but not the additional tenfold 
margin/factor when EPA has a complete data base under existing 
guidelines and when the severity of the effect in infants or children 
or the potency or unusual toxic properties of a compound do not raise 
concerns regarding the adequacy of the standard margin/factor.
    The Agency FQPA Safety Factor Committee removed the additional 10x 
safety factor to account for sensitivity of infants and children. Rohm 
and Haas Company concludes that there is a reasonable certainty that no 
harm will result from exposure to fenbuconazole residues to the U.S. 
population or to infants and children.

G. International Tolerances

    There are no Codex maximum residue limits (MRLs) for fenbuconazole, 
but the fenbuconazole database was evaluated by the WHO and FAO Expert 
Panels at the Joint Meeting on Pesticide Residues (JMPR) in September, 
1997. An ADI (RfD) of 0.03 mg/kg/day was proposed and accepted 
(Pesticide Residues in Food--WHO/FAO Report 1997; No. 145), and a total 
of 36 Codex MRLs, including MRLs for pecans, stone fruit, and bananas, 
have been submitted for review.
[FR Doc. 98-32426 Filed 12-4-98; 8:45 am]
BILLING CODE 6560-50-F