[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: [email protected].
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:
    [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 5.1/6.1 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 Q1* 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 (DEEMTM, 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 Q1* 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]]



----------------------------------------------------------------------------------------------------------------
       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 <

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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