[Federal Register Volume 63, Number 20 (Friday, January 30, 1998)]
[Notices]
[Pages 4631-4640]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-2363]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-788; FRL-5766-2]


Notice of Filing of Pesticide Petitions

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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SUMMARY: This notice announces the initial filing of pesticide 
petitions proposing the establishment of regulations for residues of 
certain pesticide chemicals in or on various food commodities.
DATES: Comments, identified by the docket control number PF-788, must 
be received on or before March 2, 1998.
ADDRESSES: By mail submit written comments to: Public Information and 
Records Integrity Branch (7502C), Information Resources and Services 
Division, Office of Pesticides Programs, Environmental Protection 
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments 
to: Rm. 119, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
    Comments and data may also be submitted electronically to: opp-
[email protected]. Follow the instructions under ``SUPPLEMENTARY 
INFORMATION.'' No confidential business information should be submitted 
through e-mail.
    Information submitted as a comment concerning this document may be 
claimed confidential by marking any part or all of that information as 
``Confidential Business Information'' (CBI). CBI should not be 
submitted through e-mail. Information marked as CBI will not be 
disclosed except in accordance with procedures set forth in 40 CFR part 
2. A copy of the comment that does not contain CBI must be submitted 
for inclusion in the public record. Information not marked confidential 
may be disclosed publicly by EPA without prior notice. All written 
comments will be available for public inspection in Rm. 119 at the 
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday, 
excluding legal holidays.

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

------------------------------------------------------------------------
                                   Office location/                     
        Product Manager            telephone number          Address    
------------------------------------------------------------------------
Joanne Miller (PM 23).........  Rm. 237, CM #2, 703-    1921 Jefferson  
                                 305-6224, e-mail:       Davis Hwy,     
                                 miller.joannes@epamai   Arlington, VA  
                                 l.epa.gov.                             
Cynthia Giles-Parker (PM 22)..  Rm. 229, CM #2, 703-    Do.             
                                 305-7740, e-mail:                      
                                 giles-
parker.cynthia@epamai
l.epa.gov.                             
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SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as 
follows proposing the establishment and/or amendment of regulations for 
residues of certain pesticide chemicals in or on various food 
commodities under section 408 of the Federal Food, Drug, and Comestic 
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these petitions 
contain data or information regarding the elements set forth in section 
408(d)(2); however, EPA has not fully evaluated the sufficiency of the 
submitted data at this time or whether the data supports granting of 
the petition. Additional data may be needed before EPA rules on the 
petition.
    The official record for this notice of filing, as well as the 
public version, has been established for this notice of filing under 
docket control number [PF-788] (including comments and data submitted 
electronically as described below). A public version of this record, 
including printed, paper versions of electronic comments, which does 
not include any information claimed as CBI, is available for inspection 
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal 
holidays. The official record is located at the address in 
``ADDRESSES'' at the beginning of this document.
    Electronic comments can be sent directly to EPA at:
    [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 or ASCII file 
format. All comments and data in electronic form must be identified by

[[Page 4632]]

the docket control number [PF-788] and appropriate petition number. 
Electronic comments on this notice may be filed online at many Federal 
Depository Libraries.

List of Subjects

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

    Dated: January 22, 1998.

James Jones,

Acting Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

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

1. FMC Corporation

PP 7F4795

    EPA has received a pesticide petition (PP 7F4795) from FMC 
Corporation, 1735 Market Street, Philadelphia, PA 19103, proposing 
pursuant to section 408(d) of the Federal Food, Drug and Cosmetic Act, 
21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance 
for residues of carfentrazone-ethyl in or on the raw agricultural 
commodities (RAC) cereal grain at 0.1 parts per million (ppm), 0.3 ppm 
in or on hay; 0.2 ppm in or on straw; 1.0 ppm in or on forage; 0.15 ppm 
in or on stover and 0.1 ppm in or on sweet corn, K + CWHR (kernels plus 
cob with husk removed) and in or on the RACs soybeans and soybean seed 
at 0.1 ppm. EPA has determined that the petition contains data or 
information regarding the elements set forth in section 408(d)(2) of 
the FFDCA; however, EPA has not fully evaluated the sufficiency of the 
submitted data at this time or whether the data supports granting of 
the petition. Additional data may be needed before EPA rules on the 
petition.

A. Residue Chemistry

    1. Plant metabolism. The metabolism of carfentrazone-ethyl in 
plants is adequately understood. Corn, wheat, and soybean metabolism 
studies with carfentrazone-ethyl have shown uptake of material into 
plant tissue with no significant movement into grain or seeds. All 
three plants extensively metabolized carfentrazone-ethyl and exhibited 
a similar metabolic pathway. The residues of concern are the combined 
residues of carfentrazone-ethyl and carfentrazone-ethyl-chloropropionic 
acid.
    2. Analytical method. There is a practical analytical method for 
detecting and measuring levels of carfentrazone and its metabolites in 
or on food with a limit of quantitation (LOQ) that allows monitoring of 
food with residues at or above the levels set in the tolerances. The 
analytical method for carfentrazone-ethyl involves separate analyses 
for parent and its metabolites. The parent is analyzed by GC/ECD. The 
metabolites are derivatized with boron trifluoride and acetic anhydride 
for analysis by GC/MSD using selective ion monitoring.
    3. Magnitude of residues. Carfentrazone-ethyl 50DF was applied 
postemergent to 28 wheat trials, 24 corn trials, and 22 soybean trials 
in the appropriate EPA regions. The RACs were harvested at the 
appropriate growth stages and subsequent analyses determined that the 
residues of carfentrazone-ethyl and its metabolites will not exceed the 
proposed tolerances of 1.0, 0.3, 0.2, and 0.1 ppm for wheat forage, 
hay, straw, and grain, respectively; 0.1 ppm each for corn forage, 
fodder, and grain; and 0.1 ppm for soybean seed. Residue data from a 
cow feeding study demonstrated that no accumulation of carfentrazone-
ethyl or its metabolites occurred in milk or tissues.

B. Toxicological Profile

    1. Acute toxicity. Carfentrazone-ethyl demonstrates low oral, 
dermal and inhalation toxicity. The acute oral LD50 value in 
the rat was greater than 5,000 milligram/kilograms (mg/kg), the acute 
dermal LD50 value in the rat was greater than 4,000 mg/kg 
and the acute inhalation LC50 value in the rat was greater 
than 5.09 mg/L/4h. Carfentrazone-ethyl is non-irritating to rabbit skin 
and minimally irritating to rabbit eyes. It did not cause skin 
sensitization in guinea pigs. An acute neurotoxicity study in the rat 
had a systemic No observed adverse effect level (NOAEL) of 500 mg/kg 
based on clinical signs and decreased motor activity levels; the NOAEL 
for neurotoxicity was greater than 2,000 mg/kg (highest dose tested); 
(HDT) based on the lack of neurotoxic clinical signs or effects on 
neuropathology.
    2. Genotoxicity. Carfentrazone-ethyl did not cause mutations in the 
Ames assay with or without metabolic activation. There was a positive 
response in the Chromosome Aberration assay without activation but a 
negative response with activation. The Mouse Micronucleus assay (an in 
vivo test which also measures chromosome damage), the CHO/HGPRT forward 
mutation assay and the Unscheduled DNA Synthesis assay were negative. 
The overwhelming weight of the evidence supports the conclusion that 
Carfentrazone-ethyl is not genotoxic.
    3. Reproductive and developmental toxicity. Carfentrazone-ethyl is 
not considered to be a reproductive or a developmental toxin. In the 2-
generation reproduction study, the No observed effect level (NOEL) for 
reproductive toxicity was greater than 4,000 ppm (greater than 323 to 
greater than 409 mg/kg/day). In the developmental toxicity studies, the 
rat and rabbit maternal NOELs were 100 mg/kg/day and 150 mg/kg/day, 
respectively. The developmental NOEL for the rabbit was greater than 
300 mg/kg/day which was the highest dose tested and for the rat the 
NOEL was 600 mg/kg/day based on increased litter incidences of 
thickened and wavy ribs at 1,250 mg/kg/day. These two findings 
(thickened and wavy ribs) are not considered adverse effects of 
treatment but related delays in rib development which are generally 
believed to be reversible.
    4. Subchronic toxicity. Ninety-day feeding studies were conducted 
in mice, rats and dogs with Carfentrazone-ethyl. The NOEL for the mouse 
study was 4,000 ppm (571 mg/kg/day), for the rat study was 1,000 ppm 
(57.9 mg/kg/day for males; 72.4 mg/kg/day for females) and for dogs was 
150 mg/kg/day. A 90-day subchronic neurotoxicity study in the rat had a 
systemic NOEL of 1,000 ppm (59.0 mg/kg/day for males; 70.7 mg/kg/day 
for females) based on decreases in body weights, body weight gains and 
food consumption at 10,000 ppm; the neurotoxicity NOEL was greater than 
20,000 ppm (1,178.3 mg/kg/day for males; 1,433.5 mg/kg/day for females) 
which was the highest dose tested.
    5. Chronic toxicity. Carfentrazone-ethyl is not carcinogenic to 
rats or mice. A 2-Year Combined Chronic Toxicity/Oncogenicity study in 
the rat was negative for carcinogenicity and had a chronic toxicity 
NOEL of 200 ppm (9 mg/kg/day) for males and 50 ppm (3 mg/kg/day) for 
females based on red fluorescent granules consistent with porphyrin 
deposits in the liver at the 500 and 200 ppm levels, respectively.

[[Page 4633]]

 An 18 Month Oncogenicity study in the mouse had a carcinogenic NOEL 
that was greater than 7,000 ppm (>1,090 mg/kg/day for males; >1,296 mg/
kg/day for females) based on no evidence of carcinogenicity at the 
highest dose tested. A 1-Year Oral Toxicity study in the dog had a NOEL 
of 50 mg/kg/day based on isolated increases in urine porphyrins in the 
150 mg/kg/day group (this finding was not considered adverse).
    Using the Guidelines for Carcinogen Risk Assessment, carfentrazone-
ethyl should be classified as Group ``E'' for carcinogenicity -- no 
evidence of carcinogenicity -- based on the results of carcinogenicity 
studies in two species. There was no evidence of carcinogenicity in an 
18-month feeding study in mice and a 2-year feeding study in rats at 
the dosage levels tested. The doses tested are adequate for identifying 
a cancer risk. Thus, a cancer risk assessment is not necessary.
    6. Animal metabolism. The metabolism of carfentrazone-ethyl in 
animals is adequately understood. Carfentrazone-ethyl was extensively 
metabolized and readily eliminated following oral administration to 
rats, goats, and poultry via excreta. All three animals exhibited a 
similar metabolic pathway. As in plants, the parent chemical was 
metabolized by hydrolytic mechanisms to predominantly form 
carfentrazone-ethyl-chloropropionic acid which was readily excreted.
    7. Endocrine disruption. An evaluation of the potential effects on 
the endocrine systems of mammals has not been determined; however, no 
evidence of such effects were reported in the chronic or reproductive 
toxicology studies described above. There was no observed pathology of 
the endocrine organs in these studies. There is no evidence at this 
time that carfentrazone-ethyl causes endocrine effects.

C. Aggregate Exposure

    1. Dietary exposure-- i. Acute dietary. The Agency has determine 
that there is no concern for an acute dietary risk assessment since the 
available data do not indicate any evidence of significant toxicity 
from a 1-day or single event exposure by the oral route (Federal 
Register: September 30, 1997, 62 FR 51032-51038). Thus an acute dietary 
risk assessment is not necessary.
    ii. Chronic dietary. Based on the available toxicity data, the EPA 
has established a provisional Reference Dose (RfD) for carfentrazone-
ethyl of 0.06 mg/kg/day. The RfD for carfentrazone-ethyl is based on a 
90-day feeding study in rats with a threshold NOEL of 57.9 mg/kg/day 
and an uncertainty factor of 100, with an additional modifying factor 
of 10 to account for the fact that the chronic studies have not yet 
been reviewed by the EPA. For purposes of assessing the potential 
chronic dietary exposure, a Tier 1 dietary risk assessment was 
conducted based on the Theoretical Maximum Residue Contribution (TMRC) 
from the proposed tolerances for carfentrazone-ethyl on soybeans at 0.1 
ppm, wheat at 0.2 ppm and corn (field) at 0.15 ppm. (The TMRC is a 
``worse case'' estimate of dietary exposure since it is assumed that 
100% of all crops for which tolerances are established are treated and 
that pesticide residues are present at the tolerance levels.) At this 
time the dietary exposure to residues of carfentrazone-ethyl in or on 
food will be limited to residues on soybeans, wheat and corn. There are 
no other established U.S. tolerances for carfentrazone-ethyl, and there 
are no registered uses for carfentrazone-ethyl on food or feed crops in 
the U.S. In conducting this exposure assessment, the following very 
conservative assumptions were made--100% of soybeans, wheat and corn 
will contain carfentrazone-ethyl residues and those residues would be 
at the level of the tolerance which result in an overestimate of human 
exposure.
    2. Food. Dietary exposure from the proposed uses would account for 
1.3% or less of the RfD in subpopulations (including infants and 
children).
    3. Drinking water. Studies have indicated that carfentrazone-ethyl 
will not move into groundwater, therefore water has not been included 
in the dietary risk assessment.
    4. Non-dietary exposure. No specific worker exposure tests have 
been conducted with carfentrazone-ethyl. The potential for non-
occupational exposure to the general population has not been fully 
assessed. No specific worker exposure tests have been conducted with 
carfentrazone-ethyl.

D. Cumulative Effects

    EPA is also required to consider the potential for cumulative 
effects of carfentrazone-ethyl and other substances that have a common 
mechanism of toxicity. EPA consideration of a common mechanism of 
toxicity is not appropriate at this time since EPA does not have 
information to indicate that toxic effects produced by carfentrazone-
ethyl would be cumulative with those of any other chemical compounds; 
thus only the potential risks of carfentrazone-ethyl are considered in 
this exposure assessment.

E. Safety Determination

    1. U.S. population. Using the conservative exposure assumptions 
described and based on the completeness and reliability of the toxicity 
data, the aggregate exposure to carfentrazone-ethyl will utilize 0.61% 
of the RfD for the U.S. population. EPA generally has no concern for 
exposures below 100% of the RfD. Therefore, based on the completeness 
and reliability of the toxicity data and the conservative exposure 
assessment, there is a reasonable certainty that no harm will result 
from aggregate exposure to residues of carfentrazone-ethyl, including 
all anticipated dietary exposure and all other non-occupational 
exposures.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of carfentrazone-ethyl, 
EPA considers data from developmental toxicity studies in the rat and 
rabbit and the 2-generation reproduction study in the rat. The 
developmental toxicity studies are designed to evaluate adverse effects 
on the developing organism resulting from pesticide exposure during 
prenatal development. Reproduction studies provide information relating 
to effects on the reproductive capacity of males and females exposed to 
the pesticide. Developmental toxicity was not observed in developmental 
toxicity studies using rats and rabbits. In these studies, the rat and 
rabbit maternal NOELs were 100 mg/kg/day and 150 mg/kg/day, 
respectively. The developmental NOEL for the rabbit was greater than 
300 mg/kg/day which was the highest dose tested and for the rat was 600 
mg/kg/day based on increased litter incidences of thickened and wavy 
ribs. These two findings are not considered adverse effects of 
treatment but related delays in rib development which are generally 
believed to be reversible.
    In a 2-generation reproduction study in rats, no reproductive 
toxicity was observed under the conditions of the study at 4,000 ppm 
which was the highest dose tested.
    FFDCA section 408 provides that EPA may apply an additional safety 
factor for infants and children in the case of threshold effects to 
account for pre- and post-natal toxicity and the completeness of the 
database. Based on the current toxicological data requirements, the 
database relative to pre- and post-natal effects for children is 
complete and an additional uncertainty factor is not warranted. 
Therefore at this time, the provisional RfD of 0.06 mg/kg/day is

[[Page 4634]]

appropriate for assessing aggregate risk to infants and children.
    3. Reference dose (RfD). Using the conservative exposure 
assumptions described above, the percent of the RfD that will be 
utilized by aggregate exposure to residues of carfentrazone-ethyl for 
non-nursing infants (<1 year old) would be 0.28% and for children 1-6 
years of age would be 1.37% (the most highly exposed.

F. International Tolerances

    There are no Codex Alimentarius Commission (Codex) Maximum Residue 
Levels (MRLs) for carfentrazone-ethyl on any crops at this time. 
However, MRLs for small grains in Europe have been proposed which 
consist of carfentrazone-ethyl and carfentrazone-ethyl-chloropropionic 
acid.   (PM 23)

2. Rohm and Haas Company

PP 2F4127 2F4135, 3F4194, 3H5663, 7F4887, and 7F4900

    EPA has received six pesticide petitions (PP 2F4127, 2F4135, 
3F4194, 3H5663, 7F4887, and 7F4900) from Rohm and Haas Company, 100 
Independence Mall West, Philadelphia, PA 19106-2399, proposing pursuant 
to section 408(d) of the Federal Food, Drug and Cosmetic Act (FFDCA), 
21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing permanent 
tolerances for almond, apple, and grapefruit and time-limited 
tolerances for wheat and animal commodities for residues of [alpha-(2-
(4-chlorophenyl)-ethyl)-alpha-phenyl-3-(1H-1,2,4-triazole)-1-
propanenitrile (fenbuconazole) in or on the raw agricultural 
commodities (RAC) almond nuts at 0.05 parts per million (ppm); almond 
hulls at 3.0 ppm; apples at 0.4 ppm; apple pomace, wet at 1.0 ppm; 
grapefruit at 1.0 ppm; citrus oil (grapefruit) at 35.0 ppm; grapefruit 
pulp, dried at 4.0 ppm; sugar beet root at 0.2 ppm; sugar beet top at 
9.0 ppm; sugar beet pulp, dried at 1.0 ppm; sugar beet molasses at 0.4 
ppm; wheat grain at 0.05 ppm; wheat straw at 10.0 ppm; fat of cattle, 
hogs, horses, goats, and sheep at 0.05 ppm; and liver of cattle, hogs, 
horses, goats, and sheep at 0.3 ppm. The analytical method involves 
soxhlet extraction, partitioning, redissolving, clean-up, and analysis 
by gas-liquid chromatography using nitrogen specific thermionic 
detection. EPA has determined that the petitions contain data or 
information regarding the elements set forth in section 408(d)(2) of 
the FFDCA; however, EPA has not fully evaluated the sufficiency of the 
submitted data at this time or whether the data supports granting of 
the petitions. Additional data may be needed before EPA rules on the 
petitions.

A. Residue Chemistry

    The tolerance expression for fenbuconazole residues in or on almond 
nuts or hulls, apples or apple process fractions, grapefruit and all 
related commodities, sugar beets, and wheat grain or straw is 
-(2-(4-chlorophenyl)-ethyl)--phenyl-(1H-1,2,4-
triazole-1-propanenitrile, plus cis-5-(4-chlorophenyl) dihydro-3-
phenyl-3-(1H-1,2,4-triazole-1-ylmethyl-)-2(3H)-furanone, plus trans-5-
(4-chlorophenyl) dihydro-3-phenyl-3-(1H-1,2,4-triazole-1-ylmethyl-)-
2(3H)-furanone. Residues of these compounds are combined and expressed 
as parent compound to determine the total residue in or on almond nuts 
or hulls, apples or apple process fractions, grapefruit and all related 
commodities, sugar beets and all related commodities, and wheat grain 
or straw.
    The tolerance expression for fenbuconazole residues in or on animal 
fat is -(2-(4-chlorophenyl)-ethyl)--phenyl-(1H-1,2,4-
triazole-1-propanenitrile, plus 4-chloro--(hydroxymethyl)-
-phenyl-benzenebutanenitrile. Residues of these compounds are 
combined and expressed as parent compound to determine the total 
residue.
    The tolerance expression for fenbuconazole residues in or on animal 
liver is -(2-(4-chlorophenyl)-ethyl)--phenyl-(1H-
1,2,4-triazole-1-propanenitrile, plus cis-5-(4-chlorophenyl) dihydro-3-
phenyl-3-(1H-1,2,4-triazole-1-ylmethyl-)-2(3H)-furanone, plus trans-5-
(4-chlorophenyl) dihydro-3-phenyl-3-(1H-1,2,4-triazole-1-ylmethyl-)-
2(3H)-furanone, plus 4-chloro--(hydroxymethyl)--
phenyl-benzenebutanenitrile. Residues of these compounds are combined 
and expressed as parent compound to determine the total residue.
    Analytical methods to measure the components of the residue in or 
on almond nuts and almond hulls, apples, apple process fractions, 
grapefruit, sugar beets, wheat grain and wheat straw, and animal 
commodities have been validated and accurately quantify residues of 
fenbuconazole. The residues of fenbuconazole will not exceed the 
proposed Permanent Tolerances in/on apples or apple process fractions, 
in/on almonds or related commodities, in/on grapefruit or related 
commodities following foliar treatment, on sugar beets or related 
commodities, or in/on wheat or related commodities following foliar or 
seed treatment.
    1. Analytical method. Fenbuconazole residues (parent plus lactones) 
are measured at an analytical sensitivity of 0.01 mg/kg in apples, and 
wheat grain and straw by soxhlet extraction of samples in methanol, 
partitioning into methylene chloride, redissolving in toluene, clean-up 
on silica gel, and gas-liquid chromatography (GLC) analysis using 
nitrogen specific thermionic detection. Fenbuconazole residues are 
measured at an analytical sensitivity of 0.01 mg/kg in fat and liver in 
essentially the same manner except that one of the analytes in these 
matrices, 4-chloro--(hydroxymethyl)--phenyl-
benzenebutanenitrile, is measured at a sensitivity of 0.05 ppm.
    2. Magnitude of residues-- i. Wheat. Residue studies have been 
conducted in accordance with the geographic distribution mandated by 
the EPA for wheat. In the wheat grain, the raw agricultural commodity, 
the fenbuconazole residues ranged from no detectable residue (NDR < LOQ 
= 0.01 mg/kg) to approximately 0.01 ppm. In wheat straw the 
fenbuconazole residues ranged from approximately 0.05 ppm to 
approximately 4.5 ppm. Residues were measured in processed fractions of 
wheat including cleaned grain, bread, patent flour, flour, red dog, 
bran, shorts/germ, and middlings. The EPA concluded that no 
concentration above the residue levels in the RAC occurred so no 
tolerances for any of these commodities were required. Tolerances of 
0.05 ppm in wheat grain and 10 ppm in wheat straw are proposed based on 
these data.
    Feeding studies in the cow, goat, and hen indicated that the only 
animal commodities which require tolerances are fat and liver. There 
were no significant residues in eggs or milk at any dose level. In cows 
there were residues in fat only at the 10x level in one animal at 0.06 
mg/kg. Liver contained quantifiable residues in all dose groups and the 
magnitude of the residue correlated closely with the dose level. At 
study day 28 the 1 x livers averaged 0.08 mg/kg. Residues declined 
significantly during the depuration period. In the fat and liver one of 
the components of the fenbuconazole tolerance expression has a LOQ = 
0.05 mg/kg. Because there were detectable residues only in liver, not 
fat, at the 1x level, the LOQ of the least sensitive component drives 
the fat tolerance. Tolerances of 0.05 ppm in fat and 0.3 ppm in liver 
are proposed based on the animal data.
    Tolerances for wheat process fractions and wheat rotation crops are 
not required because no concentration of residues occurs in process 
fractions of wheat and no residues occur in rotation crops.

[[Page 4635]]

    ii. Apples. Residue studies have been conducted in accordance with 
the geographic distribution mandated by the EPA for apples. In the 
apples, the raw agricultural commodity (RAC), the fenbuconazole 
residues ranged from approximately 0.1 mg/kg to approximately 0.3 mg/
kg. Residues were measured in process fractions of apples, apple juice, 
and apple pomace. Concentration above the residue levels in the RAC 
occurred only in the pomace at approximately two-fold. Thus, no 
tolerance for juice is required, but a tolerance for pomace is 
required.
    Seven field trials on apples were carried out in 1990 in six 
states: Pennsylvania, Washington, North Carolina, Michigan, Virginia, 
and West Virginia. Two application rates were used in each of the 
studies, the anticipated maximum application rate of 0.14 kg ai/ha and 
a 2x exaggerated rate of 0.28 kg ai/ha. A total of eight to ten 
applications were made at the normal timing in each trial, and the 
fruit was harvested at 0, 7, and 13 or 14 days after the final 
application. All samples were frozen immediately after they were 
harvested and were kept frozen until analysis, or shipped fresh 
immediately after harvest and processed and frozen immediately upon 
receipt and kept frozen until analysis. Samples were analyzed using the 
residue analytical method for RH-7592 parent and metabolites in stone 
fruit, and residues were corrected for average fortification 
recoveries. As would be expected, the residue levels were seen to 
increase with decreased PHI and increased application rate. The average 
half-life of residue decline for six studies was 11.9 days. The average 
parent residue at 13-14 PHI at the 0.14 kg ai/ha rate was 0.086 mg/kg.
    Formulation bridging studies were conducted on apples in 1993. 
Apples grown in Washington and Pennsylvania were treated, in separate 
plots, with the 2F and 75 WP formulations of fenbuconazole at a rate of 
0.14 kg ai/ha/application. A total of ten or twelve applications were 
made using an airblast sprayer at the normal timing of each trial, and 
the fruit was harvested at 14 days after the final application (14 day 
Pre-Harvest Interval or PHI). Samples were shipped fresh immediately 
after harvest and frozen immediately upon receipt and kept frozen until 
processing and subsequent analysis. Samples were analyzed using the 
residue analytical method for RH-7592 parent and metabolites in stone 
fruit, but residues were not corrected for average fortification 
recoveries. Total residues from the two trials were 0.226 and 0.135 mg/
kg in the 2F formulation, and 0.184 and 0.162 mg/kg in the 75WP 
formulation. There were no significant differences in apparent residues 
found from the use of the two formulations, and residues due to parent 
compound constituted greater than 85% of the total residues found on 
the fruit.
    Seven field residue trials were conducted on apples in 1995, in 
California, Colorado, Michigan, New York, Ohio, Oregon, and Washington. 
Apples were treated with dilute (0.014 kg ai/hl) and concentrate (0.035 
kg ai/hl) sprays of the 2F formulation of fenbuconazole at a 0.14 kg 
ai/ha. A total of eight to ten applications were made using airblast 
sprayers, with first application at early bud break and subsequent 
applications on a 10-14 day schedule through bloom and a 14 to 21 day 
schedule in the cover sprays until harvest. The apples were harvested 
by hand at a PHI of 14 days. Residue samples were analyzed using the 
residue analytical method for RH-7592 parent and metabolites in stone 
fruit, but residues were not corrected for average fortification 
recoveries. Samples from three sites were also analyzed using the 
residue analytical method for metabolite RH-7905. Metabolite RH-7905 
was not detected in any of the samples. The total residues from the 
concentrate sprays ranged from 0.015 to 0.274 mg/kg and averaged 0.137 
mg/kg. The total residues from the dilute sprays ranged from 0.019 to 
0.295 mg/kg and averaged 0.139 mg/kg. There is not a significant 
difference in the magnitude of the residues between dilute and 
concentrate spray volumes of the 2F formulation of fenbuconazole.
    An additional residue study was conducted on apples grown in 
Pennsylvania in 1994 and the fruit was used for a processing study. The 
apples received nine foliar applications of the 2F formulation of 
fenbuconazole at the normal timing at a rate of 0.14 kg ai/ha/
application. The fruit was harvested 14 days after the last treatment. 
The RAC samples were shipped fresh and either immediately processed or 
frozen for storage. All RAC and processed samples were analyzed within 
a less than 30 day period, eliminating the need for generation of 
storage stability data. The apples were processed at the Food Research 
Laboratory of Cornell University using methodology simulating 
commercial apple processing. Briefly, the processing consisted of 
washing the apples in water, grinding in a hammer mill to apple mash, 
and pressing of the mash to form both fresh apple juice and wet pomace. 
The juice was either canned (sampled as unpasteurized juice) or canned 
and pasteurized (sampled as pasteurized juice). The wet pomace 
(moisture content 69%) was also sampled. All samples were frozen on 
generation and stored frozen until analysis. Samples were analyzed 
using the residue analytical method for RH-7592 and metabolites in 
stone fruit, and residues were not corrected for average fortification 
recovery. The average total residues for each component, and its 
concentration factor, were as follows: unwashed fruit 0.065 mg/kg NA, 
washed fruit 0.070 mg/kg NA, wet pomace 0.159 mg/kg 2.46, unpasteurized 
juice 0.004 mg/kg 0.06, pasteurized juice 0 mg/kg 0.00. No 
concentration of residues was seen in the human diet component, i.e. 
apple juice. Concentration of residues of approximately 2-fold was seen 
in wet pomace, which is not a component of the human diet.
    Feeding studies in the cow, goat, and hen indicated that the only 
animal commodities which require tolerances are fat and liver. There 
were no significant residues in eggs or milk at any dose level. 
Residues in animals declined significantly during the depuration 
period. In the fat and liver one of the components of the fenbuconazole 
tolerance expression has a LOQ = 0.05 mg/kg. Because there were 
detectable residues only in liver, not fat, the LOQ of the least 
sensitive component drives the fat tolerance. Tolerances of 0.05 ppm in 
fat and 0.3 ppm in liver were proposed based on the animal data.
    Tolerances for other apple process fractions and for rotation crops 
are not required because no concentration of residues occurs in other 
process fractions of apples and rotation crops are not a concern for 
perennial crops.
    iii. Almonds. Residue studies have been conducted in accordance 
with the geographic distribution mandated by the EPA for almonds. There 
are no process fractions of almonds. Six field trials in almonds were 
carried out at five sites in California in 1987. In all of the studies, 
the anticipated maximum application rate of 0.11 kg ai/ha and a 2X 
exaggerated rate of 0.22 kg ai/ha. A total of three applications were 
made at the normal timing in all trials, and the almonds were harvested 
at maturity, 127-200 days after the final application. Samples were 
shipped fresh or frozen. Hulls were separated from the nuts and 
processed in a Hobart food processor with dry ice or in a Wiley Mill 
without dry ice. Nuts were shelled and the nutmeat homogenized in a 
Waring food processor with dry ice. The processed samples were stored 
frozen until analysis. Samples were analyzed using the residue 
analytical method for RH-

[[Page 4636]]

7592 and metabolites. No residue in any nutmeat sample at the 1x 
application rate reached 0.01 mg/kg. Residues in the hull at the 1x 
rate ranged from 0.1 to 1.5 mg/kg. One nutmeat sample treated at the 2x 
rate had a quantifiable residue of 0.027 mg/kg. The remainder had no 
detectable residue. Hull sample residues from the 2x rate ranged from 
0.5 to 6.6 mg/kg.
    Feeding studies in the cow, goat, and hen indicated that the only 
animal commodities which require tolerances are fat and liver. There 
were no significant residues in eggs or milk at any dose level. 
Residues in animals declined significantly during the depuration 
period. In the fat and liver one of the components of the fenbuconazole 
tolerance expression has a LOQ = 0.05 mg/kg. Because there were 
detectable residues only in liver, not fat, the LOQ of the least 
sensitive component drives the fat tolerance. Tolerances of 0.05 ppm in 
fat and 0.3 ppm in liver were proposed based on the animal data.
    Tolerances for almond process fractions and rotational crops are 
not required because there are no process fractions of almonds and 
rotational crops are not a concern for perennial crops.
    iv. Grapefruit. Trials included both grapefruit and orange, so the 
following text covers the residue results for both. Six residue trials 
were conducted in 1993 on grapefruit and oranges grown in Texas, 
Florida and California (one grapefruit and one orange trial at each 
site). Three airblast sprayer applications of the 2F formulation of 
fenbuconazole at the rate of 0.28 kg ai/ha/application were made at the 
normal timing, and the fruit was harvested by hand at Pre-Harvest 
Intervals (PHIs) of 0 days (all trials), and approximately 15, 30 and 
60 days (three trials). The whole fruit was analyzed using the residue 
analytical method for RH-7592 parent and metabolites in stone fruit and 
residues were not corrected for average fortification recoveries. The 
average total residue in whole grapefruit at 0 day PHI was 0.344 mg/kg, 
with a range of 0.190 - 0.499 mg/kg. The average total residue in whole 
oranges at 0 day PHI was 0.438 mg/kg, with a range of 0.339 - 0.528 mg/
kg. For both fruits, the 0 day PHI residues were >97% parent. In the 
three trials which measured residue decline, the average total residue 
value had decreased to about 40% of the original value by 60 PHI.
    Residue trials were conducted in 1993 and 1994 on grapefruit and 
oranges grown in seven different locations. Sites with both grapefruit 
and orange trials were in Texas (2) and Florida (3), and in California 
there was one site for oranges and another for grapefruit. Three 
airblast sprayer applications of the 2F formulation of fenbuconazole at 
the rate of 0.28 kg ai/ha/application were made at the normal timing, 
and the fruit was harvested by hand on the day of the final application 
(for a 0 day Pre-Harvest Interval). The fruit was processed in two 
different ways: as whole fruit, or as pulp only with the peel 
discarded. Samples were analyzed using the residue analytical method 
for RH-7592 parent and metabolites in stone fruit, and residues were 
not corrected for average fortification recoveries. Six of the RAC 
samples were also analyzed using the residue analytical method for 
metabolite RH-7905 (the glucoside conjugate). No detectable residues of 
RH-7905 were found in any sample. Average total residue for whole 
oranges was 0.238 mg/kg, and 0.0082 mg/kg for orange pulp. Average 
total residue for whole grapefruit was 0.141 mg/kg, and 0.0078 mg/kg 
for grapefruit pulp. Nearly all of the fenbuconazole residues lie on 
the peel, and [NDR] no detectable residue to LOQ levels are seen in the 
edible portion of the fruit, i.e. the pulp.
    Feeding studies in the cow, goat, and hen indicated that the only 
animal commodities which require tolerances are fat and liver. There 
were no significant residues in eggs or milk at any dose level. 
Residues in animals declined significantly during the depuration 
period. In the fat and liver one of the components of the fenbuconazole 
tolerance expression has a LOQ = 0.05 mg/kg. Because there were 
detectable residues only in liver, not fat, the LOQ of the least 
sensitive component drives the fat tolerance. Tolerances of 0.05 ppm in 
fat and 0.3 ppm in liver were proposed based on the animal data. 
Tolerances for rotational crops are not required for tree fruits.
    v. Sugar beets. Residue studies have been conducted in accordance 
with the geographic distribution mandated by the EPA for sugar beets. 
Following full season foliar treatment, the residues of fenbuconazole 
were higher in the sugar beet tops than in the root. Combined residues 
in root averaged 0.415 mg/kg. Residues in tops were more variable, and 
ranged from 0.56-8.89 mg/kg. In a formulation bridging study the 
residues were higher in the sugar beet tops compared to the root. Total 
root residues in the 75WP formulation ranged from 0.0061 to 0.268 mg/kg 
and averaged 0.0616 mg/kg. Total root residues in the 2F formulation 
ranged from 0.0223 to 0.0523 mg/kg and averaged 0.0328 mg/kg. Total top 
residues averaged 2.15 mg/kg in the 75WP formulation, and 2.69 mg/kg in 
the 2F formulation. There was no significant difference in residues 
between formulations of fenbuconazole. In a processing study the 
concentration factor for each component was: root - 1.0X, dry pulp - 
5.39X, molasses - 1.82X, and refined sugar - 0.1X. Compared to raw 
roots, a reduction of residues was seen in the human diet component, 
sugar. Concentration of residues was seen in molasses and dry pulp, 
neither of which is a component of the human diet.
    Tolerances for rotational crops are not required because EPA 
determined under the wheat petition that rotational crops are not a 
concern for fenbuconazole.

B. Toxicological Profile

    The toxicology of fenbuconazole is summarized in the following 
sections. There is no evidence to suggest that human infants and 
children will be more sensitive than adults, that fenbuconazole will 
modulate human endocrine systems at anticipated dietary exposures, or 
cause cancer in humans at the dietary exposures anticipated for this 
fungicide. While the biochemical target for the fungicidal activity of 
members of the DMI class is shared, it cannot be concluded that the 
mode of action of fenbuconazole which produces phytotoxic effects in 
plants or toxic effects in animals is also common to a single class of 
chemicals.
    1. Acute toxicity. Fenbuconazole is practically nontoxic after 
administration by the oral, dermal and respiratory routes. The acute 
oral LD50 in mice and rats is >2,000 mg/kg. The acute dermal 
LD50 in rats is >5,000 mg/kg. Fenbuconazole was not 
significantly toxic to rats after a 4-hour inhalation exposure, with an 
LD50 value of >2.1 mg/L. Fenbuconazole is classified as not 
irritating to skin (Draize score = 0), inconsequentially irritating to 
the eyes (mean irritation score = 0), and it is not a sensitizer. No 
evidence exists regarding differential sensitivity of children and 
adults to acute exposure.
    2. Mutagenicity. Fenbuconazole has been adequately tested in a 
variety of in vitro and in vivo mutagenicity tests. It is negative in 
the Ames test, negative in in vitro and in vivo somatic and germ cell 
tests, and did not induce unscheduled DNA synthesis (UDS). 
Fenbuconazole is not genotoxic.
    3. Reproductive and developmental toxicity. These conclusions were 
extracted from the Federal Register of May 24, 1995 (60 FR 27419). 
Fenbuconazole is not teratogenic. The maternal no observable effect 
level (NOEL) in rabbits was 10 mg/kg/day and

[[Page 4637]]

30 mg/kg/day in rats. The fetal NOEL was 30 mg/kg/day in both species. 
The parental NOEL was 4.0 mg/kg/day (80 ppm) in a 2-generation 
reproduction study in rats. The reproductive NOEL in this study was 
greater than 40.0 mg/kg/day (800 ppm; highest dose tested). 
Fenbuconazole had no effect on male reproductive organs or reproductive 
performance at any dose. The adult lowest observed effect level (LOEL) 
was 40.0 mg/kg/day (800 ppm; highest dose tested). Systemic effects of 
decreased body weight gain; maternal deaths; and hepatocellular, 
adrenal, and thyroid follicular cell hypertrophy were observed. No 
effects on neonatal survival or growth occurred below the adult toxic 
levels. Fenbuconazole does not produce birth defects and is not toxic 
to the developing fetus at doses below those which are toxic to the 
mother.
    4. Subchronic toxicity. In a 21-day dermal toxicity study in the 
rat, the NOEL was greater than 1,000 mg/kg/day, with no effects seen at 
this limit dose.
    5. Chronic toxicity. In 2-year combined chronic toxicity/
oncogenicity studies in rats, the NOEL was 80 ppm (3.03 mg/kg/day for 
males and 4.02 mg/kg/day for females) based on decreased body weight, 
and liver and thyroid hypertrophy. In a 1-year chronic toxicity study 
in dogs, the NOEL was 150 ppm (3.75 mg/kg/day) based on decreased body 
weight, and increased liver weight. The LOEL was 1,200 ppm (30 mg/kg/
day). In a 78-week oncogenicity study in mice, the NOEL was 10 ppm 
(1.43 mg/kg/day). The LOEL was 200 ppm (26.3 mg/kg/day, males) and 650 
ppm (104.6 mg/kg/day, females) based on increased liver weights and 
histopathological effects on the liver. These effects were consistent 
with chronic enzyme induction from high dose dietary exposure.
    A Reference Dose (RfD) for systemic effects at 0.03 mg/kg/day was 
established by EPA in 1995 based on the NOEL of 3.0 mg/kg/day from the 
rat chronic study. This RfD adequately protects both adults and 
children.
    6. Carcinogenicity. Twenty-four-month rat chronic feeding/
carcinogenicity studies with fenbuconazole showed effects at 800 and 
1,600 ppm. Fenbuconazole produced a minimal, but statistically 
significant increase in the incidence of combined thyroid follicular 
cell benign and malignant tumors. These findings occurred only in male 
rats following life-time ingestion of very high levels (800 and 1,600 
ppm in the diet) fenbuconazole. Ancillary mode-of-action studies 
demonstrated that the increased incidence of thyroid tumors was 
secondary to increased liver metabolism and biliary excretion of 
thyroid hormone in the rat. This mode of action is a nonlinear 
phenomenon in that thyroid tumors occur only at high doses where there 
is an increase in liver mass and metabolic capacity of the liver. At 
lower doses of fenbuconazole in rats, the liver is unaffected and there 
is no occurrence of the secondary thyroid tumors. Worst-case estimates 
of dietary intake of fenbuconazole in human adults and children 
indicate effects on the liver or thyroid, including thyroid tumors, 
will not occur, and there is a reasonable certainty of no harm.
    In support of the findings above, EPA's Science Advisory Board has 
approved a final thyroid tumor policy, confirming that it is reasonable 
to regulate chemicals on the basis that there exists a threshold level 
for thyroid tumor formation, conditional upon providing plausible 
evidence that a secondary mode of action is operative. This decision 
supports a widely-held and internationally respected scientific 
position.
    In a 78-week oncogenicity study in mice there was no statistically 
significant increase of any tumor type in males. There were no liver 
tumors in the control females and liver tumor incidences in treated 
females just exceeded the historical control range. However, there was 
a statistically significant increase in combined liver adenomas and 
carcinomas in females at the high dose only (1,300 ppm; 208.8 mg/kg/
day). In ancillary mode-of-action studies in female mice, the increased 
tumor incidence was associated with changes in several parameters in 
mouse liver following high doses of fenbuconazole including: an 
increase in P450 enzymes (predominately of the CYP 2B type), an 
increase in cell proliferation, an increase in hepatocyte hypertrophy, 
and an increase in liver mass (or weight). Changes in these liver 
parameters as well as the occurrence of the low incidence of liver 
tumors were nonlinear with respect to dose (i.e., were observed only at 
high dietary doses of fenbuconazole). Similar findings have been shown 
with several pharmaceuticals, including phenobarbital, which is not 
carcinogenic in man. The nonlinear relationship observed with respect 
to liver changes (including the low incidence of tumors) and dose in 
the mouse indicates that these findings should be carefully considered 
in deciding the relevance of high-dose animal tumors to human dietary 
exposure.
    The Carcinogenicity Peer Review Committee (PRC) of the Health 
Effects Division (HED) classified fenbuconazole as a Group C tumorigen 
(possible human carcinogen with limited evidence of carcinogenicity in 
animals). The PRC used a low-dose extrapolation model. The 
Q1* risk factor applied (1.06 x 10-2 (mg/kg/
day)-1) was based on the rat oncogenicity study and surface 
area was estimated by (body weight) 3/4.
    Since the PRC published the above estimate they have agreed that 
low-dose extrapolation for fenbuconazole, based on rat thyroid tumors, 
is inappropriate given the EPA's policy regarding thyroid tumors and 
the data which exist for fenbuconazole. The PRC agrees that the more 
appropriate dataset for the low-dose extrapolation and risk factor 
estimate is the mouse. From these data a Q1* of (0.36 x 
10-2 (mg/kg/day)-1) is calculated when surface 
area is estimated by (body weight) 3/4. All estimates of 
dietary oncogenic risk are based on this risk factor.
    Since fenbuconazole will not leach into groundwater (see below) 
there is no increased cancer risk from this source. Neither is 
fenbuconazole registered for residential use, so there is no risk from 
non-occupational residential exposure either. All estimates of excess 
risk to cancer are from dietary sources.
    7.  Endocrine effects. The mammalian endocrine system includes 
estrogen and androgens as well as several other hormone systems. 
Fenbuconazole does not interfere with the reproductive hormones. Thus, 
fenbuconazole is not estrogenic or androgenic.
    While fenbuconazole interferes with thyroid hormones in rats by 
increasing thyroid hormone excretion, it does so only secondarily and 
only above those dietary levels which induce metabolism in the liver. 
These effects are reversible in rats, and humans are far less sensitive 
to these effects than rats. The RfD protects against liver induction 
because it is substantially below the animal NOEL. As noted previously, 
maximal human exposures are far below the RfD level, and effects on 
human thyroid will not occur at anticipated dietary levels.
    We know of no instances of proven or alleged adverse reproductive 
or developmental effects to domestic animals or wildlife as a result of 
exposure to fenbuconazole or its residues. In fact, no effects should 
be seen because fenbuconazole has low octanol/water partition 
coefficients and is known not to bioaccumulate. Fenbuconazole is 
excreted within 48 hours after dosing in mammalian studies.

[[Page 4638]]

C. Aggregate Exposure

    1. Dietary exposure-- Food. i. Wheat. For wheat, children 1 to 6 
years old, not infants, are the highest consumers (g/kg bw/d basis). 
For children 1-6 the dietary TMRC for existing tolerances utilizes only 
5% of the RfD. The dietary TMRC for wheat in this group is estimated to 
be 0.00016 mg/kg/day and uses 0.52% of the RfD. Additional dietary 
exposure (TMRC) to fenbuconazole from residues which might be 
transferred to animal fat and liver from treated wheat is estimated to 
be 0.00006 mg/kg/day and uses 0.22% of the RfD. No residues occur in 
animal meats, milk, or eggs. Thus, the TMRC, the worst-case exposure, 
in the two most sensitive subpopulations of consumers, non-nursing 
infants less than one year old and children 1 to 6 years old, still 
utilizes less than 18% and less than 6%, respectively, of the 
fenbuconazole RfD. The dietary TMRCs for other children and for adults 
utilize less than this.
    The calculated additional cancer risk for wheat (Q1* = 
0.36 x 10-2 (mg/kg/day)-1) has an upper-bound of 
0.2 x 10-6. The calculated additional cancer risk for animal 
fat and liver has an upper-bound of 0.1 x 10-6. The upper 
bound estimate on excess cancer risk for all uses including wheat is 
0.7 x 10-6. The estimate shows that the TMRC, the worst-case 
exposure, for consumers to fenbuconazole presents a reasonable 
certainty of no harm. The actual residue contribution is anticipated to 
be significantly less than this estimate.
    ii. Apples. The EPA used the DRES model to estimate consumer 
dietary exposure to fenbuconazole residues for the most recently 
approved tolerance in bananas (memorandum of E.A. Doyle, February 8, 
1995). (memorandum of E.A. Doyle, 8 February 1995). The EPA used the 
Theoretical Maximum Residue Contribution (TMRC) for pecans and bananas, 
and adjusted the TMRC for the stone fruit crop group by excluding 
plums/prunes and limiting sales volume to 12.8% of the available stone 
fruit market. From this EPA calculated an upper-bound risk of 0.9 x 10-
6 for additional cancer risk (Q1* = 1.06 x 10-2 
(mg/kg/day)-1). (Federal Register of May 24, 1995 (60 FR 27419)). This 
estimate does not reflect the change in Q1*, the use of the 
DEEM database, the percent crop treated for all crops, or average 
residues. When these factors are included the aggregate lifetime 
exposure for consumers to fenbuconazole has an upper bound risk 
estimate of 0.18 x 10-6 for apples and 0.28 x 
10-6 for all pending and approved uses combined. The 
theoretical maximum estimated exposure to the most sensitive 
subpopulation, non-nursing infants less than one year old, for this 
same scenario utilizes no more than 0.89% of the RfD. Thus, the 
addition of fenbuconazole use on apples meets the EPA criterion of 
reasonable certainty of no harm.
    iii. Almonds. The consumer dietary exposure to fenbuconazole 
residues was estimated for the most recently approved tolerance in 
bananas (memorandum of E.A. Doyle, 8 February 1995). The EPA used the 
Theoretical Maximum Residue Contribution (TMRC) for pecans and bananas, 
and adjusted the TMRC for the stone fruit crop group by excluding 
plums/prunes and limiting sales volume to 12.8% of the available stone 
fruit market. From this EPA calculated an upper-bound risk of 0.9 x 
10-6 for additional cancer risk (Q1* = 1.06 x 
10-2 (mg/kg/day)-1). (Federal Register of May 24, 
1995 (60 FR 27419)). This estimate does not reflect the change in 
Q1*, the use of the DEEM database, the percent crop treated 
for all crops, or average residues. When these factors are included the 
aggregate lifetime exposure for consumers to fenbuconazole has an upper 
bound cancer risk estimate of 7.5 x 10-11 for almonds and 
0.28 x 10-6 for all pending and approved uses combined. The 
theoretical maximum estimated exposure to the most sensitive 
subpopulation, non-nursing infants less than one year old, for this 
same scenario utilizes no more than 0.89% of the RfD. Thus, the 
addition of fenbuconazole use on almonds meets the EPA criterion of 
reasonable certainty of no harm.
    This estimate shows that the estimated exposure for consumers to 
fenbuconazole presents a reasonable certainty of no harm. The actual 
dietary residue contribution will likely be less than this estimate.
    iv. Grapefruit. The consumer dietary exposure to fenbuconazole 
residues was estimated for the most recently approved tolerance in 
bananas (memorandum of E.A. Doyle, 8 February 1995). The EPA used the 
Theoretical Maximum Residue Contribution (TMRC) for pecans and bananas, 
and adjusted the TMRC for the stone fruit crop group by excluding 
plums/prunes and limiting sales volume to 12.8% of the available stone 
fruit market. From this EPA calculated an upper-bound risk of 0.9 x 
10-6 for additional cancer risk (Q1* = 1.06 x 
10-2 (mg/kg/day)-1). (Federal Register of May 24, 
1995 (60 FR 27419)). This estimate does not reflect the change in 
Q1*, the use of the DEEM database, the percent crop treated 
for all crops, or average residues. When the new Q1* of 
(0.36 x 10-2 (mg/kg/day)-1) and surface area 
estimated by (body weight)3/4 plus the other factors are 
included, the aggregate lifetime exposure to consumers to fenbuconazole 
has an upper bound risk estimate of 7.0 x 10-8 for 
grapefruit and 0.17 x 10-6 for all pending and approved uses 
combined. The theoretical maximum estimated exposure to the most 
sensitive subpopulation, non-nursing infants less than one year old, 
for this same scenario utilizes no more than 0.39% of the RfD. Thus, 
the addition of fenbuconazole use on grapefruit meets the EPA criterion 
of reasonable certainty of no harm.
    This estimate shows that the estimated exposure for consumers to 
fenbuconazole presents a reasonable certainty of no harm. The actual 
dietary residue contribution will likely be less than this estimate.
    v. Sugar beets. The consumer dietary exposure to fenbuconazole 
residues was estimated for the most recently approved tolerance in 
bananas (memorandum of E.A. Doyle, 8 February 1995). The EPA used the 
TMRC for pecans and bananas, and adjusted the TMRC for the stone fruit 
crop group by excluding plums/prunes and limiting sales volume to 12.8% 
of the available stone fruit market. From this EPA calculated an upper-
bound risk of 0.9 x 10-6 for additional cancer risk 
(Q1* = 1.06 x 10-2 (mg/kg/day)-1). 
(Federal Register of May 24, 1995 (60 FR 27419)). This estimate does 
not reflect the change in Q1*, the use of the DEEM database, 
the percent crop treated for all crops, or average residues. When the 
new Q1* of (0.36 x 10-2 (mg/kg/
day)-1)) and surface area estimated by (body 
weight)3/4 plus the other factors are included the aggregate 
lifetime exposure for consumers to fenbuconazole has an upper bound 
cancer risk estimate of 1.0 x 10-8 for sugar beets and 0.17 
x 10-6 for all pending and approved uses combined. The 
theoretical maximum estimated exposure to the most sensitive 
subpopulation, non-nursing infants less than one year old, for this 
same scenario utilizes no more than 0.01% of the RfD for sugar beets 
and 0.39% of the RfD for all crops combined. Thus, the addition of 
fenbuconazole use on sugar beets meets the EPA criterion of reasonable 
certainty of no harm.
    2. Drinking water. Fenbuconazole has minimal tendency to 
contaminate groundwater or drinking water because of its adsorptive 
properties on soil, solubility in water, and degradation rate. Data 
from laboratory studies and field dissipation studies have been used in 
the USDA PRZM/GLEAMS computer model to predict the movement of 
fenbuconazole. The model predicts that fenbuconazole will not leach 
into groundwater, even if heavy rainfall is simulated. The modeling 
predictions are

[[Page 4639]]

consistent with the data from environmental studies in the laboratory 
and the results of actual field dissipation studies. There are no data 
on passage of fenbuconazole through water treatment facilities and 
there are no State water monitoring programs which target 
fenbuconazole.
    3. Non-dietary exposure. Fenbuconazole has no veterinary 
applications and is not approved for use in swimming pools. It is not 
labeled for application to residential lawns or for use on ornamentals, 
nor is fenbuconazole applied to golf courses or other recreational 
areas. Therefore, there are no data to suggest that these exposures 
could occur. Any acute exposures to children would come from dietary 
exposure or inadvertent dermal contact. As previously discussed, 
fenbuconazole is neither orally or dermally acutely toxic. Thus, there 
is a reasonable certainty that no exposure would occur to adults, 
infants or children from these sources.

D. Cumulative Effects

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

E. Safety Determination

    1. U.S. population-- i. Wheat. The Rohm and Haas Company estimates 
the risk to the U.S. adult population from use of fenbuconazole on 
wheat as utilizing approximately 0.36% of the RfD. Using the EPA low 
dose extrapolation model and the risk factor based on the mouse data 
(0.36 x 10-6 (mg/kg/day)-1) the excess cancer risk from 
dietary sources for fenbuconazole use on wheat and the associated 
animal commodities is estimated at 0.3 x 10-6. The upper 
bound estimate on excess cancer risk for all uses including wheat is 
0.7 x 10-6.
    This assumes that all of the wheat consumed in the U.S. will 
contain residues of fenbuconazole (in actuality a small fraction of the 
total crop is likely to be treated). The combined risk for wheat plus 
registered uses will not exceed either the dietary risk standard 
established by the Food Quality Protection Act (FQPA) for the US 
population, (one x 10-6), or the RfD.
    The sole acute risk would be for women of childbearing age. The 
EPA/OREB calculated that the worst-case Margin of Exposure (MOE) for 
fenbuconazole measured against the developmental LOEL would be greater 
than 30,000. This is clearly adequate. The MOE would be even higher for 
consumer dietary exposure from any source. Thus, there is adequate 
safety for this group and there is a reasonable certainty that no harm 
will result from fenbuconazole use on wheat.
    ii. Apples. When the DEEM database is used and the assumptions in 
the above calculations the Rohm and Haas Company estimates the risk to 
the U.S. adult population from use of fenbuconazole on apples as 
utilizing approximately 0.17% of the RfD. The calculated upper bound 
estimate on excess cancer risk for all uses (apples, apricots, almonds, 
bananas, cherries, nectarines, peaches, pecans, and wheat, plus the 
associated processing and animal commodities) is 0.28 x 
10-6.
    The combined risk for apples plus registered uses plus almonds and 
wheat will not exceed the dietary risk standards established by the 
FQPA for the US population (one x 10-6 excess cancer risk, 
or the RfD).
    The sole acute risk would be for women of childbearing age. The 
EPA/OREB calculated that the worst-case Margin of Exposure (MOE) for 
fenbuconazole measured against the developmental LOEL would be greater 
than 30,000. This is clearly adequate. The MOE would be even higher for 
consumer dietary exposure from any source. Thus, there is adequate 
safety for this group and there is a reasonable certainty that no harm 
will result from fenbuconazole use on apples.
    iii. Almonds. When the DEEM database is used and the assumptions in 
the above calculations the Rohm and Haas Company estimates the risk to 
the U.S. adult population from use of fenbuconazole on almonds as 
utilizing approximately 0.00007% of the RfD. The calculated upper bound 
estimate on excess cancer risk for all uses (apples, apricots, almonds, 
bananas, cherries, nectarines, peaches, pecans, and wheat, plus the 
associated processing and animal commodities) is 0.28 x 
10-6.
    The combined risk for almonds plus registered uses plus apples and 
wheat will not exceed the dietary risk standards established by the 
FQPA for the US population (one x 10-6 excess cancer risk, 
or the RfD).
    The sole acute risk would be for women of childbearing age. The 
EPA/OREB calculated that the worst-case Margin of Exposure (MOE) for 
fenbuconazole measured against the developmental LOEL would be greater 
than 30,000. This is clearly adequate. The MOE would be even higher for 
consumer dietary exposure from any source. Thus, there is adequate 
safety for this group and there is a reasonable certainty that no harm 
will result from fenbuconazole use on almonds.
    iv. Grapefruit. When the DEEM database is used and the assumptions 
in the above calculations the Rohm and Haas Company estimates the risk 
to the U.S. adult population from use of fenbuconazole on grapefruit as 
utilizing approximately 0.06% of the RfD. The calculated upper bound 
estimate on excess cancer risk for all uses (apples, apricots, almonds, 
bananas, cherries, grapefruit, nectarines, peaches, pecans, sugar 
beets, and wheat, plus the associated processing and animal 
commodities) is 0.17 x 10-6.
    The combined risk for grapefruit plus registered and pending uses 
will not exceed the dietary risk standards established by the FQPA for 
the U.S.

[[Page 4640]]

population (one x 10-6 excess cancer risk, or the RfD).
    The sole acute risk would be for women of childbearing age. The 
EPA/OREB calculated that the worst-case Margin of Exposure (MOE) for 
fenbuconazole measured against the developmental LOEL would be greater 
than 30,000. This is clearly adequate. The MOE would be even higher for 
consumer dietary exposure from any source. Thus, there is adequate 
safety for this group and there is a reasonable certainty that no harm 
will result from fenbuconazole use on grapefruit.
    v. Sugar beets. When the DEEM database is used and the assumptions 
in the above calculations the Rohm and Haas Company estimates the risk 
to the U.S. adult population from use of fenbuconazole on sugar beets 
as utilizing approximately 0.009% of the RfD. The calculated upper 
bound estimate on excess cancer risk for all uses (apples, apricots, 
almonds, bananas, cherries, grapefruit, nectarines, peaches, pecans, 
sugar beets, and wheat, plus the associated processing and animal 
commodities) is 0.17 x 10-6. Therefore, the combined risk 
for sugar beets plus registered and pending uses will not exceed the 
dietary risk standards established by the FQPA for the U.S. population 
(one x 10-6 excess cancer risk, or the RfD).
    The sole acute risk would be for women of childbearing age. The 
EPA/OREB calculated that the worst-case Margin of Exposure (MOE) for 
fenbuconazole measured against the developmental LOEL would be greater 
than 30,000. This is clearly adequate. The MOE would be even higher for 
consumer dietary exposure from any source. Thus, there is adequate 
safety for this group and there is a reasonable certainty that no harm 
will result from fenbuconazole use on sugar beets.
    2. Infants and children-- i. Wheat. The reproductive and 
developmental toxicity data base for fenbuconazole is complete. There 
is no selective increase in toxicity to developing animals. Thus, there 
is no evidence that prenatal and postnatal exposure would present 
unusual or disproportionate hazard to infants or children. Therefore, 
there is no need to impose an additional uncertainty factor to protect 
infants and children.
    The EPA calculated the dietary risk to infants and children for 
existing tolerances. The estimated dietary exposure (TMRC) for this 
subpopulation is 0.00522 mg/kg/day which represents only 17% of the 
RfD; no other subgroup used in excess of 17% of the RfD. The EPA 
estimated lifetime oncogenic risk in the range of one in a million at 
0.9 x 10-6, using (Q1* = 1.06 x 10-2 
(mg/kg/day)-1). (Federal Register of May 24, 1995 (60 FR 
27419)).
    For the wheat use the most sensitive subgroup is children 1 to 6 
years old and the estimated risk to this subgroup is less than 18% of 
the RfD. Utilizing the risk factor (Q1* = 0.36 x 
10-2 (mg/kg/day)-1), the estimated excess cancer 
risk for the U.S. population is less than 1 x 10-6. 
Therefore the wheat use is safe within the meaning of the FQPA and 
there is a reasonable certainty that no harm will result to infants or 
children from the approval of fenbuconazole use on wheat.
    ii. Apples and almonds. The reproductive and developmental toxicity 
data base for fenbuconazole is complete. There is no selective increase 
in toxicity to developing animals. Thus, there is no evidence that 
prenatal and postnatal exposure would present unusual or 
disproportionate hazard to infants or children. Therefore, there is no 
need to impose an additional uncertainty factor to protect infants and 
children. The dietary exposure estimate for children utilizes only 
0.89% of the RfD.
    iii. Grapefruit and sugar beets. The reproductive and developmental 
toxicity data base for fenbuconazole is complete. There is no selective 
increase in toxicity to developing animals. Thus, there is no evidence 
that prenatal and postnatal exposure would present unusual or 
disproportionate hazard to infants or children. Therefore, there is no 
need to impose an additional uncertainty factor to protect infants and 
children. The dietary exposure estimate for children utilizes only 
0.39% of the RfD.

F. Environmental Fate

    Fenbuconazole has little to no mobility in soil (Koc = 4425). It is 
stable to hydrolysis and aqueous photolysis in buffered solutions, but 
does degrade photolytically in natural waters and soil (half-life 87 
and 79 days, respectively). Laboratory soil metabolism half-lives or 
DT50 values for fenbuconazole range from 29 to 532 days under 
terrestrial conditions and from 442 to 906 days in soil exposed to 
aquatic conditions. Field-trial soil dissipation studies had half-lives 
ranging from 157 to 407 days and indicated no significant downward 
movement of residues. These field trials show fenbuconazole degrades 
more rapidly outdoors than in laboratory metabolism studies. When 
material was applied in a single application, fenbuconazole degraded to 
about 50% of the applied material in less than 60 days. In wheat the 
DT50 in green heads was measured as 18 days and in green wheat stalks 
the DT50 was 84.4 days. These results only reflect foliar dissipation 
in wheat at the particular growth stage(s) during the study and not at 
all stages of wheat. The results of residue decline analyses in a 
number of environmental media support the EPA conclusion that there is 
no environmental hazard associated with the proposed agricultural use 
of this chemical.

G. International Tolerances

    There are no Codex Maximum Residue Levels (MRLs) for fenbuconazole, 
but the fenbuconazole database will be evaluated by the WHO and the FAO 
Expert Panels at the Joint Meeting on Pesticide Residues (JMPR) in 
September 1997. An Allowable Daily Intake (ADI (RfD)) of 0.03 mg/kg/day 
is proposed and a total of 36 Codex MRLs are proposed in the data 
submission.    (PM 22)

[FR Doc. 98-2363 Filed 1-29-98; 8:45 am]
BILLING CODE 6560-50-F