[Federal Register Volume 62, Number 180 (Wednesday, September 17, 1997)]
[Notices]
[Pages 48842-48848]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-24693]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-753; FRL-5735-5]


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-753, must 
be received on or before October 17, 1997.
ADDRESSES: By mail submit written comments to: Public Information and 
Records Integrity Branch (7506C), 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. 1132, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
    Comments and data may also be submitted electronically by following 
the instructions under ``SUPPLEMENTARY INFORMATION.'' No confidential 
business information should be submitted through e-mail.
    Information submitted as a comment concerning this document may be 
claimed confidential by marking any part or all of that information as 
``Confidential Business Information'' (CBI). CBI should not be 
submitted through e-mail. Information marked as CBI will not be 
disclosed except in accordance with procedures set forth in 40 CFR part 
2. A copy of the comment that does not contain CBI must be submitted 
for inclusion in the public record. Information not marked confidential 
may be disclosed publicly by EPA without prior notice. All written 
comments will be available for public

[[Page 48843]]

inspection in Rm. 1132 at the address given above, from 8:30 a.m. to 4 
p.m., Monday through Friday, excluding legal holidays.

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

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                                   Office location/                     
        Product Manager            telephone number          Address    
------------------------------------------------------------------------
Joanne Miller (PM 23).........  Rm. 237, CM #2, 703-    1921 Jefferson  
                                 305-6224, e-            Davis Hwy,     
                                 mail:<a href="/cdn-cgi/l/email-protection" class="__cf_email__" data-cfemail="ed80848181889fc387828c838388ad889d">[email protected]</a>   Arlington, VA  
                                 amail.epa.gov.                         
Cynthia Giles-Parker (PM 22)..  Rm. 229, CM #2, 703-    Do.             
                                 305-7740, e-mail:                      
                                 <a href="/cdn-cgi/l/email-protection#43242a2f26306e493322312826316d203a2d372b2a22032633222e222a492f6d2633226d242c35">giles-
<span class="__cf_email__" data-cfemail="a3d3c2d1c8c6d18dc0dacdd7cbcac2e3c6d3c2cec2ca">[email protected]</span>
l.epa.gov</a>.                             
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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-753] (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:
    <a href="/cdn-cgi/l/email-protection#e58a9595c8818a868e8091a580958488848c89cb809584cb828a93"><span class="__cf_email__" data-cfemail="741b040459101b171f11003411041519151d185a1104155a131b02">[email protected]</span></a>


    Electronic comments must be submitted as an ASCII file avoiding the 
use of special characters and any form of encryption. Comment and data 
will also be accepted on disks in Wordperfect 5.1 file format or ASCII 
file format. All comments and data in electronic form must be 
identified by the docket number [PF-753] 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: September 5,1997

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. DowElanco

PP 7F4851

    EPA has received a pesticide petition (PP 7F4851) from DowElanco, 
9330 Zionsville Road, Indianapolis, IN 46268-1054, 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 flumethsulam in or on the raw agricultural commodity dry 
beans at 0.05 ppm. The proposed analytical method involves 
homogenization, filtration, partition and cleanup with analysis by high 
performance liquid chromatography using UV detection. 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 in plants is adequately 
understood. No metabolites of significance were detected in plant 
metabolism studies.
    2. Analytical method. There is a practical analytical method for 
detecting and measuring levels of flumetsulam in or on food with a 
limit of quantitation (LOQ) of 0.010 ppm, and a limit of detection of 
0.005 ppm that allows monitoring of food with residues at or above the 
levels set in these tolerances. EPA has provided information on this 
method to FDA. The method is availabe to anyone who is interested in 
pesticide residue enforcement.
    3. Magnitude of residues. No detectable residues of flumetsulam 
were found in any of the drybean samples obtained from multiple sites 
and multiple varieties and analyzed using a method with a limit of 
detection of 0.005 ppm.

B. Toxicological Profile

    1. Acute toxicity. Flumetsulam has low acute toxicity. The rat oral 
LD<INF>50</INF> is >5,000 mg/kg or greater for males and females. The 
rabbit dermal LD<INF>50</INF> is >2,000 mg/kg and the rat inhalation 
LC<INF>50</INF> is >1.2mg/L air (the highest attainable concentration). 
In addition, flumetsulam is not a skin sensitizer in guinea pigs, is 
not a dermal irritant and is not an ocular irritant. Therefore based on 
the available acute toxicity data, flumetsulam does not pose any acute 
dietary risks.
    2. Genotoxicty. Flumetsulam is not genotoxic. The following studies 
have been conducted and all were negative for genotoxic responses: a 
dominant lethal assay, an In vivo rat cytogenic study, an In vitro 
Salmonella and Saccharomyces assay, an in vivo mouse host-mediated 
assay, and an unscheduled DNA synthesis assay in rats.
    3. Reproductive and developmental toxicity. In a 2-generation 
reproduction study in rats, there was no compound-related reproductive 
toxicity. The No-Observed-Effect Level (NOEL) was greater than 1,000 
mg/kg/day. Developmental toxicity was studied using rats and rabbits. 
The developmental study in rats resulted in a developmental NOEL 
greater than 1.000 mg/kg/day (highest dose tested) and a maternal NOEL 
of 500 mg/kg/day. A study in rabbits resulted in a

[[Page 48844]]

developmental NOEL equal to or greater than 700 mg/kg/day (highest dose 
tested) with a maternal NOEL of 100 mg/kg/day and a maternal LOEL 
(lowest observed effect level) of 500 mg/kg/day evidenced by decreased 
body weight gain. Based on all of the data for flumetsulam, there is no 
evidence of developmental toxicity at dose levels that do not result in 
maternal toxicity.
    4. Subchronic toxicity . In a 13-week oral feeding study in mice at 
5,000 mg/kg/day, slight effects on the liver, kidney, and cecum 
appeared to represent adaptive responses to treatment and have 
questionable toxicological significance. The NOEL was 1,000 mg/kg/day 
(limit dose). In a 13-week oral feeding study in dogs, the lowest-
observed-effect level (LOEL) for both male and female dogs was 500 mg/
kg/day. A NOEL was not established for males or females. In a 13-week 
dietary study in rats, the NOEL was 250 mg/kg/day and the LOEL was 
1,000 mg/kg/day.
    5. Chronic toxicity. In a 1-year dietary study in dogs, the NOEL 
was 100 mg/kg/day and the LOEL was 500 mg/kg/day. The animals were 
administered feed containing 0, 20, 100, and 500 mg/kg/day. Reduced 
body weights and inflammatory and atrophic changes in the kidneys 
occurred in the 500 mg/kg/day dose groups. In a combined feeding 
carcinogenicity/chronic study in mice there were no treatment-related 
effects and there was no evidence of a carcinogenic response. Systemic 
NOEL was greater than or equal to 1,000 mg/kg/day (limit dose); a LOEL 
was not established. In a combined feeding carcinogenicity/chronic 
study in rats, renal pathological alterations were seen in males. No 
treatment-related effects were seen in females at the highest dose 
(1,000 mg/kg/day) which is the limit dose. There was no carcinogenic 
response. The NOELs were 500 mg/kg/day in males and 1,000mg/kg/day in 
females. The LOEL was 1,000 mg/kg/day in males; a LOEL was not 
established in females. Based on the chronic toxicity data, EPA has 
established the RfD for flumetsulam at 1.0 milligram (mg)/kilogram 
(kg)/day. The RfD for flumetsulam is based on the 1-year chronic study 
in dogs with a NOEL of 100 mg/kg/day and an uncertainty (or safety) 
factor of 100. Thus, it would not be necessary to require the 
application of an additional uncertainty factor above the 100-fold 
factor already applied to the NOEL.
    6. Animal metabolism. Disposition and metabolism of flumetsulam 
were tested in male and female rats and male mice at an oral dose of 5 
and 1,000 mg/kg for rats and 1,000 mg/kg for mice Flumetsulam was 
rapidly excreted. The majority of a radioactive dose was excreted in 48 
hours of all dose groups. The principle route for elimination was the 
urine and to a lessor extent by fecal elimination. Detectable levels of 
residual radioactivity were observed in the carcass and stomach at 72 
hours post-dose. HPLC and TLC analysis of urine and fecal extracts 
showed no apparent metabolism of flumetsulam.
    7. Metabolite toxicology. There are no flumetsulam metabolites of 
toxicological significance.
    8. Endocrine effects. There is no evidence to suggest that 
flumetsulam has an effectt on any endocrine system.

C. Aggregate Exposure

    1. Food. For purposes of assessing the potential dietary exposure 
under these tolerances, exposure is estimated based on the Theoretical 
Maximum Residue Contribution (TMRC) from the existing and pending 
tolerances for flumetsulam on food crops. The TMRC is obtained by 
multiplying the tolerance level residues by the consumption data which 
estimates the amount of those food products eaten by various population 
subgroups. Exposure of humans to residues could also result if such 
residues are transferred to meat, milk, poultry or eggs. The following 
assumptions were used in conducting this exposure assessment: 100% of 
the crops were treated, the RAC residues would be at the level of the 
tolerance, certain processed food residues would be at anticipated 
(average) levels based on processing studies and all current and 
pending tolerances were included. This results in an overestimate of 
human exposure and a conservative assessment of risk. Based on a NOEL 
of 100 mg/kg/day in a 1-year chronic feeding study in the dog and a 
hundredfold safety factor the reference dose (RfK) would be 1.0 mg/kg/
day. The TMRC for the general population would be 4.1 X 10<SUP>-5</SUP> 
mg/kg/day or 0.0041% of the RfD. For non-nursing infants, the TMRC wold 
be 1.37 X 10<SUP>-5</SUP> mg/kg/day or 0.014% of the RfD.
    2. Drinking water. Another potential source of dietary exposure to 
residues of pesticides are residues in drinking water. There is no 
established Maximum Concentration Level for residues of flumetsulam in 
drinking water. Although there has been limited detections at ppb 
levels in some of the specially designed studies under highly 
vulnerable test conditions and at elevated non-labeled application 
rates, no ongoing monitoring studies, have reported residues of 
flumetsulam in ground or surface waters.
    Based on the physical and chemical characteristics of flumetsulam, 
such as water solubility and its stability under hydrolysis and 
photolysis, it has potential for downward movement through the soil 
profile. Degradation based on over 20 laboratory studies indicated a 
half-life range of 2 weeks to 4 months with 80% less than 2 months. 
Degradation is driven primarily by microbial processes. However based 
on the low application rate and detection in groundwater samples only 
under extremely vulnerable soil conditions at elevated non-labeled 
application rates with detections in single digit ppb levels, 
flumetsulam is not anticipated to be a groundwater contaminant.
    In summary, these data on potential water exposure indicate 
insignificant additional dietary intake of flumetsulam and any exposure 
is more than compensated for in the conservative dietary risk 
evaluation. Therefore, it is concluded that there is a reasonable 
certainty of no harm even at potential upper limit exposures to 
flumetsulam from drinking water.
    3. Non-dietary exposure. There are no non-dietary uses for 
flumetsulam registered under the Federal Insecticide, Fungicide and 
Rodenticide Act. Potential exposures for children is therefore limited 
to dietary exposure.

D. Cumulative Effects

    The potential for cumulative effects of flumetsulam and other 
substances that have a common mechanism of toxicity was considered. The 
mammalian toxicity of flumetsulam is well defined. However, no reliable 
information exists to indicate that toxic effects produced by 
flumetsulam would be cumulative with those of any other chemical 
compound. Additionally, flumetsulam does not appear to produce a toxic 
metabolite produced by other substances. Therefore, consideration of a 
common mechanism of toxicity with other compounds is not appropriate at 
this time. Thus only the potential exposures to flumetsulam were 
considered in the aggregate exposure assessment.

E. Safety Determination

    1. U.S. population. Based on a NOEL of 100 mg/kg/bwt/day from a 
one-year dog feeding study with a reduced weight and inflammatory and 
atrophic kidney effect, and using an uncertainty factor of 100 to 
account for the interspecies extrapolation and intraspecies 
variability, a Reference Dose (RfD) of 1.0 mg/kg bwt/day was used for 
this assessment of chronic risk. As indicated, there is no endpoint of 
concern identified with acute and short-or intermediate-term exposures. 
The existing and proposed tolerances

[[Page 48845]]

would utilize 0.000041 mg/kg bwt/day or less than 0.01% of the RfD for 
the U.S. population. And, as indicated previously, whatever upper limit 
might be used for drinking water exposure, the exposure estimate for 
flumetsulam would not exceed the RfD. Generally, exposures below 100 
percent of the RfD are of no concern because the RfD represents the 
level at or below which daily aggregate dietary exposure over a 
lifetime will not pose appreciable risk to human health. Thus, there is 
a reasonable certainty that no harm will result from aggregate exposure 
to flumetsulam residues.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of flumetsulam, data 
from developmental toxicity studies in the rat and rabbit and a 2-
generation reproduction study in the rat were considered. The 
developmental toxicity studies are designed to evaluate adverse effects 
on the developing organism during prenatal development resulting from 
pesticide exposure to one or both parents. Reproduction studies provide 
(1) information relating to effects from exposure to the pesticide on 
the reproductive capability of mating animals and (2) data on systemic 
toxicity.
    As indicated previously, reproductive and developmental toxicity 
was studied using rats and rabbits. The data base is complete and based 
on all of the data for flumetsulam, there is no evidence of 
reproductive or developmental toxicity at dose levels that do not 
result in maternal toxicity.
    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. These data suggest minimal concern for developmental or 
reproductive toxicity and do not indicate any increased pre- or post-
natal sensitivity. Therefore, an additional uncertainty factor is not 
necessary to protect the safety of infants and children and that the 
RfD at 1.0 mg/kg/day is appropriate for assessing aggregate risk to 
infants and children.
    The percent of the RfD that will be utilized by the aggregate 
exposure from all tolerances to flumetsulamill be less than 0.1% for 
non-nursing infants and for children (1-6 years of age). Therefore, 
based on the completeness and reliability of the toxicity data and the 
conservative exposure assessment, it is concluded that there is a 
reasonable certainty that no harm will result to infants and children 
from aggregate exposure to flumetsulam residues.

F. International Tolerances

    There are no Codex maximum residue levels established for 
flumetsulam. (Joanne Miller)

2. Rohm and Haas Company

PP 2F4127

    EPA has received a pesticide petition (PP 2F4127) 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 a permanent tolerance 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 wheat grain; wheat straw; milk; eggs; and meat, fat, and 
meat by-products of cattle, goats, horses, hogs, poultry, and sheep. 
The analytical method involves soxhlet extraction, partitioning, 
redissolving, cleanup, and analysis by gas-liquid chromatography using 
nitrogen specific thermionic detection. 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

    The tolerance expression for fenbuconazole residues in or on wheat 
grain or straw is: <greek-a>-(2-(4-chlorophenyl)-ethyl)-<greek-a>-
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 are combined and expressed as parent compound to 
determine the total RAC residue in or on wheat grain and wheat straw.
    The tolerance expression for fenbuconazole residues in or on animal 
fat is: <greek-a>-(2-(4-chlorophenyl)-ethyl)-<greek-a>-phenyl-(1H-
1,2,4-triazole-1-propanenitrile, plus 4-chloro-<greek-a>-
(hydroxymethyl)-<greek-a>- phenyl-benzenebutanenitrile
    Residues are combined and expressed as parent compound to determine 
the total residue.
    The tolerance expression for fenbuconazole residues in or on animal 
liver is: <greek-a>-(2-(4-chlorophenyl)-ethyl)-<greek-a>-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-<greek-a>-(hydroxymethyl)-<greek-a>-
phenyl-benzenebutanenitrile
    Residues are combined and expressed as parent compound to determine 
the total residue.
    Analytical methods to measure the components of the residue in or 
on wheat grain and wheat straw, and in or on animal commodities have 
been validated and accurately quantify residues of fenbuconazole. The 
residues of fenbuconazole will not exceed the proposed Permanent 
Tolerances on wheat or related commodities following foliar or seed 
treatment of wheat.
    1. Analytical method. Fenbuconazole residues (parent plus lactones) 
are measured at an analytical sensitivity of 0.01 mg/kg in 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) 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-<greek-a>-(hydroxymethyl)-<greek-a>-phenyl-benzenebutanenitrile, 
is measured at a sensitivity of 0.05 ppm.
    2. Magnitude of residues. 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.

[[Page 48846]]

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 LD<INF>50</INF> in mice and rats is >2,000 mg/kg. The acute dermal 
LD<INF>50</INF> in rats is >5,000 mg/kg. Fenbuconazole was not 
significantly toxic to rats after a 4-hour inhalation exposure, with an 
LD<INF>50</INF> 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. Genotoxicity. Fenbuconazole has been adequately tested in a 
variety of in vitro and in vivo mutagenicity tests. It is negative in 
the Ames test and negative in an in vitro and in vivo somatic and germ 
cell tests; it did not induce unscheduled DNA synthesis (UDS). 
Fenbuconazole is not genotoxic.
    3. Reproductive and developmental toxicity. These data cited at 60-
FR-27419, May 24,1995. Fenbuconazole is not teratogenic. The maternal 
no observable effect level (NOEL) in rabbits was 10 mg/kg/day and 30 
mg/kg/day in rats. The fetal NOEL was 30 mg/kg/day in both species. The 
parental no observable effect level (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, 
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<SUP>-2</SUP> (mg/kg/day)-1) was based on the 
rat oncogenicity study and surface area was estimated by (body 
weight)<INF>3/4</INF>.
    Since the PRC published the above estimate they have agreed that 
low-dose extrapolation for fenbuconazole, based on rat thyroid tumors, 
is inappropriate given the EPA's policy regarding thyroid tumors and 
the data which exist for fenbuconazole. The PRC agrees that the more 
appropriate data set for the low-

[[Page 48847]]

dose extrapolation and risk factor estimate is the mouse. From these 
data a Q1* of (0.36 x 10<SUP>-2</SUP>(mg/kg/day)-1) is calculated when 
surface area is estimated by (body weight)<INF>3/4</INF>. All estimates 
of dietary risk must be adjusted to reflect this change.
    Since fenbuconazole is unlikely to 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 additional 
risk from this source 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.

C. Aggregate Exposure

    1. Food. 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<SUP>-6</SUP> for additional cancer risk (Q1* = 1.06 x 
10<SUP>-2</SUP> (mg/kg/day)-1). (60 FR 27419; 24 May 1995). This 
estimate does not reflect the change in Q1*. Using the EPA model and 
the new risk factor based on the mouse data (Q1* = 0.36 x 
10<SUP>-2</SUP> (mg/kg/day)-1) the dietary risk for currently 
registered uses is 0.3 x 10<SUP>-6</SUP>. The TMRC for existing 
tolerances utilizes 17% of the RfD for the most sensitive 
subpopulation, non-nursing infants less than 1-year old. This is 
unaffected by the change in Q1*.
    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 1- 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<SUP>-2</SUP> (mg/kg/day)-1) has an upper-bound of 0.2 x 
10<SUP>-6</SUP>. The calculated additional cancer risk for animal fat 
and liver has an upper-bound of 0.1 x 10<SUP>-6</SUP>. The upper bound 
estimate on excess cancer risk for all uses including wheat is 0.7 x 
10<SUP>-6</SUP>. 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.
    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 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

[[Page 48848]]

tumorigenic in animals even at maximally tolerated doses and has a 
different spectrum of toxicological effects.

E. Safety Determination

    1.  US population. 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<SUP>-6</SUP> (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<SUP>-6</SUP>. The upper bound 
estimate on excess cancer risk for all uses including wheat is 0.7 x 
10<SUP>-6</SUP>.
    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<SUP>-6</SUP>), 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.
    2. Infants and children. 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<SUP>-6</SUP>, using (Q1* = 1.06x10<SUP>-2</SUP> (mg/kg/day)-
1). (60 FR 27420; May 24,1995).
    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* = 0.36x10<SUP>-2</SUP> (mg/kg/
day)-1), the estimated excess cancer risk for the U.S. population is 
less than 1 x 10<SUP>-6</SUP>. 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.

F. 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.

G. Environmental Fate Summary

    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 
DT<INF>50</INF> values for fenbuconazole range from 29 to 532 days 
under terrestrial conditions and from 442 to 906 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 
DT<INF>50</INF> in green heads was measured as 18 days and in green 
wheat stalks the DT<INF>50</INF> 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.
[FR Doc. 97-24693 Filed 9-16-97; 8:45 am]
BILLING CODE 6560-50-F


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