[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
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Joanne Miller (PM 23)......... Rm. 237, CM #2, 703- 1921 Jefferson
305-6224, e- Davis Hwy,
mail:miller.joanne@ep Arlington, VA
amail.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-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:
[email protected]
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comment and data
will also be accepted on disks in Wordperfect 5.1 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket number [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
LD50 is >5,000 mg/kg or greater for males and females. The
rabbit dermal LD50 is >2,000 mg/kg and the rat inhalation
LC50 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 10-5
mg/kg/day or 0.0041% of the RfD. For non-nursing infants, the TMRC wold
be 1.37 X 10-5 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: -(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 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: -(2-(4-chlorophenyl)-ethyl)--phenyl-(1H-
1,2,4-triazole-1-propanenitrile, plus 4-chloro--
(hydroxymethyl)-- 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: -(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 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--(hydroxymethyl)--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 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. 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 10-2 (mg/kg/day)-1) was based on the
rat oncogenicity study and surface area was estimated by (body
weight)3/4.
Since the PRC published the above estimate they have agreed that
low-dose extrapolation for fenbuconazole, based on rat thyroid tumors,
is inappropriate given the EPA's policy regarding thyroid tumors and
the data which exist for fenbuconazole. The PRC agrees that the more
appropriate data set for the low-
[[Page 48847]]
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 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
10-6 for additional cancer risk (Q1* = 1.06 x
10-2 (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
10-2 (mg/kg/day)-1) the dietary risk for currently
registered uses is 0.3 x 10-6. 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
10-2 (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.
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
10-6 (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.
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 10-6, using (Q1* = 1.06x10-2 (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* = 0.36x10-2 (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.
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
DT50 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
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.
[FR Doc. 97-24693 Filed 9-16-97; 8:45 am]
BILLING CODE 6560-50-F