Mr. Dan Fay
Manager, Registration & Regulatory Affairs
Valent U.S.A. Corporation
1333 North California Boulevard
P.O. Box 8025
Walnut Creek, California 94596-8025
Dear Mr. Fay:
Re: Registration of the Valor Herbicide (EPA Reg. No. 59639-99) Containing the New Active
The New York State Department of Environmental Conservation (Department) has completed its
technical review of your
application and data packages submitted in support of the registration of Valor Herbicide.
Valor Herbicide (EPA Reg.
No. 59639-99) contains the new active ingredient flumioxazin, not previously registered in
New York State. The product
is labeled for control of susceptible weeds in peanuts and soybeans, and can also be used as
part of an early preplant
burn down program in cotton, field corn, rice, sorghum, sunflowers, and wheat. The Department
has registered this
product for labeled use on the above-listed crops in New York State.
Flumioxazin is a light-dependent peroxidizing herbicide (LDPH), which acts by blocking heme
and chlorophyll biosynthesis
resulting in an endogenous accumulation of phototoxic porphyrins. This class of herbicides
are known to have a
phototoxic mode of action in plants and possibly in fish. The formulated product contains 51%
flumioxazin in a water
soluble granule. The product is applied as a foliar spray at a maximum application rate of
three ounces per acre per
year, or 0.0956 lb. active ingredient/acre/year.
The United States Environmental Protection Agency (USEPA) issued a conditional registration
for Valor Herbicide on
April 12, 2001. The USEPA accepted a label amendment to add aerial application on July 31,
2002. The product labeling
that has been registered for use in New York State neither allows aerial application nor
application through any type
of irrigation equipment. The label "Environmental Hazards" section warns of toxicity to
nontarget plants and aquatic
invertebrates and warns against contamination of surface waters. Product effectiveness is
contingent on soil moisture
and weather conditions.
The Valor Herbicide new active ingredient (NAI) application was received on January 13, 2003.
The Department notified
Valent USA Corporation of an incomplete application via letter dated March 5, 2003. Valent
USA Corporation submitted
three data packag
es, received by the Department on the following dates: April 18, 2003; April 23, 2003; and
June 12, 2003 to complete
their application for a new active ingredient review of Valor Herbicide. The Valor Herbicide
application package was
declared complete as per Department letter dated June 25, 2003.
Pursuant to the review time frame specified in ECL §33-0704.2, a registration decision
date of November 21, 2003
was established. Valent USA Corporation requested an extension of 30 days in order for the
Department to evaluate
supplemental information that Valent USA Corporation submitted on November 13, 2003. A new
registration decision date
of December 21, 2003 was established. The Department conducted the following technical reviews
with regard to the
registration of Valor Herbicide for impacts to human health, nontarget organisms, and the
environment. Review summaries are provided below:
HUMAN HEALTH SUMMARY:
The New York State Department of Health (DOH) reviewed the application and supporting data
submitted by Valent USA
Corporation to register the pesticide product Valor Herbicide (EPA Reg. No. 59639-99) in
New York State. This product
contains the new active ingredient flumioxazin
and is labeled for control of susceptible weeds in peanuts and soybeans, and can also be
used as part of an early
preplant burn down program in cotton, field corn, rice, sorghum, sunflowers, and wheat.
Neither flumioxazin nor Valor Herbicide was very toxic in acute oral or dermal exposure studies
in laboratory animals,
nor were they very irritating to the eyes or skin (tested on rabbits). Also, neither the active
ingredient nor the
formulated product was a dermal sensitizer (tested on guinea pigs). In acute inhalation studies,
nor Valor Herbicide was very toxic, but the formulated product caused some laryngeal lesions in
the higher dose groups.
Flumioxazin caused some toxicity in chronic animal feeding studies. In a chronic feeding/oncogenicity
study in rats,
flumioxazin caused kidney damage in males at a dose of 18.0 milligrams per kilogram body weight per
day (mg/kg/day) and
in females caused anemia at 21.8 mg/kg/day; the respective no-observed-effect levels (NOELs) were
1.8 and 2.2
mg/kg/day. No effects were noted in mice at doses up to 754 mg/kg/day in males and 859 mg/kg/day
in females, the
highest doses tested. In dogs, an increase in liver weights and alkaline phosphatase activity
was reported at 1,000
mg/kg/day; the NOEL was 100 mg/kg/day. The USEPA Office of Pesticide Programs established a
reference dose (RfD) of
0.02 mg/kg/day based on a NOEL of 2.2 mg/kg/day in the chronic feeding/oncogenicity study in
rats and an uncertainty
factor of 100. This RfD has not yet been adopted by the USEPA's Integrated Risk Information
Flumioxazin caused some developmental toxicity in the offspring of pregnant rats. In a rat oral
study, an increase in the incidence of cardiovascular effects (especially ventricular septal
abnormalities, fetal resorptions and a decrease in the number of viable fetuses were observed
at ten mg/kg/day; the
NOEL was three mg/kg/day. No maternal toxicity was observed at the highest dose tested, which
was 30 mg/kg/day. In a
second rat developmental toxicity study, but with dermal administration of flumioxazin,
were reported at 100 mg/kg/day; the NOEL was 30 mg/kg/day. Again, no maternal toxicity was
observed at up to the
highest dose tested (300 mg/kg/day). In a rabbit oral developmental toxicity study, no
developmental effects were
reported at doses up to 3,000 mg/kg/day. However, at this dose, some maternal toxicity,
characterized by a decrease in
body weight and food consumption was reported. In a multigeneration reproduction study in rats,
flumioxazin caused a
decrease in the number of liveborn pups and pup body weight at 12.7 mg/kg/day; the NOEL was
6.3 mg/kg/day. Parental
toxicity characterized by an increase in mortality and liver effects in females was reported
at 22.7 mg/kg/day, with a NOEL of 15.1 mg/kg/day.
Flumioxazin did not cause oncogenic effects in either rat or mouse chronic feeding studies. It
also was negative in a
number of genotoxicity studies. The USEPA classified flumioxazin as "not likely" to be carcinogenic
The USEPA established tolerances for flumioxazin residues in or on peanuts and soybean seed each
at 0.02 parts per
million (ppm). The chronic population adjusted dose (cPAD) for flumioxazin is 0.002 mg/kg/day
based on the RfD of 0.02
mg/kg/day and an additional uncertainty factor of ten to account for the greater sensitivity of
the fetus in the rat
developmental and reproductive toxicity studies. The USEPA estimated that chronic dietary exposure
residues would be 0.5% of the cPAD for the general U.S. population and 2.3% for infants less than
one year old. This
chronic exposure analysis is based on the conservative assumption that 100% of crops are treated
and contain tolerance level residues.
The USEPA conducted a risk assessment for dermal and inhalation exposure of workers to flumioxazin
from its use on
peanuts and soybeans. For mixer/loaders/applicators, margins of exposure (MOEs) were estimated to
be 1,200 and above.
For these estimates, it was assumed that workers wore long pants, long-sleeved shirt, but did not
use gloves or a
respirator (the label requires pants, shirt and gloves, but not a respirator). The NOELs used for
estimating these MOEs
were 30 mg/kg/day from the rat dermal developmental toxicity study (for comparing to short- and
dermal exposures), three mg/kg/day from the rat oral developmental toxicity study (for comparing
inhalation exposures), and two mg/kg/day from the rat chronic feeding/oncogenicity study (for
intermediate-term inhalation exposures). For post-application occupational activities (i.e.,
irrigation, scouting, hand
weeding), the estimated MOEs ranged from 700 to 11,000. Generally, the USEPA considers MOEs
of 100-fold or greater to provide adequate worker protection.
DOH concluded that the labeled use of Valor would not pose significant direct risks to workers
or the general public.
However, DOH requested that the registrant clarify how an issue was resolved with the USEPA.
The issue revolved around
an acute inhalation toxicity study in rats which indicated that the formulated product caused
lesions in the larynx of
these animals. As a result of these findings, the USEPA reviewers of this study recommended
that the product label
require that handlers use a dust-filtering respirator. This requirement was apparently waived
later in the federal
review of this product, but no documentation for how the issue was resolved was provided.
Although the registrant was not able to supply any documentation from the USEPA regarding this
matter, they submitted a
risk assessment calculation for workers exposed to the active ingredient flumioxazin from the
handling of Valor
Herbicide based on the results of the acute inhalation study in rats. In making this calculation,
assumed that the cause of lesions in the larynx of rats was due to the active ingredient. Results
from this study
indicate, however, that the cause of these lesions was instead the other ingredients in the
product, not the active
ingredient, as similar effects on the larynx were reported in studies using only the "inert"
ingredients. Thus, in
estimating a margin of exposure (MOE), the registrant should have compared the no-observed-effect
air exposure level
for the "inert" ingredients alone (expressed in terms of dose as 1.46 milligrams per kilogram
body weight per day) with
the corresponding estimate of worker inhaled dose (0.00021 milligrams per kilogram body weight
per day) for these
ingredients. When this comparison is made, the estimated MOE from inhalation exposure to the
"inert" ingredients in the
Valor product is approximately 7,000. This MOE, although about two-fold less than the registrant's
estimated MOE, is
still well within the range that the USEPA generally considers as providing adequate worker
There are no chemical specific federal or State drinking water/groundwater standards for
flumioxazin. Based on its
chemical structure, this compound falls under the 50 microgram per
liter New York State drinking water standard for unspecified "organic contaminants" (10 NYCRR
Part 5, Public Water Systems).
Human Health Review Summary:
The available information on flumioxazin and Valor Herbicide indicates that overall the active
formulated product are not very acutely toxic in laboratory animal studies. The results of the
above risk assessment
analysis addressed our concern regarding respiratory protection for workers in lieu of
documentation from the USEPA
regarding this issue. Although data from chronic and developmental/reproductive studies on
flumioxazin showed that this
chemical has the potential to cause some toxicity, the expected exposure from the labeled
uses of Valor Herbicide
should not pose a significant risk to workers or the general public.
NONTARGET ORGANISM SUMMARY:
The New York State Department of Environmental Conservation Bureau of Habitat reviewed the
application and supporting
data submitted by Valent USA Corporation to register the pesticide product Valor Herbicide
(EPA Reg. No. 59639-99) in
New York State. Flumioxizan exhibited low toxicity to birds and mammals. It is somewhat more
toxic to fish and aquatic
invertebrates. It is very toxic to all aquatic plants, macrophytes and algae that were tested.
The freshwater aquatic invertebrate test was declared unacceptable and unrepairable by the USEPA.
The study was deemed
unacceptable due to some of the doses tested, exceeding the solubility (1.79 mg/L), and forming
a precipitate, thus the
actual content of the test solution was not accurately evaluated. However, the USEPA apparently
did not require the
study be redone.
Flumioxazin has a relatively short life in the environment. In water, it degrades quickly by
photolysis and hydrolysis,
with half-lives measured in hours. Two degradation products,
6-Amino-7-fluoro-4-(2-propynyl)-1,4,-benzoxazin-3(2H)-one (APF) and 3,4,5,6-tetrahydrophthalic
acid (THPA) accounted for 42% and 48% of the parent flumioxazin degraded by hydrolysis. The
toxicity of these
degradation products was not described, but they did appear to be more soluble and persistent
than the parent
On soil, flumioxazin was broken down between three and 12 days by microbial metabolism and
photolysis. APF and THPA
were very minor degradates from fate processes in soil.
Pesticide Screening System (PSS) models were run using data extracted from the data support
package supplied by the
applicant using standard parameters. Because of the flumioxazin KOW of 354.8, the PONDTOX
model selected values of one
percent, three percent and five percent as appropriate estimates of the percentage of pesticide
active ingredient that could be removed by runoff.
Both the MAMTOX and AVTOX models showed no acute or chronic adverse impacts to mammal and bird
populations that were
likely to result from consumption of vegetation that was treated with flumioxazin at the maximum
labeled application rate.
The PONDTOX model similarly showed no acute or chronic adverse impacts to fish, aquatic
marine/estuarine organisms from flumioxazin transported to water via runoff, using runoff
rates as high as five
percent. However, at all runoff levels, from 0.25% to one percent and above, impacts to both
aquatic macrophytes and
Anabena flos-aquae, the most sensitive algae species tested, were evident. At one percent
runoff, the Lemna gibba EC50
and NOEC were exceeded in all three pond depths (one, three, and six feet). The magnitude of
exceedances as measured by
Risk Quotients (RQs), ranged from 1.1 (EC50 in six-foot pond) to 8.8 (NOEC in one-foot pond).
For Anabena flos-aquae,
the EC50 was exceeded in the one- and three-foot ponds, with RQs of 2.3 and 1.1, indicating
only marginal exceedances.
flos-aquae NOEC was exceeded in all three pond depths by a considerable margin, with RQs
ranging from 23.5 in the
six-foot pond to 87.6 in the one-foot pond.
When a runoff percentage of 0.25% was used, adverse impacts to aquatic life were still
predicted, but at a much lower
magnitude. No EC50s were exceeded. The Lemna gibba NOECs were marginally exceeded (RQs = 2.2
and one) in the one- and
three-foot ponds. The Anabena flos-aquae NOECs were exceeded in all three pond depths with
RQs ranging from 5.9 to 21.9.
The PONDTOX model clearly predicts the potential for significant impacts to aquatic plants,
both algae and macrophytes
from flumioxazin residue in runoff water. Because, as would be expected from an herbicide,
these species were very
sensitive to flumioxazin, a separate analysis was run using all of the algae and macrophyte
data available. This
analysis showed that at one percent runoff, all five of the plant species for which data
were available showed some
level of impact. For Skeletonema costatum, a marine diatom, the no effects concentration
was exceeded in the one-foot
pond only. For Lemna gibba, a freshwater macrophyte, both the EC50 and NOEC were exceeded
in all three pond depths. At
0.25% runoff, no EC50s were exceeded. There were no toxicity thresholds exceeded at all for
Skeletonema costatum or
Selenastrum capricornutum, a freshwater green algae. For the others, the RQs ranged from one
The PONDTOX models clearly show that Valor, when applied as labeled, has the potential to be
harmful to aquatic plants,
both macrophytes and algae, when transferred to water bodies via runoff.
The PONDTOX model does not take into consideration either the terrestrial or aquatic degradation
of pesticides. The
rate of degradation can significantly impact the volume of pesticide available for runoff. Valor
is applied one time
only per season. It is also applied very early in the growing season, because it is used as either
herbicide or to burn off weeds as part of a preplant control program. Valor degrades fairly
quickly on land, by both
photolysis and microbial degradation with an average half-life of around three to 12 days. Also,
Valor degrades very
rapidly by hydrolysis and photolysis in water, with half-lives measured in minutes to hours,
depending upon the ambient water pH.
The aquatic plant toxicity tests were five-day tests, with the exception of the Lemna gibba test,
which was a 14-day
study. In all likelihood, most flumioxazin would degrade before it could have a serious impact on
aquatic vegetation. Valor begins degrading shortly after being applied, continuously decreasing
the amount of
flumioxazin that is available to be washed off the soil in runoff. Once in the water, it will
degrade very rapidly.
The formation of two persistent, soluble degradates was documented during aqueous hydrolysis
studies, APF and THPA. The
toxicity of these degradates is unknown. However, hydrolysis is a slower fate process than
photolysis in water, and
these degradates are formed at much lower rates during daylight. They are also only minor
(i.e., < ten percent of
parent) in terrestrial degradation. The formation of significant concentrations of these
degradates is only likely to
occur during hours of darkness. APF and THPA do degrade, both in water and on soil, albeit
much more slowly.
Nontarget Organism Review Summary:
Because of the rapid fate processes that actively reduce the flumioxazin concentration both on
land and in water, it is
unlikely that a large enough concentration of flumioxazin is likely to exist in water long
enough to harm aquatic
plants. The use of Valor Herbicide should not impact wildlife, birds, or aquatic species when
used as labeled in New York State.
ENVIRONMENTAL FATE SUMMARY:
The Department reviewed the application and supplemental data packages for impact to groundwater
resources in New York
State. All but two data evaluation records (DERs) were submitted. The main Environmental Fate &
(EF&GWB) review memorandum was not submitted; however, a shorter memorandum dated July 21,
1993 that discussed several studies was submitted.
Hydrolysis: The DER for this study was not submitted. However, according to the USEPA
memorandum dated July 21,
1993, this study was acceptable. Flumioxazin (or V-53482) had average calculated half-lives of
3.4 to 5.1 days, 21.4 to
24.6 hours and 14.6 to 22.0 minutes in solutions with pH of 5, 7, and 9 , respectively. Two
degradates were found in the phenyl-labeled ring
482-HA, reached a maximum of 5.4 in the pH 5 solution, 60.2 in pH 7 solution, and 100% in
pH 9 solution. The second
degradate, 6-amino-7-fluoro-4-(2-propynyl)-1,4-benzoxazin-3(2H)-1 or APF, reached 90% in the
pH 5 solution, 82.2% in
the pH 7 and was ND in the pH 9. In the tetrahydrophthalimido ring-labeled study, three
degradates were found. First,
482-HA at 6.7 % in pH 5 solution, 70.3% in the pH 7 solution and 98% in the pH 9 solution.
tetrahydrophthalic acid or THPA as 96.6% in pH 5 solution, 84.2% in the pH 7 solution, and
ND in the pH 9 solution. The
third degradate, 3,4,5,6-tetrahydrophthalic acid anhydride or 1 -TPA, reached 8.8% in pH 5
solution, 8.7% in pH 7
solution, and ND in the pH 9 solution.
Aqueous Photolysis: This study did not meet Subdivision N Guidelines. The
registrant-calculated half-life was
20.9 hours in a sterile pH 5 aqueous buffer solution. The reviewer-calculated half-life was
25.4 hours. Two
unidentified major degradates were found. Unknown one reached 74.6% and Unknown three reached
16.8%. USEPA required
that these studies be repeated and data submitted by April 12, 2003.
Soil Photolysis: USEPA found this study partially acceptable. In the phenyl ring-labeled
study, flumioxazin had
a half-life of 3.2 days on a sandy loam soil. Five minor degradates were found. In the THP
flumioxazin had a half-life of 8.4 days on a sandy loam soil. Five minor degradates were
found. 1-TPA reached 21.6% of
applied, and THPA reached 12.9% of applied.
Aerobic Soil Metabolism: This study did not meet Subdivision N Guidelines. Degradates
were not determined.
Flumioxazin had a half-life in sandy loam, clay loam, sand and loam of 5.0 days, 18.6 days,
18.9 days and 15.6 days,
Anaerobic Aquatic Metabolism: This study did not meet Subdivision N Guidelines. In the
study, flumioxazin had a half-life of 4.2 hours on a sandy loam soil. In the water phase, major
reached 45.4% and SAT-482-HA-2 reached 16.2%. In the THP ring-labeled study, flumioxazin had a
half-life of 4.3 hours
on a sandy loam soil. In the water phase, major degradate 482-HA reached 52.8% and SAT-482-HA-2
reached 15.7%. USEPA
required that these studies be repeated and data submitted by April 12, 2003.
Adsorption/Desorption: This study did not meet Subdivision N Guidelines. The Kocs of
flumioxazin in sand, sandy
loam, silt loam and clay loam were 265-277, 105-118, 675-1705 and 497-816, respectively. No
degradates were noted.
Mobility and Aged Leaching: No DER was submitted for the phenyl-labeled ring study, but
in the July 21, 1993
memorandum, USEPA indicated that this study was scientifically sound and partially acceptable.
USEPA also had concerns
about the length of time of the aging of the soil. However, no major degradates were noted, so
no additional data was
required for the aged leaching study. The DER for the TPA-ring labeled study indicated the
half-life was 17.5 days with
no major degradates.
Terrestrial Field Dissipation: MRID44295045 - This study did not meet Subdivision N
Guidelines because the
registrant did not analyze for degradates. USEPA believed the registrant calculated half-life
of 10.3 days was
questionable for many reasons.
MRID44295047 - This study was partially acceptable. The registrant calculated half-life was
4.8 days on a loam soil.
Only minor degradates were found.
MRID44295043 - This study was partially acceptable. The registrant calculated half-life was
27 days in a loamy sand
soil. Only minor degradates were found.
MRID44295046 - This study did not meet Subdivision N Guidelines because the registrant did
not analyze for degradates.
The registrant calculated half-life was 42 days in a silt loam soil.
MRID44295044 - This study did not meet Subdivision N Guidelines because the registrant did
not analyze for degradates.
USEPA believed the half-life was questionable. The registrant calculated half-life was 12.5
days in a silt loam soil.
Modeling: Staff modeled flumioxazin on Riverhead soil (to simulate upstate aquifers as
well as Long Island)
using a Koc of 105 (the lowest for sandy loam), a half-life of 18.9 days (the longest) and the
maximum application rate
of 0.0956 lb ai/a/yr. The model projected several peaks, all less than 0.015 ppb.
Environmental Fate Summary:
There appear to be no major degradates of Flumioxazin formed during its breakdown in the
environment. Although a low
Koc is typically an indicator of mobility and contamination of groundwater, Flumioxazin has
a short half-life. Coupled
with the very low application rate, the registration of this product for use as labeled will
have no significant impact
to groundwater resources.
The Department will register Valor Herbicide for use as labeled in New York State. Enclosed
for your record is a copy
of the stamped accepted label and the Certificate of Registration for Valor Herbicide (EPA
Reg. No. 59639-99). Please
note that a proposal by Valent USA Corporation or any other registrant, to register a product
flumioxazin, and whose labeled uses are likely to increase the potential for significant
impact to humans, nontarget
organisms, or the environment, would constitute a major change in labeled (MCL) use pattern.
Such an application must
be accompanied by a new application fee and meet the requirements listed in Appendix 1.B. of
"New York State Pesticide
Product Registration Procedures" (August 1996). Such information, as well as forms, can be
accessed at our website as
listed in our letterhead.
Please be aware that any unregistered product may not be sold, offered for sale, distributed,
or used in New York State.
Please contact our Pesticide Product Registration Section, at (518) 402-8768, if you have any questions.
Maureen P Serafini
Maureen P. Serafini
Bureau of Pesticides Management
cc: w/enc. - N. Kim/D. Luttinger - NYS Dept. of Health
R. Zimmerman/R. Mungari - NYS Dept. of Ag. & Markets
W. Smith - Cornell University, PSUR