New York State Department of Environmental
Division of Solid & Hazardous Materials
Bureau of Pesticides Management
Pesticide Product Registration Section
625 Broadway, Albany, New York 12233-7257
Phone 518-402-8768 FAX 518-402-9024
June 9, 2004
RETURN RECEIPT REQUESTED
Mr. Michael Peplowski
Manager, Product Registrations
ISK Biosciences Corporation
7470 Auburn Road, Suite A
Concord, Ohio 44077
Mr. Michael Zucker
Senior Registration & Label Specialist
FMC Corporation - Agricultural Products
1735 Market Street - Rm 2298
Philadelphia, Pennsylvania 19103
Dear Messrs. Peplowski and Zucker:
Re: Registration of Technical Flonicamid
Insecticide (EPA Reg. No. 71512-7) and F1785 GH 50 WG Insecticide
(EPA Reg. No. 279-3264) Containing the Active Ingredient Flonicamid
The New York State Department of Environmental
Conservation (Department) has completed its technical review of
ISK Biosciences Corporation (ISK) application and data package
submitted on 12/08/03 to register Technical Flonicamid Insecticide
and FMC Corporation (FMC) application and data package submitted
on 12/12/03 to register F1785 GH 50 WG Insecticide (EPA Reg. No.
279-3264). The active ingredient, flonicamid, is a low dosage
pyridine insecticide for control of aphids and other sucking and
chewing insects. The formulated product is labeled for use in
commercial greenhouses and interiorscapes. The Department has
registered these products for sale, distribution, and use in New
York State, in accordance with the enclosed approved labeling.
The new active ingredient (NAI) review on F1785
GH 50 WG Insecticide (EPA Reg. No. 279-3264) was conducted concurrently
with the review on the Technical Flonicamid Insecticide (EPA Reg.
No. 71512-7) manufacturing use product (MUP) application. The
MUP contains 98.4% flonicamid while FMC's formulated product contains
50% flonicamid and is applied at a maximum use rate of 120 grams
of product (0.134 lb. flonicamid) per 100 gallons of water. A
volume of 200 gallons/acre may be applied to plants greater than
six feet in height (maximum use rate = 0.268 lb. active ingredient
per acre). The product may be reapplied every seven to 28 days
as necessary. To limit pest resistence to this product, it is
recommended that the user rotate to a different chemistry after
two consecutive applications of this product. The label also states
that a NPDES permit is required if water containing flonicamid
is discharged into the waters of the State. Flonicamid was registered
by the United States Environmental Protection Agency (USEPA) as
a potential organophosphate replacement product.
Pursuant to the review time frame specified by
New York State ECL ß33-0704.2, registration decision dates
of July 2, 2004 (ISK) and August 20, 2004 (FMC) were established.
The Department has conducted the following technical reviews with
regard to the registration of both products for impact to human
health, nontarget organisms, and the environment. Review summaries
are provided below:
Human Health Review:
Neither the active ingredient flonicamid nor the
formulated product was very toxic in acute oral, dermal or inhalation
toxicity studies in laboratory animals. Also, neither material
was a skin irritant (tested on rabbits) nor a skin sensitizer
(tested on guinea pigs). The active ingredient was not an eye
irritant (tested on rabbits), but the formulated product showed
severe eye irritation properties.
Several subchronic toxicity studies were conducted
on flonicamid. In a 90-day rat feeding study, histopathological
changes (hyaline deposition) in the kidneys of males and females
were reported at 60 and 340 milligrams per kilogram body weight
per day (mg/kg/day), respectively. Also, liver effects (centrilobular
hypertrophy) were observed in female rats at a dose of 340 mg/kg/day.
The no-observed-effect levels (NOELs) for males and females were
12.1 and 72.3 mg/kg/day, respectively. In a subchronic neurotoxicity
feeding study in rats, no neurotoxic effects were observed either
in males or females at doses up to 625 and 722 mg/kg/day, respectively
(the highest doses tested). Mice fed flonicamid for 90 days had
increased liver and spleen weights, and showed histopathological
changes in bone marrow, spleen and kidney at a dose of 154 mg/kg/day
in males and 192 mg/kg/day in females. The respective NOELs were
15.3 and 20.1 mg/kg/day. In a 90-day dog study, oral administration
of flonicamid resulted in increased adrenal weights and decreased
thymus weights in males at 20 mg/kg/day. In females, lower red
blood cell counts and an increase in kidney tubular vacuolations
were observed at 50 mg/kg/day. The respective NOELs for males
and females were eight and 20 mg/kg/day.
Because the formulated product is labeled for nonfood
use only, the USEPA did not require chronic feeding/oncogenicity
studies, a multigeneration reproduction study or a rabbit developmental
toxicity study for its registration. Several genotoxicity studies
were required, in which flonicamid yielded negative results. In
the required rat developmental toxicity study, some evidence of
developmental effects, characterized by increased fetal skeletal
variations, was reported in rats at a dose (500 mg/kg/day), which
also caused maternal toxicity. Observed maternal effects included
increased liver weight, hypertrophy of centrilobular liver cells
and vacuolation of proximal tubular cells of the kidneys. The
reported NOEL for both developmental and maternal toxicity was
Even though chronic feeding/oncogenicity studies
and some developmental/reproduction toxicity studies were not
required for the labeled nonfood use of flonicamid in the formulated
product F1785 GH 50 WG Insecticide, a summary of these toxicity
studies was presented in the Federal Re ister (Vol. 68, May 23,
2003; pages 28, 218-28, 222). In regard to these studies, no developmental
toxicity was observed in rabbits at the highest dose of flonicamid
tested, which was 25 mg/kg/day. In addition, no effects on reproductive
performance was reported in rats, also at the highest doses tested
of 197 and 402 (mg/kg/day)-1 for males and females, respectively.
In chronic rodent feeding studies, flonicamid caused some toxicity
including liver and hematological effects in mice and rats at
doses of about 30 and 37 mg/kg/day, respectively. The NOEL was
7.3 (mg/kg/day)-1 for rats. No NOEL was observed in the mouse
chronic feeding/oncogenicity study. In a chronic oral dog study,
reduced body weights in females and effects on circulating red
blood cells were reported at 20 mg/kg/day; the NOEL was eight
Flonicamid did not cause oncogenic effects in the
rat chronic feeding study. In mice, however, a statistically significant
increase in the incidence of lung (alveolar/bronchiolar) adenomas
occurred in all three dose groups (30, 89 and 264 mg/kg/day) of
both sexes. Lung carcinomas were only significantly increased
in the high dose female mice. Although the USEPA did not calculate
a cancer potency slope factor for flonicamid, the registrant using
data on lung tumors in mice, calculated a value of 0.031 (mg/kg/day)-1.
The registrant conducted an occupational risk
assessment for dermal and inhalation exposure of workers exposed
to flonicamid in the handling and application of the formulated
product in greenhouses. For estimating exposures, it was assumed
that workers wore personal protective equipment (long-sleeved
shirt and long pants, shoes plus socks, protective eyewear, waterproof
gloves) as required by the product's label. Inhalation exposures
were estimated assuming 100% absorption of flonicamid, whereas
for dermal exposures, the estimated percent of active ingredient
absorbed was either 1.2 or six percent. Using the registrant's
derived cancer potency slope factor of 0.031 (mg/kg/day)-1 and
estimated dermal and inhalation exposures, an increased lifetime
cancer risk of about 2.5 x 10-5 can be calculated. This value
is within the range of what USEPA generally considers to be acceptable
(1 x 10-4 or less) for occupational exposures. For post-application
exposures of greenhouse workers, the highest increased lifetime
cancer risk estimated was 5 x 10-6. Comparing the same occupational
exposure estimates to a NOEL of 7.3 (mg/kg/day)-1 from the rat
chronic feeding/oncogenicity study, margins of exposures (MOEs)
for handling/application of flonicamid in greenhouses and for
post-application exposure were 9,000 and 46,000, respectively.
Generally, the USEPA considers MOEs of 100-fold or greater to
provide adequate worker protection.
There are no chemical specific federal or State
drinking water/groundwater standards for flonicamid. 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).
Using the cancer potency slope factor for flonicamid of 0.031
(mg/kg/day)-1 and 6 NYCRR Part 702.4 procedures for deriving ambient
water quality standards and guidelines based on oncogenic effects,
the ambient water quality value associated with a one in one million
increased lifetime cancer risk is 1.1 micrograms per liter for
The available information indicates that neither
flonicamid nor F1785 GH 50 WG Insecticide is very acutely toxic.
Although the formulated product can cause severe eye irritation,
the use of protective eyewear, as required by the product label,
should mitigate this potential effect. Flonicamid caused limited
developmental toxicity, but only at doses that also caused maternal
toxicity. Chronic feeding/oncogenicity studies in rodents indicate
that flonicamid caused lung tumors in both male and female mice,
but did not cause oncogenic effects in rats. The USEPA noted "[T]hat
the lung effects are unique to the mouse and are not likely to
translate to other species including the rat." Nevertheless,
the registrant conducted an occupational cancer risk assessment
for greenhouse exposure to flonicamid. This assessment showed
that the occupational health risks, both cancer and noncancer,
posed by using the formulated product, are within the USEPA acceptable
range. Overall, the weight of evidence indicates that flonicamid
should not pose a significant risk to workers or the general public.
However, given that flonicamid appears to have some oncogenic
potential, the Department would require a reanalysis of risks
and a comparison to other products also registered for those same
uses if a registrant seeks to add use of flonicamid on food crops.
Nontarget Organism Review:
The USEPA either waived many ecological data requirements
or did not require certain studies because of the indoor use pattern.
Many other studies were classified as supplemental. From the limited
data that were provided, flonicamid appears to exhibit relatively
low toxicity to fish, aquatic organisms, birds, or mammals. It
is stable to photolysis and hydrolysis in water or soil. The primary
fate process is microbial metabolism. The half-life for this fate
process was 3.1 days.
Modeling: AVTOX and MAMTOX models could not be run because no
residue data were provided. Aquatic modeling was run with PONDTOX.
The model showed that a direct application of flonicamid at the
highest labeled rate to a one-acre pond 0.5 feet deep would not
exceed toxicity thresholds or NOECs for rainbow trout, bluegill,
green algae (Selenastrum capricornutum) or Daphnia magna.
Nontarget Organism Review Summary: Flonicamid appears to be relatively
nontoxic to fish and wildlife. Used as labeled, i.e., commercial
greenhouses and interior plantscapes, this insecticide is not
likely to have adverse ecological effects. However, flonicamid
must not be registered for outdoor uses in New York State unless
the product is reviewed again with a comprehensive data support
package to justify proposed outdoor uses.
Environmental Fate Review:
Hydrolysis: This study was found to be acceptable. At 25? C,
flonicamid was stable in pH 5 and 7 aqueous buffer solutions.
The half-life was estimated to be 204 days in a pH 9 buffer solution.
In the pH 9 solution, the major degradate TFNG-AM (N-(4-trifluoromethyl-nicotinoyl)glycinamide)
at 30.5% at 120 days was found and the minor degradate TFNG [N-(4-trifluoromethylnicotinoyl)
lycine] averaged < 3%.
Aqueous Photolysis: USEPA found this study to be acceptable.
At pH 7, flonicamid had a half-life of 534 days. No major transformation
products were noted.
Soil Photolysis: This study was found to be acceptable. In a
loamy sand soil, flonicamid had a calculated half-life of 22.4
days. TFNG-AM and TFNG were both minor transformation products.
Aerobic Soil Metabolism: This study was found to be supplemental.
In a loamy sand, the half-life was 3.1 days. Major transformation
products were 4-trifluoromethyl nicotinic acid (TFNA) at 36.9%;
6-hydroxy-4-trifluoromethyl nicotinic acid (TFNG-OH) at 21.8%;
TFNG-AM at 10.3%; and CO2. Minor transformation products were
4-trifluoromethylnicotinamide (TFNA-AM) at eight percent and TFNG
three percent. \
Adsorption/Desorption: These studies were found to be acceptable.
Kocs ranged from 7.9 to 34.9 in various UK or German loamy sands
and sandy loams, treated with either five mg/kg or 12 mg/kg of
parent and with or without 0.01 % HgCl.
Computer Modeling: Modeling was done using Riverhead sand, an
application rate of 0.067 ai/a/app (the application rate of one-
to two-foot high plants), a Koc of 34.9, and an aerobic half-life
of 3.1 days. The label allows an application every seven to 28
days, with no more than two consecutive applications before switching
to another insecticide. Assuming two applications per month, and
assuming the greenhouse runs all year around, 24 applications
were applied. The model projected one peak of approximately 0.4
Environmental Fate Summary: Flonicamid has very low Kocs and
is very mobile. It also has a very short half-life under environmental
conditions coupled with low application rates. These two factors
limit accumulation of the chemical to well below the level of
concern to human health as reported by the Department's Human
Health Review. Modeling indicates that use of F1785 GH 50 WG Insecticide
as labeled, should not negatively impact groundwater.
Enclosed for your record is a copy of your stamped
accepted label and the Certificate of Registration for your product.
Please note that a proposal by ISK/ FMC, or any other registrant,
to register a product that contains flonicamid for outdoor use,
use on food crops, or any other labeled uses that 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 note that any application for outdoor use
will require review of additional analytical methodology for soil
and water matrices.
Please be aware that any unregistered product may
not be sold, offered for sale, distributed, or used in New York
If you have any questions on this matter, please
contact our Pesticide Product Registration Section, at (518) 402-8768.
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, PMEP