Mr. Jerry Harrison
Manager, State Registration and Regulatory Support
Novartis Crop Protection, Inc.
PO Box 18300
Greensboro, NC 27419-8300
Dear Mr. Harrison:
Re: Registration of Two New Pesticide Products Fulfill Insecticide
(EPA Reg. No. 100-912) and Endeavor Insecticide (EPA Reg. No. 100-913),
Which Contain the New Active Ingredient Pymetrozine
The New York State Department of Environmental Conservation
(the Department) has reviewed your application, received July 6, 2000,
for registration of Fulfill Insecticide (EPA Reg. No. 100-912) and Endeavor
Insecticide (EPA Reg. No. 100-913) in New York State. The products contain
the new active ingredient pymetrozine. The application was deemed complete
for purposes of review September 1, 2000 and a registration decision is due
by January 29, 2001.
Fulfill Insecticide and Endeavor Insecticide are both water
dispersible granules with 50% of the active ingredient pymetrozine. Fulfill
Insecticide is labeled for control of certain aphids in cucurbit vegetables,
fruiting vegetables, potatoes (and other tuberous and corm vegetables) and
tobacco. The application rate is 0.086 lb. pymetrozine per acre per
application, with a maximum application rate of 0.17 lb. pymetrozine
per acre per year. Endeavor Insecticide is labeled "For Professional Use Only"
for control of aphids and whiteflies on landscape ornamentals, container
grown ornamentals, non-bearing fruit and nut trees in nurseries, Christmas
trees, ground covers and ornamental plants in greenhouses, lath and shadehouses,
and interiorscapes. The application rate is 0.3125 lb. pymetrozine per acre
per application. The maximum application rate is 1.5 lbs. pymetrozine per
acre per year outdoors and 3.125 lbs. pymetrozine per acre per year
The Department has reviewed the information supplied to date
in support of the pesticide product registration application for Fulfill
Insecticide (EPA Reg. No. 100-912) and Endeavor Insecticide (EPA Reg. No.
The New York State Department of Health (DOH), the
Department's Division of Fish, Wildlife & Marine Resources' Bureau of
Habitat and the Department's groundwater staff have reviewed the information
submitted to date in support of the application for registration of Fulfill
Insecticide (EPA Reg. No. 100-912) and Endeavor Insecticide (EPA Reg. No.
The DOH stated that neither the active ingredient nor the
formulated product was very toxic in acute oral, dermal or inhalation exposure
studies in laboratory animals, nor were they very irritating to skin or eyes.
The active ingredient, pymetrozine, demonstrated a slight dermal sensitization
with an intradermal challenge, but not with an epidermal challenge. The
formulated product did not produce sensitization with either challenge.
In an acute neurotoxicity feeding study with pymetrozine in
rats, neurotoxic effects (reduced body temperature, function observation
battery changes, and decreased motor activity in males) were reported at
125 milligrams per kilogram per day (mg/kg/day) which was the lowest dose
tested; the no-observed-effect level (NOEL) was less than 125 mg/kg/day.
In a subchronic (13 week) neurotoxicity feeding study with pymetrozine in
rats, neurotoxic effects (stereotypy in males and tiptoe gait in females) were
reported at 201 mg/kg/day; the NOEL was 68 mg/kg/day.
Pymetrozine also caused some toxicity in chronic animal feeding
studies. In rats pymetrozine caused liver effects (hepatocellular hypertrophy)
at 3.76 mg/kg/day in males and 46.26 mg/kg/day in females. The respective
NOEL's were 0.377 and 4.48 mg/kg/day. In mice, increases in liver weight as
well as hepatocellular hypertrophy and hemosiderosis (increase in storage of
iron) were reported at a dose level of about 250 mg/kg/day; the corresponding
NOEL was about 12 mg/kg/day. In dogs, intestinal myopathy (muscle disease)
and anemia were reported at a dose level of 27.8 mg/kg/day; the NOEL was about
5.33 mg/kg/day. The United States Environmental Protection Agency (USEPA)
established a chronic population adjusted dose (cPAD) of 0.0038 mg/kg/day for
the general U.S. population and 0.0013 mg/kg/day for infants, children and
females 13 years of age and older. These values were based on the NOEL from
the rat chronic feeding study (0.377 mg/kg/day) and uncertainty factors of 100
and 300, respectively. These cPADs have not yet been placed as reference doses
in the USEPA's Integrated Risk Information System.
Developmental studies with pymetrozine were conducted in
rats and rabbits. Maternal toxicity (decreased body weight gain and food
consumption and efficiency) occurred in rats and rabbits at dose levels of
100 and 75 mg/kg/day, respectively; the respective NOELs were 30 and 10
mg/kg/day. In rats, the developmental toxicity lowest-observed-effect
level (LOEL) was 300 mg/kg/day, based on increased incidence of skeletal
abnormalities; the NOEL was 100 mg/kg/day. In rabbits, there was also an
increased incidence of skeletal abnormalities at doses of 75 mg/kg/day;
the NOEL was 10 mg/kg/day. Also, there were increased resportions and
post-implantation losses and reduced litter sizes at 125 mg/kg/day. In
a two-generation reproduction study in rats, parental toxicity was
observed as increases in liver effects. The LOELs were 13.9-17.0 and
16.0-18.1 mg/kg/day for males and females, respectively. The parental
NOEL was 1.4-1.7 mg/kg/day for males and 1.6-1.8 mg/kg/day for females.
No reproductive effects were noted in either generation at the highest doses
tested (136.9-179.0 mg/kg/day for males and 151.6-186.5 mg/kg/day for females).
However, offspring systemic/developmental toxicity occurred as decreased
pup weight and delay in eye opening in both generations. The LOEL was
136.9-179.0 mg/kg/day for males and 151.9-186.5 mg/kg/day for females.
The respective NOELs were 13.9-17.0 and 16.0-18.1 mg/kg/day.
Pymetrozine caused liver tumors in chronic rodent studies. In
female rats, there were significant positive trends for hepatomas and combined
hepatomas and/or carcinomas. There was also a significant pair-wise comparison
for these tumors between the controls and the highest dose group,
148.3 mg/kg/day. The USEPA determined that the tumor incidence in male rats was
within historical control range. In mice, both males and females had
significant positive trends for liver carcinomas, hepatomas and combined
hepatomas and/or carcinomas. There was also a significant pair-wise comparison
between controls and the highest dose group (675.0 mg/kg/day) for liver
carcinomas and combined hepatomas and/or carcinomas in males and for hepatomas
and combined adenomas and/or carcinomas in females. The USEPA classified
pymetrozine as a "likely human carcinogen" and calculated a cancer potency
slope factor for this compound of 0.205 (mg/kg/day)-1. Pymetrozine, however,
was negative in a number of genotoxicity tests.
The USEPA established tolerances for residues of pymetrozine
in or on curcurbit vegetables and fruiting vegetables at 0.05 parts per
million (ppm) each, and for tuberous and corm vegetables at 0.02 ppm. The
USEPA estimated that chronic dietary exposure from pymetrozine use on these
crops would be 4.5 x 10-4 mg/kg/day for the general U.S. population and 9.6
x 10-4 mg/kg/day for children one to six years of age. These exposure
estimates represent 12 percent and 74 percent of the respective chronic
population adjusted doses. This chronic dietary exposure analysis was based
on the assumption that 100 percent of all commodities for which tolerances
are established are treated and that they contain tolerance level residues.
The USEPA also did a more refined exposure analysis based on 20 percent crop
treatment and anticipated residue levels. Based on a chronic dietary exposure
estimate of 8 x 10-7 mg/kg/day for tuberous and corm vegetables only and the
cancer potency slope factor of 0.205 (mg/kg/day)-1, an increased lifetime
cancer risk of 1.7 x 10-7 was calculated for the general U.S. population.
The USEPA also evaluated worker risks from the use of the
Fulfill and Endeavor products. For mixer/loader/applicators of pymetrozine
on potatoes, average daily exposures ranged from 1.8 x 10-6 to 3.6 x 10-5
mg/kg/day, and for pymetrozine on ornamentals and Christmas Trees, the average
daily exposure estimates ranged from 1.9 x 10-7 to 5.6 x 10-6 mg/kg/day. When
these exposure estimates are compared to a NOEL from the rat chronic feeding
study (0.377 mg/kg/day), margins of exposure ranging from about 10,500 to
209,000 and 67,300 to 1,980,000, respectively, can be calculated.
Generally, margins of exposure 100-fold or greater are considered adequate
by the USEPA. The cancer risk estimates for mixer/loader/applicators of
pymetrozine on potatoes, and ornamentals and Christmas trees ranged from
1.8 x 10-7 to 3.9 x 10-6; and 1.8 x 10-8 to 5.9 x 10-7, respectively. These
values are within the general USEPA acceptable level of comparison (1 x 10-4
or less) for occupational exposures.
There are no chemical specific federal or State drinking
water standards for pymetrozine. Based on its chemical structure, pymetrozine
falls under the 50 microgram per liter (ug/L) general New York State drinking
water standard for "unspecified organic contaminants" (10 NYCRR Part 5, Public
Water Systems). Using the USEPA cancer slope factor of 0.205 (mg/kg/day)-1
and 6 NYCRR Part 702.4 procedures for deriving ambient water quality standards
and guidelines based on oncogenic effects, the value associated with a one
in one million increased lifetime cancer risk is 1.4 ug/L for pymetrozine.
Using the USEPA cPAD of 0.0013 mg/kg/day for infants, children and females
and 6 NYCRR Part 702.5 procedures for deriving ambient water quality standards
and guidelines based on non-oncogenic effects, a value of 9.1 ug/L can be
Neither pymetrozine nor the formulated Fulfill/Endeavor
products were very toxic following acute exposures in laboratory animal
studies. The data indicate that pymetrozine caused developmental effects
only at doses that also were parentally toxic. In addition, it was not
genotoxic. However, pymetrozine did cause liver effects at relatively
low doses, including the formation of liver tumors in mice and rats exposed
over their lifetimes and the USEPA classified this chemical as a "likely
human carcinogen." Both a dietary and occupational cancer risk assessment
conducted by the USEPA indicated that the estimated increased lifetime cancer
risk to the public and workers generally would not exceed USEPA acceptable
levels and estimated non-cancer risks to the public and workers also are
While the estimated risks posed by the Fulfill/Endeavor
products are within the USEPA acceptable range, we generally have concerns
for registering a pesticide product that has carcinogenic potential unless
either the needs for the product are significant or it replaces products that
pose greater risks. To address this issue, the registrant submitted a reduced
risk rationale document for pymetrozine and its associated end-use products.
This document compares the properties of pymetrozine to those of nine other
active ingredients that have the same uses on certain crops. Of the possible
alternatives to pymetrozine in this document, imidacloprid and acephate are
the only other chemicals reported to have the "CAUTION" signal word. Other
chemicals considered in this comparison (dimethoate, endosulfan,
fenpropathrin, oxydemeton-methyl, methamidophos, oxamyl, and methomyl)
have the signal words WARNING, DANGER or DANGER-POISON which indicate a
greater acute toxicity or irritancy risk.
Imidacloprid, a "CAUTION" signal word product, did not show
oncogenic potential in laboratory animal studies and is classified by the
USEPA as a Group E (evidence for non-carcinogenicity in humans) carcinogen;
acephate, the other "CAUTION" signal word product, is classified as a
Group C (possible human carcinogen). In total, six of the alternatives
are reported to be Group E carcinogens, two are Group C carcinogens and
one (oxydemeton-methyl) has not been classified. The USEPA Office of
Pesticide Programs reference dose values for the alternative compounds range
from 0.0002 to 0.057 mg/kg/day. The cPAD value for pymetrozine is either
0.0013 or 0.0038 mg/kg/day depending on the population group. These values
for pymetrozine are about in the middle of the range for the alternate
compounds. Acephate, dimethoate, oxydemeton-methyl, methamidophos, oxamyl,
and methomyl are all cholinesterase inhibitors. Oxamyl and methomyl are
classified as carbamates. Acephate, dimethoate, oxydemeton-methyl and
methamidophos are organophosphates.
The application rate of pymetrozine on potatoes
(39 grams per acre) is about 4 to
12-fold less than those of the alternative active ingredients. Similarly,
the tolerance for pymetrozine on potatoes (0.02 ppm) is reported to be
between 5 and 40-fold lower than those for the other active ingredients.
Consequently, pymetrozine use could reduce dietary exposure to insecticides
on potatoes. Also, many of the other alternatives have physicochemical
properties which, along with their environmental persistence in certain
cases, raises some concern about potential impacts on groundwater/drinking
water in areas where soils are permeable and the water table is shallow.
Pymetrozine's environmental fate properties do not raise these concerns.
Our groundwater staff stated that the pymetrozine parent
has very high Kocs, and modeling indicated that there would be no leaching
at the labeled rate. The major mode of degradation when used as labeled
would be aerobic metabolism or photolysis from the foliage. The use of the
products as labeled should not cause an impact to ground or surface water
in New York State.
The Bureau of Habitat reviewed the information submitted
and indicated that there were no fish and wildlife concerns associated with
the use of the products, when used as labeled.
Pymetrozine is an insecticidal compound which belongs to
a new chemical class known as pyridine azomethines. It exhibits a unique
mode of action which can be characterized as neural inhibition of feeding
behavior. Pymetrozine is a low use rate product which controls aphids at
lower rates than most commonly used insecticide standards.
Pymetrozine is an organophosphate alternative and has
potential for utility in both integrated pest management (IPM) and resistance
management programs because of its unique mode of action, its selectivity,
and its safety to predators, parasites, and other beneficial mites and
insects. Pymetrozine poses minimal risk to birds, bees, fish and aquatic
invertebrates. The pymetrozine environmental fate profile indicates no
major issues in the areas of soil mobility and fish bioaccumulation.
Pymetrozine is not acutely toxic and is not a mutagen, neurotoxin or a
teratogen. The labeled uses of Fulfill Insecticide and Endeavor Insecticide
do not appear to pose a significant risk to workers or the
Therefore, the Department hereby accepts for registration
Fulfill Insecticide (EPA Reg. No. 100-912) and Endeavor
(EPA Reg. No. 100-913).
Endeavor Insecticide is labeled "For Professional Use Only" and
is, therefore, classified as restricted use in New York State in accordance
with rules and regulations
6 NYCRR 326.2(g). As such the product is restricted in its purchase,
distribution, sale, use, and possession in New York State. According
to the New York State Department of Environmental Conservation
Regulations 6 NYCRR 326.3 (a): "It shall be unlawful for any person to
distribute, sell, offer for sale, purchase for the purpose of resale,
or possess for the purpose of resale, any restricted pesticide unless
said person shall have applied for, and been issued a commercial permit."
Furthermore, the product may only be purchased and used by certified
applicators in New York State.
Please contact the Pesticide Certification Section, at
(518) 457-7482, if you require information concerning commercial permits
or pesticide applicator certification.
Enclosed are your New York State stamped "ACCEPTED" labels
and a copy of the Certificate of Registration.
If you have any questions, please contact Francis X.
Hegener, Chief of our Pesticide Product Registration Section, at (518)
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
G. Good/W. Smith - Cornell University, PMEP