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fipronil
NYS DEC Letter - Registration of Major Changes in Label 4/99


New York State Department of Environmental Conservation
Division of Solid & Hazardous Materials
50 Wolf Road, Albany, New York 12233-7250
Phone 518-457-6934 FAX 518-457-0629

April 26, 1999

CERTIFIED MAIL
RETURN RECEIPT REQUESTED

Louis S. Grosso, Ph.D.
Director, Regulatory Affairs
Merial Limited
2100 Ronson Road
Iselin, NJ 08830-3077

Dear Dr. Grosso:

Re: Registration of Major Changes in Labeling for Frontline@ Products Which Contain the Active
    Ingredient Fipronil

This Department has completed the review of your applications for the registration of the new
pesticide product Frontline@ Spray Treatment for Dogs, Puppies, Cats and Kittens (EPA Reg.
No. 65331-1) and amended labeling for Frontline@ Top Spot for Cats and Kittens (EPA Reg. No.
65331-2), Frontline@ Top Spot for Dogs & Puppies up to 22 lbs. (EPA Reg. No. 65331-3),
Frontline@ Top Spot for Dogs 23-44 lbs. (EPA Reg. No. 65331-3), Frontline@ Top Spot for
Dogs 45-88 lbs. (EPA Reg. No. 65331-3) and Frontline@ Top Spot for Dogs 89-132 lbs. (EPA
Reg. No. 65331-3) in New York State. The applications were received by this Department on
August 27, 1998 and December 4, 1998, respectively. The products represent major changes in
labeling for the active ingredient fipronil. The applications were deemed complete on January
5, 1999 and a registration decision is due by June 4, 1999.

Frontline® Spray Treatment for Dogs, Puppies, Cats and Kittens (EPA Reg. No. 65331-1) is
labeled to control fleas and ticks on adult dogs and cats and on puppies and kittens eight
weeks of age or older. Frontline® Top Spot for Cats and Kittens (EPA Reg. No. 65331-2) is
labeled to control fleas and ticks on adult cats and on kittens 12 weeks of age or older.
Frontline® Top Spot for Dogs (EPA Reg. No. 65331-3) is labeled to control fleas and ticks on
adult dogs and on puppies ten weeks of age or older.

The application for registration of Frontline® Spray Treatment for Dogs, Puppies, Cats and
Kittens was previously reviewed and denied by the Department on November 6, 1996 and
February 7, 1997. The Department had unmitigated concerns about chronic risks to commercial
pet groomers who were exposed to the spray treatment product. The Department recommended that
the product not be considered for registration in the State until additional information was
provided which would lessen concerns for exposure risks to commercial pet groomers.

The Frontline® Top Spot products were previously reviewed and registered by the Department on
November 6, 1996. Risk of significant exposure of groomers or pet owners was not a concern
with the Top Spot products due to the application of the product by pre-measured pipette.
Also, the label required that latex gloves be worn during application.

A new application for Frontline@ Spray Treatment for Dogs, Puppies, Cats and Kittens was
received by this Department on August 27, 1998 and additional information was submitted on
November 3, 1998 and December 4, 1998. Merial Limited also submitted an application, on
December 4, 1998, for amended labeling for the Frontline® Top Spot products. The amended
labeling removed the following sentence from the "Precautionary Statements" section of the
Frontline® Top Spot product labels: "Persons applying this product must wear household latex
gloves." The Department determined that the removal of the requirement to wear latex gloves
from the precautionary statements section represented a major change in labeling for the
products.

The Department has reviewed the information supplied to date in support of the above-mentioned
pesticide product registration applications. The Department concluded that while fipronil is
relatively toxic, exposure potential from the use of the Frontline® Spray Treatment and the
Frontlme® Top Spot products to control fleas and ticks on dogs, puppies, cats and kittens is
limited.

As a condition of federal registration, Menial Limited was required to conduct studies on
fipronil exposure to commercial pet groomers from the use of the Frontline® products. Both
dermal and inhalation exposure were measured from 16 commercial pet groomers who made
applications to eight dogs each. Exposure was also estimated for homeowners applying the
Frontline® products to one of their dogs based on the outcome of these studies. Margins of
Exposure (MOE) were calculated for short-term exposures based on the no-observed-effect
level (NOEL) of 5.0 milligrams per kilogram body weight per day (mg/kg/day) for decreased
body weight gain and food consumption from a 21-day dermal toxicity study in rabbits. MOEs
for chronic exposures were calculated using the NOEL of 0.019 mg/kg/day for clinical signs
and alterations in clinical chemistry and thyroid parameters from a chronic study in rats
corrected to 1.9 mg/kg/day to account for conversion from an oral study to dermal exposure
(dermal absorption of fipronil was measured to be less than one percent of that applied).

The short-term MOE for dermal exposure for commercial pet groomers applying the Frontline
Spray Treatment product is estimated to be about 200 and the long-term MOE is about 400.
The dermal MOE for homeowners using Frontline® Spray Treatment is estimated to be about 1,700
based on short-term use. The short-term estimated MOEs for commercial groomers using the
Frontline® Top Spot products are 3,600 with gloves and 2,000 without gloves. Long-term MOEs
for commercial groomers are 11,000 and 6,700 for use with and without gloves, respectively.
For homeowners applying the Top Spot products, the estimated MOE when gloves are worn is
28,000. When gloves are not worn, the MOE is estimated to be 16,000 for homeowners. Generally,
MOEs equal to or greater than 100 are considered to provide an adequate measure of protection.
In the exposure studies, inhalation exposure was considerably less than one percent of dermal
exposure and did not significantly alter the MOE estimates.

The application methods and rates should provide an adequate margin of exposure to pet owners
and commercial pet groomers. The Department has no objections to the removal of the label
statement requiring the use of gloves when applying Frontline® Top Spot products, as long
as the product labels continue to retain the precautionary statement: "Avoid contact with
skin, eyes or clothing."

Therefore, the Department hereby accepts for registration Frontline® Spray Treatment for
Dogs, Puppies, Cats and Kittens (EPA Reg. No. 65331-1), Frontline® Top Spot for Cats &
Kittens (EPA Reg. No. 65331-2), Frontline® Top Spot for Dogs & Puppies up to 22 lbs.
(EPA Reg. No. 65331-3), Frontline® Top Spot for Dogs 23-44 lbs. (EPA Reg. No. 65331-3),
Frontline® Top Spot for Dogs 45-88 lbs. (EPA Reg. No. 65331-3), and Frontline® Top Spot for
Dogs 89-132 lbs. (EPA Reg. No. 65331-3).

Please be reminded that Merial Limited is required to submit all information, which is
required to be submitted under Federal Insecticide, Fungicide and Rodenticide Act 6 (a)(2)
and implementing regulation 40CFR Part 159, regarding adverse effects of a
pesticide product or any of its ingredients to the Department within thirty (30) days
after the reportable information is first possessed or known.

Enclosed are your New York State stamped "ACCEPTED" labels and a copy of the Certificate of
Registration.

If you have any questions, please contact Maureen P. Serafini, Chief of our Pesticide Product
Registration Section, at (518) 457-7446.

Sincerely,

Stephen Hammond, P.E.
Director
Division of Solid & Hazardous Materials

Enclosures
cc: w/enc. - N. Kim/D. Luttinger/J. Leach - NYS Dept. of Health
             E. Biel/ R. Mungari - NYS Dept. of Ag. & Markets
             G. Good/W. Smith - Cornell University, PMEP