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pyrimethanil Registration of the New Active Ingredient Pyrimethanil, Contained in the Pesticide Product Scala Brand SC Fungicide 4/05

New York State Department of Environmental Conservation
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
Website: http://www.dec.state.ny.us/website/dshm/pesticid/pesticid.htm
E-Mail: ppr@gw.dec.state.ny.us

April 7, 2005

CERTIFIED MAIL
RETURN RECEIPT REQUESTED


Ms. Princy Jesudason
State Licensing Specialist
Bayer CropScience, LP
P.O. Box 12014
Research Triangle Park, North Carolina 27709

Dear Ms. Jesudason:

Re: Registration of the New Active Ingredient Pyrimethanil, Contained in the Pesticide Product Scala Brand SC Fungicide (EPA Reg. No. 264-788)

The New York State Department of Environmental Conservation (Department) has reviewed the application, received September 13, 2004, to register the above-mentioned product in New York State. This pesticide product contains the new active ingredient pyrimethanil (4,6-dimethyl-N-phenyl-2-pyrimidinamine) (chemical code 288201) and is labeled for use on almonds, pistachios, bulb vegetables, grapes, stone fruits (except cherries), pome fruits, potatoes and other tuberous and corm vegetables, strawberries and tomatoes.

The application was deemed complete for purposes of review on November 8, 2004 and a registration decision was due by April 7, 2005. However, in order to submit a supplemental label for the Department to review, Bayer CropScience waived the registration decision date until April 15, 2005.

HUMAN HEALTH REVIEW:

The New York State Department of Health (DOH) states that on an acute basis, Scala Brand SC Fungicide was not very toxic to laboratory animals by the oral, dermal or inhalation routes of exposure. It also was neither very irritating to rabbit skin or eyes nor did it cause dermal sensitization (tested on guinea pigs).

Also, on an acute basis, pyrimethanil was not very toxic nor was it very irritating to the eyes or skin. It was not a skin sensitizer. Pyrimethanil caused some liver, thyroid and hematological effects in chronic animal studies. It also caused some developmental/reproductive effects, but at doses that also caused maternal/parental toxicity. This chemical gave negative results in a number of genotoxicity tests. The United States Environmental Protection Agency (USEPA) classified pyrimethanil as a Group C carcinogen (possible human carcinogen) based on an increase in thyroid tumors in rats. The USEPA Office of Pesticide Programs derived an oral reference dose (RfD) of 0.17 milligrams per kilogram body weight per day (mg/kg/day) for pyrimethanil based on a no-observed-effect level (NOEL) of 17 mg/kg/day in a rat chronic feeding toxicity study and an uncertainty factor of 100.

The USEPA established tolerances for pyrimethanil residues on almonds at 0.20 parts per million (ppm); pome fruit at 3.0 ppm; stone fruit (except cherry) at 3.0 ppm; grape at 5.0 ppm; strawberry at 3.0 ppm; tomato at 0.5 ppm; onion dry bulb at 0.1 ppm; pistachio at 0.2 ppm; and tuberous and corm vegetables at 0.05 ppm. The chronic population adjusted dose (cPAD) for pyrimethanil is 0.17 mg/kg/day and has the same basis as the RfD. The USEPA estimated that chronic dietary exposure to pyrimethanil residues from the above crops would be less than 1.0% of the cPAD for females 13 to 49 years old, 1.0% for the general U.S. population, 4.5% for infants less than one year old and 5.3% of the cPAD for children one to two years old. This dietary noncancer exposure analysis is primarily based on the use of percent crop treated information and average crop field trial residue values. For the cancer dietary risk assessment, the USEPA's Cancer Peer Review Committee used a margin of exposure (MOE) approach instead of a cancer potency slope factor approach, utilizing the NOEL of 17 mg/kg/day as a point of departure for thyroid tumors in rats. The MOE calculated in this manner is 9,200 for the general U.S. population. The USEPA considered an MOE of 100-fold or above to be adequate in the case of pyrimethanil given that they determined this compound to have a well understood mode of action for thyroid carcinogenesis. The studies conducted on pyrimethanil provide support for the mechanistic evidence needed to demonstrate chemically-induced changes in thyroid-pituitary functioning that can lead to thyroid tumor development in rats.

The USEPA conducted a risk assessment for dermal and inhalation exposure of pyrimethanil from its use on a variety of crops for which tolerances have been established, as noted above. For mixers/loaders supporting aerial applications and mixers/loaders/applicators involved in airblast ground applications, the combined MOE for dermal and inhalation exposures were estimated to be 270 and 240, respectively. For these estimates, it was assumed that workers wore long-sleeved shirt, long pants, shoes plus socks (as required on the current pesticide product label) and protective gloves (not required on the current pesticide product label). Without protective gloves, the combined MOE for dermal and inhalation exposures for workers involved in aerial application was reduced to a value of two, whereas for airblast ground applications the MOE decreased to a value of 170. For all dermal and inhalation exposures, the USEPA used a dermal absorption factor of 100% and assumed 100% absorption via inhalation. The NOEL used for estimating all the above-stated MOEs was 23.1 mg/kg/day from a rat multigeneration reproduction study on pyrimethanil (for comparing to dermal and inhalation exposures). For post-application exposures of workers to pyrimethanil-treated crops, estimated MOEs ranged from 140 to 210 on day one (at eight hours after application). Generally, the USEPA considers MOEs of 100-fold or greater to provide adequate worker protection. Finally, although pyrimethanil has been classified by the USEPA as a Group C carcinogen (possible human carcinogen), the USEPA did not conduct a cancer risk assessment for workers, since the expected duration of exposure for handlers and post-application workers is limited to short-term and, according to the USEPA, the carcinogenic mode of action of pyrimethanil is due to a "disruption in the thyroid-pituitary status" which they considered to be reversible following shorter exposures.

The DOH briefly reviewed the environmental fate data of pyrimethanil and its major degradate, 2-amino-4,6-dimethyl-pyrimidine. These data indicate that the parent compound and its degradate have relatively low adsorption coefficients (Koc), i.e., less than a value of 500, in certain soil types. These Koc values suggest the potential for high mobility of these compounds through these soils and a capacity to contaminate groundwater/drinking water.

There are no chemical specific federal or State drinking water/groundwater standards for pyrimethanil or its major degradate, 2-amino-4,6-dimethyl-pyrimidine. Based on their chemical structures, these compounds fall under the 50 microgram per liter (_g/L) New York State drinking water standard for "unspecified organic contaminants" (10 NYCRR Part 5, Public Water Systems). The New York State drinking water standard for the sum of "unspecified organic contaminants" and "principal organic contaminants" is 100 _g/L.

Overall, the information in the registration package for Scala Brand SC Fungicide indicate that the labeled uses of the Scala Brand product should not pose significant risks to the general public or to workers, particularly if workers use personal protective equipment including chemical-resistant gloves. Because the current label for the Scala brand product does not include a requirement for the use of these gloves, the DOH recommends that such a requirement be included on the label before this product is registered in New York State. In addition, because the active ingredient pyrimethanil appears to have some oncogenic potential, the DOH has concerns for registering the Scala Brand product unless either the need for this product is significant or it replaces products that pose greater risks. Also of concern is that the Scala Brand SC Fungicide product use does not pose unreasonable risks to groundwater/drinking water. If these concerns can be adequately answered, then the DOH does not object to registration of Scala Brand SC Fungicide in New York State.

In response to these concerns, Bayer CropScience has submitted an amended label to the USEPA which would add waterproof gloves to the Scala Brand SC Fungicide label as part of the PPE for mixer/loader/applicators. Bayer CropScience has agreed to distribute a supplemental label (containing the additional PPE statement concerning the use of gloves which was approved by the USEPA March 28, 2005), and will be responsible for this supplemental label being distributed with every container of product sold, or intended, for use in New York State.

In response to other concerns of DOH (i.e., the need for this product), the Department requested input from Cornell University. According to several Associates of the University, this product will be useful for switching to an alternate class of product with a different mode of action to avoid the development of resistance. For groundwater/drinking water concerns, please refer to the environmental fate review later in this letter.

NONTARGET ORGANISM REVIEW:

CHEMICAL DESCRIPTION
Pyrimethanil (C12H13N3) is a foliar fungicide for preharvest control of certain plant diseases on almonds, pistachios, bulb vegetables, grapes, stone fruits (except cherries), pome fruits, potatoes and other tuberous and corm vegetables, strawberries and tomatoes. Pyrimethanil is the class of chemistry called anilinopyrimidines (fungicides). This class acts to inhibit the secretion of fungal enzymes which are required during the infection process, blocking the ability of fungi to degrade and digest the plant tissues, thus stopping penetration and development of the disease.

The maximum application rate is 0.7 pound of active ingredient per acre and the maximum annual application rate is 2.14 pounds of active ingredient per acre per season. Formulations of the chemical include water dispersable granules and a soluble concentrate. For resistance management, fungicide should be applied no more than four times in any one season, and it is recommended not to make more than two consecutive applications without alternating between another fungicide.

TOXICITY
Pyrimethanil exhibits low toxicity to mammals and birds. (See tables below).

Mammalian Toxicity
Lowest acute oral LD50 Species:
Rat
LD50:
4149 mg/kg/bw
 
Lowest dietary LC50 (ppm) Species:
Rat
LOEC:
800 ppm
NOEC:
80 ppm
Lowest reproductive/ chronic (ppm) Species:
Rat
LOEC:
850 ppm
NOEC:
70 ppm


Avian Toxicity
Lowest acute oral LD50 Species:
Bobwhite Quail
LD50:
>2012 mg/kg/bw
NOEL:
2012 mg/kg/bw
Lowest dietary LC50 (ppm) Species:
Bobwhite Quail
LC50:
>4874 mg/kg/bw
 
Lowest reproductive/ chronic (ppm) Species:
Bobwhite Quail
LOEC:
184 ppm
NOEC:
184 ppm

Lowest acute LC50
Species:
Rainbow trout
LC50:
10.14 mg/L
NOEL:
4.0 mg/L
Lowest freshwater invertebrate LC50 Species:
Daphnia magna
LC50:
3.04 mg/L
NOEL:
1.4 mg/L
Lowest marine/ estuarine LC50 Species:
Sheepshead minnow
LC50:
2.80 mg/L
NOEL:
1.4 mg/L
Lowest algae LC50 Species: Selenastrum capricornutum LC50:
1.8 mg/L
NOEL:
.33 mg/L
Lowest macrophyte LC50 Species:
Lemna gibba
LC50:
7.8 mg/L
NOEL:
<1.9 mg/L
Lowest fish chronic Species:
Rainbow trout
LC50:
.039 mg/L
NOEL:
.02 mg/L
Lowest invertebrate chronic Species:
Mysid shrimp
LOEL:
.50 mg/L
NOEL:
.25 mg/L


EXPOSURE
The applicant submitted environmental fate studies that were conducted to meet USEPA pesticide registration guidelines, including hydrolysis, photolysis (water and soil), aerobic soil metabolism, anaerobic soil metabolism, aerobic aquatic metabolism, anaerobic aquatic metabolism, adsorption/desorption (leaching potential), and terrestrial field dissipation.

The studies showed that Pyrimethanil is stable to aquatic photolysis. Environmental degradation from hydrolysis is also minimal with half-lives of 962 and 722 days at pH 7 and pH 9, respectively. Aquatic anaerobic metabolism is not considered a major pathway for degradation.

The major pathway for environmental degradation is through terrestrial degradation. Mean terrestrial photolysis half-life is 22 days. For aerobic soil metabolism the mean half-life is 81.3 days and for anaerobic soil metabolism the mean half-live is 365 days. For the terrestrial field dissipation study, which most represents real life conditions, the geometric mean half-life is 131 days. Pyrimethanil was shown to have low mobility in loamy sand, and has medium mobility in sandy loam.

RISK ASSESSMENT
A. Model parameters
For Aquatic Modeling, tests were run using three different run-off rates (1%, 3% and 5%) and three different pond depths were used (1 ft., 3 ft. and 6 ft.).

B. Model Results and Analysis
Acute modeling of the toxicity of pyrimethanil to mammals revealed that there were no impacts. The chronic model for mammals revealed that risk quotients were 1.1 and 1.3, for residue levels found on short grass. This exceedence is not great enough to cause concern. Avian models for acute and chronic toxicity indicated that levels were safe.

Aquatic toxicity models revealed that even in the worst case scenario where there was maximum application (2.14 lbs a.i/acre), no allowance for foliar interception, and maximum runoff, risk quotients were only exceeded in Rainbow trout early life stage, but were not exceeded in any way that would cause concern.

MITIGATION, ALTERNATIVES
In terms of mitigation and alternatives, pyrimethanil was shown in the half-life models to be persistent, but it was also shown that residue levels will not build up to high enough concentration that would cause concern for wildlife or for the environment. Therefore, mitigation is not needed. When used as labeled, this product should not be a concern for fish, wildlife or the environment.

ENVIRONMENTAL FATE REVIEW:

Bayer CropScience is applying to register Scala Brand SC Fungicide for foliar use to control certain diseases on almonds, pistachios, bulb, tuberous and corm vegetables, grapes, stone fruits (except cherries), pome fruits, potatoes, strawberries and tomatoes. The product is packaged as a liquid and contains 54.6% active ingredient by weight, or 5 pounds active ingredient per gallon. Multiple applications are allowed. The maximum application rate is 2.1 pounds per active ingredient per acre per crop. The inerts do not appear to be solvent carriers.

Technical Review
Solubility: The solubility of pyrimethanil is 121 mg/L.

Hydrolysis: USEPA found this study acceptable. Pyrimethanil is stable at pHs 5, 7 and 9.

Aqueous Photolysis: USEPA found this study to be supplemental but upgradable. Pyrimethanil is stable at pH 5, 7, and 9.

Soil Photolysis: USEPA found this study to be supplemental. In a loamy sand soil, the half-life was 22 days with no major transformation products.

Anaerobic Aquatic Metabolism: USEPA found these studies acceptable. In a German sandy loam, the half-life was > 365 days with one major transformation product: 2-Amino 4,6-dimethyl- pyrimidine (ZK 512 723 or SN 512 723 or AE F132593) at 15.2% maximum. In a pond water-sandy loam sediment from North Carolina, the half-life in the total system was >364 days with no major transformation products.

Aerobic Soil Metabolism: USEPA found these studies acceptable. In a German loamy sand, the half-life was 110.7 days. In a German loam, the half-life was 97.4 days. In a German sandy loam, the half-life was 81.3 days. CO2 was the only major transformation product in each study.

Aerobic Soil Metabolism ZK 512 723: USEPA found this study supplemental. In a German loamy sand, the half-life was 170.5 days with no major transformation products.

Aerobic Aquatic Metabolism: USEPA found this study partially acceptable. In a stream water-sandy loam sediment from Germany, the half-life was < 120.7 days. No major transformation products were found. In a stream water-sand sediment from Germany, the half-life in the system was 37 days with one major transformation product: ZK 512 723 at 11.8% maximum.

Adsorption/Desorption: USEPA found all studies supplemental.

Soil Type % OC Soil pH Ads/Des
Koc Parent
Ads/Des Koc ZK 512 723
or SN 512 723
loam 3.5 7.64   56/60
clay loam 0.9 7.52   240/256
loamy sand 1.32 7.77 299/242 94/76
sand 3.12 4.78 751/295 167/109
loamy sand 3.23 4.35 543/319 107/74
sandy loam 1.58 4.60 682/481 197/139
sand .75 6.1 500/223  
loamy sand 2.45 7.1 320/176  
sandy loam .95 5.9 265/195  
sandy loam 3.5 7.5 75/52  
sandy clay loam .9 7.6 345/244  
sandy loam .58 8.0 439/383  
loamy sand 1.97 6.3 686/875  


Column Leaching: USEPA found these studies unacceptable (MRIDs 45656914 and 45656912).

Terrestrial Field Dissipation: USEPA found this study acceptable. Product was applied at 2.1 pounds per active ingredient per acre. In a fine sandy loam, sandy loam and loamy sand, the half-lives were 106, 162 and 131 days, respectively. No major transformation products were found.

Modeling: Staff modeled pyrimethanil on Riverhead soil using a Koc of 481, a half-life of 110 days and the maximum application rate of 2.1 pounds of active ingredient per acre per year. The model projected cyclical peaks, ranging between 0.08 and 0.25 ppb.

The aerobic degradation study did not indicate major degradates, therefore, degradates were not modeled.

USEPA Comments: The major route of dissipation for pyrimethanil is expected to be aerobic metabolism for both aqueous and terrestrial environments. Pyrimethanil partitions into the sediment, but is stable to anaerobic (total system) degradation in both soil and sediment systems. Pyrimethanil is stable to both hydrolysis and aqueous photolysis at environmental pHs, but is susceptible to photolysis in soil.

Pyrimethanil is expected to have varying mobility and low volatility in the environment. Pyrimethanil may move off-site as dissolved residues or on suspended solids in runoff, as well as by spray drift. However, nine out of the 11 K oc values submitted for the parent compound were determined using foreign soils. USDA Taxonomic Classification System citations were not provided for these foreign soils, and it could not be determined if these soils are representative of soils found in the proposed use areas.

Pyrimethanil is a moderately persistent compound and may accumulate in aquatic environments following repeated applications. It could contaminate surface or ground waters at or near sites of application and, due to its relative persistence, could accumulate to significant levels in benthic sediments, according to model predictions, over the course of 30 years of repeated applications.

Environmental Fate Summary: Even though this product is moderately persistent (aerobic half-life is 110 days in a loamy sand), the Koc is sufficiently high enough that the model projects no significant leaching when used as labeled. Staff, therefore, have no objections to the registration of Scala Brand SC Fungicide as labeled.

SUMMARY:

The Department concludes that Scala Brand SC Fungicide should not have an adverse effect on the health of workers or the general public, the fish and wildlife resources, or the ground and surface water of New York State when used as labeled.

Please be reminded that Bayer CropScience has agreed to distribute a supplemental label (containing the additional PPE statement concerning the use of gloves which was approved by the USEPA March 28, 2005), and will be responsible for this supplemental label being distributed with every container of product sold, or intended, for use in New York State. The use of this supplemental label is intended for this growing season only. The new stamped "Accepted" label issued by the USEPA dated March 28, 2005 which list gloves as part of the PPE, must be in use by the beginning of the 2006 growing season.

Therefore, the Department hereby accepts for general use registration in New York State Scala Brand SC Fungicide (EPA Reg. No. 264-788) which contains the new active ingredient pyrimethanil.

Enclosed is your Certificate of Pesticide Registration, New York State stamped "ACCEPTED" label, and New York State stamped "Accepted" Supplemental Label.

Bayer CropScience, LP is reminded that if New York State registration is requested for this product or for any other product which contains pyrimethanil with an increased application rate and/or expanded use sites, the product will be considered a Major Change in Labeling and the Department will require an extensive review.

If you have any questions, please contact Samuel Jackling, Chief of our Pesticide Product Registration Section, at (518) 402-8768.

Sincerely,

Maureen P. Serafini
Director
Bureau of Pesticides Management

Enclosures
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