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propamocarb hydrochloride (Previcur Flex) Withdrawal of Application to Register a Major Change in Labeled (MCL) Use 2/03

New York State Department of Environmental Conservation
Division of Solid and Hazardous Materials
Bureau of Pesticides Management, 9th Floor
625 Broadway, Albany, New York 12233-7254
Phone: (518) 402-8788     FAX: (518) 402-9024
Website: www.dec.state.ny.us

February 26, 2003

CERTIFIED MAIL
RETURN RECEIPT REQUESTED


Ms. Karen S. Cain
State Regulatory Affairs Team Lead
Bayer CropScience
P.O. Box 12014, 2 T.W. Alexander Drive
Research Triangle Park, North Carolina 27709

Dear Ms. Cain:

Re: Withdrawal of Application to Register a Major Change in Labeled (MCL) Use Pattern for the Active Ingredient Propamocarb Hydrochloride Contained in the Pesticide Product PREVICURTM FLEX Fungicide (EPA Reg. No. 264-678)

    The New York State Department of Environmental Conservation (Department) accepts Bayer CropScience's petition, dated February 6, 2003, to withdraw, without prejudice to any future filings, the application for the subject product. Pursuant to your request, a synopsis of the Department's reviews and risk assessments developed during the review of PREVICURTM FLEX Fungicide (EPA Reg. No. 264-678) follows.

    The Department received an application on February 22, 2002 from Aventis CropScience USA LP (Aventis) to register PREVICURTM FLEX Fungicide (EPA Reg. No. 264-678) containing the active ingredient propamocarb hydrochloride (propyl [3-(dimethylamino) propyl] carbamate monohydrochloride). During the review of this application, Aventis merged with Bayer and is now known as Bayer CropScience.

    PREVICURTM FLEX Fungicide contains 66.5% propamocarb hydrochloride and is labeled for protection of potatoes from late blight and tuber blight. Product is applied only in a tank mixture with other fungicides at the rate of 0.7 to 1.2 pints per acre at 7-10 day intervals. The maximum seasonal use rate of 6 pints product is equivalent to 4.5 pounds propamocarb hydrochloride per acre per growing season.

    Propamocarb hydrochloride is a component of three products registered in New York State for application to turf and ornamentals. The proposal to register a pesticide product labeled for food crop use represents a major change in labeled (MCL) use pattern for the subject active ingredient.

    The subject application package was deemed complete for purposes of technical review on July 23, 2002 following a determination of incompleteness (04/18/02). However, Aventis CropScience USA LP (Aventis) was notified that failure to address the deficiencies in the water residue method would result in an unfavorable registration decision. The analytical methodology requirement for propamocarb hydrochloride was subsequently deemed complete/acceptable on September 11, 2002. Pursuant to the review time frame specified in Environmental Conservation Law (ECL) 33-0704.2, a registration decision date of December 20, 2002 was established. By mutual agreement, the registration decision date was subsequently waived in order to resolve issues surrounding the terms of registration.

    Toxicological, ecological effects and environmental fate risk assessments were conducted for propamocarb hydrochloride and the PREVICURTM FLEX Fungicide formulated product.

TOXICOLOGICAL RISK ASSESSMENT:

    Acute toxicity studies were only performed on the technical grade active ingredient, propamocarb hydrochloride, since the end use product PREVICURTM FLEX Fungicide is essentially an aqueous dilution of the active ingredient. Propamocarb hydrochloride was not very toxic in acute oral, dermal or inhalation exposure studies in laboratory animals. It was slightly irritating to both skin and eyes (tested on rabbits). The available skin sensitization studies (tested on guinea pigs) provide mixed results; one yielded positive findings while another was negative. In an acute neurotoxicity study in rats, propamocarb hydrochloride caused decreased motor activity in females and soiled fur coats in both sexes at 2,000 milligrams per kilogram body weight per day (mg/kg/day); the no-observed-effect level (NOEL) for these neurobehavioral effects was 200 mg/kg/day.

    Propamocarb hydrochloride caused some toxicity in subchronic feeding and dermal exposure studies in laboratory animals. In a 90-day feeding study in rats, decreased body weight and body weight gain in females and decreased food efficiency in both sexes were reported at 716 mg/kg/day in females and 1,363 mg/kg/day in males; the NOELs were 363 mg/kg/day and 646 mg/kg/day, respectively. In a 90-day dog feeding study, propamocarb hydrochloride caused decreased body weight gain, decreased food efficiency, and erosive gastritis at 23 mg/kg/day (the lowest dose tested). In a 21-day dermal study in rabbits, propamocarb hydrochloride caused dose-related skin irritation and depressed body weight gain at 525 mg/kg/day; the NOEL was 150 mg/kg/day. However, in a 21-day dermal study in rats, propamocarb hydrochloride caused no toxicity at dose levels up to 1,000 mg/kg/day (highest dose tested).

    Propamocarb hydrochloride caused some toxicity in chronic animal feeding studies. In a two-year dog feeding study, propamocarb hydrochloride caused body weight gain depression, decreased food efficiency and erosive gastritis in males at a dose level of 33 mg/kg/day; a NOEL was not determined in this study. In a chronic feeding/oncogenicity study in mice, decreased body weight and body weight gain were reported in females at a dose level of 95 mg/kg/day; the NOELs were 12 mg/kg/day for females and greater than or equal to 690 mg/kg/day for males (the highest dose tested). In a chronic feeding/oncogenicity study in rats, propamocarb hydrochloride caused decreases in body weight, body weight gain, food consumption, water consumption, and an increase in the incidence of vacuolation of choroid plexus ependymal cells in the brain at dose levels of 682 mg/kg/day in males and 871 mg/kg/day in females; the NOELs were 84 mg/kg/day and 112 mg/kg/day, respectively.

    The United States Environmental Protection Agency (USEPA) classified propamocarb hydrochloride as "not likely" to be a human carcinogen based on the lack of evidence of carcinogenicity in rats and mice. Propamocarb hydrochloride was also negative in a number of genotoxicity studies.

    Propamocarb hydrochloride caused developmental effects in offspring of pregnant rabbits and rats administered this compound during organogenesis at doses that also caused maternal toxicity. In the rat study, fetal death at gestation day 20 and a possible increase in minor skeletal anomalies were reported in offspring at 740 mg/kg/day; the NOEL was 221 mg/kg/day. The only reported endpoint of maternal toxicity was mortality at a dose level of 740 mg/kg/day; the NOEL was 221 mg/kg/day. In the rabbit study, propamocarb hydrochloride caused increased post-implantation loss of offspring at 300 mg/kg/day; the NOEL was 150 mg/kg/day. Maternal toxicity was characterized by decreased body weight gains for gestation days 6 through 18 and possible increased abortions at 300 mg/kg/day; the NOEL was 150 mg/kg/day. In a multi-generation reproduction study in rats, reduced pup weight was reported at 407 mg/kg/day for males and 467 mg/kg/day for females; the NOELs were 65 mg/kg/day and 77 mg/kg/day, respectively. Parental toxicity consisted of a reduction in body weight at 407 mg/kg/day for males and 467 mg/kg/day for females; the respective NOELs were 65 mg/kg/day and 77 mg/kg/day.

    The USEPA Office of Pesticide Programs established a reference dose (RfD) of 0.11 mg/kg/day for propamocarb hydrochloride based on a lowest-observed-effect level (LOEL) of 33 mg/kg/day in a two-year dog feeding study and an uncertainty factor of 300. An uncertainty factor of 100 was used to account for inter- and intra-species variation, and an additional uncertainty factor of 3 to account for using a LOEL instead of a NOEL. This RfD has not yet been adopted by the USEPA's Integrated Risk Information System (IRIS).

    The USEPA established a tolerance of 0.06 parts per million (ppm) for propamocarb hydrochloride on potatoes. The USEPA estimated that chronic dietary exposure to these residues would be less than 7 percent of the chronic population adjusted dose (cPAD) of 0.12 mg/kg/day for the general U.S. population, less than 23 percent for children one to six years old, and less than nine percent for all infants under one-year of age. The cPAD is based on a NOEL of 12 mg/kg/day for decreased body weight and body weight gain in the mouse oncogenicity study and an uncertainty factor of 100. This chronic dietary exposure analysis is based on the assumption that 100 percent of crops are treated and contain tolerance level residues. Actual residues and resulting exposure levels are expected to be less than this assessment estimates.

    The USEPA reported the results of an occupational risk assessment for dermal and inhalation exposures to propamocarb hydrochloride from application to potatoes. The assessment assumed that 0.9 pounds of propamocarb hydrochloride was applied per acre to 350 acres, a total of five times per season (the maximum labeled rate). For determining margins of exposure (MOEs), the USEPA compared estimated short-term dermal and inhalation exposures to the NOELs of 150 mg/kg/day each from the 21-day rabbit dermal toxicity study and the rabbit developmental toxicity study. For commercial mixer/loaders supporting aerial application (considered to have the highest exposure to propamocarb hydrochloride), the combined MOE for dermal and inhalation exposure was estimated to be 1,200. As this is considered the worst-case scenario, MOEs for other mixer/loader/applicator exposures were expected to be greater than 1,200. For post-application occupational exposure (scouting treated fields), an MOE was estimated to be 140 using the NOEL of 150 mg/kg/day from the 21-day rabbit dermal toxicity study. This estimate was based on the assumptions that 20% of the maximum application rate was available as dislodgeable residue and exposure occurred for eight hours/day. Generally, the USEPA considers MOEs of 100-fold or greater to provide adequate worker protection.

    The New York State Department of Health briefly reviewed the environmental fate data for propamocarb hydrochloride. These data (particularly the reported adsorption coefficients (Koc) of between 41 and 359) indicate that this chemical has the potential to leach through certain soil types and contaminate groundwater. The USEPA states that the "use of propamocarb on course textured soils, i.e. high sand content with low organic matter, and on alkaline soils, is likely to result in surface and groundwater contamination." Nevertheless, the PREVICURTM label does not contain any statement indicating this potential. There are no chemical-specific federal or State drinking water/groundwater standards for propamocarb hydrochloride. Based on its chemical structure, propamocarb hydrochloride falls 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).

    Propamocarb hydrochloride was not very acutely toxic by the oral, inhalation, or dermal routes of exposure. However, it caused some subchronic, chronic and developmental toxicity effects in animal studies, the latter occurring at dose levels that also caused maternal toxicity. Although estimated exposure to the PREVICURTM product should not pose a significant risk to the general public or to workers, the ability of propamocarb hydrochloride to impact vulnerable groundwater/drinking water resources (e.g., Long Island) should be considered.

ECOLOGICAL EFFECTS RISK ASSESSMENT:

    Although propamocarb hydrochloride is somewhat persistent and is likely to be mobile with precipitation, it has very low acute and chronic toxicity to non-target organisms. At maximum labeled application rates any terrestrial or aquatic non-target species exposures that do occur are expected to be well below toxicity thresholds. Fish and wildlife resources are unlikely to be adversely impacted by labeled use of PREVICURTM FLEX Fungicide.

ENVIRONMENTAL FATE RISK ASSESSMENT:

    PREVICURTM FLEX Fungicide contains 66.5% by weight active ingredient, or 6.0 pounds of active ingredient per gallon. The label recommends mixing this product with chlorothalonil for better results. Mixed product is foliarly applied either by ground, aerial or chemigation applications. The application rate ranges from 0.7 to 1.2 pints of product per acre, every seven to ten days up to a total of six pints of product (4.5 lbs. propamocarb hydrochloride/acre/year). None of the inert components of this product appear to be solvent carriers.

    The technical review of this MCL application is based on the June 26, 2000 USEPA Environmental Fate and Effects Division (EFED) memorandum, the 1996 Reregistration Eligibility Document (RED) for propamocarb hydrochloride and Data Evaluation Record (DER) reports for the environmental fate studies.

Hydrolysis: USEPA found this study marginally acceptable. Propamocarb was stable at pHs 5, 7 and 9, and had a half-life of 4.71 days at pH 14.

Aqueous Photolysis: USEPA found this study marginally acceptable. Propamocarb was stable to aqueous photolysis.

Soil Photolysis: USEPA found this study acceptable. Propamocarb had a half-life of 35.4 days on a loamy sand soil. Three minor degradates were found.

Aerobic Soil Metabolism: MRID 41278125. USEPA found this study acceptable. Propamocarb had a half-life of 14 days in a loam sand soil. Three minor degradates were found.

MRID 41278126. USEPA found this study acceptable. Propamocarb had a half-life of 7-13 days in a loamy sand soil. Six minor degradates were found.

MRID 41278127. USEPA found this study marginally acceptable. Propamocarb had a half-life of 14-30 days in a loamy sand soil. Three minor degradates were found.

MRID 41278128. USEPA found this study partially acceptable. Propamocarb had a half-life of 12-13 days in a loamy sand soil. Degradates were not addressed in this study.

Anaerobic Soil Metabolism: USEPA found this study marginally acceptable. Propamocarb had a half-life 459 days. Three minor degradates were found.

Anaerobic Aquatic Metabolism: USEPA found the study performed prior to 1995 unacceptable and no data was provided. In an anaerobic aquatic metabolism study completed in 2001 with a clay loam, the half-life in the water phase was 13 days and in sediment phase was 93 days. In the total test system it was 100 days. Four minor degradates were noted.

Adsorption/Desorption: MRID 41278130. USEPA found this study acceptable and that it partially fulfilled the Subdivision N Guidelines. Propamacarb is mobile to relatively immobile with Kocs of 140 in a sand, 41 in a loamy sand (lowest clay content), and 359 in a sandy loam (highest clay content). No relationship between adsorption and soil organic matter was observed. Adsorption increased with increasing soil clay content and CEC.

MRID 41278131. USEPA found this study unacceptable and no data was provided.

MRID 00071472. USEPA found this study provided supplemental information, but the data could not be used.

MRID 41278132. USEPA found this study acceptable and that it partially fulfilled the Subdivision N Guidelines. Propamacarb is very mobile in sand soil and mobile to relatively immobile in two loamy sand soils.

Field Dissipation: USEPA found that portions of the studies conducted in New York and California do not meet Subdivision N guidelines. Information from supplemental field dissipation studies conducted in California and New York suggest propamocarb dissipates rapidly under field conditions with DT50s ranging from 10-15 days in the upper 8 inches of soil. Limited detections of propamocarb were observed to >91 cm in New York and up to 46 cm in California. USEPA felt that the New York study was unacceptable because soil samples were not collected deep enough to define the potential for leaching under field conditions.

MRID 44001601. USEPA found this study scientifically valid. Information from two other supplemental field dissipation studies conducted in Illinois and North Carolina indicates that propamocarb dissipation was biphasic. The first half-lives of the parent were 6.9 days (0-42 days) and 23.3 days (0-124 days) at the Illinois and North Carolina field sites, respectively; the respective second half-lives were 165 days (22-365) and 187 days (28-546 days).

Studies completed in 2001 indicated a half-life of 14 days on a German loamy sand (pH 6.6). A half-life of 27 days was found in a California loamy sand (pH 5.2). A half-life of ten days was found in a European loamy sand (pH 5.2) and 13 days in a German loamy sand (pH 6.6).

USEPA Comments: Propamocarb is a mobile (Koc=180), moderately persistent compound (t_=12-35 days). Its primary route of degradation is through aerobic metabolism (t _=12 days). Based on field dissipation studies, propamocarb dissipates rapidly (DT50 range: 10-15 days) and is unlikely to bioaccumulate. Because of a lack of environmental fate data for propamocarb on alkaline soils, EFED remains uncertain about the persistence and mobility of propamocarb under alkaline conditions.

Computer Modeling: The Department's groundwater model (LEACHM) was run on Riverhead sand using a maximum application rate of 4.5 pounds propamocarb hydrochloride/acre/year and a range of Kocs and aerobic metabolism half-lives.

Using a Koc of 41, an aerobic half-life of 30 days (worst case values), and an application rate of 4.5 lbs, the model projected cyclical peaks starting in the second year ranging between 0 and 48 ppb.

Using a Koc of 41, an aerobic half-life of 13 days (which corresponds to the field dissipation studies), and an application rate of 4.5 lbs, the model projected cyclical peaks starting in the second year ranging between about 0.5 to 9 ppb.

Using the Koc of 140 for soil whose grain size matches most closely with Riverhead soils, an aerobic half-life of 30 days, and an application rate of 4.5 lbs, the model projected cyclical peaks starting in the second year ranging from 0.005 to 0.014 ppb.

Using a Koc of 140, an aerobic half-life of 13 days, and an application rate of 4.5 lbs, the model projected cyclical peaks starting in the second year ranging between about 0.003 to 0.023 ppb.

Simulations were not run using the Koc of 359 because Long Island sand would not have a clay content equal to that used in the study soil.

    The adsorption/desorption data indicate that adsorption increases with increasing clay content and is not correlated with amount of organic carbon. Groundwater modeling using various Kocs and aerobic soil metabolism half-lives indicates the potential for leaching, especially in vulnerable areas of New York State. Of particular concern are groundwater resources on Long Island, where sandy soils and shallow depth to groundwater are prevalent.

CONCLUSION:

    The active ingredient, propamocarb hydrochloride, has never been the subject of a technical review by this Department. Two of the three previously registered products labeled for use on turf and ornamentals in New York State have a maximum turf application rate equivalent to 25 pounds propamocarb hydrochloride/acre/year. This rate is more than five times the maximum annual labeled rate of PREVICURTM FLEX Fungicide. There are no geographical restrictions regarding sale/use of the currently registered propamocarb hydrochloride products.

    Preliminary Pesticide Reporting Law (PRL) data for year 2000 indicate 894 gallons (5,364 pounds of propamocarb hydrochloride) were used in Nassau and Suffolk counties. According to Cornell Cooperative Extension data, 4,500 acres of potatoes are grown on Long Island. Approval of PREVICURTM FLEX Fungicide and utilization at the maximum labeled rate presents the potential for an additional 20, 250 pounds (4,500 acres @ 4.5 pounds propamocarb hydrochloride/acre/year) of propamocarb hydrochloride use on Long Island each year.

    As stated above, the Department accepts Bayer CropScience's withdrawal of the application to register PREVICURTM FLEX Fungicide (EPA Reg. No. 264-678). Since there is no groundwater monitoring data available for propamocarb hydrochloride, this active ingredient will be included in the Department's groundwater monitoring program in Nassau and Suffolk counties. Groundwater monitoring data will be used to determine if the existing propamocarb hydrochloride registrations should be: 1) maintained as is; 2) reclassified as "restricted use" products; or 3) prohibited from use in Nassau and Suffolk counties.

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

Sincerely,

Maureen P. Serafini
Director
Bureau of Pesticides Management

cc: N. Kim/D. Luttinger, NYS Dept. of Health
R. Zimmerman/R. Mungari, NYS Dept. of Ag. & Markets
G. Good/W. Smith, Cornell University, PMEP