|April 16, 2001|
RETURN RECEIPT REQUESTED
Laura L. Whatley, Ph.D.
Senior Registration Scientist
P.O. Box 13528
Research Triangle Park, NC 27709-3528
Dear Dr. Whatley:
Re: Registration of the New Active Ingredient Prohexadione Calcium Contained in the Pesticide Product ApogeeŽ Plant Growth Regulator (EPA Reg. No. 7969-188)
The New York State Department of Environmental Conservation ("The Department") has completed review of your application (received 07/21/00) and supplemental information supplied to date regarding registration of the referenced pesticide product in New York State. The subject application and data package were deemed complete for purposes of technical review on November 27, 2000 following one determination of incompleteness (09/12/00). Pursuant to the review time frame specified in Environmental Conservation Law (ECL) §33-0704.2, a registration decision date of April 26, 2001 was established.
ApogeeŽ Plant Growth Regulator (EPA Reg. No. 7969-188), containing 27.5% prohexadione calcium, is labeled as a production management tool for apple orchards that reduces vegetative growth allowing a balance between canopy development and fruit production. The "General Restrictions and Limitations" section of the label limits the maximum seasonal use rate to a total of 99 ounces (6.2 pounds) of ApogeeŽ per acre, per season. This is equivalent to 1.7 pounds prohexadione calcium/acre/season.
After completion of the technical reviews, the Department received (03/27/01) amended ApogeeŽ product labeling bearing peanut crop uses and other minor changes which were approved by the United States Environmental Protection Agency (USEPA) on February 5, 2000. Since these labeling changes did not require further technical assessment, the new label (Form NVA 2000-04-080-0405p) was substituted for the label originally proposed for registration.
The Department conducted toxicological, ecological effects and environmental fate risk assessments for prohexadione calcium and the ApogeeŽ formulation.
TOXICOLOGICAL RISK ASSESSMENT:
Neither prohexadione calcium nor the ApogeeŽ formulation was very toxic in acute oral, dermal or inhalation exposure studies in laboratory animals, nor were they very irritating to the eyes or skin (tested on rabbits). Neither the active ingredient nor the formulated product was a dermal sensitizer (tested on guinea pigs).
In a 90-day dog study, dietary administration of prohexadione calcium resulted in histopathological changes in the kidneys at a dose level of 400 milligrams per kilogram body weight per day (mg/kg/day); the no-observed-effect level (NOEL) was 80 mg/kg/day. Prohexadione calcium caused similar toxicity in a chronic one-year dog feeding study at a dose level of 200 mg/kg/day; the NOEL was 20 mg/kg/day. In a chronic feeding/oncogenicity study in rats, prohexadione calcium caused a decrease in white blood cells in males at a dose of 469 mg/kg/day; the NOEL was 94 mg/kg/day. In a chronic feeding/oncogenicity study in mice, decreased body weight gains and food consumption as well as microscopic changes in the stomachs of males were observed at a dose of 2,847 mg/kg/day for males; the NOEL was 279 mg/kg/day. The USEPA Office of Pesticide Programs established a reference dose (RfD) of 0.8 mg/kg/day based on a NOEL of 80 mg/kg/day in the subchronic dog study and an uncertainty factor of 100. This RfD has not yet been adopted by the USEPA's Integrated Risk Information System (IRIS). The results from the one-year dog study were also considered by USEPA in determining this RfD for prohexadione calcium. They determined that an uncertainty factor of 100 was adequate given the similarity in effects and their onset in both the 90-day and one-year dog studies.
Prohexadione calcium did not cause any developmental effects in one-rat and two-rabbit developmental toxicity studies in the highest doses tested, which were 1,000, 200 and 350 mg/kg/day, respectively. In the rat study, no maternal effects were noted at the highest dose tested (1,000 mg/kg/day). In one of the rabbit studies, maternal toxicity consisted of increased mortality, abortions and decreased body weight gains at 200 mg/kg/day with a NOEL of 40 mg/kg/day. Maternal toxicity in the other rabbit study consisted of premature deliveries at a dose of 350 mg/kg/day; the NOEL was 100 mg/kg/day. In a two-generation reproduction study in rats, prohexadione calcium was associated with decreased pup body weight at a dose of 3,850 mg/kg/day; the NOEL was 385 mg/kg/day. Parental toxicity which also was observed, consisted of increased mortality at a dose of 385 mg/kg/day; the NOEL was 36 mg/kg/day.
Prohexadione calcium did not cause oncogenic effects in either rat or mouse chronic feeding studies. It also was negative in a number of genotoxicity studies. The USEPA classified prohexadione calcium as "not likely to be carcinogenic to humans."
The USEPA established a tolerance for prohexadione calcium residues in or on pome fruit crop group at 3.0 parts per million (ppm). The USEPA estimated that chronic dietary exposure to these residues would be less than 1.0 percent of the chronic population adjusted dose (cPAD) of 0.8 mg/kg/day for the general United States population and less than 2.3 percent for all infants less than one-year old. This chronic exposure analysis is based on the assumption that 100 percent of crops are treated and contain tolerance level residues.
The USEPA reported the results of a risk assessment for dermal and inhalation exposure of workers to prohexadione calcium. For commercial handlers, margins of exposure (MOEs) were estimated to be 1,400 and above. The MOE for post-application occupational exposures from harvesting apples from treated trees was estimated to be 130. The NOEL used for estimating these MOEs was 100 mg/kg/day from a rabbit developmental toxicity study. Also used for this occupational risk assessment was a default value of 25 percent dermal absorption. 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 prohexadione calcium. Based on the chemical structure of the free acid prohexadione, this compound (the free acid) falls under the 50 micrograms per liter ( g/L) New York State drinking water standard for "unspecified organic contaminants" (10 NYCRR Part 5, Public Water Systems).
The available information on prohexadione calcium and ApogeeŽ indicates that they are not very acutely toxic in laboratory animal studies. Although data from chronic studies on prohexadione calcium showed that this chemical has the potential to cause certain kidney and other effects, the expected exposure from the labeled use of ApogeeŽ should not pose a significant risk to the general public or to workers. However, the limited information on post-application exposures of apple pickers suggests somewhat borderline MOEs. If the registrant proposes labeling changes such as reducing the pre-harvest interval, increasing application rates, or other parameters that could increase residues that apple pickers may contact, such exposures may be an issue.
ECOLOGICAL RISK ASSESSMENT:
ApogeeŽ is labeled for use as a production management tool in apple orchards. It achieves the same benefits as and reduces the need for manual summer and dormant pruning. ApogeeŽ also reduces the treated trees susceptibility to the fire blight bacterium Erwinia amylovora.
ApogeeŽ may be applied to thin the entire canopy, shape the canopy by treating the areas where growth suppression is desired, reduce "June drop" in trees that produced a light bloom, and to reduce shoot fire blight infections. It is applied in water at 12 to 48 ounces of formulation, 0.21 to 0.83 lb prohexadione calcium per acre at 7 to 21 day intervals. No more than 48 ounces of ApogeeŽ may be applied in a 21 day period. It may not be applied within 45 days of harvest.
Prohexadione calcium inhibits synthesis of gibberellin, the plant hormone that regulates cell elongation, thereby inhibiting shoot growth. Technical prohexadione calcium has a water solubility of 174 mg/L at 25O C. Its vapor pressure is low, 1 x 10-7 mmHg at 20O C, volatilization will not contribute significantly to its dissipation. With an octanol/water partitioning coefficient (KOW) of 0.00125 it is not likely to bioaccumulate. The parent compound showed moderate to very high mobility in four different soils during laboratory column leaching studies.
Potential ecological impacts of ApogeeŽ were modeled using the MAMTOX, AVTOX and AQUALIFE models. All toxicity and fate input parameters were taken from the applicants data submission. Prohexadione calcium hydrolysis is strongly pH dependant with half-lives (T1/2) of 4.4 days at pH 5, 65 days at pH 7, and is stable to hydrolysis at pH 9. In laboratory studies its aqueous photolytic T1/2 was also pH dependant being 9.9 days at pH 5, and 23.2 days at pH 9. Acceptable soil photolysis study results were not submitted.
Aerobic microbial metabolism is the primary route of prohexadione calcium degradation in the environment. Laboratory aerobic soil metabolism studies show degradation to be weakly biphasic with rapid breakdown during the initial phase of roughly three days with slightly slower degradation thereafter. The T1/2 during the initial phase is calculated to be approximately 34 hours. Linear representation of the decline incorporating both phases gives a T1/2 of 9.8 days.
Terrestrial field dissipation studies conducted in Texas, North Carolina, Oregon, New York, and California resulted in field half-lives of 0.8, 1.0, 5.7, 15, and 20 days respectively. The significantly longer New York and California results are thought to be at least in part due to dry field conditions that occurred during the studies. The half-life used for modeling purposes is the geometric mean of all the values reported or 4.2 days.
Prohexadione calcium is rainfast within eight hours post application. It has very low acute toxicity to all terrestrial and aquatic organisms it was tested with. Prohexadione calcium also exhibits low chronic toxicity and is not neurotoxic, mutagenic, or carcinogenic. Maximum prohexadione calcium soil residues were calculated for two application scenarios using the HALFLIFE program. Terrestrial feeding exposure modeling was conducted using Hoerger and Kenaga vegetation residue estimates.
Aquatic exposure screening modeling (AQUALIFE) was conducted for two application scenarios (0.33 lbs prohexadione calcium/acre, six times at seven-day intervals; one application at the maximum rate of 0.83 lbs prohexadione calcium/acre) utilizing the toxicity endpoints provided in the data submission.
The MAMTOX and AVTOX model results indicated that no mammalian or avian feeding toxicity thresholds were exceeded by predicted vegetation residue levels. The AQUALIFE model indicated that no aquatic toxicity thresholds are exceeded by model pond concentrations resulting from runoff transported prohexadione calcium even at the exaggerated worst-case levels modeled here. Lemna is by far the most sensitive aquatic species tested with toxicity thresholds averaging an order of magnitude below those of other tested organisms. The prohexadione calcium water concentrations would have to be increased four-fold over the predicted levels to equal the Lemna NOEC.
The combination of low toxicity and rapid degradation make it unlikely that ApogeeŽ, used as labeled, will have adverse effects on non-target fish or wildlife resources. There is a large safety margin for non-target species even at the highly conservative screening level modeling conducted for this assessment.
ENVIRONMENTAL FATE RISK ASSESSMENT:
Prohexadione calcium is a productive management tool used in apple orchards to reduce vegetative growth. ApogeeŽ contains 27.5% prohexadione calcium, and acts to inhibit the biosynthesis of gibberellin, which regulates cell elongation. Growth suppression typically lasts for 2-5 weeks per application. Using this product will also help control the susceptibility of fire blight on shoots, and may allow the tree to retain more of their fruit. Apogee is applied foliarly via ground equipment to the portion of the tree where growth control is desired. Two applications of up to 48 ounces per acre may be applied, or a total of 99 ounces, or 27.2 oz prohexadione calcium/acre/yr. The inerts do not appear to be solvent carriers.
All environmental fate Data Evaluation Records (DERs) reports were submitted except for aerobic aquatic metabolism, which was waived by the USEPA. There were no dates or signatures on DERs, but they may have been electronic copies printed out.
According to the aerobic soil metabolism DER, prohexadione calcium degrades with a non-linear half-life of 1.4 days in sandy loam soil. The major degradate is CO2 at 79.8% at 30 days. The adsorption Kocs in sand, clay, chloroform fumigated loamy sand and loamy soil were 173, 155, 1428 and 421 respectively. Prohexadione calcium is very highly mobile in sandy soil and has a low mobility in a loamy sand soil. The loamy sand had 80% sand, 14% silt 6% clay, 1.1% OM and pH 5.7. The sand had 96% sand, 2% silt, 2% clay .5% OM and pH 6.9. The sand has properties similar to the Riverhead soils.
The Department's groundwater model (LEACHM) was run on Riverhead soil using a Koc of 173 for sand, a half-life of 1.4 days and an application rate of 27.2 oz prohexadione calcium/acre/year (maximum use rate). The model projected no leaching of the parent during the ten-year modeling cycle.
USEPA determined that several studies had to be upgraded, and one repeated. However, based on the Koc, the application rate and the very short half-life, it is not expected that this product will have a significant negative impact on groundwater when used as labeled.
The environmental fate data suggest that prohexadione calcium may have the ability to leach through certain soil types and contaminate groundwater. These concerns are mitigated by the ApogeeŽ application method (directly to the foliage of apple trees) and the active ingredient's relatively rapid degradation rate. As previously discussed in the toxicological risk assessment, the limited information on post-application exposures of apple pickers suggests somewhat borderline MOEs. If BASF Corporation proposes labeling changes such as reducing the pre-harvest interval, increasing application rates, or other parameters that could increase residues that apple pickers may contact, such exposures may be an issue.
When used as labeled, ApogeeŽ should not cause unreasonable adverse effects to humans or the environment. The Department hereby accepts ApogeeŽ Plant Growth Regulator (EPA Reg. No. 7969-188) for registration in New York State. Enclosed for your files are the Certificate of Pesticide Registration and New York State stamped-"ACCEPTED" labeling (Form NA 2000-04-080-0405p).
Please note that a proposal by BASF Corporation or any other registrant to register a product containing prohexadione calcium, whose labeled uses are likely to increase the potential for significant impact to humans, property 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).
Please contact Frank Hegener, Chief of our Pesticide Product Registration Section, at (518) 457-7446, if you have any questions.
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 PMEP