Toxicological Risk Assessment:

Transcription

1 New York State Department of Environmental Conservation Division of Solid and Hazardous Materials Bureau of Pesticides Management, 11th Floor 625 Broadway, Albany, New York Phone: (518) FAX: (518) Website: CERTIFIED MAIL RETURN RECEIPT REQUESTED Ms. Princy A. Jesudason State Registrations Specialist Bayer CropScience, LP P.O. Box Research Triangle Park, North Carolina Dear Ms. Jesudason: January 29, 2007 Re: Denial of Application for Registration of the New Pesticide Product Envidor 2 SC Miticide (EPA Reg. No ), Which Contains the New Active Ingredient Spirodiclofen (Chemical Code ) The New York State Department of Environmental Conservation (Department) has reviewed your application, received November 9, 2005, to register Envidor 2 SC Miticide (EPA Reg. No ) in New York State. This product contains the new active ingredient spirodiclofen. The application was deemed complete for purposes of review on January 4, 2006 and, due to Department concerns, a registration decision has been extended until February 4, Toxicological Risk Assessment: The Department of Health (DOH) reviewed the information submitted by Bayer CropScience to register the pesticide product Envidor 2 SC Miticide (EPA Reg. No ) in New York State. This product contains the new active ingredient spirodiclofen (3-(2,4-dichlorophenyl)-2-oxo-1- oxaspiro [4,5] dec-3-en-4-yl 2,2-dimethylbutanoate) and is labeled for use against a variety of mites on citrus, grapes, pome fruit, stone fruit and tree nuts. Neither the active ingredient spirodiclofen nor the Envidor product was very acutely toxic to laboratory animals via the oral, dermal or inhalation routes of exposure. Neither of these materials was very irritating to animal eyes or skin (tested on rabbits). The active ingredient and formulated product, however, were skin sensitizers (tested on guinea pigs). Spirodiclofen caused a number of effects in chronic laboratory animal studies. In a one-year dog feeding study, an increase in relative weights and histopathological findings in the adrenal gland in both males and females, and an increase in relative testes weight in males were reported at dose levels of 4.33 and 4.74 milligrams per kilogram body weight per day (mg/kg/day) for males and females, respectively; the respective no-observed-effect levels (NOELs) were 1.38 and 1.52 mg/kg/day. In a chronic feeding/oncogenicity study in mice, spirodiclofen caused increased

2 Ms. Princy A. Jesudason 2. testicular and adrenal gland weights and degeneration of Leydig cells (testosterone-secreting cells) in the testes of males at a dose of 610 mg/kg/day. Also observed at this dose was an increase in liver weights and a decrease in kidney weights. In females, increases in weight, pigmentation and vacuolization of the adrenal gland, as well as decreased kidney weights, were reported at a dose of 722 mg/kg/day. The NOELs were 4.1 and 5.1 mg/kg/day for males and females, respectively. In a chronic feeding/oncogenicity study in rats, an increased incidence of Leydig cell hyperplasia and a decrease in body weights and body weight gain were reported in males at a dose of 14.7 mg/kg/day; the NOEL was 4.1 mg/kg/day. In female rats, increase in thyroid stimulating hormone (TSH), uterine nodules and histopathological findings in the small intestine and decreased body weight and body weight gains were reported at a dose of mg/kg/day with a NOEL of 19.9 mg/kg/day. Spirodiclofen caused limited developmental toxicity in offspring of pregnant rats and rabbits administered this chemical during organogenesis. In rats, an increased incidence of slight dilation of the renal pelvis in offspring was observed at a maternal dose of 1,000 mg/kg/day; the NOEL was 300 mg/kg/day. No maternal toxicity was observed up to the highest dose tested, which was 1,000 mg/kg/day. In rabbits, no developmental effects were noted at the highest dose tested, which was 1,000 mg/kg/day. Maternal toxicity, characterized by body weight loss and decreased food consumption occurred at 300 mg/kg/day, with a NOEL of 100 mg/kg/day. In a rat multigeneration reproduction study, a delay in sexual maturation, a decrease in sperm count, as well as atrophy of the testes, epididymides, seminal vesicles and prostate gland were observed in males at doses ranging from to mg/kg/day; the NOELs ranged from 26.2 to 30.2 mg/kg/day. In females, histopathological changes of ovarian luteal cells were reported at doses ranging from to mg/kg/day; the NOEL ranged from 27.6 to 34.4 mg/kg/day. Parental toxicity, characterized by histopathological changes of the adrenal gland in male and female animals as well as a decrease in body weights and absolute and relative liver weights in males, was reported at doses of 26.2 to 30.2 mg/kg/day (males) and 27.6 to 34.4 mg/kg/day (females). The respective NOELs ranged from 5.2 to 6.4 mg/kg/day and 5.5 to 7.0 mg/kg/day. A developmental neurotoxicity study in rats was also conducted. In this study, decreased memory in the water maze test was reported in females on postnatal day 60 following spirodiclofen exposures at the lowest dose tested, which was 6.5 mg/kg/day. Maternal toxicity was not observed up to the highest tested dose, which was mg/kg/day. The United States Environmental Protection Agency (USEPA) Office of Pesticide Programs calculated an oral reference dose (RfD) for spirodiclofen of mg/kg/day based on the lowest-observed-effect level (LOEL) of 6.5 mg/kg/day in the rat developmental neurotoxicity study and an uncertainty factor of 1,000 (10x for intraspecies variation, 10x for interspecies variation and 10x for the use of a LOEL). This RfD value has not yet been adopted by the USEPA s Integrated Risk Information System (IRIS). Spirodiclofen caused oncogenic effects in mice and rats in chronic feeding studies. In mice, there was a significant increase by pair-wise comparison with the controls for hepatocellular adenomas and combined adenomas/carcinomas at doses of 610 and 1,216 mg/kg/day in males, and at 722 mg/kg/day for combined hepatocellular adenomas/carcinomas in females. In addition, there were significant positive trends for hepatocellular adenomas, carcinomas and adenomas/carcinomas combined in both sexes. In the rat study, males had a significant positive trend for Leydig cell adenomas and a significant increase by pair-wise comparison with the controls for this tumor at the highest dose tested, which was mg/kg/day. Female rats showed a significant increasing trend for uterine adenocarcinomas and combined adenomas/carcinomas with a significant difference in pair-wise comparison to controls at the highest dose tested (152.9 mg/kg/day). Spirodiclofen was negative in several genotoxicity studies. The USEPA s Health Effects Division Cancer Assessment Review Committee (CARC) classified this chemical as likely to be carcinogenic to humans based

3 Ms. Princy A. Jesudason 3. on the occurrence of Leydig cell adenomas in male rats, uterine adenocarcinomas in female rats and liver tumors in male and female mice. The USEPA Office of Pesticide Programs calculated a cancer potency slope factor for spirodiclofen of (mg/kg/day) -1 using data on Leydig cell tumors. The USEPA established tolerances for spirodiclofen residues in or on citrus fruit at 0.5 parts per million (ppm); pome fruit at 0.8 ppm; stone fruit at 1.0 ppm; grapes at 2.0 ppm and tree nuts at 0.1 ppm. The chronic population adjusted dose (cpad) for spirodiclofen is mg/kg/day and has the same basis as the RfD. The USEPA estimated that chronic dietary exposure to spirodiclofen residues would be less than 3.7% for the general U.S. population, 8.0% for infants under one year of age, less than 7.9% for children one to two years old and less than 5.8% for children three to five years old. This chronic exposure analysis is based on average percent crop treated estimates and average field trial residues. Based on the chronic dietary exposure estimate of less than 3.7% for the general population and the cancer potency slope factor of (mg/kg/day) -1, an increased lifetime cancer risk of about 1.59 x 10-6 can be calculated. The USEPA generally considers an increased lifetime cancer risk level of less than or equal to 1 x 10-6 to be acceptable for the general population. The USEPA conducted an occupational risk assessment for combined dermal and inhalation exposures to spirodiclofen. For mixer/loaders, the combined margin of exposure (MOE) was 11,000, and for applicators the MOE was 2,000. In estimating these MOEs, it was assumed that workers wore a single layer of clothing and used gloves (the Envidor product label requires the use of waterproof gloves in addition to long-sleeved shirt, long pants and shoes plus socks). The LOEL of 6.5 mg/kg/day from the rat developmental neurotoxicity study was used in estimating the MOEs. In addition, the USEPA used a dermal absorption factor of 2% obtained from a dermal absorption study in monkeys, and assumed 100% absorption from inhalation exposure. Because a LOEL instead of a NOEL was used for estimating MOEs, the USEPA in this case considered MOEs of 1,000-fold or greater to provide adequate worker protection. In regard to cancer risks from occupational exposure to spirodiclofen, the estimated risks were 1.2 x 10-7 and 6.7 x 10-7 for mixer/loaders and applicators, respectively. These values are within the range that the USEPA generally considers to be acceptable (1 x 10-4 or less) for occupational exposures. For postapplication exposures of workers during the course of agricultural activities (e.g., hand harvesting and thinning) the estimated MOEs ranged from 1,900 to 3,800, except for grapes (MOEs 200 to 410). However, by increasing the restricted entry interval (REI) from less than one day to six days for certain post-application activities on grapes, estimated MOEs of greater than 1,000, which are generally considered adequate by USEPA to protect agricultural workers, can be achieved. Accordingly, the Envidor product label requires this six-day REI for such post-application activities. The USEPA estimated increased cancer risks for post-application exposures of workers ranging from 2.8 x 10-7 (hand harvesting citrus fruit) to 6.5 x 10-6 (tying and training table/raisin grape canes). The DOH briefly reviewed the environmental fate data on spirodiclofen. These data indicate that at least two of this active ingredient s degradates (spirodiclofen enol and spirodiclofen dihydroxy) have the potential to leach through certain soil types and contaminate groundwater; the average adsorption coefficients (K oc ) of the enol and dihydroxy degradates were 17.8 and 71.3, respectively. There are no chemical specific federal or New York State drinking water/groundwater standards for spirodiclofen or its degradates. Based on their chemical structures, these compounds fall under the 50 microgram per liter New York State drinking water standard for unspecified organic contaminants (10 NYCRR Part 5, Public Water Systems). The New York State drinking

4 Ms. Princy A. Jesudason 4. water standard for the sum of unspecified organic contaminants and principal organic contaminants is 100 micrograms per liter (parts per billion, ppb). If one uses the RfD of mg/kg/day and procedures for deriving ambient water quality standards and guidelines based on non-oncogenic effects (6 NYCRR Part 702.5), a value of 45.5 micrograms per liter can be derived for spirodiclofen. Using the USEPA cancer potency slope factor of (mg/kg/day) -1 and 6 NYCRR Part procedures for deriving ambient water quality standards and guidelines based on oncogenic effects, the ambient water quality value associated with a one in one million increased lifetime cancer risk is 2.35 micrograms per liter for spirodiclofen. This value could be used to derive a screening value for comparison to estimated impacts to groundwater and surface water. Neither spirodiclofen nor Envidor 2SC Miticide was very toxic or irritating to the skin or eyes following acute exposures in laboratory animals. However, both the active ingredient and formulated product demonstrated skin sensitizing properties. To help mitigate this adverse effect, the product label includes the precautionary statement: Prolonged or frequent repeated skin contact may cause allergic reactions in some individuals. Also, the label requires handlers of the Envidor product to wear waterproof gloves and other clothing. Spirodiclofen caused reproductive and other noncancers effects, including effects on several endocrine glands. In addition, this active ingredient caused liver tumors in male and female mice and tumors in the reproductive systems of male and female rats. Based on these oncogenic effects, the USEPA classified spirodiclofen as likely to be carcinogenic to humans. While the estimated dietary and occupational risks posed by the Envidor product are within the USEPA acceptable range, we have generic concerns for registering pesticide products that have carcinogenic potential and cause effects on endocrine glands unless either the needs for the products are significant or they replace products that pose greater risks. Also, we have concerns about the potential for some of spirodiclofen s degradation products to contaminate groundwater and drinking water, as the environmental fate data indicate high mobility of these degradates in some soils. Finally, the Envidor label should be revised under the Personal Protective Equipment section by changing waterproof gloves to read waterproof and chemical-resistant gloves. This is warranted since the Envidor product demonstrated sensitizing properties (in laboratory animals) and the product label warns that allergic dermal reactions may occur in some individuals. Consequently, the DOH did not at this time support the registration of Envidor 2SC Miticide in New York State. The DOH was willing to review any detailed comparison that the registrant submited on the application rates, toxicological characteristics (including carcinogenicity) and dietary and occupational risks of the Envidor product as it relates to the currently registered alternative miticides labeled for the same use in New York State. Additional information on the relative needs and benefits of this product would also be helpful. In response to the above-stated concerns, the registrant submitted some toxicological information, recieved July 6, 2006, that compares the major miticide active ingredients currently registered in New York State for use on apples, as according to the registrant, pome fruit is the principal target crop for Envidor 2 SC Miticide. The alternative miticides, as noted by Bayer CropScience, are Danitol, Apollo, Nexter, Acramite, Zeal, Savey and Agri-Mek containing the respective active ingredients fenpropathrin, clofentezine, pyridaben, bifenazate, etoxazole, hexythiazox and abamectin. For these alternative active ingredients, the registrant compared their RfDs, USEPA carcinogenicity classifications and application rates to that of spirodiclofen. This comparison indicates that except for the active ingredients fenpropathrin, pyridaben and abamectin, spirodiclofen has an RfD that is numerically lower than the alternatives (generally indicating higher toxicity). Spirodiclofen is also classified as likely to be carcinogenic to humans, whereas the alternative active ingredients, except for clofentezine and hexythiazox ( possible human carcinogens ), are classified as not likely to be human carcinogens. Except for abamectin, whose

5 Ms. Princy A. Jesudason 5. application rate compared to spirodiclofen is approximately 10-fold lower, the application rates of all the other alternative active ingredients are only slightly lower or higher than that of spirodiclofen. In the Bayer CropScience submission of additional information to justify the use of Envidor 2 SC Miticide without increasing risks to workers or the general public, the registrant stated: Mechanistic work has shown that neoplastic and non-neoplastic endocrine effects are well understood and are indirect, threshold effects. The registrant also submitted a document to serve as a basis for this conclusion. By contrast, the USEPA s Health Effects Division, CARC classified spirodiclofen as likely to be carcinogenic to humans based on the occurrence of Leydig cell (testosterone-secreting cell) adenomas in male rats, uterine adenocarcinomas in female rats and liver tumors in male and female mice. Furthermore, the USEPA Office of Pesticide Programs did not consider the carcinogenic potential of spirodiclofen to be associated with threshold effects, since the USEPA calculated a cancer potency slope factor for this chemical of (milligrams per kilogram per day) -1 using data on Leydig cell tumors; calculation of a cancer potency slope factor is indicative of a non-threshold effect, where it is assumed that any amount of exposure will lead to some degree of cancer risk. The registrant also addressed the issues of pesticide efficacy and resistance management, claiming that the Envidor product [W]ill bring a unique, highly efficacious and much needed tool for resistance control to New York apple growers. In support of this statement, the registrant submitted data obtained from private and university researchers comparing the efficacy of the Envidor product to some currently registered alternative products against European red mite, two spotted mite and apple rust mite. In three out of five studies, the efficacy of Envidor against mites on New York State apples averaged approximately two- to five-fold greater than alternative miticides such as Acramite and Zeal. In support of the need for additional miticides to prevent the proliferation of resistance development among mites, the registrant submitted an endorsement from two professors of entomology at the Cornell University Cooperative Extension (see correspondence from H. Reissig and A. Agnello to S. Jackling, July 19, 2006), for the use of the Envidor product on apples grown in New York State. These professors, however, did not indicate that Envidor was more effective than any currently registered products labeled for use against a variety of mites on apples. In regard to the issue of DOH s recommendation that the Envidor label should be revised under the Personal Protective Equipment section by changing waterproof gloves to read waterproof and chemical-resistant gloves, the registrant responded by citing the Code of Federal Regulations (40 CFR , paragraphs (e) and (f) (3)), which indicates that for pesticide products with aqueous-based formulations (such as Envidor), the glove statement may specify waterproof gloves instead of chemical-resistant gloves. However, contrary to the registrant s claim in their response that Waterproof and chemical resistant gloves is not a permissible category under the statute, 40 CFR , paragraph (f) (1) states that The registrant shall specify a glove type other than that selected through the criteria in paragraphs (f) (2) through (5) of this section if information available to the registrant indicates that such a glove type is more appropriate or more protective than the glove type specified in this section. Accordingly, the Department and DOH believe that our recommendation for a revision in label from waterproof gloves to waterproof and chemical-resistant gloves or chemical-resistant gloves is warranted and is consistent with CFR paragraph (f) (1), since the Envidor product demonstrated skin sensitizing properties (in laboratory animals) and the product label warns that allergic dermal reactions may occur in some individuals. Moreover, this specification helps reduce the potential that handlers will use inadequate waterproof gloves such as examination gloves. The requirement for chemical-resistant gloves also

6 Ms. Princy A. Jesudason 6. appears to be consistent with the 2003 USEPA s Label Review Manual, Chapter 10, Section VI, A, 3. From the comparative toxicological data submitted by the registrant with respect to both noncancer and cancer parameters, the Envidor product does not clearly seem to pose lesser health risks than the other available alternatives as discussed above. The registrant presented some information to support their statement that the use of the Envidor product [W]ill bring a unique, highly efficacious and much needed tool for resistance control to New York apple growers. Since Envidor has carcinogenic potential, causes effects on endocrine tissues and does not appear to pose lesser risks than the alternatives, the DOH continues to have reservations about registering Envidor 2 SC Miticide in New York State. Environmental Fate Risk Assessment: Bayer CropScience is applying to register this product for use on citrus, grapes, pome and stone fruit, and tree nuts to control or suppress various mites and San Jose Scale. This product contains 22.3% by weight or 2 lbs/gallon of spirodiclofen. One application is allowed on all crops, and the product must contact the insects. It does not affect adult males, just the eggs, all nymphal stages and adult females. The maximum application rate is 18 fl oz/a/season, or 0.28 lb ai/a as one application on grapes, pome and stone fruit. The maximum application rate on citrus is 20 fl oz/a/season, or 0.31 lb ai/a. The maximum application rate on tree nuts is 34 fl oz/a/season, or 0.53 lb ai/a/yr. Technical Review Transformation Products: BAJ2510 BAJ2740-enol KTS9301A BAJ2740-ketohydroxy KTS9313 BAJ2740-dihydroxy KTS9322 BAJ2740-lactide FHW0107B 2,4-dichlorobenzoic acid DCBA Not provided BAJ2740-dioxoketone. Solubility: The solubility of spirodiclofen is 50 mg/l. Hydrolysis: (MRID ): In a study that USEPA found to be acceptable, the half-life at ph 4 was days, and days at ph 7. At ph 9, the half-life was 1.86 days based on 7-day data and 4.73 days based on 10-day data. The major transformation product at all phs was BAH2510. Aqueous Photolysis: Parent: (MRID ): In a study that USEPA found to be supplemental, the half-life of spirodiclofen was 13.7 days. Major transformation products included BAJ2510 and BAJ2740-dioxoketone. In a second study (MRID ) that USEPA found to be supplemental, the half-life was 2.4 days. Transformation products were not addressed. BAJ2510 (MRID ): USEPA found this study to be supplemental. The half-life in a Rhine river water was 7.53 hours with one major transformation product: BAJ2740- dioxoketone.

7 Ms. Princy A. Jesudason 7. Soil Photolysis: (MRID ): In a study that USEPA found to be acceptable, the half-life in a sandy loam soil was 16.1 days with one major transformation product: DCBA. Aerobic Soil Metabolism: Parent 1 MRID and Acceptable 2 MRID supplemental. Soil Type % OC Soil ph Aerobic Half-life sandy loam All data: 64.2 days days: 64.2 days Best fit: 17.1 days Applicant: 9.82 days Graphically: 10.0 days sand All data: 17.2 days days: 16.8 days Best fit: 8.1 days Applicant: 7.24 days Graphically: 8.0 days loamy sand All data: 24.6 days days: 23.8 days Best fit: 9.5 days Applicant: 6.23 days Graphically: 7.0 days silt All data: 24.2 days days: 10.0 days Best fit: 1.7 days Applicant: 1.05 days Graphically: 1.0 days sandy loam days 24.4 days Graphically: <14 days Degradates/% BAJ % KTS9301A 28.1% KTS % BAJ % KTS9301A 44.4% DCBA 39.6% BAJ % KTS9301A 20.7% BAJ % KTS9301A 10.6% BAJ % KTS9301A MRID and Acceptable. Soil Type % OC Soil ph Aerobic Half-life sandy days 53.7 days loam Applicant: 10.11days Graphically: 50 days sand days: 43.6 days Applicant: days Graphically: 58 days loamy days: 16.8 days sand Applicant: 3.39 days Graphically: 15 days silt days: 5.6 days Applicant: 0.56 days Graphically: 3.5 days

8 Ms. Princy A. Jesudason 8. BAJ 2510 MRID and Acceptable. Soil Type % OC Soil ph Aerobic Half-life sandy days 18.9 days loam Applicant: 2.95 days Graphically: 12 days sand days: 18.9 days Applicant: 9.79 days Graphically: 23 days loamy days: 8.9 days sand Applicant: 1.91 days Graphically: 10 days silt days: 3.7 days Applicant: 2.76 days Graphically: 4.5 days KTS MRID Acceptable; 2 MRID Supplemental. days Soil Type % OC Soil ph AerobicHalf-life loamy days: 4.3 sand 1 Graphically: 4.5 days silt days: 4.8 days Graphically: 4.5 days silt days 49.9 days 0-30 days 27.6 days Graphically: 26 days DCBA MRID and 310 Supplemental. Soil Type % OC Soil ph Aerobic Half-life sand days: 12.1 days 0-30 days: 17.5 days Graphically: 25 days sandy loam days: 13.9 days 0-30 days: 32.2 days Graphically: 30 days silt days 4.4 days Graphically: 6 days silty clay days 17.5 days loam Graphically: 18 days Anaerobic Aquatic Metabolism: (MRID ): In a study that USEPA found to be acceptable, the half-life in water was <1 hour, in the sediment was 40.6 days, and in the total system it was 40.4 days. BAJ2510 was the only major transformation product found. Aerobic Aquatic Metabolism: (MRID ): In a study that USEPA found to be acceptable, in a pond water-sandy loamy silt sediment the half-life in the water was <1 day, in the

9 Ms. Princy A. Jesudason 9. sediment was 14.3 days. In the total sediment, the half-life was 13.4 days. In a lake water-silty sand sediment, the half-life in water was <1 day, in the sediment was 4.0 days and in the total system was 3.7 days. In both systems, BAJ2510 was the only major transformation product found. Adsorption/Desorption: Parent: (MRID ): USEPA found this study to be unacceptable. (MRID ): In a study that USEPA found to be supplemental, the Koc was 31,037. The DER did not indicate the soil type. (MRID ): In a study that USEPA found to be supplemental, the K oc of spirodiclofen was 51,097 to 101,366; KTS9310A had a K oc of 2,722 (by HPLC); KTS9313 had a K oc of 8.9 to131.2; BAJ2510 had a K oc of 11.2 to 28.6; and DCBA had a K oc of 4.7 to 128. BAJ2510 (MRID ): In a study that USEPA found supplemental, the adsorption K oc s were 12.09, 28.69, and 11.2, and the desorption K oc s were 147, 137.4, and in a sandy loam (0.53% OC and 6.6 ph), clay loam (1.3% OC and 5.1 ph), sand (0.59% OC and 6.2 ph), and silt (2.62% OC and 7.8 ph), respectively. KTS9310A (MRID ): USEPA found this study unacceptable and K oc s could not be calculated. (MRID ): In a study that USEPA found supplemental, a mean K oc was 612. BAJ2740-dioxoketone (MRID ): In a study that USEPA found supplemental, the mean K oc was 3,720. KTS9313 (MRID ): In a study that USEPA found supplemental, the adsorption K oc s were 8.9, 131.2, 40.2 and 104.7, and the desorption K oc s were 51, 453, 117 and 298 in a sandy loam (1.2% OC and 6.9 ph), sand (0.19% OC and 6.3 ph), silt (2.62% OC and 7.8 ph) and silty clay loam (0.89% OC and 8.6 ph), respectively. DCBA (MRID ): In a study that USEPA found supplemental, adsorption K oc s were 8.8, 21.8, 4.7, 8.4, 7.0, and the desorption K oc s were 141.5, 36.8, 2.0, 122.6, 6.5, in a sandy loam (0.53% OC and 6.6 ph), sand (0.19% OC and 6.3 ph), silt (2.62% OC and 7.8 ph), sandy loam (0.53% OC and 7.9 ph) and silty clay loam (0.89% OC and 8.6 ph), respectively. Aged Leaching: (MRID ): In a study that USEPA found supplemental, in a sandy loam soil spirodiclofen was found to be immobile. K oc s were >6,411 for spirodiclofen, 214 for KTS9313, 120 for KTS9310A, 47 for BAJ2510 and 29 for DCBA. (MRID ): In a study that USEPA found supplemental, the K oc s were 2,737, 4,386, 3,640 and 689 in a sand (0.38% OC and 5.9 ph), loamy sand (0.22% OC and 6.1 ph), sandy loam (0.23% OC and 9.0 ph) and loamy silt (1.55% OC and 7.3 ph), respectively. Terrestrial Field Dissipation: (MRID and 303): USEPA found this study acceptable. In a sand soil, the half-life was 4.6 days with one transformation product: BAJ2510 at 86%. (MRID and 303): USEPA found this study acceptable. In a sandy loam soil, the half-life was 4.5 days with two transformation products: BAJ2510 at 61% and DCBA at 33%.

10 Ms. Princy A. Jesudason 10. (MRID and 303): USEPA found this study acceptable. In a loamy sand soil, the half-life was 3.3 days with three transformation products: BAJ2510 at 63%, BAJ2740- ketohydroxy at 14% and DCBA at 32% (MRID and 303): USEPA found this study acceptable. In a loamy sand soil, the half-life was 5.0 days with three transformation products: BAJ2510 at 68%, BAJ2740- ketohydroxy at 17% and DCBA at 22%. Label Statements: Surface Water Advisory and Runoff Management. This product may contaminate water through runoff or drift of spray in wind. Poorly draining soils and soils with shallow water tables are more prone to produce runoff that contains this product. A level, well maintained vegetative buffer strip between areas to which this product is applied and surface water features such as ponds, streams, and springs will reduce the potential for contamination of water from rainfall runoff. Runoff of this product will be reduced by avoiding applications when rainfall is forecasted to occur within 48 hours. Modeling: Staff modeled spirodiclofen on Riverhead soil using a K oc of 57,097, a half-life 51 days and the tree nut application rate of 0.53 lb ai/a/yr. The model projected no leaching. Modeling the transformation product BAJ2510 on Riverhead soil using a K oc of 28.6, and 17.5% of the maximum application rate, or lb ai/a/yr, the model projected several peaks ranging up to about 1 ppb. Modeling the transformation product KTS9301A on Riverhead soil using a K oc of 612 and 28.1% of the maximum application rate, or 0.15 lb ai/a/yr, the model projected peaks up to ppb. Modeling the transformation product KTS9313 on Riverhead soil using a K oc of 8.9 and 16.7% of the maximum application rate, or lb ai/a/yr, the model projected occasional peaks ranging up to about 1.4 ppb. Groundwater/Drinking Water Summary: The Department s groundwater staff noted that the MSDS contains incorrect information. It states that the maximum use rate is 20 fl oz, when the use rate on tree nuts is 34 fl oz. oc, the parent will not leach into groundwater. The transformation products BAJ2510 and KTS9313 had low Kocs but also have short half-lives. Based on the K oc s, short half-lives, and modeling, it appears that the degradation products will not have a significant negative impact on groundwater in vulnerable areas when used as labeled. Therefore, the Department s groundwater staff does not object to the registration of this product as labeled. Ecological Risk Assessment: All use, toxicity, chemical, and environmental fate information contained herein was included in the spirodiclofen data package submitted by Bayer CropScience. Use Profile: Envidor 2 SC Miticide is labeled for control of 17 different pest mite species and/or San Jose scale insects on citrus, grapes, pome fruit, stone fruit, and tree nut crops.

11 Ms. Princy A. Jesudason 11. One application of 14 to 18 fluid ounces 0.22 to 0.28 pounds active ingredient, lbs. ai, of Envidor 2 SC per acre is allowed per year on all crops listed on the label. Envidor may not be applied aerially or through any type of irrigation equipment. Mode of Action & Chemical Description: Spirodiclofen, 3-(2,4-dichlorophenyl)-2-oxo-1-oxaspiro[4.5]dec-3-en-4-yl 2,2- dimethylbutanoate, is a new tetronic acid derivative active ingredient belonging to a new class of pesticides, the spirocyclic tetronic acids. This class of pesticides was developed from the bicyclic tetramic acid herbicides which are selective against monocotyledonous plants and also exhibit some acaricidal activity. Spirodiclofen inhibits lipid biosynthesis and is reported to be active against all developmental stages of mites. Spirodiclofen s water solubility is reported most often in the submitted materials as 50 ug/l, ppb, but is also reported as 88 and >800 ug/l. Using the different solubilities makes no difference in the results of the Bureau of Habitat (BOH) aquatic modeling, the 50 ppb value is used in this review. With an octanol/water partitioning coefficient, K OW of 676,083, spirodiclofen has the potential to bioaccumulate. In a Bluegill Sunfish bioaccumulation study, fish were exposed to nominal concentrations of 2 or 20 ppb for 29 days under flow-through conditions which was followed by a 13- day depuration period. Accumulation was rapid, steady State concentrations were reached in 2 to 3 days. Observed bioaccumulation factors, BCFs, were very similar for both concentrations. BCFs for whole fish, nonedible, and edible tissues were 699/682, 1,439/1,371, and 166/159 in the 2 and 20 ppb exposures, respectively. Depuration was rapid following exposure cessation, 66% to 70% of accumulated residues were eliminated in 1 day, 97% to 98% after 13 days. In the high-dose fish edible tissue, parent spirodiclofen was not detected, residues were comprised of 4 transformation products. In nonedible tissue, the parent compound was 0.33% of the total burden. Five metabolites representing 0.9% to 29.5% of the total residue made up the remainder. Parent spirodiclofen s soil organic carbon partitioning coefficient, K OC, ranged from 51,097 to 101,366 ml/g with a mean of 72,205. A compound with a K OC of >5,000 is expected to be immobile in soil. Spirodiclofen has low vapor pressure, 2.3x10-9 mmhg; volatilization will not contribute significantly to post-application dissipation. Toxicity & Environmental Fate: Spirodiclofen generally exhibits low toxicity to terrestrial and adult aquatic nontarget organisms and dissipates relatively rapidly following application. It is practically nontoxic to both birds and mammals on an acute basis. Although avian and mammalian chronic toxicity is possible with long-term high dose exposures, it is not likely to occur with labeled field use. All mammalian mutagenicity and cytotoxicity studies produced negative results. In all aquatic acute toxicity studies for which results were submitted, there were no mortalities or sublethal effects reported at any concentration up to and including the highest concentrations tested. Results are all reported as having an LC 50 or LOEC greater than some value generally between 35 and 51 ppb. The applicant reports that 50 ppb can be considered the practical solubility limit. The highest reported concentration was the 50.8 ppb, achieved in the Daphnia study. Developing organisms appear much more sensitive to this mode of action than adults. LOEC s in

12 Ms. Princy A. Jesudason 12. Rainbow Trout Early Life-Stage and Daphnia Life-Cycle studies were 3.8 and 20.2 ppb, respectively. The LOEC and NOEC in a 28-day Chironomid Development and Emergence study were 126 and 32 ppb, respectively. Algae and aquatic macrophyte studies showed no effects up to the water solubility limit. The Envidor 2SC label includes language in the Environmental Hazards section warning of a chronic toxicity risk to honey bee larva and hive stability. This warning is a result of a semi-field study, reviews of which were included in the supporting data package. Hives were placed in netting tunnel cages constructed over rows of trees within an apple orchard in a treatment/control design. Bees were allowed to forage normally for 6 days, within their respective cages, from trees which were at approximately 50% bloom. Spirodiclofen was applied to the treatment block at a rate of lbs. ai/acre, slightly less than _ of the maximum allowed rate of 0.28 lbs. ai/acre. Six (6) days post-application, the hives were removed from the study orchard to an untreated area where the bees were allowed to forage unrestricted. The hives were monitored for an additional 21 days following removal from the study orchard. There was no effect on adult bees. As compared to controls, however, treatment hives experienced statistically significant and biologically significant (as judged by USEPA EFED staff) decreases in colony strength (population density), pupal abundance, and larval abundance which persisted through study termination. The primary post-application dissipation route for spirodiclofen will be via microbial metabolism with lesser amounts degrading by hydrolysis and aqueous photolysis. Spirodiclofen s hydrolysis half-life, T 1/2, is ph dependant; it is 120, 52, and 2.5 days at phs 4, 7, and 9, respectively. Based on rates observed in a laboratory study, its environmental aqueous photolysis T 1/2 is predicted to be 43.8 days in Phoenix, AZ and 61.6 days in Edmonton, Alberta, Canada. It is stable to soil surface photolysis. The laboratory aerobic soil T 1/2 ranged from 1.7 days to 17.1 days in 4 different soils, with a mean of 6.9 days. The mean observed time to 90% degradation, DT 90, for the same 4 soils was 17.8 days. Additionally, aerobic soil T 1/2 s for 4 spirodiclofen metabolites were provided. For purposes of this review, they will only be identified as the keto-, enol-, dihydroxy, and DCBA metabolites; they had mean aerobic soil T 1/2 s of 6.9, 21.7, 10.4, and 14.4 days, respectively. In laboratory aerobic pond and lake sediment/water system studies, spirodiclofen degraded readily. It rapidly sorbed to the sediments; the water column T 1/2 was <1 day, where it degraded with a T 1/2 of 4 to 14 days. Degradation in anaerobic sediment/water systems was similar. Observed anaerobic DT 50 s were <1 hr in the water column, and 14 days for the total system. Terrestrial Field Dissipation trial results were submitted for sites in 3 U.S. states and Ontario, Canada. The mean dissipation T 1/2 for the 4 sites was 4.3 days; the mean DT 90 was 14.2 days. Parent spirodiclofen was never detected below the 15cm depth. At 2 sites, neither parent or metabolites were detected below the 15cm depth. At the remaining 2 sites, Florida sand soil and California sandy loam, low levels of metabolites were detected to a depth of 30 cm. The primary metabolite is the enolwhich represented 61% to 86% of the applied parent within 1 day. The last detections of the enolwere 7 to 14 days post application. Exposure Modeling: Screening level aquatic and terrestrial exposure modeling shows that spirodiclofen should have little or no adverse impacts on nontarget organisms with legal use.

13 Ms. Princy A. Jesudason 13. Direct application of Envidor 2SC to the surface of a water body at the single application rate would result in lethal toxicity to all aquatic organisms for which data were submitted. Highly conservative runoff modeling, however, shows little aquatic exposure should occur with responsible applications. The highest likely runoff rate for a chemical with spirodiclofen s K OW following application of the maximum yearly Envidor 2 SC label rate results in a model pond water concentration that exceeds the Rainbow Trout Early Life Stage LOEC. If 60% of the applied material is intercepted by the target foliage, pome fruit, no toxicity thresholds are exceeded in the model pond using these conservative parameters. Risk Assessment: The highest predicted spirodiclofen vegetation residue concentration immediately following application is less than 50% of the lowest mammalian chronic LOEC and is less than 22% of the avian reproductive NOEC. No risk should be posed to birds or mammals with labeled Envidor 2SC use. The PONDTOX Direct Application modeling is designed to evaluate the aquatic risks associated with aerial application of a product and to determine when runoff modeling is warranted. Envidor 2SC may not be applied aerially so those results serve only to trigger runoff modeling. The conservative runoff scenario results show there is little, if any, potential for impacts to aquatic resources from labeled Envidor use. It should be kept in mind that all acute test results are expressed as greater than some value and that at the reported values there were no mortalities or sublethal effects. The combination of conditions required to make the PONDTOX model exceed the Rainbow Trout chronic thresholds is unlikely to occur in the field. The fact that spirodiclofen is likely to remain in the water column for a very short period of time should it ever reach a surface water make chronic aquatic effects highly unlikely. Therefore, when used as labeled, Envidor 2 SC Miticide should not pose an unreasonable ecological risk. Conclusion: As identified above in the Toxicological Risk Assessment, the Department continues to have unmitigated concerns regarding the potential for this product to negatively affect human health. Envidor has carcinogenic potential and causes effects on endocrine tissues. Additionally, there are other less toxic products available to control the same pests as the Envidor 2 SC Miticide product. Therefore, your application for registration of Envidor 2 SC Miticide (EPA Reg. No ) in New York State is denied. You may pursue the options available under Article of the New York State Environmental Conservation Law. Please be reminded that the application fee is nonrefundable. If you wish to reapply, you must submit a new application for registration as a New Active Ingredient, applicable application fee and above-required data. The application should only be resubmitted when information pertaining to the above-mentioned concerns is available for submission. Please be aware that any unregistered product may not be sold, offered for sale, distributed, or used in New York State.

14 Ms. Princy A. Jesudason 14. If you have any questions, please contact Samuel Jackling, Chief of our Pesticide Product Registration Section, at (518) Serafini Sincerely, Maureen P cc: N. Kim/D. Luttinger - NYS Dept. of Health R. Mungari - NYS Dept. of Ag. & Markets W. Smith - Cornell University, PMEP Maureen P. Serafini Director Bureau of Pesticides Management