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**EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER**  **EPA Registration**  **Division contact: William Cutchin**  **; 703 -**  **305 -**  **7990 TEMPLATE:**  **Bayer CropScience** 3F8182EPA has rec eived a pesticide petition (**3F 8182**  ) from **Bayer CropScience** proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing the tolerance s for residues of **aluminum tris(**  **O -**  **ethylphosphonate)** in or on the raw agricultural commodity **P epper** **/Eggplant ,**  **subgroup 8**  **- 10B,**  at **0.01** parts per million (ppm) and **Non -**  **bell (chili) pepper dried fruits** at **0.01** parts per million (ppm) **.** EPA has determined that the petition contains data or in formation regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may

be needed before EPA rules on the petition. A. Residue Chemistry 1. Plant metabolism. **The metabolism of fosetyl -**  **al in plants is adequately understood. Adequate data on the nature of the residues in plants, including**  **i dentification of major metaboli** **tes and degradates of fosetyl -**  **al, are available. Radiolabeled studies on the uptake, translocation and metabolism in plants show**  **that the chemical proceeds through hydrolytic cleavage of the ethyl ester. The major residues are fosetyl** **- al, phosphorus acid,**  **and ethanol. The tolerances are established for the parent only, that is fosetyl**  **- al**  **as specified in 40 CFR 180.4 15**  **.** 2. Analytical method. **An enforcement method for plant commodities has been validated on various commodities. It ha**  **s undergone successful EPA validation and has been submitted for inclusion in PAM II. The animal method has also been**  **approved as an adequate enforcement method.** 3. Magnitude of residues. **Magnitude of residue data in/** **on bell**  **and non -**  **bell (chili) pepper**  **fresh fruits and non -**  **bell (chili) pepper dried fruits were**  **determined from**  **fourteen field trials conducted in Mexico (6 trials), Peru (3 trials) and**  **California ( 5**  **trials) .**  **Prior to transplant, all seedlings were grown in greenhouse trays and received thr**  **ee foliar spray applications ranging from 8.09 to 8.69 lbs fosetyl**  **- al/A/application (9.07 to 9.74 Kg fosetyl** **- al/A/application) with a 10**  **- day**  **treatment interval. T**  **o tal**  **foliar application rates ranged from**  **24.5 to**  **25.4 lbs** 2

**fosetyl -**  **al /** **A (27.5 to**  **28 .**  **4 Kg**  **fose tyl**  **- al** **/A ). Following transplant of the previously**  **treated seedlings, plants received either 3 drench applications or 3 chemigation applications ranging from 0.83 to 0.84 lb fosetyl**  **- al/A/application (0.93 to 0.94 Kg**  **fosetyl -**  **al/ha/application) with a 10 day treatment interval and 5**  **- day PHI.**  **Total combined seasonal application rates for both treatment regimens (foliar + drench**  **and foliar + chemigation) ranged from 27.0 to 27.8 lbs fosetyl -**  **al/A (30.3 to 31.2 Kg fosetyl**  **- al/ha)**  **. Duplicate composite**  **samples of bell and non**  **- bell**  **pepper ,**  **fresh fruits were collected from the treated plots at**  **4 -**  **to 5 -**  **day p**  **re -**  **harvest intervals (PHIs). In**  **the non -**  **bell/chili pepper trials, samples of fresh non -**  **bell peppers to be dried were collected at the same intervals as samples fo**  **r fresh non -**  **bell peppers. These samples**  **were allowed to dry either outside, inside at room temperature, or in a low**  **** **temperature drying oven for 7 to 20 days, according to typical local agricultural**  **practices. Six of the trials were conducted as decline t**  **rials with fresh fruit samples collected at 0, 2, 4, 5, 7 and 9 to 10 days.**  **Residue values for dried**  **non -**  **bell (chili) pepper s**  **were calculated by multiplying**  **residue values measured in fresh non**  **- bell (chili) peppers by a processing factor**  **determined from the dry**  **weight of each of the respective non -**  **bell chili pepper samples.**  **Fosetyl residues, quantitated as f**  **osetyl -**  **al only,**  **in bell pepper, fresh fruits,**  **non -**  **bell (chili)**  **pepper, fresh fruit s**  **and non -**  **bell (chili) pepper, dried fruits were**  **<0.01 ppm.** B. Toxicological Profile 1. Acute toxicity. **A complete battery of acute toxicity studies**  **fo r fosetyl** **- Al**  **technical has been conducted. The lethal dose L**  **D 50**  **from the acute oral rat is**  **5.4 g/kg and the L**  **D 50**  **fr om**  **an a cute dermal rabbit study is >2 g/kg.**  **The L**  **C 50**  **for a rat inhalation study is >1.73 mg** **/ L.**  **The acute oral rat and primary dermal irritation**  **studies indicate category IV toxicity. A guinea pig dermal**  **sensitization study shows fos**  **etyl -** **Al is not a skin sensit** **izer. The primary eye irritation study in rabbits shows fosetyl**  **- Al to be an eye**  **irri t**  **ant with Category I toxicity.**  2. Genotoxicty. **Fosetyl -**  **Al is neither mutagenic nor genotoxic**  **. The genetic**  **toxicity potential of fosetyl** **- Al was**  **a ssessed in several**  **assays. Eight mutagenicity**  **tests performed with fosetyl -** **Al were negative. The tests included two**  **Am es assays**  **with S. typhimur u**  **m, tw o phase induction assays using E. coli, two micronucle**  **u s**  **studies in mice, one DNA rep air assay using E. coli and one mutation assay in**  **Saccharomyces cereviseae**  **.** 3. Reproductive and developmental toxicity. **Fosetyl -** **Al is not a reproductive toxicant and shows no evidence**  **o f**  **estrogertic or androgenic related e f**  **fects. a.**  **In a three generatio n reproduction study, fosetyl**  **- Al was administered to rats**  **at dietary levels o**  **f 0, 6,000, 12,000 or 24,000 ppm.**  **No adverse effects on r**  **eproductive pe r**  **formance or pup survival were observed in any dose group.**  **The lowest -**  **observed adverse effe**  **ct level (LOAEL ) was**  **established at 12,000 ppm based on effects on**  **a nimal weights and urinary tract changes.**  **The no**  **-**3 **observed adverse e f** 

**fect level (NOA EL**  **) for all effects w a**  **s 6,000 ppm. b.**  **A teratology study in rats dosed via oral g a** **vage at 500**  **, 1,000 or 4,000**  **mg/kg/day showed a**  **developmental NOA EL**  **o f 1,000 mg/kg.**  **At 4,000**  **mg /** **kg, there was maternal toxicity as evidenced by**  **effects on animal**  **weights, maternal deaths, increased resorptions and delayed**  **fetal ossification.**  **c. A rabbit teratology study showed no toxic effects**  **at or a**  **l doses up to 500**  **mg/kg. Effects o**  **f fosetyl -** **Al on fe**  **tal development were observed only in the rat at a dose producing**  **severe maternal toxicity. In the absence of**  **ma ternal toxicity, no adverse**  **effec ts on fetal**  **development were observed, i.e. at 100**  **0 m**  **g /** **kg/day in rats or at 500 mg/kg/day in rabbits.** 4. Subchronic toxicity. **I n**  **subchronic studies, no signi** **f icant toxicity was**  **observed even at doses exceeding the limit of 1000 mg /k** **g/day. a.**  **A 21 -**  **day dermal study in rabbits showed mild to moderate skin irri** **t ation**  **and a NOAEL of 1**  **.5 g** **/ kg** **/d ay.**  **b. A 90**  **- day feeding study in rats showed a NOAEL of**  **>5000 ppm; the LOAEL**  **was 25,000 ppm with extramedullary hematopoiesis in the spleen.**  **c. A 90**  **- day dog feeding stu**  **d y sh**  **owed a NOAEL of 10,000 ppm and a LOAEL at**  **50,000 ppm, at which the test animals had a lower serum potassium level**  **than untreated animal.** 5. Chronic toxicity. **Chronic toxicity studies have been conducted in dogs and**  **rats :**  **a. Dog: Fosetyl**  **- Al was fed to do**  **gs for two years at concentrations qf 0, 10,000, 20,000, and**  **40,000 ppm. The NOA** **EL was 10,000 ppm, equivalent to**  **250 mg** **/k g/day. The**  **N OAEL was**  **20,000 ppm bused on a slight degenerative eff**  **ect on the testes. These testicular changes, as well as a few scatte**  **red clinical changes, were seen in the high dose dogs.**  **No e f**  **fects were observed in the urinary tract.**  **b. Rat: Fosetyl** **- Al was administered via admixture in the diet to CD rats at**  **target levels o**  **f 0, 2,000, 8,000, and 30,000/40,000 ppm for approximately two**  **years. Based on these levels, respective doses were 100, 400 and 2000/1500**  **mg/kg/day. After two weeks at 40,000 ppm, this dietary level was reduced to**  **30,000 pp m due to the occurrence of red coloration o**  **f the**  **u rine and**  **a decrease in body weight gain. Alth**  **ough these findings were no longer**  **apparent a fte**  **r Week 2, analytical verification of dietary levels revealed that**  **the highest dietary level ranged fro m**  **approximately 3 8,**  **000 to 61,000 ppm during the first 32 weeks of the study.**  **No sign ific**  **ant di**  **ffe rences i**  **n body weight or food consumption were noted at 2,000 or 8,000 ppm.**  **No biologically significant di**  **ffe rences were observed in ophthalmoscopy,**  **hematology, clinical chemistry or urinalysis for treated and control animnls.**  **Calculi in the urinary bladder were observed for several male and female**  **rats in the high dose group. Non**  **- neoplastic findings**  **consisted of epithelial hyperplasia and in**  **f**

**la mm**  **ation in the urinary bladders o f**  **males at 30,000**  **/ 40,000**  **ppm. Increased inci**  **d ences of hydronephrosis, in**  **f lammation,**  **a nd epithelial**  **hyperplasia in the kidney were also observed in males from the**4 **high dose group. Females from**  **the same group exhibited increased incidences qf epithelial hyperplasia in the urinary bladder**  **and hydronephrosis in the kidney.**  **The NOAEL in the ch ronic rat study was**  **8,000 ppm (400 mg/kg/day).**  **The lowest NOA EL**  **f o**  **r chronic e ff** 

**ects of**  **fosetyl -** **Al is 1**  **0, 000**  **ppm (250 m**  **g/kg/day) based on the dog study. This**  **NOAEL is based on minor changes at 20,000 ppm. I**  **n t h**  **e rat, calculi in the u**  **r i**  **nary bladder and rel ated histopathological changes in the bl**  **a dder and**  **kidneys of males and females were observed**  **a t 30,000**  **/ 40,000**  **ppm.** 6. Chronic Toxicity and Carcinogenicity **Long -**  **term feeding studies were conducted with technical grade fosetyl** **- al in mice and rats and with**  **monosodium phosphite, the primary urinary metabolite of fosetyl** **- al, in rats. These studies, in**  **addition to a mechanistic study in rats, are described below: a.**  **Rat. Fosetyl** **- al was administered via admixture in the diet to CD**  **rats at target levels of 0, 2,**  **000, 8,000, and 30,000/40,000 ppm for approximately 2**  **years. After 2 weeks at 40,000 ppm, this dietary level was reduced to 30,000**  **ppm due to the occurrence of red coloration of the urine and a decrease in**  **body weight gain. Although, these findings**  **were no longer apparent after**  **week 2, analytical verification of dietary levels revealed that the highest**  **dietary level ranged from a**  **pproximately 38,000 to 61,000 ppm during the first 32 weeks of the**  **study. Calculi**  **in the urinary bladder were observed for severa**  **l male and female rats at 30,000/40,000 ppm.**  **Microscopic examination revealed**  **transitional cell carcinomas and papillomas in the urinary bladders of**  **high dose males. In addition, a statistically significant increase in**  **adrenal pheochromocytomas (benign a**  **nd malignant combined) was observed in**  **males at 8,000 and 30,000/40,000 ppm. The adrenal slides were**  **independently reread by two consulting pathologists who found no significant dose**  **- related increases in the incidence of**  **pheochromocytomas or hyperplasia.**  **The NOAEL for fosetyl -**  **al in the chronic rat study was 8,000 ppm.**  **A subsequent mechanistic study in rats conducted with dietary levels of**  **8,000, 30,000 and 50,000 ppm demonstrated that the massive doses of 30,000**  **and 50,000 ppm fosetyl -**  **al alter calcium/pho sphorous homeostasis**  **resulting in severe acute renal injury, similar to that observed in the**  **chromic rat s**  **tudy, and the formation of calculi in kidneys, ureters, and bladder. Under**  **c onditions of chronic exposure, these effects could**  **lead to the formation of**  **bladder tumors as seen in the chronic rat study. At 8,000 ppm, no evidence of**  **renal injury was observed, a result consistent with the absence of bladder**  **tumors. Thus, the bladder tumors induced by fosetyl**  **- al were the result of**  **acute renal injury followe d by**  **a chronic toxic reaction rather than a true carcinogenic effect.**  **An carcinogenicity study in rats was conducted with**  **monosodium phosphite administered via dietary mixture at levels of 2,000,**  **8,000, and 32,000 ppm. No evidence of carcinogenicity was o**  **bserved in this study.**  **b. Mouse.**  **A 2 -** **year feeding/carcinogenicity study was conducted in mice f**  **ed diets containing fosetyl**  **- al at 0, 2,500, 10,000, or 20,000/30,000 ppm. The** 5 **20,000 ppm dose was increased to 30,000 ppm during week 19 of the study.**  **The NOAEL for all effects was 20,000/30,000 ppm**  **(3,000/4,500 mg/kg/day). There were no**  **carcinogenic effects observed under the conditions of this study.**  **c. EPA's Carcinogenicity Peer Review Committee (CPRC) concluded**  **in their report of June 29, 1993 that the pesti**  **cidal use of fosetyl -**  **al is unlikely to pose**  **a carcinogenic hazard for humans given that: (a) Tumors develop in rats**  **under extreme conditions that are unlikely to be achieved other than under**  **laboratory conditions (at a dose in excess of the EPA dose limit**  **for carcinogenicity studies); (b) tumors in rats are**  **believed to develop only at doses that produce stones; (c) human**  **dietary exposure to fosetyl -**  **al is only about one**  **- 500,000th of the NOAEL**  **for stone formation in the rat (the most sensitive experimental mo**  **del); and (d) the dose of fosetyl**  **- al which can be**  **absorbed dermally by applicators is also probably too low to result in stone**  **formation. Therefore, a cancer dietary exposure analysis for fosetyl**  **- al is not**  **performed.** 7. Animal metabolism. **Rat metabolism studies showed that most of the**  **radiolabel rapidly appeared in exhaled carbon dioxide. There was also some**  **radiolabel excreted in the urine as phosphite, along with a smaller amount as the**  **unchanged parent compoun d. It appears that**  **fosetyl -**  **al is essentially completely absorbed after ingestion and**  **extensively hydrolyzed to carbon dioxide which is exhaled. The**  **phosphite is excreted in the urine without further oxidation to phosphate. Aluminum does not appear to be ab**  **sorbed to a significant extent from**  **the gastrointestinal tract.** 8

. Metabolite toxicology

. **There are no metabolites of toxicological concern.**  **The tolerances are established for the parent only, that is fosetyl**  **- al.**  9

. Endocrine disruption

. **No evidence of estrogenic or androgenic**  **effects were noted in any study with fosetyl** **- al. No adverse effects on**  **mating or fertility indices and gestation, live birth, or weaning**  **indices were noted in a three -**  **generation rat reproduction study at**  **doses well above EPA's lim it of 1,000 mg/kg/day. Therefore,**  **Bayer CropScience concludes that fosetyl**  **- al does not have any effect on the**  **endocrine system.** C. Aggregate Exposure 1. Dietary exposure. **For all currently registered and proposed uses of fosetyl****** **al ,**  **acute and chronic food exposure for various subgroups of the U.S. population**  **were estimated**  **using the Dietary Exposure Evaluation Model with the Food**  **Commodity Intake Database (DEEM -**  **FCID) software Version 3.14. The DEEM analysis evaluated the individual**  **food consumption as reported by respondents in the USDA’s National Health and Nutrition Examination Survey (NHANES) from**  **2003 to 2008 nationwide continuing surveys of food intake by individuals. A Tier 1**  **dietary assessment was evaluated based on establish ed tolerances for all registered**  **uses and 100% crop treated. For the proposed use on Bell Peppers and Non -**  **Bell**6

**Peppers, the proposed tolerance of 0. 01 ppm was used in this**  **assessment. For acute risk, EP** **A found**  **n o appropriate endpoint attributable to a**  **s ingle dose**  **exposure was identified in oral acute**  **toxicity studies. Therefore, an acute RfD was**  **not established and there was**  **no expectation of acute risk.**  **For chronic risk, EPA**  **established the chronic reference dose (RfD) for fosetyl**  **- al at 2.5 mg/kg/day.**  **This reference dose (RfD) is**  **based on a NOAEL of 250 mg/kg/day from a 2 -**  **year feeding study in dogs**  **and the use of a 100 fold safety factor to account for interspecies and intraspecies differences.**  **Since no dermal or systemic toxicity was seen at the lim** **it dose following repeated dermal applications in the 21**  **- day**  **toxicity study using rats, no endpoint value was calculated for short**  **and intermediate**  **- term exposure and**  **risk. The Agency has concluded that fosetyl**  **- al is unlikely to pose a carcinogenic**  **hazard t o humans.**  **Therefore, a cancer exposure and risk assessment is not appropriate.**  i. Food. **For food, Tier 1 acute and chronic dietary exposure assessment s**  **were performed. Acute exposure was not required since there was no acute**  **reference dose established for this endpoint**  **. The chronic exposure to fosetyl** **- al**  **from food utilizes 4% of the chronic population adjusted dose (cPAD) for the U.S. population,**  **5 % of the cPAD for infants, and**  **12 % of the cPAD for children**  **1 -**  **2 years**  **old, the subpopulation at greatest exposure.**  **Based on the results of this conservative analysis, exposure to fosetyl**  **- al residues from the proposed uses is**  **expected to be minimal. Bayer CropScience concludes**  **that dietary exposure to fosetyl**  **- al resulting from the currently**  **registered uses a nd the proposed use of the**  **product will be well below the Agency's level of concern.**  ii. Drinking water. **The potential for ground water and/or surface water**  **contamination by fosetyl -**  **al and its degradates is expected to be very low, in most**  **cases, due t o the rapid degradation of the compound**  **in soil to non -**  **toxic degradates under both aerobic and anaerobic**  **conditions. Ground water estimations were**  **based on “maximum loading” conditions using the SCI -**  **GROW2 screening level model. The estimated ground water**  **concentration was 0.006 ppb for all uses. Surface water estimations were based on environmental fate data and pesticide label**  **application using the FIRST model. The estimated surface water concentration s**  **were 0.0086 ppb (peak) and 0.00003 ppb (annual me an) for proposed uses.**  2. Non

- dietary exposure

. **Fosetyl -**  **al is currently registered for residential use**  **on turf and ornamental plants. Chronic exposure is not expected for residential**  **uses. There is also no exp ectation of acute**  **risk. No appropriate endpoint attributable to a single dose exposure**  **was identified in oral toxicity studies and consequently, an acute RfD**  **cannot be calculated. No endpoint value is calculable for short** **- and**  **intermediate -**  **term exposure an d a risk analysis cannot be performed**  **since no dermal or systemic toxicity was seen at the limit dose following repeated**  **dermal applications in the 21 -**  **day toxicity study using rats. The Agency has**  **previously concluded that fosetyl -**  **al is unlikely to pose a**  **carcinogenic hazard to human. Therefore, a cancer**  **exposure and risk assessment is not appropriate. Thus,**7

**Bayer CropScience concludes that the ornamental and turf uses do not add**  **significantly to the aggregate exposure for fosetyl -**  **al.** D. Cumulative Effects

. **Effects associated with fosetyl -**  **al are unlikely to be c**  **umulative with any other compound. The formation of calculi and bladder tumors in**  **rats is the only significant toxicological effect observed with**  **fosetyl -**  **a l. These effects were**  **observed in rat only at a dose which not only exceeds estimated human exposure by**  **several orders of magnitude but is in excess of the OPP dose limit for**  **carcinogenicity studies. Therefore, an aggregate assessment based on common**  **mech anisms of**  **toxicity is not appropriate as exposure to humans will be well below the levels producing calculi and bladder tumors in rats. Further,**  **considering the rapid elimination of fosetyl** **- al in the rat metabolism**  **study, any effects associated with fosety** **l -**  **al are unlikely to be cumulative with any other compound. Based on**  **these reasons, only the potential risks of fosetyl** **- al are considered in the exposure**  **assessment.** E. Safety Determination 1. U.S. population. **Chronic risk estimate s associated with exposure**  **to fosetyl**   ** al in food and water are expected to be well below the** **Agency's level of concern. The Tier I chronic exposure analysis**  **performed for all currently r**  **egistered and**  **proposed food uses show**  **that exp osure to fosetyl**  **- al uti** **lizes 4 % of the cPAD for the**  **U.S. population,**  **5 % of the cPAD for infants, and**  **12 % of the cPAD for children**  **1 -**  **2 years old, the subpopulation at greatest exposure.**  **This analysis was conducted**  **assuming 100% crop treated and tolerance level residue values fo**  **r all crops. The**  **contribution of fosetyl -**  **al residues in surface water and ground water to chronic**  **aggregate exposure was**  **minimal. Therefore, Bayer CropScience concludes that**  **even when considering the potential incremental risk resulting from the proposed**  **use on bell and non**  **- bell peppers**  **, there is a reasonable certainty that no harm will**  **result from aggregate exposure to fosetyl -**  **al residues.** 2. Infants and children

. **Infants and children. No indication of increased**  **susceptibility of**  **rat or rabbit fetuses to in utero and/or postnatal exposure was noted in the developmental and reproductive toxicity studies.**  **The Agency has**  **previously determined that no additional safety factor to protect infants and**  **children is necessary for this prod uct.**  **Using the conservative assumptions described in the exposure**  **section above, aggregate exposure to fosetyl -**  **al from currently**  **registered food uses will utilize 5% of cRfD for infants, and**  **up to 12**  **% of the**  **c RfD for children**  **1 -**  **2 years old, the subpopulat** **ion at greatest exposure. Even**  **when considering the potential incremental dietary risk resulting from the**  **proposed use on**  **bell and non -**  **bell peppers , the potential for exposure to residues in**  **drinking water and from non**  **- dietary, non**  **- occupational exposure,**  **the aggregate exposure to**  **fosetyl -**  **al is expected to be well below the level of concern. Bayer CropScience**  **concludes that there is a reasonable certainty that no harm will result to infants and**  **children from aggregate exposure to fosetyl**  **- al residues.** 8

F. In ternational Tolerances **N o maximum residue**  **limits (MRLs) have been**  **established for residues of fosetyl -**  **al in or on**  **bell or non -**  **bell peppers by the Codex Alimentarius Commission**  **(CODEX).**