1 **Study Title** Publicly Releasable Summary of the Petition for Establishment of a Tolerance for Dodine in or on the Raw Agricultural Commodity: Stone Fruits (Group 12) and Tree Nuts (Group 14) **EPA Registration A** **ction References** Petition for Establishment of Tolerances Dodine in or on Stone Fruits and Tree Nuts

(PP# to be assigned)
**Au thor**  Bert Volger, Ph.D.
**Document Date** May 9 , 20 11 **Prepared by** CERES International LLC 1087 Heartsease Drive West Chester, PA 19382 **Submitted by** Agriphar S.A. Rue de Renory 26 B
-4102 Ougree Belgium2

**EPA Registration Division contact: Mary**  **Waller, Registration Division (7505P), Office of Pesticide Programs, Environmental Protection A** **gency, 1200 Pennsy** **lv ania Ave., NW., Washington, DC 20460** **– 0001; telephone number** **: (703) 305** **– 1825; e** **- mail address:**  **waller.mary@epa.gov**
**. AG**  **RIPHA R S.** **A. PP (to be assigned)**  EPA has received a pesticide petition (PP # to be assigned) from AGRIPHAR S.A., c/o CERES International LLC, 1087 Heartsease Drive, West Chester, PA 19382 , proposing pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance for residues of dodine (dodecylguanidine acetate) in or on the raw agricultural commodity, stone fruits (Group 12) at 5 parts per million (ppm), tree nuts (Group 14, except almond hulls) at 0.3 ppm , and almond hulls at 12 ppm
. EPA has determined that the petition contains data or information regarding the elements set forth in section 408(d)(2) of the FFDCA; 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 qualitative nature of the residue of dodine in plants is adequately understood based on acceptable apple, pecan and strawberry metabolism studies. These plant metabolism studies have demonstrated that dodine does not metabolize and is nonsystemic (does not translocate within the plant). The results observed in the plant and livestock metabolism studies show similar metabolic pathways. The residue of concern, which should be regulated, is the parent compound, dodine, per se. **2. An** **aly tical Method**  An adequate enforcement method using gas chromatography with mass selective detection (GC/MSD, Method 45137) is available for determining dodine residues in or on plant commodities. Concerning tree crops, a method using liquid chromatography with tandem mass spectrometric detection (LC/MS/MS; METH1595.02) after the samples were extracted with methanol, was submitted

. The limit of quantitation (LOQ = 0.01 ppm) was taken as the lowest level validated by this method , and the limit of detection (LOD) was 0.003 ppm

. Adequate data collection method validation, independent laboratory validation (ILV), and radio
-validation data for the method has been submitted. Since there is no reasonable expectation of finding residues of dodine in livestock or poultry, no3

analytical method for animal tissues is required. **3. Magnitude of Residues**  For stone fruits (Group 12) and tree nuts (Group 14), complete sets of residue data have been submitted in support of the petitioned tolerances. **3.1. Stone Fruits**  There is an adequate residue data base in support of a crop group tolerance for stone fruits (Group 12
- representative commodities: cherries, peaches, plums). Regarding cherries, a total of nine sweet cherry trials were conducted in 1997 covering EPA Regions 5, 10, and 1 1

. Six sequential applications were made on a 6 to 14
-day schedule at the target rate of 1.3 lbs a.i./acre, and a seasonal rate of 7.8 lbs a.i./acre. The measured dodine residues were in the range of 0.34 to 2.2 ppm, below the established tolerance for cherries of 3 ppm. In a more recent study (2008, 2009), four sweet cherry trials were conducted in Michigan (EPA Region V), New York (EPA Region I) and Washington (EPA Region XI) comparing the magnitude of dodine residues in or on cherries following six sequential applications of Syllit FL and Syllit 65W (side by side) at a total seasonal application rate of 5.2 lbs a .i./acre and a preharvest interval (PHI ) of 7 days. The detected average dodine residues were in the range of 1.5 to 2.9 ppm. Regarding peaches, a total of twelve trials were conducted in 1997 covering EPA Regions 1, 2, 5, 6, and 10. Five sequential applications were made at 1.3 to 2.6 lbs a .i./acre, a total seasonal application rate of 6.5 to 9.1 lbs a .i./acre, and a PHI of 14 to 15 days . The measured dodine residues were in the range of 0.43 to 4.04 ppm, below the established tolerance for peaches of 5 ppm
. In the recently submitted 2008 field residue study, three trials were conducted in locations representative of the major peach production areas in the U nited States: New York (EPA Region I), Georgia (EPA Region II) and Michigan (EPA Region V) comparing the magnitude of dodine residues in or on peaches following five in season applications of Syllit FL and Syllit 65Wat a total seasonal application rate of 7.8 lbs a .i./acre and a PHI of 15 days. The detected average dodine residues were in the range of 0.75 to 1. 1 ppm
. Regarding plums, a total of six plum trials were conducted in 1995 covering EPA Regions 5, 10, and 12. Six sequential applications were made at 1.3 lbs a .i./acre, a total seasonal application rate of 7.8 lbs a .i./acre, and a PHI of 7 days. The measured dodine residues were in the range of 0.36 to 1.84 ppm
. However, the submitted residue data base is complete and adequate in support of the Stone Fruits Group tolerance. **3. 2** 
**. Tree Nuts**  There is an adequate residue data base in support of a crop group tolerance for tree nuts (Group 14
- representative commodities: almonds, pecans).4

Regarding almonds, in 2010 a total of five field trials were conducted in Region 10 representing most of the US almond production. I n each trial, four applications were made to the almonds at a rate of 1.88 lbs a
. i

./acre , resulting in a total seasonal application rate of 7.52 lbs a
. i

./acre
. Applications were made at full bloom, petal fall, 2 weeks after petal fall and 5 weeks after petal fall. Samples were collected at normal harvest, with the exception of the decline trial, in which samples were also collected 10 days before normal harvest, 5 days before normal harvest, 5 days after normal harvest and 10 days after normal harvest. Dodine was detected at low levels in almond nutmeat (range <0.01 ppm to 0.106 ppm) and at higher levels in almond hulls (range 1.2 ppm to 12.2 ppm, average 4.8 ppm). Regarding pecans, there are field trials from 12 different locations covering the major US pecan growing areas (EPA Region 4, and 6), depicting dodine residues in or on pecan nutmeat and shells

. These studies were conducted in 1967 following one to eight air blast applications at 0.5 to 4.0 lbs a
. i

./acre before shuck split

. The measured residues at various post
-treatment intervals did not exceed 0.8 ppm for nutmeat and shells combined. In a pecan metabolism study, pecans were treated 3 times prior to shuck split at a nominal rate of 1.7 lbs a
. i

./acre yield ing a dodine residue level of 0.04 ppm in the nutmeat

. Therefore, the tolerance for dodine residues in nutmeat was established at 0.3 ppm

. It can be concluded, when almond residue data are combined with previously submitted pecan data , the proposed tolerance of 0.3 ppm on tree nuts (Group 14) is adequately supported

. The data also support the proposed tolerance of 12 ppm for almond hulls. **B. Toxicological Profile**  **1. Ac** **ute Toxicity** Dodine has moderate acute toxicity (Category III) in oral (LD50 = 1,456 mg/kg), dermal (LD50 > 2,000 mg/kg), and inhalation studies (LC50 = 1.05 mg/kg). No significant differences exist between females and males. The only potential systemic toxicity observed in the acute dermal toxicity study was a slight decrease in body weight at the limit dose. Dodine is a severe eye irritant in rabbits and a severe dermal irritant or sensitizer (both Category I). **2. Genotoxicity**  The mutagenic potential of dodine was investigated in several in vivo and in vitro studies. Results for gene mutation from in vitro mammalian gene mutation tests as well as from a structural chromosomal aberration assay with and without metabolic activation were negative. Negative results also occurred in a mouse bone marrow chromosomal aberration test. Based on all of these assays, dodine is considered to have no potential to induce mutagenicity.5

**3. Reproductive and Developmental Toxicity**  i. A two generation rat reproduction study was conducted with dose levels of 0, 200, 400, and 800 ppm (0, 13, 26, and 53 mg/kg/day for males and females, respectively). There were no effects on fertility or pregnancy at any dose level in rats over two generations. There was a decrease in parental body weight, body weight gain or food consumption in both generations of rats. The offspring of both generations demonstrated decreased body weight in the high dose group. The no observed adverse effect level (NOAEL) was determined to be 400 ppm for systemic effects (26 mg/kg/day for parents and offspring), and 800 ppm for reproductive parameters (53 mg/kg/day, LOAEL can not be determined). ii. Teratology studies were conducted in the rat and rabbit. No treatment
related mortalities were observed in either study. No ef fect on survival, development or growth of fetuses was noted in either species in either study. The maternal and fetal NOAEL was determined to be 80 mg/kg/day (highest dose tested, LOAEL can not be determined) in the rabbit study. In the rat study, the maternal and fetal NOAEL was 10 mg/kg/day based on decreased body weight, body weight gain, and food consumption (parents) and decreased body weight (pups). These two studies demonstrate that dodine was not teratogenic in either rats or rabbits. **4. Sub** **chronic Toxicity** Rats, mice and dogs all show the same toxicologic response. The most common effects for intermediate
- or long
-term oral toxicity studies were a decrease in food consumption, body weight and /or body weight gain. There were some clinical signs observed including excessive salvation (dog and mice) and hunched posture/hypoactivity (rats), but only the dog showed treatment
-related dose response. In a 28
-day dermal study in rats treated with dodine, no clinical signs were observed in males or females. Body weight, body weight gain, food consumption, hematology and clinical chemistries showed no significant changes. Histopathological adnormalities were limited to the dermal lesions. The incidence and severity of dermal irritation increased with the dose. The established systemic NOAEL was ≥200 mg/kg/day (highest dose tested, LOAEL could not be determined). Based on severe dermal irritation the dermal LOAEL was 50 mg/kg/day (lowest dose tested, NOAEL could not be identified). **5. Chronic Toxi** **city** i. Chronic toxicity and oncogenicity was evaluated in the rat, mouse and dog. The rat chronic toxicity and oncogenicity was conducted with dose levels of 0, 200, 400, and 800 ppm (Male: 0, 10, 20, and 42 mg/kg/day; Female: 0, 13, 27, and 54 mg/kg/day). The NOAEL was 20 mg/kg/day based on decreased body weight gain (LOAEL = 42 mg/kg/day for males and 54 mg/kg/day for females). There was no evidence of carcinogenicity in this study.6 ii. Amouse chronic toxicity study was conducted with dose levels of 0, 200, 750, and 1500 ppm (Males: 0, 29, 110, and 225 mg/kg/day; Female: 0, 38, 136, and 277 mg/kg/day). The NOAEL was 110 or 38 mg/kg/day for males or females, respectively, based on decreased body weight, body weight gain, and food consumption. There was also no evidence of carcinogenicity in this study. iii. Chronic toxicity was investigated in dogs using dose levels of 0, 2, 10, and 20 mg/kg/day. The NOAEL of 10 or 2 mg/kg/day for males or females was based on decreased food consumption, and decreased weight gain. There were no treatment
related effects in hematology, clinical chemistry, urine analysis, ophthalmoscopic examinations, organ weights, gross
- or histopathology in either sex. **6. An**  **imal Metabolism** The metabolic pathway of dodine appears to be similar in animals and plants. In rats dodine was rapidly absorbed, distributed, metabolized and excreted at all dosing levels without significant gender differences. The major routes of excretion for dodine are through urine and feces with a total recovery of the administered dose. After 5 days post
-exposure 40 to 45% of the dose was excreted in the urine, and 48 to 60% in the feces. The key metabolic route involved is a β

–oxidation pathway similar to medium
- and long
-chain fatty acid. Oxidation takes place by forming intermediate products with shorter chain lengths, apparently 2 carbon atoms at a time, until the terminal metabolites, guanidine or urea, are formed and then eliminated in the urine. Four metabolites were identified in the urine with the most common being an alcohol derivative of dodine. Dodine was not identified in the urine, but found in the feces. Total C 14

-recovery after 5 days ranged from 94 to 102% of the administered dose. Only a small amount (≤3.4%) of the administered dose was found in tissues, mainly in the gastrointestinal tract (0.16 to 1.1%), muscle (0.02 to 0.61%), and skin (0.06 to 0.21%). **7**

. **Metabolite Toxicology** There are no metabolites of toxicological concern, and therefore no metabolites need to be included in the tolerance expression and require regulation. **8. Endocrine Disruption**  Special studies investigating potential estrogenic or other endocrine effects of dodine have not been conducted. However, in
-life data from the available toxicology studies for dodine do not indicate that dodine is an endocrine disruptor. Specifically, endocrine organ weights (e.g., thyroid, testes, ovaries, pituitary from the two
generation study) were not adversely affected by dodine. M ilestones of sexual development were not affected by dodine, and reproduction was not adversely affected. Based on these observations, there is no evidence to suggest that dodine has an adverse effect on the endocrine system.7

**C. Ag** **gregate Exposure 1.**  **Dietary**

**Exposure** A tolerance is proposed for residues of dodine in or on stone fruits (Group 12), tree nuts (Group 14
- except almond hulls), and almond hulls

. For the purpose of assessing the potential dietary exposure (food + water) for these proposed tolerances, an exposure assessment was conducted using Exponent’s Dietary Exposure Evaluation Model (DEEM

– FCID version 2.16), consumption data derived from the 1994
- 1998 USDA Continuing Surveys of Food Intake by Individuals (CSFII), dodine residues at proposed tolerance levels, DEEM default processing factors, percent crop treated values for registered uses (100% for proposed crops), and an Estimated Drinking Water Concentration (EDWC) point estimate for drinking water contribution. **i. Food** 
a. Acute Dietary Exposure. No acute dietary assessments were conducted since no toxicological endpoint attributable to a single exposure was identified in the available toxicology studies, including the rat and rabbit developmental studies. b. Chronic Dietary Exposure. The chronic dietary endpoint is based upon the NOAEL of 2 mg/kg/day from the one-year dog study, and an uncertainty factor of 100 (10X for inter
-species extrapolation and 10X for intra
-species variation and 1X FQPA Safety Factor). Therefore, the chronic Population Adjusted Dose (cPAD) was calculated as 0.02 mg/kg/day. The chronic dietary exposure estimate for the overall US population is 3.4% of the cPAD of 0.02 mg/kg/day. Children 1
-2 years old, the most exposed population subgroup, utilize 20.4% of the cPAD. The chronic exposure estimates for the overall US population and 32 population subgroups, including infants and children, were less than 21 % of the cPAD. Based on these exposure estimates, AGRIPHAR concludes that there is reasonable certainty of no harm for the use of dodine on stone fruits and tree nuts

. **ii**

. **Drinking Water** Because of its high soil adsorption, and given the application pattern of dodine (applied to full crop canopy), its potential to reach surface and/or ground water is very limited. Therefore exposure via drinking water is negligible. There are no monitoring data for dodine, so Estimated Drinking Water Concentrations (EDWC) were calculated using FIFRA Index Reservoir Screening Tools (FIRST) to estimate dodine concentrations in surface water, and also using the Screening Concentration In Ground Water (SCI
-GROW) model for estimates in ground water. E PA calculated a chronic EDWC value of 4 ppb and 0.08 ppb for surface and ground water, respectively, assuming the maximum use rate of 13 lbs a.i/acre/year based on the application rate for peaches, pecans, and walnuts. This annual application rate is twice the rate of the presently used or proposed for stone fruits and tree nuts (label8

range from 3.9 to 7.8 lbs a.i./acre/year). However, worst
-case estimated dodine residues of 4 μg/L in drinking water were included in the chronic dietary exposure assessment

. **2. Non** **- Dietary Exposure**  Not applicable

. There are no current non-food uses for dodine registered under FIFRA, as amended, and no non
-food uses are proposed for dodine. **D. Cumulative Effects**  To our knowledge there are currently no available data or other reliable information indicating that any toxic effects produced by dodine would be cumulative with those of other pesticides; thus only the potential risks of dodine have been considered in this assessment of its aggregate exposure. **E. Safety** 

**Determination 1.**  **US Population** No acute dietary assessment was conducted because there is no toxicological endpoint attributable to a single exposure. Aconservative chronic exposure analysis was conducted, using tolerance level residues, with percent crop treated information for the registered crops obtained by EPA
-BEAD (apricots = 1%, apples = 5%, bananas = 100%, cherries = 5%, nectarines = 1%, peaches =1 %, peanuts = 100%, pears = 10%, pecans = 5%, plums = 1%, walnuts = 5%), and no adjustment for tree nuts other than walnuts and pecans (100% treated). The overall chronic dietary exposure (food + water) to dodine is low, accounting for 1. 7% to 20.4% of the cPAD, depending on the population subgroup. The chronic exposure for the general US population is 0.000685 mg/kg/day, which uses 3.4% of the cPAD (0.02 mg/kg/day). The most sensitive population subgroup, children 1 to 2 years of age, have a chronic exposure (food + water) of 0.004081 mg/kg/day, which utilizes only 20.4% of the cPAD. Based on the lack of acute toxicity and the chronic exposure analyses, AGRIPHAR concludes that there is reasonable certainty that no harm will result from acute and chronic exposure to dodine. **2. Infants and Children**  The toxicology database for dodine regarding potential prenatal and postnatal effects in children is complete according to existing Agency data requirements and does not indicate any developmental or reproductive concerns. The developmental toxicity studies in rats and rabbits revealed no increased sensitivity of rats or rabbits to in
-utero exposure to dodine. The 2
-generation reproduction study did not reveal any increased sensitivity of rats to in
-utero or postnatal exposure to dodine. Furthermore, none of the other toxicology studies revealed any data demonstrating that young9

ani mals were more sensitive to dodine than adult animals. The data taken collectively clearly demonstrate that application of a Food Quality Protection Act (FQPA) uncertainty factor for increased sensitivity of infants and children is not necessary for dodine

. **F. International Tolerances**  At present, there are Codex maximum residue limits (MRLs) established for dodine on cherries at 3 ppm, nectarines, peaches and pome fruits at 5 ppm. There is no Codex maximum residue limit (MRL) established for dodine on tree nuts

. Therefore, international harmonization is not an issue at this time.