**Interregional Research Project Number 4 (IR -**  **4)**

4E8312 EPA has received a pesticide petition ( 4E8312 ) from **Interregional Research Project Number 4 (IR** **- 4)**  , **500 College Road East, Princeton, NJ 08540** request ing, pursuant to section 408(d) of the Federal Fo od, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing tolerance s for residues of c lofentezine in or on the raw agricultural commodi ties avocado at 0.3 parts per million (ppm) ; p apay a at 0.3 ppm ; f ruit, pome, group 11

- 10 at 0.5 ppm ; c herry , subgroup 12

- 12A at 1.0 ppm ; p each, subgroup 12

- 12B at 1.0 ppm ; and f ruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F at 1 .0 ppm . Upon the approval of the aforementioned tolerances, IR

- 4 proposes that the existi ng tolerances for apple at 0.5 ppm; pear at 0.5 ppm; cherry

at 1.0 ppm; nectarine at 1.0 ppm; peach at 1.0 ppm; and grape at 1.0 ppm be removed as unnecessary

. EPA has determined that the petition contains data or information regarding the elements set fo rth 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 qualitative nature of clofentezine residues in plants is adequatel y understood. The metabolism of clofentezine has been studied in three crops representative of the use pattern for APOLLO SC: Apples (pome fruit), peache s (stone fruit), and grapes (vines/small fruit). In each case, unchanged clofentezine was the major extractable residue present. Non

- extractable residues (fiber

- bound) were negligible. Minor amounts of 2

- chlorobenzonitrile, the major photo

- degradation prod uct, were detected, predominantly

on the fruit surface. Dissipation of this component may be a significant route in the degradation of clofentezine on the surface of these crops. The nature of the residue in grapes, and in all the other registered crops, i s therefore adequatel y understood. The residue of concern is the parent, clofentezine. 2. Analytical method. An adequate method for purposes of enforcement of the proposed clofentezine tolerance is available. An independent method validation was successf ull y completed, and the method was found acceptable. An extensive database of method validation data using this method on various crop commodities is available. The Limit of Quantitation (LOQ) and Minimum Detection L imit (MDL) were determined to be 0.01 pp m and 0.003 ppm, respectivel y. The method was forwarded to FDA for inclusion in PAM

- II 3. Magnitude of residues. Adequate crop field trial data are available for clofentezine in/on almonds, peaches, nectarines, persimmons, and grapes following application of a SC formulation containing 0.25 lb ai/A. The established tolerances range from 0.02 ppm in walnuts to 5.0 ppm in almond hulls (40 CFR §180.446). The magnitude of residues for the proposed tolerance is adequately understood. The results demonstrate that the maximum residue of clofentezine in or on avocado was 0.0305 ppm, measured2

133 to 140 day s after application (0.25 pounds active ingredient (lb a.i.)/acre).

B. Toxicological Profile 1. Acute toxicity. Clofentezine has a relatively low degree of a cute toxicity and irritation potential. It is classified as toxicity category I II for oral, dermal and inhalation toxicity , and toxicity

category IV for ey e and skin irritation. The acute oral lethal dose (LD 50) of clofentezine was determined to be 5,200 milligrams/kilograms (mg/kg) in rats and mice, 3,200 mg/kg in hamsters, and 2,000 mg/kg in beagle dogs. The acute rat dermal LD 50 was 2,100 mg/kg. Clofentezine is considered to be practically non irritating to ey es and skin but is considered to be a week skin sensitizer in the guinea pig maximization assay

. 2. Genotoxicty. No evidence of genotoxicity was noted in a battery

of in vitro and in vivo studies. Studies submitted included Ames Salmonella and mouse lymphoma gene mutation assay , a mouse micronucle us assay , a rat dominant lethal assay , and a gene conversion and mitotic recombination assay in y east. Therefore, the registrant concludes that clofentezine has no potential to induce genotoxicity

. 3. Reproductive and developmental toxicity. A multigeneration rate reproduction study was conducted at dietary concentrations of 0, 4, 40, and 400 ppm. The parental no observed adverse effect level (NOAEL) was 40 ppm based on slightl y reduced bod y weights, increased liver weights and hepatocellular h ypertroph y at 400 ppm. No treatment
- related reproductive effects were noted at any dose level. In a rat developmental toxicity study , clofentezine was administered by gavage at dose levels of 0, 320, 1, 280 and 3,200 mg/kg/day during gestation day s 6 to 20. Evidence o f maternal toxicity

was noted at 3,200 mg/kg/day and consisted of decreased weight gain, increased liver weights and centrilobular hepatocellular enlargement. No developmental effects were observed at any dose level. In a rabbit developmental toxicity stu dy , clofentezine was administered b y gavage at dose levels of 0, 250, 1,000 and 3,000 mg/kg/day during gestation day s 7 to 28. Slight maternal toxicity

(decreased maternal food consumption and weight gain) and a slight decrease in fetal weight were noted at 3,000 mg/kg/day . Thus, the NOAEL was considered to be 1,000 mg/kg/day for both maternal and developmental effects. 4. Subchronic toxicity. Ina preliminary 90

- day feeding study

designed to select a suitable high dose level for a subsequent chronic rate study , clofentezine was administered to rats at dietary concentrations of 0, 3,000, 9,000 and 27,000 ppm. A significant reduction in weight gain was noted at 9,000 and 27,000 ppm. In addition, a marked, dose

- related hepatomegal y and centrilobular hepatocyt e enlargement was noted in all treatment groups. In a subsequent 90

- day

feeding study , clofentezine was administered to rats at dietary concentrations of 0, 40, 400, and 4,000 ppm. Slightly reduced weight gain, alterations in several clinical pathology parameters, increased liver, kidney and spleen weights, and centrilobular hepatocy

te enlargement were noted at 400 and/or 4,000 ppm. Thus, 40 ppm (2.8 mg/kg/day) was considered to be the NOAEL for this study

.3

Clofentezine was administered to beagle dogs for 90 day s at dietary concentrations of 0, 3,200, 8,000 and 20,000 ppm. Increased liver weights were noted at all dose levels but no histopathological changes nor an y other treatment

- related effects were observed. 5. Chronic toxicity. Ina 12

- month feeding study , clofentezine was administered to beagle dogs at dietary

concentrations of 0, 50, 1,000, and 20,000 ppm. An increase in adrenal and thy

roid weights, as well as moderate hepatotoxicity consisting of minimal periportal hepatocy

te enlargement with cy

to plasmic eosinophilia, hepatomegal y and increased plasma cholesterol, trigl yc erides and alkaline phosphatase levels, were noted at 20,000 ppm. Evidence of slight hepatotoxicity was also noted at 1,000 ppm. Thus, the NOAEL for this stud y was considered to be 50 ppm (1.25 mg/kg/day). In a 27

- month feeding study , clofentezine was administered to rats at dietary concentrations of 0, 10, 40, and 400 ppm. Effects noted at 400 ppm were limited to the liver and thy

roid, primarily

of males, and consisted of increase d liver weights, a variet y of microscopic liver lesions (centrilobular hepatocyte h yp ertroph y and vacuolation, focal cy stic hepatocellular degeneration and diffuse distribution of fat deposits), increased serum thy roxine levels, and a slight but statistica lly significant increase in the incidence of thy roid follicular cell tumors. The NOAEL was considered to be 40 ppm (2 mg/kg/day). Clofentezine was not oncogenic to mice when administered for 2 y ears at dietary concentrations of 0, 50, 500, and 5,000 ppm. Decreased weight gain, increased liver weights, and increased mortality were noted at 5,000 ppm. An increased incidence of eosinophilic or basophilic hepatocy tes was noted at 5,000 ppm, and possibly 500 ppm.Show citation box Numerous studies were conducte d to investigate the mechanism for the increased incidence of male th yroid follicular tumors that was observed in the chronic rat study. These studies suggest that the tumors may have been caused b y increased thyroid stimulating hormone (TSH) levels, which , in turn, resulted from clofentezine's liver toxicity , and were not attributable to a genotoxic mode of action. 6. Animal metabolism. The metabolism, tissue distribution and excretion of clofentezine have been evaluated in a number of species. In all spe cies, almost all of the administered dose was recovered within 24 to 48 hours after treatment, primarily via the feces. The major route of metabolism was found to be ring h ydrox yl ation, sometimes preceded b y the replacement of a chlorine atom with a methyl

- thio group. Blood and tissue levels in the fetuses of pregnant rats that had been treated with clofentezine were much lower than the levels found in the mother, indicating that clofentezine does not readil y pass across the placenta. In addition, less than 1% of the administered dose was absorbed through the skin of rats following a 10

- hour exposure to the end use formulation of clofentezine, APOLLO SC. Following oral dosing of a cow and three goats with 14C

- labeled clofentezine, the residue in milk was id entified as a single metabolite, 4

- hy drox yclofentezine. Similarly, 4

- hydrox yc lofentezine has been shown to be the only metabolite present in fat, liver, and kidney . No unchanged clofentezine or other metabolites were found. Therefore, the4

nature of the res idue in animals is adequatel y understood. The residues of concern in ruminant commodities and milk are the combined residues of the parent, clofentezine, and the 4

- hydrox yclofentezine metabolite. 7. Metabolite toxicology

. There are no metabolites of toxi cological concern and therefore, no metabolites need to be included in the tolerance expression and require regulation. 8. Endocrine disruption

. Except for the thy roid mechanistic studies mentioned above, no special studies have been conducted to investig ate the potential of clofentezine to induce estrogenic or other endocrine effects. However, the standard battery of required toxicity studies has been completed. These studies include an evaluation of the potential effects on reproduction and development, and an evaluation of the pathology of the endocrine organs following repeated or long

- term exposure. Repeated dose studies are generall y considered to be of substantial value as a means for detection of any endocrine effects. However, with the exception of a slightl y i ncreased incidence of th yroid tumors in male rats, no such effects were noted in an y of the repeated dose toxicity studies with clofentezine. The male rat is known to be much more susceptible than humans to the carcinogenic effects resulting f rom thy roid hormone imbalance and/or increased levels of TSH. Therefore, the alterations in thy roid hormone and subsequent th yroid pathological changes, which have been noted following administration of high doses of clofentezine, are considered to be of m inimal relevance to human risk assessment, particularly considering the low levels of clofentezine to which humans are likel y to be exposed. C. Aggregate Exposure 1. Dietary exposure. The chronic dietary exposure estimates from food and drinking water do not exceed HED’s level of concern. The cancer dietary exposure estimates from food and drinking water result in a cancer risk estimate of 2.8 x 10

- 7. Tolerances for bean, snap, succulent, dry , seed; for vegetable, fruiting, group 8; for fruit, pome, group 11; for cherry ; and for fruit, stone, group 12, except cherry have previousl y been established and the updates to the crop grouping is not likely to influence assessment calculations. As avocado is considered minor crops, contribution from these sources i s not likely

to have significant impact on this assessment. i. Food. Clofentezine chronic and cancer dietary risk assessments were previously conducted using the Dietary Exposure Evaluation Model DEEM

- FCIDTM, Version 3.16 which uses food consumption data from the USDA’s NHANES/WWEIA from 2003

- 2008. A description can be found the June 6, 2013 Human Health Risk Assessment (PC Code: 125501; Decision No.: 464564; DP Barcode: D401611). ii. Drinking water
. There are no monitoring data currentl y available for c lofentezine or its residues of concern in drinking water. Estimated drinking water concentrations (EDWCs) were generated b y the Environmental Fate and Effects Division (EFED) using computer modeling methods. Tier II EDWCs were generated to support clofente zine use on almonds, apples, Christmas trees, nectarines, containerized plants, peaches, pears, persimmons, pecans, and walnuts (R. Parker; D404287; 08/03/2012). The surface water EDWCs are based on the USEPA Pesticide Root Zone Model (PRZM) and Exposure Analy sis Modeling Sy stem (EXAMS) using the EXPRESS shell. Estimated groundwater EDWCs were calculated using the screening model SCI

- GROW (Screening Concentrations in Ground Water, version 2.3, 07/29/03). The highest surface water5

EDWCs values are 7.59 ppb ( 1

- in

- 10 y ear acute) and 0.062 ppb (1

- in

- 10 year annual average). The SCI

- GROW groundwater concentration is 0.04 ppb. 2. Non

- dietary exposure

. There are currently no registered residential uses associated with clofentezine; therefore, a residential/non

- oc cupational exposure assessment is not required. As a result, the clofentezine aggregate risk assessment includes only

dietary exposure (food and water). D. Cumulative Effects Unlike other pesticides for which EPA has followed a cumulative risk approach bas ed on a common mechanism of toxicity , EPA has not made a common mechanism of toxicity

finding as to clofentezine and any other substances. For the purposes of this assessment, therefore, EPA has not assumed that clofentezine has a common mechanism of toxic ity with other substances. E. Safety Determination 1. U.S. population. An acute dietary exposure assessment was not performed as no appropriate endpoints were identified from the available clofentezine toxicity studies for the acute dietary

scenario. A so mewhat refined chronic dietary exposure assessment was previousl y performed that directly incorporated potential drinking water residues. The estimated exposure to the general U.S. population resulted in an estimated risk of <1% of the chronic population a djusted dose (cPAD). 2. Infants and children

. The estimated exposure to the highest population subgroup (children 1 < 2 y ears old) resulted in an estimated risk of <1% of the chronic population adjusted dose (cPAD). F. International Tolerances At present, no Canadian, Mexican, or CODEX maximum residue limits (MRLs) are established for clofentezine on avocado. Codex maintains a clofentezine MRLof 0.5ppm set on “stone fruit” which could impact sweet and tart cherries. The tolerance for Fruit, small, vine c limbing, except fuzzy kiwifruit, subgroup 13

- 07F, is set at 1.0ppm. This does not harmonize with the 2.0ppm Codex tolerance. We would like to keep the tolerance at 1.0ppm because several countries including Japan and Korea also maintain a 1.0ppm tolerance and it would create export issues were the tolerance changed.