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EPA REGI STRATION DIVISION COMPANY NOTICE OF FILING FOR PESTI CI DE PETI TI ONS PUBLISHED IN THE FEDERAL REGI STER EPA Registration Division contact: Laura Nollen, (703) 305

- 7390 Petition Number 1E7882 EPA has received a pestic ide petition , PP# 1E7882, from Interregional Research Project Number 4 (IR
- 4 ), IR
- 4 Project Headquarters, Rutgers , The State University of New Jersey , 500 College Road East, Suite 201 W, Princeton, NJ 08540 proposing, pursuant to section 408(d) of the Fed eral Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180. 431 by establishing a tolerance for residues of clopy ralid : (3,6

- dichloro

- 2
- py

rindinecarboxylic acid) in or on the raw agricultural commodity apple at 0.05 parts per mil lion (ppm) ; b rassica , leafy greens, subgroup 5B at 5.0 ppm; rapeseed subgroup 20A, except g old of pleasure, seed at 3.0 ppm; rapeseed subgroup 20A, except g old of pleasure, meal at 6.0 ppm; rapeseed subgroup 20A, except g old of pleasure, forage at 3.0 ppm
. Upon the approval of the aforementioned tolerances, IR
- 4 additionally

proposes to remove established tolerances for residues of the herbicide, clopy ralid, in or on the following raw agricultural commodities: canola, seed at 3.0 ppm; canola, meal at 6.0 ppm; flax, seed at 3.0 ppm; flax, meal at 6.0 ppm; rapeseed, seed at 3.0 ppm; rapeseed, forage at 3.0 ppm; and mustard greens at 5.0 ppm. EPA has determined that the petition contains data or information 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 me tabolism

. The Agency has previousl y concluded that the nature of the residue in plants and animals is adequatel y understood. Additionally the Agency

has determined that tolerances should be comprised of the parent compound only as no metabolites of toxico logical significance were detected in metabolism studies. 2. Analytical method. Apple: An adequate anal yt ical method is available for enforcement of the tolerance expression in or on food. Dow AgroSciences Method No. ACR 79.5 was utilized to determine r esidues of clopy ralid in apples, fruits and apple fractions in support of the proposed tolerance. This method determines clopy ralid as the methyl ester by

gas chromatography

using electron capture detection. This method has been successfull y validated by EPA and has been published in FDA’s Pesticide Analy tical Manual, Volume II (PAM II).2 3. Magnitude of residues. Apple: IR
- 4 has conducted a magnitude of residue study for clop yralid in/on apple. D ata were collected from twelve field trials conducted over two years in the major apple growing regions of the U.S. At each trial, a single orchard floor broadcast application of the test substance was made to the treated plot 28 to 30 day s before harvest. The application rate was 0.25 lb acid equivalent (a.e.) /A. The applications were made using appropriate spray equipment, and the spray volume was sufficient to provide adequate dispersal of the test substance. Samples were harvested 28 to 30 day s after the application. No detectable residues were found in the treated or untreated apple fruit , or apple juice

. T here was no concentration of the clop yralid residues in apple pomace processed fractions. These data demonstrate that clopy ralid applied to pome fruit in accordance with the proposed use directions wi ll not result in residues exceeding the proposed tolerance. Leafy Brassica Greens Subgroup 5B: Proposed is using the clop yr alid tolerance on mustard greens at 5.0 ppm as surrogate data to support tolerance on Leafy Brassica Greens subgroup 5B. As per EPA CFR 180.41(Crop group tables) mustard greens is representative commodity for Leafy Brassica Greens subgroup 5B. Rapeseed Subgroup 20A, except camelina ( gold of pleasure ) : Clopy ralid has tolerances for c anola for meal and seed at 6.0 ppm and 3.0 ppm, respe ctivel y. The final rule for revision to the new Oilseed crop group 20 was published in F ederal Register/Vol.75, No.235, on December 8, 2010. All of the members in the Rapeseed subgroup 20A can obtain a tolerance based on rapeseed. Canola is the primary ty pe of rapeseed grown in the United States. The nature of the residues of c lopy ralid is adequately

understood, and an acceptable anal yt ical method is availa ble for enforcement purposes. B. Toxicological Profile 1. Acute toxicity

. For acute risk asses sments, EPA has established an acute reference dose (aRfD) of 0.75 mg/kg/day for all population sub

- groups including infants and children. The aRfD is based on the developmental toxicity study on rats with a NOAEL of 75 mg/kg/day and uncertainty

factor of 100 accounting for both interspecies extrapolation (10x) and intraspecies variability (10x). A decrease in weight gain was observed during gestation of 6

- 9 day s at a maternal L OAEL of 250 mg/kg/day . EPA determined that an additional factor to protect in fants and children was not appropriate. Clopy ralid has low acute toxicity . The rat oral LD50 is 5,000 mg/kg or greater for males and females. The rabbit dermal LD50 is >2,000 mg/kg and the rat inhalation L C50 is >1.0 mg/L air (the highest attainable c oncentration). In addition, clopy ralid is not a skin sensitizer in guinea pigs and is not a dermal irritant in rabbits. Technical clopy ralid is an ocular irritant, but ocular exposure to the technical material would not normally be expected to occur to i nfants or children or the general public. End use formulations of3

clopy ralid have similar low acute toxicity profiles and most have low ocular toxicity as well.] 2. Genotoxicty

. [ Clopy ralid is not genotoxic. The following in vitro and in vivo studies h ave been conducted and all were negative for genotoxic responses: Ames bacterial mutagenicity

assay (with and without exogenous metabolic activation); Host

Mediated assay

In vivo cy

tog enetic test, rat; In vivo cy togenetic test, mouse; In vivo dominant lethal test, rat; In vitro unscheduled DNA sy nthesis assay

in primary

rat hepatocy te cultures; In vitro mammalian cell gene mutations assay in Chinese hamster ovary cell cultures (with and without exogenous metabolic activation). 3. Reproductive and develop mental toxicity. Developmental toxicity was studied using rats and rabbits. The developmental study i n rats resulted in a developmental NOEL of >250 mg/kg/day (a maternally toxic dose) and a maternal toxicity NOEL of 75 mg/kg/day . A 1974 study in rabbits revealed no evidence of developmental or maternal toxicity at 250 mg/kg/day ; thus, the developmental and maternal NOEL was >250 mg/kg/day . A more recent study in rabbits (1990) resulted in developmental and maternal NOELs of 110 mg/kg/day based on matern al toxicity at 250 mg/kg/day . Based on all of the data for clopy ralid, there is no evidence of developmental toxicity at dose levels that do not result in maternal toxicity . In a 2
- generation reproduction study in rats, pups from the high dose group whic h were fed diets containing clop yr alid had a slight reduction in body

weight during lactation and an increase in liver weights in F1a and F1b weanlings. The NOEL for parental sy stemic toxicity was 500 mg/kg/day . There was no effect on reproductive parame ters at >1,500 mg/kg/day nor was there an adverse effect on the morphology , growth or viability of the offspring; thus, the reproductive NOEL is >1,500 mg/kg/day

. 4. Subchronic toxicity. The following studies have been conducted using clopy ralid. In a r at 90
- day

feeding study , Fischer 344 rats were fed diets containing clopy ralid at doses of 5, 15, 50 or 150 mg/kg/day with no adverse effects attributed to treatment. In a second study , Fischer 344 rats were fed diets containing clopy ralid at doses of 300 , 1,500 and 2,500 mg/kg/day . Effects at the highest doses were decreased food consumption accompanied b y decreased body weights and weight gains in both males and females. Slightly increased mean relative liver and kidney weights were noted in males of all doses and in females at the top 2 doses. Because there were no other effects, the kidney

and liver weight effects were judged as being adaptive rather than directly toxic. The no

- observed

- adverse

- effect level (NOAEL) was 1,500 mg/kg/day for males and females. The no

- observed

- effect level (NOEL) was 300 mg/kg/day for females. In a mouse 90

- day feeding study , B6C3F1 mice were fed diets containing clopy ralid at doses of 200, 750, 2,000 or 5,000 mg/kg/day . A slight decrease in body weight occurred at th e top dose in both sexes. The liver was identified as the target organ based on slight increases in liver weights and minimal microscopic alterations at the higher dose levels. The liver changes were considered to be reversible and adaptive. The NOEL fo r males was 2,000 mg/kg/day and for females was 750 mg/kg/day . In a 180
- day feeding study, beagle dogs were fed diets containing clop yr alid at doses of 15, 50 or 150 mg/kg/day ; there were no adverse effects. In a second dietary study , dogs also were fed4

diets containing clop yr alid at doses of 15, 50 or 150 mg/kg/day ; the onl y effect was an increase in the mean relative liver weight in females at the 150 mg/kg/day . In a 21
- day dermal study , clopy

ralid was applied b y repeated dermal application to New Zeal and White rabbits at dose levels up to 1,000 mg/kg/day . Treatment produced no sy stemic effects. 5. Chronic toxicity. For chronic dietary risk assessments, EPA has established a chronic reference dose (cRfD) of 0.15 mg/kg/day for all population sub

- group s. The cRfD is based on the 2

- year combined chronic feeding

- carcinogencity study in rat s with a NOAEL of 15 mg/kg/day and uncertainty factor of 100 accounting for both interspecies extrapolation (10x) and intraspecies variability (10x). An increase in ep ithelial hy perplasia and thickening of the limiting ridge of the stomach was observed in both sexes with a L OAE L of 150 mg/kg/day . No tumorigenic response was present. EPA determined that an additional factor to protect infants and children was not appropriate. Clopy ralid has been classified as “not likel y” to be a human carcinogen based on no evidence of carcinogencity in rats and mice and no evidence of genotoxicity in an acceptable mutagenicity studies. Thus, an exposure assessment to address cancer risk is not required. 6. Animal metabolism. Disposition and metabolism of clopy ralid were tested in male and female rats at a dose of 5 mg/kg (oral). The majority of a radioactive dose was excreted in 24 hours of all dose groups through urine. Fecal e limination was minor. Detectable levels of residual radioactivity were observed in the carcass and stomach at 72 hours post

- dose. HPL C and TL C anal ys is of urine and fecal extracts showed no apparent metabolism of clopy

ralid. Following oral administrati on, clopy ralid was rapidly

and completel y eliminated from goats, chickens and sheep. In goats and sheep, the majority of the administered dose was excreted in the urine. This residue was found to be mostly unchanged clopy

ralid, and in goats, the remainde r was found to be a gl ycine conjugate of clop yr alid. Residues in milk were low, reaching a plateau of 0.03

- 0.05 mg/kg after 3

- 4 day s. Radioactivity levels in milk fat were below the limit of detection, indicating that there is no tendency for clopy ralid to accumulate in milk fat. Tissue residue levels were also low and comprised unchanged clopy

ralid only . The residues in the eggs and chicken tissues were unchanged clopy ralid. Based on the ruminant and poultry nature of residue (NOR) studies, the residu e definition for animal tissue is clopy ralid, the parent compound. In animal feeding studies, calves fed clop yralid at levels as high as 1,000 ppm showed no ill, effects due to ingestion of the chemical. Additionally , no difference is observed between the control and treated groups in weight gain and feed consumption. After withdrawal from treated feed, residues in all tissues diminished rapidly from the levels found after feeding clop yralid at 1,000 ppm for 28 days. At the levels of herbicide that wou ld be expected in grains used at cattle feed, no residues would occur above the 0.05 ppm level.5 7. Metabolite toxicology

. Following oral administration in the rat, clop yralid was rapidly and completel y (>80%) absorbed and excreted quantitativel y unchange d in the urine. There were no differences in distribution of radioactivity between dose rates, sex, route (oral vs. iv) or frequency of administration. Clopy ralid was not metabolized in the rat. The Residue of Concern (ROC) in plant and animal products is the parent compound, clopy

ralid. 8. Endocrine disruption

. There is no evidence to suggest that clop yr alid has an effect on the endocrine sy stem. C. Aggregate Exposure 1. Dietary exposure. Dietary exposure to US
- general population and sensitive popu lation subgroups was assessed from all clopyralid currently listed uses, plus the newly proposed use on apple orchards , Rapeseed Subgroup 20A except camelina (gold of pleasure), and Leafy

Brassica Greens Subgroup 5B

. Water from direct and indirect exposur e was also included in the dietary exposure and risk assessment. i. Food. Tolerances are established for residues of the herbicide, clopy ralid (3,6

- dichloro

- 2
- py

ridinecarboxylic acid) in or on the raw agricultural commodities and are published in 40 CFR Section 180.431. Parent clopy ralid, only , is the residue definition in animal and plant commodities. Tolerances have been proposed for the residues of clopy ralid in or on apple, raw and processed commodities at 0.05 ppm. Additional tolerances are propos ed for Rapeseed Subgroup 20A except camelina (gold of pleasure), and Leafy Brassica Greens Subgroup 5B. These proposed tolerances are adequate to cover the highest expected field residues from the labeled use of clopy ralid. In conducting the acute and chronic dietary assessments, Dow AgroSciences used the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID, Version 2.0) which incorporates food consumption data as reported in the CSFII Survey

1994
- 1996 and 1998. A conservative anal ys is (Tier 1) was performed with the assumptions that 100% of crops with approved and proposed uses of clopy ralid would be treated with the pesticide and that the residues would be present at the tolerance levels. Based on these conse rvative assumptions and using an aRfD of 0.75 mg/kg/day , for the U.S. general population, the Tier I acute dietary exposure at the 95th percentile from food to clopy ralid was estimated to be 0.034 mg/kg/day, or 4.6% of the aPAD for the U.S. population; and 0.0 70 mg/kg/day , which represents 9. 3 % of the aPAD for children (1

- 2 ye ars), the population sub

- group predicted to be potentially most exposed. Adverse effects are not expected for exposures utilizing <100% of the aPAD , therefore, acute dietary exposure and risk for the general U.S. population and children are well within the acceptable levels. Based on these conservative assumptions and using an cRfD of 0.15 mg/kg/day , for the U.S. general population, the Tier I chronic dietary exposure from food to cl opy ralid was estimated to be 0.013 mg/kg/day , or 8.7 % of the c PAD for the U.S. population; and6

0.035 mg/kg/day , or 23. 6 % of the c PAD for children (1

- 2 years), the population sub

group predicted to be potentially most exposed. Adverse effects are not exp ected for exposures utilizing <100% of the cPAD , therefore, chronic dietary exposure and risk for the general U.S. population and children are well within the acceptable levels. ii. Drinking water
. Since the Agency lacks sufficient monitoring data to complete a comprehensive exposure and risk assessment for florasulam in drinking water, drinking water concentration estimates are made on simulation taking into account data on the phy sical characteristics of clopy ralid. Guidance from EPA has indicated th at Tier 1 screening level models, such as FIRST (FQPA Index Reservoir Screening Tool), and SCI

- GROW, may be used to estimate upper - bound pesticide residues in surface water and ground water when assessing potential exposure through drinking water. FIRST i s an extremely

conservative estimate for predicting surface water concentrations, and considers adsorption of the pesticide to soil or sediment, incorporation of the pesticide at application, direct deposition of spray drift into the water body , and degrad ation of the pesticide in soil before runoff and within the water body. In an assessment published in Federal Register: March 24, 2010 (Volume 75, Number 56), FRL

- 8814
- 2] , EPA used FIRST and SCI

- GROW models to estimate the environmental concentration (E EC) for surface water and ground water, respectivel y. The EECs of clop yralid estimated by EPA for ground water is 0.39 parts per billion (ppb) for both acute and chronic exposures. The EECs for surface water were estimated to be 45 ppb for acute exposure and 11.9 ppb for chronic exposure. Estimated environmental concentrations (EEC) of pesticide in surface water were then inputted into DEEM model for estimation of dietary exposure from water both direct and indirect sources. The input of water residues along with food into the DEEM model provides a conservative estimate of the total exposure from food and water sources. When water exposure was aggregated with food, acute dietary exposure was 9. 5 % of the aPAD for children 1

- 2 years, the most highl y expo sed population sub

- group. Additionally , chronic dietary exposure was 23. 8 % of the c PAD for children 1

- 2 years, the most highly

exposed population sub

- group. Therefore, aggregate exposure to clopy ralid in drinking water would not result in unacceptable l evels of human health risk. 2. Non

- dietary exposure

. Clopy ralid is no longer registered for residential turf uses that would result in residential exposure. Thus, the risk from non

- dietary exposure is considered negligible. D. Cumulative Effects Curr ently , no methodologies are available to resolve the complex scientific issues concerning common mechanism of toxicity and cumulative exposure and risk. The U.S.7

EPA has begun a pilot process to study this issue further through the examination of particul ar classes of pesticides. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity , clop yralid does not appear to produce a toxic metabolite produced b y other substances. For the purposes of thi s notice, therefore, EPA has not assumed that clopy ralid has a common mechanism of toxicity with other substances. As such, Dow AgroSciences believes it is appropriate to consider onl y the potential risks of clop yralid in this exposure assessment. E. Saf ety Determination 1. U.S. population. Using the conservative exposure assumptions (Tier I) described above, and based on the completeness and reliability of the toxicity

data, the aggregate exposure (food and water onl y) to clopyralid on registered uses as well as the proposed uses , as determined under the guidance of the FQPA, will utilize 4.7 % of the aPAD for the U.S. population and 2.9% of the aPAD for females 13

- 49 years old. The aggregate exposure (food and water onl y) to clopyralid, on registered u ses as well as the proposed uses as determined under the guidance of the FQPA, will utilize 8.9% of the cPAD from the dietary

exposure for the U.S. population, and 6.5% of the cPAD for females 13

- 49 years old. The calculated exposure was greatest from wat er as estimated by FIRST surface water modeling. Generall y, and under the FQPA, the U.S. EPA has no concern for exposures below 100% of the cPAD . Therefore, there is a reasonable certainty that no harm will result to the general U.S. population from aggr egate exposure to clopy ralid residues from the approved and proposed uses. 2. Infants and children

. In assessing the potential for additional sensitivity of infants and children to residues of clop yralid, data from developmental toxicity studies in rats and rabbits and a multi

- generation reproduction study in the rat are considered. The developmental toxicity

studies are designed to evaluate adverse effects on the developing organism resulting from pesticide exposure during prenatal development. Reprodu ction studies provide information relating to effects from exposure of both parents to the pesticide on the reproductive capability and potential sy stemic toxicity of mating animals and on various parameters associated with the well being of offspring. Th ere was no effect on reproductive parameters at >1,500 mg/kg/day nor was there an adverse effect on the morphology , growth or viability of the offspring. FFDCA section 408 provides that the U.S. EPA may appl y an additional safety factor for infants and children in the case of threshold effects to account for pre

- and post

- natal toxicity and the completeness of the database. Based on the current toxicological data requirements, the database for clop yr alid relative to pre

- and post

- natal effects for children is complete. The EPA determined that an additional FQPA factor to protect infants and children is not required for clop yr alid as there is no indication of increased sensitivity of infants and children relative to adults.8

Thus, based on the completene ss and reliability of the toxicity

data and the conservative exposure assessment, the aggregate exposure (food and water only) to clopy ralid, as determined under the guidance of the FQPA, will utilize 9. 5 % of the aPAD and 23

. 8 % of the c PAD from the dietary exposure for the most sensitive population sub

- group, children 1

- 2 years old. Itis concluded then that there is a reasonable certainty that no harm will result to infants and children from acute

- and chronic

- term aggregate exposures to clopy ralid resi dues from the approved and proposed uses. F. International Tolerances T here are no Codex , Canadian or Mexican M aximum R esidue limits (MRLs) for residues of clop yr alid in or on the requested commodities. International harmonization is therefore not an i ssue for this notification.