EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: Andrew Ertman; 703

- 308

- 9367

Inter

- Regional Project No. 4 (IR

- 4)

PP #3E8147

EPA has received a pesticide petition ( 3E8147 ) from IR

- 4 Project Headquarters

, 500 College Road East, Suite 201W, Princeton, NJ, 08540 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 a tolerance for residues of acetamiprid including its metabolites and degradates in or on the raw agricultural commodit ies c orn, sweet, kernel plus cob with husks removed at 0.0 1 ppm; c orn, sweet, forage at 15 ppm; and

c orn, sweet, stover at 30 ppm . The petition also proposes to increase the existing tolerances for acetamiprid including its metabolites and degradate s in meat, meat by products, and milk

. Tolerances for cattle, goat, horse, and sheep meat are proposed at 0.30 ppm; cattle, goat, horse, and s heep fat at 0.2 0 ppm; cattle, goat, horse, and sheep meat byproducts at 0.70 ppm; and milk at 0.30 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 no t 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 acetamiprid in pla nts is well understood, having been investigated in eggplant, apples, cabbage, carrots, and cotton.

2. Analytical method. Based upon the metabolism of acetamiprid in plants and the toxicology of the parent and metabolites , quantification of the parent acetamiprid is sufficient to determine residues of concern for enforcement purposes . As a result a method was developed that involves extraction of acetamiprid from crop matrices with a solvent followed by a decantation and filtration and finally analysis by a LC/MS/MS method. For sweet corn mat rices , the respective LOD s and LOQ s were: KCHR

— 0.0029 and 0.0088, forage

— 0.0028 and 0.0084, stover

- 0.0017 and 0.0051. The lowest level of method validation (LLMV) for each sweet corn matrix was 0.01 ppm for acetamiprid. Based on acceptable recoveries, t he analytical method was reliable for the tested matrices.

3. Magnitude of residues. Magnitude of residue was determined in a test s designed to simulate a representative worst

- case exp osure . The trial s were conducted as specified in the Residue Chemistry Guideline s

. Separate magnitude of the residue studies with sweet corn were conducted by the IR

- 4 Project in the U.S. and AAFC in Canada.2

In the IR

- 4 study, magnitude

- of

- residue data were collected from seven field trials. At each trial, the Trt 01 plot was the untreated control. The Trt 02 plot received four foliar applications of the test substance 6

- 8 days apart, except in the GA*14 trial in which the intervals were as short as 4 days. The application rates were in the range 0.053

- 0.057 lb ai/A per application for a total rate range of 0.212

- 0.220 lb ai/A per season. The Trt 03 plot received two foliar applications of the test substance 12

- 16 days apart. The application rates were in the range 0.094

- 0.109 lb ai/A per application for a total rate range of 0.195

- 0.214 lb ai/A per season. All applications were made using appropriate spray equipment, and the spray volume was suffi cient to provide adequate dispersal of the test substance. Sampling started in the untreated control plot and ended in the treated plots. At all the field trials, samples were harvested from the Trt 02 plot one day after the last application and from the Trt 03 plot 5

- 8 days after the last application. Samples were collected from each plot of kernel plus cob with husks removed (KCHR), forage, and stover. Stover was dried after harvest as needed prior to sample collection. (In the New York trial, stalks for stover samples were not cut {harvested} until the sampling date.) No residues above the LLMV were found in samples of KCHR from the Trt 02 plots (4 applications at 0.054 lb ai/acre, PHI=1 day) or from the Trt 03 plots (2 applications at 0.10 lb ai/acr e, PHI=5

- 8 days). Forage samples from the Trt 02 plots had residues in the range 0.42

- 8.1 ppm, whereas forage samples from the Trt 03 plots had residues in the range 0.39

- 10 ppm. Stover samples from the Trt 02 plots had residues in the range 0.12

- 16 ppm, whereas stover samples from the Trt 03 plots had residues in the range 0.21

- 21
ppm. In the Canadian study, magnitude

- of

- residue data were collected from eight field trials. Each field trial site consisted of one untreated control plot and one treated p lot. It was proposed that four foliar broadcast applications of Assail Brand 70 WP (acetamiprid), at a target rate of 60.2 grams a.i./ha, should be applied to the treated plots at a preharvest interval (PHI) of 1+1 days for sweet corn kernel plus cob with husk removed (“K+CWHR”) and forage, and at normal harvest for stover. The actual rate of application ranged from 59 to 63 g a.i./ha/application (total, 239 to 245 g a.i./ha/season), with the exception of Trial ID# 138 where the first three applications w ere made at 83 to 87 g a.i./ha. The fourth spray application was made at 59.5 g a.i./ha (making the total, 315 g a.i./ha/season); which resulted in sweet corn residues that were comparable to samples obtained from the other trials with the exception of th e stover fraction which resulted in higher residues. The actual PHI was 1 or 2 days for the harvest of K+CWHR and forage, and 38 to 89 days for stover. There was a 6 to 8 day retreatment interval between applications.

Residues of acetamiprid were below t he limit of quantification in all sweet corn K+CWHR samples and were 0.23

- 1.1 ppm in the forage samples, each harvested at a 1 or 2 day PHI. Residues of acetamiprid were <0.01 ppm to 0.16 ppm in the stover samples collected at normal harvest, 38 to 89 day s after the last application.

The Trt 02 plots in the U.S. study were treated at a rate and timing similar to the Canadian treated plots. The Trt 03 plots in the U.S. study were treated at a different rate and timing, and the data are intended to show tha t this alternate use pattern will not produce residues above the proposed tolerances based on the data from the samples in the3

Trt 02 plots (U.S.) and the Canadian treated plots.

The sweet corn reports were submitted to EPA in 2011 and assigned the respect ive MRID’s 48590103 and 48590103. The Agency’s residue chemistry review dated March 6, 2012, stated that:

HED has concluded that insufficient data have been submitted to support the use on sweet corn. Although there is evidence to support residue equivalency for the 70% WP formulation and the 30% SG formulation and the combination of trials conducted with these two formulations provide for an adequate number of trials with sufficient geographic variation, it is not possible to combine the two sets due to the significant differences in the stover PHIs between the U.S. and Canadian trials. These differences are reflected in the residue data for stover. In the U.S. trials, residues (and per trial averages) of acetamiprid were <0.01 (<0.01) in K+CWHR, 0.39

- 10 (0.41

- 9.1) in forage, and 0.12

- 21 (0.19

- 20) ppm in stover. In the Canadian trials, residues (and per trial averages) were <0.01 (<0.01) in K+CWHR, 0.23

- 1.1 (0.43

- 0.82) in forage, and <0.01

- 0.35 (0.011

- 0.285) ppm in stover. Furthermore, although the use patterns were similar between the U.S. and Canadian trials for K+CWHR and forage (four applications, 1

- to 2

- day PHI), the U.S. trials performed with the 30% SG formulation included an adjuvant, whereas the Canadian trials using the 70% WP formulat ion did not include an adjuvant. Additional crop field trial data are required to support the proposed uses.

Based on the crop field trial study designs, the U.S. use pattern appears to be less restrictive for stover (1

- or 7

- day PHI in the U.S. vs. harvest at maturity in Canada); therefore, to support the proposed uses on sweet corn, five additional crop field trials must be conducted in the U.S. with the 30% SG formulation and an adjuvant in Zones 1 (1 trial), 5 (3 trials), and 12 (1 trial) to provi de a full set of field trial data for this formulation. Each trial should include an additional side

- by

- side treated plot reflecting application of the 70% WP formulation with an adjuvant. Although the available data suggest that residues are similar fol lowing application according to the four

application/1

- day PHI use pattern and the two

- application/7

- day PHI use pattern, HED recommends that each use pattern be represented in at least two of the required trials.

After r eceiving this review, the IR

- 4 Pro ject planned on conducting the additional field trials ; however, following further consultation with the Agency, it was determined that “...no additional data are needed to support the sweet corn use given the recent change in policy [ i.e., August 13, 2012, ChemSAC memo] regarding adjuvants.”

The nature of the residues of acetamiprid is adequately understood, and an acceptable analytical method is available for enforcement purposes. Based on these results, the establishment of the proposed tolerances is a ppropriate. EPA’s Health Effects Division indicated that a 30 ppm tolerance for stover, a 0.01 ppm for K+CWHR, and a 15 ppm tolerance for forage would be acceptable. They also indicated that the existing livestock tolerances would need to be increased as follows: milk at 0.30 ppm, fat of cattle, goat, horse, and sheep at 0.20 ppm, meat of cattle, goat, horse, and sheep at 0.30 ppm and meat byproducts of cattle, goat, horse, and sheep at 0.70 ppm.4

B. Toxicological Profile

1. Acute toxicity. Acute Toxicity for Technical Acetamiprid

- The acute oral LD

50 for acetamiprid was 146 mg/kg for female Sprague

- Dawley rats and 217 for male rats. The acute dermal LD

- 50 for acetamiprid was greater than 2000 mg/kg in rats. The acute 4 hour inhalation LC

- 50 for acetamiprid was greater than 1.15 mg/L, the highest attainable concentration. Acetamiprid was not irritating to the eyes or skin and was not considered to be a sensitizing agent. The NOEL for acute neurotoxicity was 10mg/kg and no evidence of neuropathy was noted. Acute Toxicity for Formulated Acetamiprid 70WP

- The acute oral LD

- 50 for Acetamiprid 70WP was 944 mg/kg for female Sprague

- Dawley rats and 1107 mg/kg for male rats. The acute dermal LD

- 50 for formulated acetamiprid was greater than 2000 mg/kg in rats. The acute inhalation LC

- 50 (four hour) for Acetamiprid 70WP was determined to be greater than 2.88 mg/L, the highest attainable concentration. Acetamiprid 70WP was concluded to be a mild eye irritant and slight skin irritant. There were no indic ations of skin sensitization for the formulated product. Acute Toxicity for Formulated Acetamiprid 30 SG

– The acute oral LD

- 50 for Acetamiprid 30 SG was 805 mg/kg for female Sprague

- Dawley rats and 886 mg/kg for male rats. The acute dermal LD

- 50 for the formulation was greater than 200 mg/kg in rats. An acute inhalation toxicity test was waived for the formulation due to the non

respirable particle size of the formulation. Acetamiprid 30 SG was found to be a moderate eye irritant and mild skin irritant. There were no indications of skin sensitization for the formulated product.

2. Genotoxicty. [ Based on the weight of the evidence provided by a complete test battery, acetamiprid is neither mutagenic nor genotoxic. The compound was found to be devoid of mutagenic activity (with and without metabolic activation) in Salmonella typhimurium and Escherichia coli (Ames assay). Acetamiprid was also not mutagenic in an in vitro mammalian cell gene mutation assay on Chinese hamster ovary (CHO) cells (HPRT locu s, with and without metabolic activation). Acetamiprid did not induce unscheduled DNA synthesis (UDS) in either rat liver primary cell cultures or in mammalian liver cells in vivo. In an in vitro chromosomal aberration study using CHO cells, acetamiprid was positive when tested under metabolic activation at cytotoxic dose levels; no effect was detected without metabolic activation. Acetamiprid was non

clastogenic in an in vivo chromosomal aberration study in rat bone marrow. It also was negative in an i n vivo mouse bone marrow micronucleus assay.

3. Reproductive and developmental toxicity. In the multi

- generation rat reproduction study a NOEL of 100 ppm was established based on decreased body weight gains and a reproduction NOEL of 800 ppm (highest dos e tested) was established for reproductive performance and fertility. In the rat teratology study the developmental NOEL was 50 mg/kg/day (maternal NOEL of 16 mg/kg/day based on decreased body weight and food consumption) and in the rabbit teratology study the developmental NOEL was 30 mg/kg/day (maternal NOEL of 15 mg/kg/day based on decreased body weight and food consumption). In both the rat and rabbit studies there were no fetotoxic or teratogenic findings.5

A developmental neurotoxicity study in rats with acetamiprid was conducted. The test article was administered orally by gavage to Crl:CD(SD)IGS BR rats once daily from gestation day 6 through lactation day 21 inclusive at dosage levels of 2.5, 10, and 45 mg/kg/day. One female in the 45 mg/kg/day g roup died during parturition on gestation day 23, following delivery of one pup. All other females survived to the scheduled necropsies. No adverse clinical signs were noted. F 0 maternal toxicity was expressed at a dose level of 45 mg/kg/day by a single mortality and reductions in body weight gain and food consumption. No maternal toxicity was exhibited at dose levels of 2.5 and 10 mg/kg/day. F 1 developmental toxicity was expressed at a dose level of 45 mg/kg/day by early postnatal mortality and reduce d post

- weaning body weights. No developmental toxicity was exhibited at dose levels of 2.5 and 10 mg/kg/day. Deficits in auditory startle response occurred in the 45 mg/kg/day group F 1 males and females without concomitant effects in other functional end points (FOB), neuropathology or brain morphometry. Based on the results of this study, the NOAEL for maternal toxicity, developmental toxicity and developmental neurotoxicity is considered to be 10 mg/kg/day.

4. Subchronic toxicity. In the 3

- month dog feeding study a NOEL of 800 ppm (32 mg/kg/day for both males and females) was established based on growth retardation and decreased food consumption.
In the 3

- month rat feeding study a NOEL of 200 ppm (12.4 and 14.6 mg/kg/day respective ly for male and female rats) was established based on liver cell hypertrophy at a dose of 800 ppm.
In the 3

- month mouse feeding study a NOEL of 400 ppm (53.2 and 64.6 mg/kg/day respectively for male and female mice) was established based on increased liver /body weight ratio and decreased cholesterol in females at 800 ppm. A 13 week dietary neurotoxicity study for acetamiprid established a NOEL of 200 ppm (14.8 and 16.3 mg/kg for male and female rats) based on reduced body weight and food consumption decreases at 800 ppm. There was no evidence of neurotoxicity. A 21 day d ermal study in rabbits at dose levels up to 1000 mg/kg/day caused no systemic toxicity, dermal irritation or histomorphological lesions in either sex tested.

5. Chronic toxicity. In the 1

- year dog study, the NOEL was established at 600 ppm (20 and 21 mg/ kg/day for male and female dogs, respectively) based on growth retardation and decreased food consumption at a dose of 1500 ppm.
In the 18

- month mouse study the NOEL was established at 130 ppm (20.3 and 25.2 mg/kg/day for male and female mice) based on gr owth retardation and hepatic toxicity at 400 ppm.
In the 2

- year rat study the NOEL was 160 ppm (7.1 and 8.8 mg/kg/day for male and female rats) based on growth retardation and hepatic toxicity. There were no indications of carcinogenicity in either the ra t or mouse chronic studies.

6. Animal metabolism. The metabolism of acetamiprid is well understood and the primary animal metabolite is IM

- 2

- 1.6

7. Metabolite toxicology

. Testing of IM

- 2

- 1 demonstrated that it is significantly less toxic than the parent acetamiprid and it is not being considered as part of the total toxic residue in plants, therefore no tolerance is being requested by the registrant. The acute oral LD50 of IM

- 2

- 1 is 2543 mg/kg for male rats and 1762 mg/kg for female rats.

8. Endocrine disruption

. Acetamiprid does not belong to a class of chemicals known or suspected of having adverse effects on the endocrine system. Developmental toxicity studies in rats and rabbits and a reproductive study in rats gave no indication that acetamiprid has any effects on endocrine function. The chronic feeding studies also did not show any long

- term effects related to endocrine systems.

9. Immunotoxicity. Dietary administration of acetamiprid to CD

- 1 mice at concentrations up to 900 ppm for four weeks caused a non

- specific toxic response at 300 ppm in females and 900 ppm in both sexes but there was no effect on the immune function, as assessed by the measurement of antigen

- specific, T

- cell dependent antibody formation. The no

- observed

- effect level in mice for immunotoxicity by acetamiprid was therefore greater than 900 ppm (i.e., >128 mg/kg/day in males and > 157 mg/kg/day in females). Dietary administration of acetamiprid to Sprague Dawley rats at concentrations up to 900 ppm for four weeks caused a non

- specific toxic response at 300 ppm in males and 900 ppm in both sexes but there was no effect on the immune function, as assessed by the measurement of antigen

- specific, T

- cell dependent antibody formation. The no

observed

- effect level in rats for imm unotoxicity by acetamiprid was therefore greater than 900 ppm (i.e., >62.9 mg/kg/day in males and > 67.7 mg/kg/day in females).

C. Aggregate Exposure

1. Dietary exposure. A cute and chronic d ietary exposure analyses were conducted by the Agency (HED memo, February 14, 2012) to estimate exposure to potential acetamiprid residues in/on the following crops: asparagus, leafy and head cole crop
group s and turnip greens, citrus crop group, fruiting vegetable crop group, pome fruit
crop gr oup, grapes, leafy vegetables, canola oil, mustard seed, cotton, tuberous and corm vegetable crop group, cucurbit crop group, stone fruit crop group, tree nut crop group (including pistachio)

, berries, bulb vegetables, succulent legumes ( excluding soybeans ), clover, tea , soybeans

, food handling establishments , and sweet corn . The asses sment also included residues in meat, milk, poultry, and eggs usin g the currently established tolerance levels for these commodities . Exposure estimates from drinking water were made based on conservative FIRST and SCI

- GROW modeling.

Even when considering the proposed increases to meat, meat byproducts, and milk tolerances t he additional dietary expos ure from the use of acetamiprid on swee t corn is expected to remain withi n acceptable levels since the dietary assessment was unrefined with assumptions of 100% crop treated and tolerance

- level crop residues for all existing and proposed uses

.

i. Food. Tolerance

- level and 100% crop treated values were used to estimate chronic and acute dietary exposure to potential residue of acetamiprid in food. Chemical

- specific processing factors were used for processed commodities. In the7

absence of chemical

- specific processing factors, DEEM TM Version 7.81 d efault processing factors were used where appropriate.

Chronic dietary exposures to acetamiprid were compared against a chronic population adjusted dose (cPAD) of 0.071 mg/kg bw/day. The cPAD is based on the chronic no observed adverse effect level (NOAE L) of 7.1 mg/kg bw/day from a chronic toxicity/oncogenicity study in rats and a n uncertainty factor of 100. No FQPA safety factor is necessary, so the cPAD is identical to the cRfD.

Chronic exposure (food + drinking water) was conservatively estimated for the overall US population and select population subgroups. Chronic exposure for the overall US populat ion was estimated to be 0.007145 mg/kg bw/d ay, representing 10 % of the cPAD. Exposure for the most highly exposed population subgroup, children 1

- 2 years ol d, was calculated to be 0.023734 mg/kg bw/day, or 33 % of the cPAD.

Acute dietary exposure to potent ial acetamiprid residues was compared agains t the NOAEL of 10 mg/kg bw/day from the developmental neurotoxicity study in rats. Based on the acute NOAEL and an uncertainty factor of 100, the acute RfD (aRfD) is 0.1 mg/kg bw/day. No FQPA safety factor is necessary so the acute population adjusted dose (aPAD) is identical to the aRfD.

Results of the conservative acute dietary (food + water) exposure analysis demonstrate that exposure at the 9 5 th percentile is less than the aPAD for all population groups. For the general US population, the 9 5 th percentile exposure is 0.020582 mg/kg/day or 21 % of the aPAD. For the most highly exposed population subgro up, children 1

- 2 years old, acute dietary exposure at the 9 5 th percentile of exposu re was calculated to be 0.051942 mg/kg/day and represents 5 2% of the aPAD.

ii. Drinking water

. R esidues in surface water were estimated by EPA ( HED memo, February 14, 2012) usi ng the FIRST model and were 95.2 ppb for acute exposure and 26.6 ppb for chronic exposure. The ground water concentra tion was estimated to be 0.035 ppb using the SCI

- GROW model. The surface and ground water es timates were based on a pending use for acetamiprid as a scatter bait for fly control (i.e. maximum use pattern) and it i s assumed that the proposed sweet corn use would not be associated with higher concentrati ons in water . The surface water estimate s of 26.6 ppb and 95.2 ppb

were used in the chronic and acute dietary assessments, respectively, because they provide the most conservative estimate s of dietary exposure via acetamiprid residues in
water.

The proposed use of acetamiprid on sweet corn is n ot expected to increase the Estimated Drinking Water Concentration (EDWC) values.

2. Non

- dietary exposure

. Residential post

- application exposures and margins of exposure (MOEs) for toddlers contacting acetamiprid residues on treated turf or following indoor crack & crevice application were e stimated by EPA in 2008 and carried forward through to the most recent EPA assessment in 2010. Aggregate MOEs for8

toddlers were estimated to be 278 for the short

- term indoor crack & crevice scenario, 484 for the short

- term turf scenario, and 673 for the i ntermediate

- term turf scenario. MOEs greater than 100 indicate that aggregate exposures for toddlers are not of concern.

D. Cumulative Effects

A determination has not been made that acetamiprid has a common mechanism of toxicity with other substances. Acetamiprid does not appear to produce a common toxic metabolite with other substances. A cumulative risk assessment was therefore not performed for this analysis.

E. Safety Determination

1. U.S. population. Based on assessments estimating the aggrega te risk from the current uses of acetamiprid an d th e potential exposure from sweet corn there is a reasonable certainty that no harm will result to the U.S. general population from aggregate exposure to acetamiprid residues.

2. Infants and children

. Base d on assessments estimating the aggregate risk from the current uses of acetamiprid and the pot ential exposure from sweet corn there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to acetamiprid residues.

F. International Tolerances

Acetamiprid is registered for use on food crops in several countries outside the United States. Ther e is a Canadian MRL established for sweet corn (KCHR) at 0.01
ppm. There are no Codex MRLs for acetamiprid.