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

EPA Registration Division contact: Mr. Mark Suarez, (703) 305

- 0120 Jessica Rogala , (703) 3 47

- 0263

Y

- TEX Corporation

[ 3F8200 ]

EPA has received a pesticide petition ( 3F8200) from Y

- TEX Corporation, 1825 Big Horn Avenue, PO Box 1450, Cody, WY 82414 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 the combined residues of the insecticide avermectin B 1 (a mixture of avermectins containing greater than or equal to 80% avermectin B 1a (5

- O

- demethyl aver mectin A 1 ) and less than or equal to 20% avermectin B 1b (5

- O

- demethyl

- 25

- de(1

- methylpropyl)

- 25

- (1

- methylethyl) avermectin A 1 )) and its delta

- 8,9

- isomer in or on the raw agricultural commodity milk at 0.0 1 parts per million (ppm) (to be increased from 0.0 0 5 ppm). Avermectin B 1 is referred to as simply abamectin throughout this document. 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 metabolism. Not applicable

2. Analytical method. The analytical method is titled “Determination of Macrocyclic Lactone Residues in Animal Tissues and Milk,” referenced as Method No. AATM

- R

- 53, Revision 9, Agrisearch Analytical Pty Ltd, August 2011. The method involves mixing the sample with acetonitrile, e vaporation
, filtration, partition, extraction and cleanup with analysis by high performance liquid chromotography (HPLC)

– fluorescence detection. The method is sufficiently sensitive to detect residues at a limit of detection of 0.002 ppm and a limit of q uantification of 0.005 ppm. Both levels are below2

the tolerances proposed. The method has undergone independent laboratory validation as required by PR Notice 96

- 1.

3. Magnitude of residues. A residue study was submitted for dairy cattle milk when cat tle were treated with the maximum dose of a product containing abamectin. Results from the study demonstrate that the highest residues found will not exceed the proposed tolerances when abamectin is applied following the proposed use directions.

B. Toxic ological Profile

1. Acute toxicity. The data base includes the following studies: i. A rat acute oral study with a lethal dose LD 50 of 4.4 to 11.8 milligram/kilogram (mg/kg) males and 10.9 to 14.9 mg/kg females. ii. An acute oral toxicity study in the CF

- 1 mouse with the delta 8,9

- isomer that has LD 50 greater than 80 mg/kg. iii. A rabbit acute dermal study with a LD 50 >2000 mg/kg. iv. A rat acute inhalation study with a LC 5 0 >5.73 mg/liter. v. A primary dermal irritation study in rabbits that showed irritation. vi. A primary dermal irritation study in rabbits that showed no irritation. vii. A primary dermal sensitization study in guinea pigs that showed no skin sensitization potential. viii. An acute oral toxicity study in monkeys w ith a no observed adverse effect level (NOAEL) of 1.0 mg/kg based upon emesis at 2.0 mg.kg.

2. Genotoxicty. The Ames assays conducted with and without metabolic activation were both negative. The V

- 79 mammalian cell mutagenesis assays conducted with an d without metabolic activation did not produce mutations. In an alkaline elution/rat hepatocyte assay, abamectin was found to induce single strand DNA breaks without significant toxicity in rat hepatocytes treated **in vitro** at doses greater than 0.2 millim eter (mm). This **in vitro** dose of 0.2 mm is biologically unobtainable **in vivo**  , due to the toxicity of the compound. However, at these potentially lethal doses, **in vivo** treatment did not induce DNA single strand breaks in hepatocytes. In the mouse bone mar row assay, abamectin was not found to induce chromosomal damage. There are also many studies and a great deal of clinical and follow

- up experience with regard to ivermectin, a closely similar human and animal drug.

3. Reproductive and developmental tox icity. In a 2

- generation study in rats the NOAEL was established at 0.12 mg/kg/day in pups based upon retinal folds, decreased body weight (bwt), and mortality. The NOAELs for systemic and reproductive toxicity were 0.4 mg/kg/day. In the 2

- generations

r eproduction study in rats with the delta 8,9

- isomer, the NOAEL was 0.4 mg/kg/day and the lowest observed adverse effect level (LOAEL) was greater than 0.4 mg/kg/day, highest dose tested (HDT). In an oral developmental toxicity study in the CF

- 1 mouse the maternal NOAEL was 0.05 mg/kg/day3

based upon decreased body weights and tremors. The fetal NOAEL was 0.20 mg/kg/day based upon cleft palates. In an oral developmental toxicity study with the delta 8,9

- isomer in CF

- 1 mice the maternal NOAEL was 0.10 mg/kg /day based upon decreased body weights. The fetal NOAEL was 0.06 mg/kg/day based upon cleft palate. In an oral developmental toxicity study in rabbits the maternal NOAEL was 1.0 mg/kg/day based upon decreased body weights and tremors. The fetal NOAELwas 1.0 mg/kg/day based upon clubbed feet. In an oral developmental toxicity study in rats the maternal and fetal NOAEL was 1.6 mg/kg/day, the HDT. In an oral developmental toxicity study with the delta 8,9

- isomer the maternal NOAEL in CF

- 1 mice that expre ssed P

- glycoprotein was greater than 1.5 mg/kg/day, the highest and only dose tested. No cleft palates were observed in fetuses that expressed normal levels of P

- glycoprotein, but fetuses with low or no levels of P

- glycoprotein had increased incidence of cleft palates.

4. Subchronic toxicity. Subchronic toxicity studies included the following:

i. A rat 8

- week feeding study with a NOAEL of 1.4 mg/kg/day based upon tremors. ii. A rat 14

- week oral toxicity study with a NOAEL of 0.4 mg/kg/day, the HDT. iii. A dog 12

- week feeding study with a NOAEL of 0.05 mg/kg/day based upon mydriasis. iv. A dog 18

- week oral study with a NOAEL of 0.25 mg/kg/day based upon mortality. v. A CD

- 1 mouse 84

- day feeding study with a NOAEL of 4 mg/kg/day based upon decreas ed body weights.

5. Chronic toxicity. A rat 53

- week carcinogenicity feeding study was negative for carcinogenicity, with a NOAEL of 1.5 mg/kg/day based upon tremors. A CD

- 1 mouse 94

- week carcinogenicity feeding study was negative for carcinogenicity, w ith a NOAEL of 4 mg/kg/day based upon decreased body weights. A dog 53

- week chronic feeding study was negative for carcinogenicity, with a NOAEL of 0.25 mg/kg/day based upon mydriasis.

6. Animal metabolism. Rats were given oral doses of 0.14 or 1.4 mg/ kg/day of abamectin or 1.4 mg/kg/day of the delta

- 8,9

- isomer. Over 7 days, the percentages excreted in urine were 0.3

– 1% of the administered dose of abamectin and 0.4% of the dose of the isomer. The animals eliminated 69

– 82% of the dose of abamectin and 94% of the dose of isomer in feces. In rats, goats and cattle, unchanged parent compound accounted for up to 50% of the total radioactive residues in tissues. The 24

- hydroxymethyl derivative of abamectin was found in rats, goats, and cattle treated w ith the compound and in rats treated with the delta

- 8,9

- isomer, and the 3”

- O

- demethyl derivative was found in rats and cattle administered abamectin and in rats administered the isomer. The delta

- 8,9

- isomer has been identified as an abamectin photodegrada tion product found in plant4

products treated with abamectin. When abamectin is applied to livestock as a veterinary product, the delta

- 8,9

- isomer is not present in animal tissues.

7. Metabolite toxicology

. There are no metabolites of concern based on a differential metabolism between plants and animals. The potential hazard of the 24

- hydroxymethyl or the 3”

- O

- demethyl animal metabolites was evaluated in toxicology studies with the abamectin photolytic break

- down product, the delta

- 8,9

- isomer.

8. End ocrine disruption

. There is no evidence that abamectin is an endocrine disrupter. Evaluation of the rat multi

- generational study demonstrated no effect on the time to mating or on the mating and fertility indices, suggesting no effects on the estrous cyc le, on mating behavior, or on male or female fertility at doses up to 0.4 mg/kg/day, the HDT. Furthermore, the range finding study demonstrated no adverse effect on female fertility at doses up to 1.5 mg/kg/day, the HDT. Similarly, chronic and subchronic toxicity studies in mice, rats, and dogs did not demonstrate any evidence of toxicity to the male or female reproductive tract, or to the thyroid or pituitary (based upon organ weights and gross and histopathologic examination). In the developmental stud ies, the pattern of toxicity observed does not seem suggestive of any endocrine effect. Finally, experience with ivermectin in breeding animals, including sperm evaluations in multiple species, shows no adverse effects suggestive of endocrine disruption.

C. Aggregate Exposure

1. Dietary exposure. Not Applicable

i. Food. In support of a previous EPA

- approved tolerance for abamectin in celeriac, an acute assessment was conducted for avermectin B 1a and B 1b residues using the Dietary Exposure Evaluation Model DEEMTM and food consumption information from United States Department of Agriculture’s (USDA’s) 1994

– 1 996 Continuing Survey of Feed Intake by Individuals (CSFII). Acute dietary exposure to the adult male subpopulation was compared to an acute refer ence dose (RfD) of 0.0025 mg/kg/day based on a NOAEL of 0.25 mg/kg/day from a 1

- year dog study and a 100X uncertainty factor (UF). For all other populations (containing females, infants and children) an acute population adjusted dose (PAD) of 0.00083 mg/k g/day was used and reflects an appropriate 300X UF. This tier 3 probabilistic analysis included the entire distribution of field trial residues and percent of crop treated information was incorporated by adding zeroes into the residue distribution file (R DF) representing the percent of crop not treated. Non

- detected residues of avermectin B 1a were entered into the software as 1⁄2 the limit of quantitation (LOQ) and non

- detected residues of avermectin B 1b were entered in as 1⁄4 LOQ since the production ratio o f B 1a :B 1b is 80:20. The acute dietary exposure results for the male (20+ years) population shows that 2.6% of the acute RfD was utilized at the 99.9 th5

percentile of exposure. For the general U.S. population at the 99.9 th percentile, exposure was 13.2% of the acute PAD. The most sensitive subpopulation was non

- nursing infants (<1 year old) with 39.3% of the acute PAD at the 99.9 th percentile. For the male subpopulation, chronic exposure was compared to the chronic RfD of 0.0012 mg/kg/day from a 2

- generati on reproduction study in rats and a 100X UF. A 300X UF was utilized for populations containing females (13+ years old) and infants and children, and the exposures were compared to a PAD of 0.0004 mg/kg/day. Residue values taken from field trials conducte d at maximum application rates and minimum pre

- harvest intervals (PHI) were averaged and incorporated into the assessment. Residue values were adjusted with percent of crop treated information. For the male population (both 13

- 19 years and 20+ years), e xposure was 0.3% of the chronic RfD. The chronic exposure results indicate that the U.S. population utilizes 1.3% of the chronic PAD. The most sensitive subpopulation was non

- nursing infants with 2.9% of the chronic PAD. These results are conservative i n that residue values were generated from field trials with maximum application rates and minimum post PHI. In addition, a significant reduction in residues would be expected as abamectin

- treated commodities travel through food commerce, food preparation and storage. A milk residue study with a Y

- TEX slow

- release product containing abamectin applied dermally to dairy cattle indicates that residue of abamectin in cattle m ilk ranged between <LOD (1 μg/kg) to 4.7 μg/kg from this use.

ii. Drinking water. [ NA

- Remove. The proposed use and increase of tolerances will not affect the drinking water supply.]

2. Non

- dietary exposure

. Abamectin’s registered residential uses include indoor crack/crevice and outdoor application to lawns. For lawn uses, EPA cond ucted a risk assessment for adult applicators and post

application exposure to abamectin using the EPA’s draft Standard Operating Procedures (SOPs) for residential exposure assessments. The highest predicted exposure, oral hand to mouth for children, resu lted in a calculated margin of exposure (MOE) of 14,000. For children’s post

- application exposure to abamectin from indoor crack/crevice products, valid exposure studies demonstrate there is no exposure and therefore no risk for indoor residential scenari os. Short

- and intermediate

- term risk for the registered uses do not exceed EPA’s level of concern. The proposed use by Y

- TEX Corporation on dairy cattle for which the increase in tolerances is requested would not subject children to exposure of abamecti n. Also, adult handlers of the Y

- TEX product will be protected from exposure by wearing rubber gloves and by the physical state of the product.6

i. **Chronic exposure and risk** . Chronic exposures for the residential uses are not expected.

ii. **Short**

**- term**  **and intermediate**

**- term exposure and risk**  . Risk for the registered uses and the proposed use by Y

- TEX Corporation do not exceed EPA’s level of concern.

D. Cumulative Effects

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to est ablish, modify, or revoke a tolerance, the Agency consider “available information” concerning the cumulative effects of a particular pesticide residue and “other substances that have a common mechanism of toxicity.” EPA stated in the Federal Register (FR) document published April 7, 1999, (64 FR 16843)(FRL

- 6070

- 6) that it does not have, at this time, available data to determine whether abamectin has a common mechanism of toxicity with other substances or how to include this pesticide in a cumulative risk a ssessment.

E. Safety Determination

1. U.S. population. Using the exposure assumptions described above and based on the completeness and reliability of the toxicity data base, aggregate exposure levels have been previously calculated for this chemical. The calculations show that chronic dietary exposure is below 100% of the RfD and the predicted acute exposure is below 100% of the acute RfD for all subpopulations. The proposed use on dairy cattle is not expected to have an impact on these calculations.

2. Infants and children

. The Food Quality Protection Act (FQPA)(Public Law 104

- 170) authorizes the employment of an additional safety factor of up to 10X to guard against the possibility of prenatal or postnatal toxicity, or to account for an incomplet e database on toxicity or exposure. EPA has chosen to retain the FQPA safety factor for abamectin based on several reasons including evidence of neurotoxicity, susceptibility of neonatal rat pups, similarity to ivermectin, lack of a developmental neurotox icity study, and concern for exposure to infants and children. EPA has evaluated abamectin repeatedly since its introduction in 1985 and has found repeatedly that the level of dietary exposure is sufficiently low to provide ample margins of safety to guar d against any potential adverse effects of abamectin. In addition, valid exposure studies demonstrate there is no exposure via indoor applications of abamectin products. It is the opinion of Y

- TEX Corporation that the proposed use of abamectin by Y

- TEX o n dairy cattle pastured outdoors will not expose infants and children to additional residues of abamectin. Additionally, there is much more information regarding human risk potential tha n is the case with most pesticides,7

because of the widespread animal

- drug and human

- drug uses of ivermectin, the closely related analog of abamectin. No evidence of toxicity was observed in n e onatal rhesus monkeys after 14

- days of repeated administration of 0.1 mg/kg/day HDT and in juvenile rhesus monkeys after repeated adm inistration of 1.0 mg/kg/day HDT. The comparative data on abamectin and ivermectin in primates also clearly demonstrate the dose response for exposure to either compound is much less steep than that seen in the neonatal rat. Single doses as high as 24 mg /kg of either abamectin or ivermectin in rhesus monkeys did not result in mortality; however, this dose was more than 2 times the LD 50 in the adult rat and more than 20 times the LD 50 in the neonatal rat. The absence of a steep dose

- response curve in prim ates provides a further margin of safety regarding the probability of toxicity occurring in infants or children exposed to abamectin compounds. The significant human clinical experience and widespread animal drug uses of ivermectin without systemically to xic, developmental or postnatal effects supports the safety of abamectin to infants and children.

F. International Tolerances

Abamectin is a broad spectrum insecticide used throughout the world to control pests of livestock, crops, ornamental plants and turf, and household, commercial and industrial use areas. Examples of international tolerances (Maximum Residue Limits) for abamectin residues in cattle tissues are shown below:

i. Australia Maximum Residue Limits (MRLs): MO 0812 cattle, edible offal ( meat byproducts) 0.1 mg/kg (ppm) MF 0812 cattle, fat 0.1 mg/kg (ppm) MM 0812 cattle, meat 0.005 mg/kg (ppm) ML 0812 cattle milk 0.02 mg/kg (ppm)

ii. CODEX Alimentarius MRLs published by the Food and Agricultural Organization (FAO) of the Wor ld Health Organization (WHO); data supplied by the Secretariat of the CODEX Alimentarius Commission, Rome, Italy: cattle, kidney* 0.05 mg/kg (ppm) cattle, liver* 0.1 mg/kg (ppm) cattle, fat* 0.1 mg/kg (ppm) cattle, meat 0.01 mg/kg (ppm) catt le, milk 0.005 mg/kg (ppm) *these MRLs accommodate external animal treatment.