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) 347-0263

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 

B1 (a mixture of avermectins containing greater than or equal to 80% 

avermectin B1a (5-O-demethyl avermectin A1) and less than or equal to 20% 

avermectin B1b (5-O-demethyl-25-de(1-methylpropyl)-25-(1-methylethyl) 

avermectin A1)) and its delta-8,9-isomer in or on the raw agricultural commodity 

milk at 0.01 parts per million (ppm) (to be increased from 0.005 ppm). 

Avermectin B1 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, evaporation, 

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 quantification of 0.005 ppm. Both levels are below 
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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 cattle 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. Toxicological Profile

1. Acute toxicity. The data base includes the following studies:

 i. A rat acute oral study with a lethal dose LD50 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 LD50 greater than 80 mg/kg.

 iii. A rabbit acute dermal study with a LD50>2000 mg/kg.

 iv. A rat acute inhalation study with a LC50>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 with 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 and 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 

millimeter (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 marrow 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 toxicity. 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 

reproduction 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/day 
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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 expressed 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 decreased 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, with 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 with 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 photodegradation product found in plant 
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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. Endocrine 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 cycle, 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 studies, 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 

B1a and B1b residues using the Dietary Exposure Evaluation Model DEEMTM 

and food consumption information from United States Department of 

Agriculture’s (USDA’s) 1994 – 1996 Continuing Survey of Feed Intake by 

Individuals (CSFII). Acute dietary exposure to the adult male subpopulation 

was compared to an acute reference 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/kg/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 (RDF) representing the percent of crop not 

treated. Non-detected residues of avermectin B1a were entered into the 

software as 1⁄2 the limit of quantitation (LOQ) and non-detected residues of 

avermectin B1b were entered in as 1⁄4 LOQ since the production ratio of 

B1a:B1b 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 99.9th
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percentile of exposure. For the general U.S. population at the 99.9th

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 99.9th percentile.

For the male subpopulation, chronic exposure was compared to the chronic 

RfD of 0.0012 mg/kg/day from a 2-generation 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 conducted 

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), exposure 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 in 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 milk 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 conducted a risk assessment for adult applicators and postapplication 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, resulted 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 scenarios. 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 abamectin. 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.
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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 establish, 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 assessment.

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 incomplete 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 neurotoxicity 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 guard 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 on 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 than is the case with most pesticides, 
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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 neonatal rhesus monkeys after 14-

days of repeated administration of 0.1 mg/kg/day HDT and in juvenile rhesus 

monkeys after repeated administration 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 LD50 in the adult rat 

and more than 20 times the LD50 in the neonatal rat. The absence of a steep 

dose-response curve in primates 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 toxic, 

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 World 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)

cattle, milk 0.005 mg/kg (ppm)

*these MRLs accommodate external animal treatment.