 

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 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 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 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 DEEM™ 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 ½ the limit of quantitation (LOQ)
and non-detected residues of avermectin B1b were entered in as ¼ 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 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
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, 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.

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,
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.

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