 

<COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE  (1/1/2007)>

<EPA Registration Division contact: [George T. LaRocca, (703) 305-6100]>

 

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<TEMPLATE:>

<[Dow AgroSciences LLC]>

<[Insert petition number]>

<	EPA has received a pesticide petition ([insert petition number]) from
[Dow AgroSciences LLC], [9330 Zionsville Road, Indianapolis, IN 46268]
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.>

<(Options (pick one)>

<	1. by establishing a tolerance for residues of>

<	2. to establish an exemption from the requirement of a tolerance for>

<	[spinosad] in or on the raw agricultural commodity [fish, shellfish,
mollusks, and crustaceans] at [4.0] parts per million (ppm).  EPA has
determined that the petition contains data or information regarding the
elements set forth in section 408 (d)(2) of the 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. The nature of the residue of spinosad in plants
(apple, cabbage, cotton, tomato and turnip) and animals (goat and
poultry) is adequately understood for the purpose of these tolerances. 
A rotational crop study showed no carryover of measurable spinosad
related residues in representative test crops.>

<2. Analytical method. [There is a practical method (LC-MS_ACPI) for
detecting and measuring levels of spinosad in or on food with a limit of
detection (0.002 ppm) that allows monitoring of food with residues at or
above the level set for these tolerances.  The method had undergone
successful EPA laboratory validation.]>

<3. Magnitude of residues. [In a recent spinosad review  EPA-EFED used
PRZM/EXAMS (R. Parker, 28th July, 2006) to estimate potential spinosad
residues in fish.  In this assessment, EFED assumed 20 consecutive
spinosad applications of 0.1 lb/acre, with a re-treatment interval of 7
days.  No degradation was assumed in the simulation, which used a static
10 cm depth water column with no flow or dilution.  Under these
conditions, EFED estimated a peak spinosad concentration of 489 ppb and
an annual average of 472 ppb.  In estimating possible fish residues, HED
looked to the existing fish bioaccumulation studies on spinosyn A (MRID
43557601) and spinosyn B (MRID 44537734).  In the study with
14C-spinosyn A, a total radioactive residue (TRR) of ~0.5 ppm was
observed in edible tissue following exposure at 19 ppb.  They concluded
that a tolerance of 4 ppm would be appropriate for the combined residues
of spinosyn A and spinosyn D in fish, shellfish, mollusks, and
crustaceans.]>

<B. Toxicological Profile>

<1. Acute toxicity.  [Spinosad has low acute toxicity.  The rat oral
LD50 is 3738 mg/kg for males and >5000 mg/kg for females, whereas the
mouse oral LD50 is >5000 mg/kg.  The rabbit dermal LD50 is >5000 mg/kg
and the rat inhalation LC50 is >5.18 mg/l air.  In addition, spinosad is
not a skin sensitizer in guinea pigs and does not produce significant
dermal or ocular irritation in rabbits.  End use formulations of
spinosad that are water-based suspension concentrates have similar low
acute toxicity profiles.> ]

<2. Genotoxicty. [Short term assays for genotoxicity consisting of a
bacterial reverse mutation assay (Ames test), and in vitro assay for
cytogenetic damage using the Chinese hamster ovary cells, an in vitro
mammalian gene mutation assay using lymphoma cells, an in vitro assay
for DNA damage and repair in rat hepatocytes, and an in vivo cytogenetic
assay in the mouse bone marrow (micronucleus test) have been conducted
with spinosad.  These studies show a lack of genotoxicity.]>

<3. Reproductive and developmental toxicity. [Spinosad caused decreased
body weights in maternal rats given 200 mg/kg/day by gavage in a
teratology study (highest dose tested).  This was not accompanied by
either embryotoxicity, fetal toxicity, or teratogenicity.  The
no-observed-effect levels (NOELs) for maternal and fetal toxicity in
rats were 50 and 200 mg/kg/day, respectively.  A teratology study in
rabbits showed that spinosad caused decreased body weight gain and a few
abortions in maternal rabbits given 50 mg/kg/day (highest dose tested). 
Maternal toxicity was not accompanied by either embryotoxicity, fetal
toxicity, or teratogenicity.  The NOELs for maternal and fetal effects
in rabbits were 10 and 50 mg/kg/day, respectively.  In a two-generation
reproduction study in rats, parental toxicity was observed in both males
and females given 100 mg/kg/day (highest dose tested).  Perinatal
effects (decreased litter size and pup weight) at 100 mg/kg/day were
attributed to maternal toxicity.  The NOEL for maternal and pup effects
was 10 mg/kg/day.>]

<4. Subchronic toxicity. [Spinosad was evaluated in 13-week dietary
studies and showed NOELs of 4.9 mg/kg/day in dogs, 6 mg/kg/day in mice,
and 8.6 mg/kg/day in rats.  No dermal irritation or systemic toxicity
occurred in a 21-day repeated dose dermal toxicity study in rabbits
given 1000 mg/kg/day.]>

<5. Chronic toxicity. [Based on chronic testing with spinosad in the dog
and the rat, the EPA has set a reference dose (RfD) of 0.027 mg/kg/day
for spinosad.  The RfD has incorporated a 100-fold safety factor to the
NOELs found in the chronic dog study to account for interspecies and
intra-species variation.  The NOELs in the chronic dog study were 2.68
and 2.72 mg/kg/day respectively, for male and female dogs.  The NOELs
(systemic) shown in the rat chronic/carcinogenicity/ neurotoxicity study
were 9.5 and 12.0 mg/kg/day, respectively for male and female rats. 
Using the Guidelines for Carcinogen Risk Assessment published September
24, 1986 (51 FR 33992), it is proposed that spinosad be classified as
Group E for carcinogenicity (no evidence of carcinogenicity) based on
the results of carcinogenicity studies in two species.  There was no
evidence of carcinogenicity in an 18-month mouse feeding study and a
24-month rat feeding study at any dosages.  The NOELs in the mouse
oncogenicity study were 11.4 and 13.8 mg/kg/day, respectively for male
and female mice.  A maximum tolerated dose was achieved at the top
dosage level in both of these studies based on excessive mortality. 
Thus, the doses tested are adequate for identifying a cancer risk. 
Accordingly, a cancer risk assess is not required. Spinosad did not
cause neurotoxicity in rats in acute, subchronic or chronic toxicity
studies.]>

<6. Animal metabolism. [There were no major differences in the
bioavailability, routes or rates of excretion or metabolism if spinosyn
A and spinosyn D following oral administration in rates.  Urine and
fecal excretions were almost completed in 48-hours post-dosing.  In
addition, the routes and rates of excretion were not affected by
repeated administration. ]>

<7. Metabolite toxicology. [The residue of concern for tolerance setting
purposes is the parent material (spinosyn A and spinosyn D).  Thus,
there is no need to address metabolite toxicity.]>

<8. Endocrine disruption. [There is no evidence to suggest that spinosad
has an effect on any endocrine system.]>

<C. Aggregate Exposure>

<1. Dietary exposure. [NA]>

™) software with the food commodity intake database which incorporates
food consumption data as reported by respondents in the USDA 1989-1992
nationwide Continuing Surveys of Food Intake by Individuals (CSFII). 
The chronic dietary analysis represents a moderately refined estimate of
dietary exposure using percent crop treated (PCT) estimates, anticipated
residues for meat and milk, and default processing factors.  Inclusion
of fish, shellfish, mollusks, and crustaceans at the proposed tolerance
of 4 ppm gave exposures to the U.S. population of 0.009012 mg/kg/day or
33.4% cPAD.  For children aged one to two years, the estimated exposure
was 0.026893 mg/kg/day or 99.6% cPAD.  When the fraction of fish
potentially exposed was considered, inclusion of spinosad residues had a
minimal effect on the total exposure for any sub-population.  After
inclusion of fish and the fraction potentially exposed to spinosad
residues, the estimated chronic exposure to the U.S. population was
0.008178 mg/kg-bwt/day (30.3% of the cPAD) while exposure to children
aged one to two years of age was 0.025788 mg/kg-bwt/day (95.5% cPAD) for
a difference of 0.000004 mg/kg/day. Adverse effects are not expected for
exposures utilizing less than 100% of the RfD, 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 for spinosad in drinking
water, drinking water concentration estimates are made on simulation
taking into account data on the physical characteristics of spinosad. 

Guidance from EPA has indicated that Tier 1 screening level models, such
as GENEEC and SCI-GROW, maybe used to estimate upper-bound pesticide
residues in surface water and ground water when assessing potential
exposure through drinking water. In a recent assessment (Federal
Register August 6, 2003, FRL-731-3), EPA used FIRST and SCI-GROW models
to estimate the environmental concentrations (EECs) of spinosad in
surface water and ground water.  The EECs for chronic exposures are
estimated to be 2.3 ppb in surface water and 0.037 ppb in ground water.

Estimated spinosad concentrations of 2.3 ppb were incorporated into the
exposure assessment, assuming water from all sources, both direct and
indirect.  The results were that, at a concentration of 2.3 ppb.  The
EPA has concluded that exposure to spinosad from food and water will
utilize 30.3% of the cPAD for the general U. S. population and 95.5% of
the cPAD for children 1-2 years old, the sub-population at greatest
exposure.  Adverse effects are not expected for exposures utilizing less
than 100% of the RfD, therefore, chronic dietary exposure and risk for
the general U.S. population and children are well within the acceptable
levels. ]>

<2. Non-Dietary Exposure. [Spinosad is also currently registered for
outdoor use on turf and ornamentals at low rates of application
(0.04-0.54 lb ai/A) that could result in short-term residential
exposure.  Intermediate-term residential exposure is considered
negligible because residues on turf after 30 days were insignificant. 
Since dermal post-application exposure is not of concern (no identified
toxicological end-point), only hand-to-mouth, object-to-mouth and
incidental ingestion of soil exposures for turf and ornamental uses were
considered for exposure.  The Agency has developed exposure formulas and
estimated doses to theoretically assess residential incidental oral
exposure.  The resulting incidental oral ingestion MOEs from the
residential use of spinosad calculated by the Agency are all below
EPA’s level of concern.  The combined incidental oral MOE is 640 as
posted in Federal Register August 6, 2003 FRL-7317-3.]>

<D. Cumulative Effects>

<[The potential for cumulative effects of spinosad and other substances
that have a common mechanism of toxicity is also considered.  In terms
of insect control, spinosad causes excitation of the insect nervous
system, leading to involuntary muscle contractions, prostration with
tremors, and finally paralysis.  These effects are consistent with the
activation of nicotinic acetylcholine receptors by a mechanism that is
clearly novel and unique among known insecticidal compounds.  Spinosad
also has effects on the gamma aminobatopic acid (GABA) receptor function
that may contribute further to its insecticidal activity.  Based on
results found in tests with various mammalian species, spinosad appears
to have a mechanism of toxicity like that of many amphiphilic cationic
compounds.  There is no reliable information to indicate that toxic
effects produced by spinosad would be cumulative with those of any other
pesticide chemical.  Thus, it is appropriate to consider only the
potential risks of spinosad in an aggregate exposure assessment. 
Spinosad is classified in a mechanism-of-action group of its own for the
purpose of resistance management in insects and for rotation with other
crop protection products. ]>

<E. Safety Determination>

<1. U.S. Population. [EPA has concluded that chronic dietary exposure to
spinosad from food and water will utilize 30.3% of the cPAD for the
general U. S. population.  Adverse effects are not expected for
exposures utilizing less than 100% of the RfD, therefore, chronic
dietary exposure and risk for the general U.S. population and children
are well within the acceptable levels.  Additionally, all MOEs for
short-term risk are below the level of concern. Thus, based on the
completeness and reliability of the toxicity data and the moderately
refined exposure assessment, it is concluded that there is a reasonable
certainty that no harm will result to the U.S. population from
short-term or chronic aggregate exposures to spinosad residues from
current and proposed uses. ]>

<2. Infants and children. [FFDCA Section 408 provides that EPA may apply
an additional safety factor for infants and children in the case of
threshold effects to account for pre-natal and post-natal toxicity and
the completeness of the database.  Based on the current toxicological
data requirements, the database for spinosad relative to pre-natal and
post-natal effects for children is complete.  Furthermore, the NOELs in
the dog chronic feeding study which were used to calculate the RfD of
0.027 mg/kg/day are already lower than the NOELs from the developmental
studies in rats and rabbits by a factor of more than 10-fold.  In the
reproductive study in rats, the pup effects shown at the highest dose
tested were attributed to the maternal toxicity.  Also, no neurotoxic
signs have been observed in any of the standard required studies
conducted.  Therefore, it is concluded that there is no indication of
increased sensitivity of infants and children relative to adults and
that an additional FQPA safety factor is not required.

EPA has concluded that chronic dietary exposure to spinosad from food
and water will utilize 95.5% of the cPAD for children 1-2 years old, the
sub-population at greatest exposure.  Adverse effects are not expected
for exposures utilizing less than 100% of the RfD, therefore, chronic
dietary exposure and risk for the general U.S. population and children
are well within the acceptable levels.  

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sment, it is concluded that there is a reasonable certainty that no harm
will result to infants and children from short-term and chronic
aggregate exposures to spinosad residues from current and proposed
uses.]>

<F. International Tolerances>

<[In 2003, Codex Alimentarius Commission adopted 29 new maximum residue
levels (MRLs) for spinosad and included cotton, almonds, corn, several
fruits and vegetables as well as animal commodities.]

>

