Document ID: EPA-HQ-OPP-2007-0310-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-05-09T04:00Z

EPA Registration Division contact: Sidney Jackson, 703-305-7610

 

Interregional Research Project Number 4 (IR-4)

PP #: 6E7148

-methyl-α- L -manno-pyranosyl)oxy]-13-[[5-(dimethyl-amino)-
tetrahydro-6-methyl-2H-pyran-2-yl]oxy]-9-ethyl-2,3,3a,5a,5b,6,9,10,11,12
,13,14,16a, 16b-
tetradecahydro-4,14-methyl-1H-as-Indaceno[3,2-d]oxacyclododecin-7,15-dio
ne. Typically, the two factors are present at an 85:15 (A:D) ratio. in
or on the raw agricultural commodity, spice crop subgroup 19B, except
black pepper at 1.7 parts per million (ppm), Pineapple at 0.02 parts per
million (ppm), Pineapple process residue at 0.08 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 (0.002ppm) 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. To support the establishment of a tolerance
for spinosad in or on spices, three field trials were conducted on dill
at 3 locations during the 2003 growing season.  At all trials, the
applications were made 9 to 11 days apart and timed so the commercially
mature dill seed could be harvested 13 to 15 days after the last
application. Spinosad was applied to dill at the rate of 0.422 lb a.i./A
at two sites and 0.63 lb a.i./A at a third site.  The measured residues
ranged from less than 0.02 ppm at the NAFTA Region 2 to 0.57 ppm  at
the NAFTA Region 9 site.  Data from this study may be used to support a
tolerance for spinosad on spices, excluding black pepper.           

To support spinosad use on pineapple, three field residue studies were
done in Hawaii, Mexico, and Costa Rica.  In Hawaii two of the three the
trials had five broadcast applications of Success™ made at the rate of
approximately 0.094 lb ai/A for a total of 0.47 lb ai/A. At a third
site, only three applications were made due to the fruit ripening sooner
than expected.  The applications were made 7 to 8 days apart and timed
so that commercially mature pineapples could be collected 6 to 7 days
after the final application.  

In Mexico, three sites were used, “Los Fratellos”, “El Kilateand
Campo Experimental Papaloapan– Isla City, Veracruz State in Mexico. 
At each site Success*,  a suspension concentrate formulation with 240 g
of spinosad/L of product, was applied to pineapple during the 2003
season. The product was applied five times at proposed label rate, 105.4
g a.i./ha (0.44 L/ha), beginning at 28 days before normal harvest with
an interval of approximately 7 days.  Samplings were collected at 3 and
7 days after the last application. Twelve fruits were manually sampled
from each plot.  At sampling, the crowns were removed using a knife. 
Samples were analyzed for residues of spinosad using high performance
liquid chromatography (HPLC) with UV detection. The quantification limit
(LOQ) of analytical method for spinosad (spinosyn A and D) was 0.01
mg/kg (ppm).  Recoveries of ground whole fruit averaged (97(2)% and
(93(3)% for spinosyn A and D, ranging from 82 to 103% (n=18) and from 83
to 102% (n=18) respectively, at the 95% confidence level.  

In Costa Rico residue studies were done at Pindeco, Buenos Aires
(Puntarenas) and El Bosque Guasimo (Limon).  At two sites, Success™
was applied five times beginning 28 days before normal harvest and
repeated at an interval of 7 days at an application rate of 105.4 g
ai/ha (total application of 0.47 lb ai/A).  At site two, Success™ was
applied six times with five applications at a rate of 105.4 g ai/ha and
the sixth application made at 421 g ai/ha for use in the pineapple juice
processing study.  Samples were collected 3 and 7 days after application
5 and 1 day after application 6.  This last sample (1 day PHI) was used
for processing into juice.  Ground whole fruit samples showed residues
ranging N.D. (not detectable) to 0.01 mg/kg for spinosyn A and N.D to
less than 0.01 mg/kg (quantification limit of analytical method) for
spinosyn D.  

In fourteen of the sixteen pineapple samples taken from the three
studies, spinosad residues were less than 0.02 ppm. In one sample,
collected at Papaloapan, Mexico, the spinosad A residue was 0.01 ppm and
at the Pindeco, Costa Rica site, with an application rate of 0.846 lb
a.i./acre, the spinosad residue was 0.02 ppm.  Residues in the juice
samples were less than0.01 ppm.  These data will support the
registration of Success™ in pineapples and also the establishment of a
tolerance for spinosad in pineapple.

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. 

i. Food. [An acute dietary exposure is not required because the Agency
did not identify an acute dietary endpoint that was applicable to
females (13+ years) or to the general US. population, including infants
and children.  EPA has recently assessed the chronic dietary exposure to
spinosad on the existing and proposed crops in an assessment dated
15-September-2005.  In conducting the chronic dietary assessment, EPA
used the Dietary Exposure Evaluation Model (DEEM™) 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.  EPA has concluded that
exposure to spinosad from food and water will utilize 30% of the cPAD
for the general U. S. population and 96% of the cPAD for children 1-2
years old, the sub-population at greatest exposure. That exposure
estimate remains unchanged with the inclusion of spinosad residues in
pineapple and the spice subgroup (excluding black pepper). 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 simulations 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 to 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% of the cPAD for the general U. S. population and 96% of the
cPAD for children 1-2 years old, the sub-population at greatest
exposure. That exposure estimate remains unchanged with the inclusion of
spinosad residues in pineapple and the spice subgroup (excluding black
pepper).  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 MO4Es 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

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nally, 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 96% of the cPAD for children 1-2 years old, the
sub-population at greatest exposure. That exposure estimate remains
unchanged with the inclusion of spinosad residues in pineapple and the
spice subgroup (excluding black pepper).  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.  

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 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.