Document ID: EPA-HQ-OPP-2007-0310-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-12-05T05:00Z

SEQ CHAPTER \h \r 1 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

Date:		19-September-2007

Subject:	Spinosad and Spinetoram.  Human-Health Risk Assessment for
Application of Spinosad to Pineapple and the Spice Subgroup (19B, except
black pepper).  

Pesticide Petition #:	6E7148	DP #:	335084

Decision #:	372546	40 CFR	180.495

PC Code:	Spinosad – 110003

Spinetoram – 110008 and 110009

From:		Tom Bloem, Chemist

			PV Shah, Ph.D., Acting Branch Chief

			Registration Action Branch 1/Health Effects Division (RAB1/HED;
7509P)

	and

	

	Breann Hanson, Biologist

	Mark I. Dow, Ph.D., Biologist

	Alternative Risk Integration and Assessment Team/Registration Division
(ARIA/RD; 7505P)

Through:	PV Shah, Ph.D., Acting Branch Chief

		RAB1/HED (7509P)

To:			Daniel Rosenblatt/Sidney Jackson; RM 05

		RD (7505P)

RD of the Office of Pesticide Programs (OPP) requested that HED evaluate
hazard and exposure data and conduct dietary, occupational, residential,
and aggregate exposure assessments, as needed, to estimate the risk to
human health that will result from all registered and proposed uses of
spinosad.  A summary of these findings is provided in this document. 
The risk assessment and dietary exposure assessment were provided by Tom
Bloem of RAB1; the toxicological review was provided by PV Shah of RAB1;
the residue chemistry review was provided by Breann Hanson of ARIA; the
occupational/ residential exposure and risk assessment was provided by
Mark Dow of RAB1; and the drinking water assessment was provided by
Ronald Parker of the Environmental Fate and Effects Division (EFED). 

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc178647649"  1.0  EXECUTIVE
SUMMARY	  PAGEREF _Toc178647649 \h  3  

  HYPERLINK \l "_Toc178647650"  2.0  PHYSICAL/CHEMICAL PROPERTIES	 
PAGEREF _Toc178647650 \h  9  

  HYPERLINK \l "_Toc178647651"  3.0  HAZARD CHARACTERIZATION	  PAGEREF
_Toc178647651 \h  10  

  HYPERLINK \l "_Toc178647652"  3.1  FQPA Assessment	  PAGEREF
_Toc178647652 \h  10  

  HYPERLINK \l "_Toc178647653"  3.2  Endocrine Disruption	  PAGEREF
_Toc178647653 \h  12  

  HYPERLINK \l "_Toc178647654"  4.0  EXPOSURE ASSESSMENT AND
CHARACTERIZATION	  PAGEREF _Toc178647654 \h  13  

  HYPERLINK \l "_Toc178647655"  4.1  Summary of Registered Uses	 
PAGEREF _Toc178647655 \h  13  

  HYPERLINK \l "_Toc178647656"  4.2  Summary of Proposed Uses	  PAGEREF
_Toc178647656 \h  13  

  HYPERLINK \l "_Toc178647657"  4.3  Dietary Exposure/Risk Pathway	 
PAGEREF _Toc178647657 \h  14  

  HYPERLINK \l "_Toc178647658"  4.4  Water Exposure and Risk Pathway	 
PAGEREF _Toc178647658 \h  16  

  HYPERLINK \l "_Toc178647659"  4.5  Dietary-Exposure Analysis	  PAGEREF
_Toc178647659 \h  17  

  HYPERLINK \l "_Toc178647660"  4.6  Residential Exposure and Risk
Pathway	  PAGEREF _Toc178647660 \h  18  

  HYPERLINK \l "_Toc178647661"  4.7  Non-occupational Off-Target
Exposure	  PAGEREF _Toc178647661 \h  19  

  HYPERLINK \l "_Toc178647662"  5.0  AGGREGATE RISK ASSESSMENTS AND RISK
CHARACTERIZATION	  PAGEREF _Toc178647662 \h  19  

  HYPERLINK \l "_Toc178647663"  6.0  CUMULATIVE RISK	  PAGEREF
_Toc178647663 \h  20  

  HYPERLINK \l "_Toc178647664"  7.0  OCCUPATIONAL EXPOSURE	  PAGEREF
_Toc178647664 \h  21  

  HYPERLINK \l "_Toc178647665"  7.1  Handler Exposure	  PAGEREF
_Toc178647665 \h  21  

  HYPERLINK \l "_Toc178647666"  7.2  Post-Application Worker Exposure	 
PAGEREF _Toc178647666 \h  22  

  HYPERLINK \l "_Toc178647667"  8.0  DEFICIENCIES / DATA NEEDS	  PAGEREF
_Toc178647667 \h  23  

  HYPERLINK \l "_Toc178647668"  8.1  Toxicology	  PAGEREF _Toc178647668
\h  23  

  HYPERLINK \l "_Toc178647669"  8.2  Chemistry	  PAGEREF _Toc178647669
\h  23  

  HYPERLINK \l "_Toc178647670"  8.3  Occupational/Residential	  PAGEREF
_Toc178647670 \h  23  

 

1.0  EXECUTIVE SUMMARY

Background:  Spinosad is a fermentation product of Saccharopolyspora
spinosa developed for the control of lepidopterous larvae, leafminers,
and thrips on a variety of crops.  It consists of two closely related
active ingredients, spinosyn A and D, present in an approximate 85:15
ratio (A:D; see Attachment 1 for structures).  Spinosad is currently
registered for application to numerous crops (tolerances ranging from
0.01-200 ppm) and has uses which result in residential exposures (turf
application) .  Spinosad mode of action in insects is thought to be
disruption of nicotinic/gamma amino butyric acid (GABA)-gated chloride
channels.  Spinetoram, a recently registered active ingredient, is also
a fermentation product of Saccharopolyspora spinosa and is structurally
very similar to spinosad (same mode of action; PC code 110008 and
110009).  

The Interregional Research Project No. 4 (IR-4) proposed application of
the wettable-powder (WP) and suspension-concentrate (SC) spinosad
formulations to pineapple and the spice subgroup (19B, except black
pepper) and proposed the establishment of the following tolerances for
the combined residues of spinosyn A and D:  

pineapple	0.02 ppm

pineapple, process residue	0.08 ppm

spice subgroup (19B), except black pepper	1.7 ppm

Hazard Assessment:  Spinosad is classified as Toxicity Category III for
acute oral and dermal toxicity and Toxicity Category IV for acute
inhalation toxicity, primary eye irritation, and primary skin
irritation.  It is not a dermal sensitizer.  No dermal toxicity was seen
at the limit dose in a 21-day dermal toxicity study in rabbits.  For
subchronic toxicity, the primary effects seen in the mouse were
increased vacuolation of cells of the lymphoid organs, liver, kidney,
stomach, female reproductive tract, and epididymis, and less severely in
the heart, lung, pancreas, adrenal cortex, bone marrow, tongue,
pituitary gland, and anemia.  In rats, thyroid follicle epithelial cell
vacuolation, anemia, multifocal hepatocellular granuloma, cardiomyopathy
and splenic histiocytosis were observed.  In dogs, microscopic changes
in a variety of tissues, anemia, and possible liver damage were seen.

Spinosad is not a neurotoxic agent.  No neurotoxic effects were seen at
the limit dose in an acute neurotoxicity study in rats and at doses up
to 42.7 mg/kg/day in a subchronic neurotoxicity study.  It is negative
for mutagenicity in various mutagenicity assays.  It is negative for
carcinogenicity in rats and mice.  In a chronic feeding study in dogs,
increases in serum alanine aminotransferase, aspartate aminotransferase,
and triglycerides levels, and the presence of tissue abnormalities,
including vacuolated cell aggregations, arteritis, and glandular cell
vacuolation (parathyroid) were seen.  Vacuolation of thyroid follicular
cells, increased absolute and relative thyroid weights were observed in
a chronic oral toxicity study in rats.  In mice, rats, and dogs, the
liver, kidney, spleen, heart, thyroid, and bone marrow (anemia) appeared
to be the target organs.

No developmental effects were seen in the rat and rabbit developmental
toxicity studies.  Decreased litter size and survival was observed in
the presence of maternal toxicity (deaths) at the highest-dose tested
(HDT) in a 2-generation reproduction study in rats.  Maternal and
offspring toxicity (deaths) were equally severe, indicating no evidence
of increased susceptibility in the 2-generation reproduction study in
rats. 

In the reproduction/fertility study in rats, spinosad produced
reproductive effects characterized by an increased incidence of dystocia
and/or vaginal bleeding after parturition with associated increases in
mortality in the dams resulting in decreases in litter size, survival
(F2 litters only) and body weights in the offspring.   Male rats
exhibited chronic active inflammation of the prostate gland.  In
addition, the other spinosyn pesticide, spinetoram, produced
reproductive effects in the female rat in the reproduction/fertility
study.  The effects were characterized by evidence of treatment-related
depletion of primordial and/or “growing” ovarian follicles, dystocia
and other parturition abnormalities, late resorptions/retained fetuses
and increased postimplantation loss.  However, there were no
treatment-related gross or microscopic changes in the reproductive
organs, and the sexual maturation of weanlings.  Additionally, parental
toxicity was expressed as cytoplasmic vacuolation of the follicular
epithelial cells of the thyroid with increased levels of TSH and
decreased levels of T4 .  The NOAELs derived from the
reproduction/fertility study are well defined, and together with the
100x UF, will provide adequate protection for potential endocrine
effects.  

There were no major differences in the bioavailability, routes or rates
of excretion or metabolism following a single low oral dose, single high
oral dose, or repeated oral doses in rats.  The feces were the major
route of excretion.  Approximately 70-80% of the dose was absorbed with
approximately 20% of the dose eliminated unabsorbed in the feces.  The
excreted metabolites were the glutathione conjugates of the parent and
O-demethylated Factor A.  Metabolites in the tissues were the N-and
O-demethylated Factor A.  Biliary excretion was rapid.  Metabolites in
the bile included the glutathione conjugates of parent as well as N-and
O-demethylated forms of Factor D.

Dose-Response Assessment and Food Quality Protection Act (FQPA)
Decision:  The HED Hazard Assessment and Policy Committee (HASPOC)
concluded that spinosad and spinetoram should be considered
toxicologically identical.  This conclusion was based on the following: 
(1) spinetoram and spinosad are large molecules with nearly identical
structures and (2) the toxicological profiles for each are similar
(generalized systemic toxicity) with similar doses and endpoints chosen
for human-health risk assessment.  The HASPOC noted that this is not a
cumulative assessment where the concepts of mechanism of toxicity and
potency are evaluated; rather, spinosad and spinetoram should be
considered toxicologically identical in the same manner that metabolites
are generally considered toxicologically identical to parent.  

The toxicological databases for spinosad and spinetoram were evaluated
and endpoints were selected; these endpoints were then compared and, as
stated above, the dose and endpoints were similar.  However, due to
variations in dosing levels used in the spinetoram and spinosad
toxicological studies, the resulting doses/endpoints were not identical.
 Since HED has concluded that spinosad and spinetoram are
toxicologically identical, for each scenario the spinosad and spinetoram
doses chosen for risk assessment were compared and the lower of these
was selected.  Based on evaluation of the spinosad and spinetoram
toxicological databases and the residue assumptions used in the dietary
and residential exposure analyses, the risk assessment team concludes
that the FQPA safety factor (SF) may be reduced to 1x.  Table 1 is a
summary of the toxicological endpoints relevant to the current
assessment.  

Table 1:  Toxicological Endpoints Relevant to the Current Assessment

Exposure Scenario	Dose Used for Risk Assessment	Study and Toxicological
Effects

acute dietary (all populations) 	Toxicological effect attributable to a
single dose was not identified in the spinosad and spinetoram databases.
This risk assessment is not required.

chronic dietary	Oral NOAEL = 2.49 mg/kg/day

chronic RfD and cPAD = 0.0249 mg/kg/day	Chronic Toxicity Study in Dogs
(spinetoram);  LOAEL = M/F 5.36/5.83 mg/kg/day; based on arteritis and
necrosis of the arterial walls of the epididymides in males and  the
thymus, thyroid, larynx, and urinary bladder in females.

short-term inhalation	Oral NOAEL = 4.9 mg/kg/day

LOC for MOEs <100	Subchronic Feeding Study in Dogs (spinosad); LOAEL =
9.73 mg/kg/day based on  microscopic changes in multiple organs,
clinical signs of toxicity, decreases in mean body weights and food
consumption and biochemical evidence of anemia and possible liver
damage.

short-term incidental oral	Oral NOAEL = 4.9 mg/kg/day

LOC for MOEs <100

	dermal - all durations	Short-,Intermediate-and Long-Term dermal risk
assessments are not required for the following reasons: 1) lack of
concern for pre and/or post natal toxicity;  2) the combination of
molecular structure and size as well as the lack of dermal or systemic
toxicity at 1000 mg/kg/day in a 21-day spinosad and spinetoram dermal
toxicity studies in rats which indicates poor dermal absorption; and 3)
the lack of long-term exposure based on the current use pattern.

cancer - oral, dermal, inhalation	Classification:  “Not likely to be
Carcinogenic to Humans” based on the spinosad carcinogenicity studies.
Based on the structural similarity of spinetoram and spinosad and the
similarity of the toxicological database for the currently-available
studies, HED concluded that in the interim, the conclusions concerning
the spinosad chronic oral carcinogenicity studies will be translated to
spinetoram (petitioner indicated they will be submitting spinetoram
carcinogenicity studies in the fall of 2007.  

NOAEL = no-observable adverse-effect level; LOAEL = lowest-observable
adverse-effect level; RfD = reference dose; cPAD = chronic population
adjusted dose; LOC = level of concern; MOE = margin of exposure

Occupational Exposure and Risk Assessment:  Since dermal risk
assessments are unnecessary and since post-application spinosad
inhalation exposure for agricultural workers is considered negligible,
HED evaluated only occupational handler inhalation exposure.  No
chemical-specific data are available with which to assess potential
exposure to pesticide handlers.  Therefore, pesticide handler exposures
were calculated based upon surrogate study data available in the
Pesticide Handler’s Exposure Database (PHED; August 1998).  For
pesticide handlers, it is HED policy to present estimates of exposure
for “baseline;” that is, with a single layer of work clothing
consisting of a long-sleeved shirt, long pants, shoes plus socks, and no
protective gloves as well as for “baseline” plus the use of
protective gloves or other personal-protective equipment (PPE) as might
be necessary.  Since the HIARC only identified inhalation endpoints (no
dermal endpoints were identified), only inhalation exposure assessments
were conducted.  All handler MOEs are ≥1900 and are, therefore, not of
concern to HED.  

Residential and Non-Occupational Exposure and Risk Assessment: 
Spinosad is currently registered for homeowner application to turfgrass
and ornamentals to control a variety of worms, moths, flies, beetles,
midges, thrips, leafminers and fire ants (granular formulation; D284802,
M. Dow and D. Vogel, 15-Aug-2002).  Spinetoram is registered for
homeowner applications to gardens, lawns/ornamentals, and turfgrass for
control of lepidopterous larvae (worms or caterpillars), dipterous
leafminers, thrips, sawfly larvae, certain psyllids and leaf-feeding
beetles, and red imported fire ants (mound application is permitted). 
Therefore, there is potential for residential handler and
post-application exposures to both spinosad and spinetoram.  Since
spinosad and spinetoram control the same pests, HED concludes that these
products will not be used in combination with each other and combining
the residential exposures is unnecessary.  The proposed spinosad
application scenarios are not expected to result in residential
exposure.    

Spinosad:  Since no dermal endpoints were identified and based on the
granular formulation and low vapor pressure for spinosad, residential
handler/applicator/post-application dermal and inhalation were not
conducted.  HED concluded that there is a potential for toddler
short-term non-dietary oral exposures (hand-to-mouth, object-to-mouth,
and soil ingestion).  The resulting combined short-term incidental oral
MOE was 640 and is, therefore, not of concern to HED.  Since HIARC did
not identify an acute dietary endpoint, episodic ingestion of granulars
was not assessed.  

HED notes that the registered fruit fly bait application scenario
permits application to non-crop vegetation and this use may result in
residential exposures.  Based on the application rates (fruit fly bait -
0.0003 lb ai/acre; turf/ornamental - 0.41 lbs ai/acre), HED concludes
that residential exposure resulting from the fruit fly application will
be insignificant when compared to the exposure resulting from the
turf/ornamental application.  Therefore, quantitative analysis of the
residential exposure resulting from the fruit fly bait application was
not performed.  

Spinetoram:  Since no dermal endpoints were identified, only short-term
inhalation risks were assessed for the handlers (postapplication
dermal/inhalation exposure expected to be negligible).  The resulting
MOEs ranged from 4,300,000-8,400,000 and are, therefore, not of concern
to HED.  HED concluded that there is a potential for toddler short-term
non-dietary oral exposures (hand-to-mouth, object-to-mouth, and soil
ingestion).  The resulting combined short-term incidental oral MOEs was
970 and is, therefore, not of concern to HED.  Since HIARC did not
identify an acute dietary endpoint, episodic ingestion of granulars was
not assessed.  

Dietary (food and water) Exposure and Risk Assessment:  As previously
stated, HED concluded that spinosad and spinetoram are toxicologically
equivalent; therefore, dietary exposure to these compounds were
aggregated.  Since both products control the same pest species, HED
concludes that it is unlikely that spinetoram and spinosad will be
applied to the same crop.  Therefore, the dietary exposure analysis did
not calculate a combined spinetoram and spinosad residue for crops. 
Based on the side-by-side spinetoram and spinosad residue data which
indicated that residues of spinosad were greater than or equal to
residues of spinetoram, HED concluded that the spinosad residues are an
acceptable estimate of spinosad or spinetoram residues in/on a crop
(note that the spinosad tolerances were translated to spinetoram).  

 of concern to HED (≤81% cPAD; children 1-2 years old were the most
highly exposed population).

 ≥180 and aggregate chronic (food and water) exposures were ≤81% of
the cPAD; therefore, aggregate exposure to spinosad and spinetoram, as a
result of all registered/proposed uses, is not of concern to HED.  

Environmental Justice Considerations:  Potential areas of environmental
justice concerns, to the extent possible, were considered in this
human-health risk assessment, in accordance with U.S. Executive Order
12898, "Federal Actions to Address Environmental Justice in Minority
Populations and Low-Income Populations," (  HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures. 
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under CSFII and are used
in pesticide risk assessments for all registered food uses of a
pesticide.  These data are analyzed and categorized by subgroups based
on age, season of the year, ethnic group, and region of the country. 
Additionally, OPP is able to assess dietary exposure to smaller,
specialized subgroups and exposure assessments are performed when
conditions or circumstances warrant.  Whenever appropriate, non-dietary
exposures based on home use of pesticide products and associated risks
for adult applicators and for toddlers, youths, and adults entering or
playing on treated areas post-application are evaluated.  Further
considerations are currently in development as OPP has committed
resources and expertise to the development of specialized software and
models that consider exposure to bystanders and farm workers as well as
lifestyle and traditional dietary patterns among specific subgroups.

HED notes that since both spinosad and spinetoram are thought to be
persistent in water and bioaccumulate in fish, the dietary exposure
analysis included residues estimates for fish/shellfish.  The
fish/shellfish residue estimates were based on the total radioactive
residues (TRRs) from a bioaccumulation study corrected for an estimated
water residue derived assuming 10 cm water depth and no inflow/outflow
(no degradation of the compound was assumed).  The dietary assessment
assumed that every fish/shellfish consumed has these conservative
residue estimates.  In addition, HED notes that the fish bioaccumulation
study included residue dissipation data which indicated that TRRs
dropped very quickly when fish were placed in water without any
residues.  Therefore, HED concludes that potential exposure to spinosad
and spinetoram from the consumption of fish as been adequately
accounted.

Recommendations for Tolerances/Registration:  HED concludes that the
toxicological, residue chemistry, and occupational/residential databases
support an unconditional registration and establishment of the following
permanent tolerances for the combined residues of spinosyn A and D: 

Spice, subgroup 19B, except black pepper	1.7 ppm

Pineapple	0.02 ppm

Pineapple, process residue	0.08 ppm



2.0  PHYSICAL/CHEMICAL PROPERTIES

-α-L-mannopyranosyloxy)-13-(4-dimethylamino-2,3,4,6-tetradeoxy-β-D-ery
thropyranosyloxy)-9-ethyl-2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b-h
exadecahydro-14-methyl-1H-8-oxacyclododeca[b]as-indacene-7,15-dione

Spinosyn D: 
(2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bR)-2-(6-deoxy-2,3,4-tri-O-methyl-α-L
-mannopyranosyloxy)-13-(4-dimethylamino-2,3,4,6-tetradeoxy-β-D-erythrop
yranosyloxy)-9-ethyl-2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b-hexade
cahydro-4,14-dimethyl-1H-8-oxacyclododeca[b]as-indacene-7,15-dione

CAS name	Spinosyn A: 
2-[(6-deoxy-2,3,4-tri-O-methyl-α-L-manno-pyranosyl)oxy]-13-[[5-(dimethy
lamino)-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-14-methyl-1H-as-Indaceno[3,2-d]oxa
cyclododecin-7,15-dione

Spinosyn D: 
2-[(6-deoxy-2,3,4-tri-O-methyl-α-L-manno-pyranosyl)oxy]-13-[[5-(dimethy
lamino)-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]o
xacyclododecin-7,15-dione

CAS #	Spinosyn A:  131929-60-7; Spinosyn D:  131929-63-0

Table 3:  Physicochemical Properties of the Technical Grade Test
Compound.

Melting range	Spinosad A: 84-99.5°C

Spinosad D: 161.5-170°C	EPA Fact Sheet

pH (10% slurry of spinosad in water)	7.74

	Density at 20°C	0.512

	Water solubility (ppm)	Spinosad A: 89.4

Spinosad D: 0.495	

	Vapor pressure at 25°C (kPa)	Spinosad A: 3.0 x 10-11

Spinosad D: 2.0 x 10-11

	Dissociation constant (pKa)	not available

	Octanol/water partition coefficient Log(KOW)	

pH 5

pH 7

pH 9	Spinosad A 2.8

4.0

5.2	Spinosad D 3.2

4.5

5.2

	UV/visible absorption spectrum	not available

	

3.0  HAZARD CHARACTERIZATION

A detailed hazard characterization for spinosad was presented in a
previous HED risk assessment (D284803, D. Vogel et al., 15-Aug-2002) and
a summary of the spinosad toxicological profile is provided in the
executive summary.  The HASPOC concluded that spinosad and spinetoram
should be considered toxicologically identical (memo in draft).  This
conclusion was based on the following:  (1) spinetoram and spinosad are
large molecules with nearly identical structures and (2) the
toxicological profiles for each are similar (generalized systemic
toxicity) with similar doses and endpoints chosen for human-health risk
assessment.  The HASPOC noted that this is not a cumulative assessment
where the concepts of mechanism of toxicity and potency are evaluated;
rather, spinosad and spinetoram should be considered toxicologically
identical in the same manner that metabolites are generally considered
toxicologically identical to parent.  

The toxicological databases for spinosad (D284803, D. Vogel et al.,
15-Aug-2002) and spinetoram (D331741, PV Shah et al., 12-Sep-2007) were
evaluated and endpoints were selected; these endpoints were then
compared and, as stated above, the dose and endpoints were similar. 
However, due to variations in dosing levels used in the spinetoram and
spinosad toxicological studies, the resulting doses/endpoints were not
identical.  Since HED has concluded that spinosad and spinetoram are
toxicologically identical, for each scenario the spinosad and spinetoram
doses chosen for risk assessment were compared and the lower of these
was selected.  

3.1  FQPA Assessment

The toxicology databases for spinosad and spinetoram are adequate for
evaluation of the FQPA SF.  The following acceptable studies are
available for spinosad and spinoteram:  developmental toxicity study in
rats, developmental toxicity study in rabbits, and two-generation
reproduction study in rats.  There is no evidence of increased
susceptibility of rat and rabbit fetuses to in-utero exposure to
spinosad or spinetoram.  In the spinosad and spinetoram rat and rabbit
developmental toxicity studies, no developmental toxicity were observed
at dose levels that induced maternal toxicity.  In the spinosad
two-generation reproduction studies, maternal and offspring toxicity
were equally severe, indicating no evidence of increased susceptibility.
 In the spinetoram 2-generation reproduction study, no adverse effects
were observed on the offspring at dose levels that produced parental. 
Therefore, there is no evidence of increased susceptibility and there
are no concerns or residual uncertainties for pre and/or post-natal
toxicity.  In addition, there was no evidence of neurotoxicity in the
acute, subchronic and chronic toxicological studies.  

Based on evaluation of the spinosad and spinetoram toxicological
databases and the residue assumptions used in the dietary and
residential exposure analyses, the risk assessment team concludes that
the FQPA SF may be reduced to 1x.  Table 4 is a summary of the endpoints
used in the current assessment.   



Table 4:  Summary of Toxicological Doses and Endpoints for Spinetoram
and Spinosad for Use in Dietary and Non-Occupational Human Health Risk
Assessments1.

Exposure/

Scenario	Point of Departure	Uncertainty/

FQPA SF	RfD, PAD, LOC for Risk Assessment	Study and Toxicological
Effects

Acute Dietary

(All populations)	Toxicological effect attributable to a single dose was
not identified in the spinosad and spinetoram databases. This risk
assessment is not required.

Chronic Dietary (All Populations)	NOAEL = 2.49 mg/kg/day 	UFA  = 10x

UFH  = 10x

FQPA SF = 1x	cRfD = 0.0249 mg/kg/day

cPAD = 0.0249 mg/kg/day	Chronic toxicity dog (spinetoram); LOAEL = 5.36
mg/kg/day in males/5.83 mg/kg/day in females based on arteritis and
necrosis of the arterial walls of the epididymides in males, and the
thymus, thyroid, larynx and urinary bladder in females.

Incidental Oral Short-Term 

(1-30 days)	NOAEL = 4.9 mg/kg/day 	UFA  = 10x

UFH  = 10x

FQPA SF = 1x

	rLOC for MOE < 100

oLOC for MOE < 100	Subchronic Feeding Study in Dogs (spinosad); LOAEL =
9.73 mg/kg/day based on microscopic changes in multiple organs, clinical
signs of toxicity, decreases in mean body weights and food consumption
and biochemical evidence of anemia and possible liver damage.

Incidental Oral Intermediate-Term 

(1-6 months)	NOAEL = 2.49 mg/kg/day1 	UFA  = 10x

UFH  = 10x

FQPA SF = 1x	rLOC for MOE < 100

oLOC for MOE < 100	Chronic toxicity dog (spinetoram); LOAEL = 5.36
mg/kg/day in males/5.83 mg/kg/day in females based on arteritis and
necrosis of the arterial walls of the epididymides in males, and the
thymus, thyroid, larynx and urinary bladder in females.

Dermal (all durations)	Short-, Intermediate-and Long-Term dermal risk
assessments are not required for the following reasons: 1) lack of
concern for pre and/or post natal toxicity;  2) the combination of
molecular structure and size as well as the lack of dermal or systemic
toxicity at 1000 mg/kg/day in a 21-day spinosad and spinetoram dermal
toxicity studies in rats which indicates poor dermal absorption; and 3)
the lack of long-term exposure based on the current use pattern.

Inhalation Short-Term (1-30 days)	NOAEL = 4.9 mg/kg/day	UFA  = 10x

UFH  = 10x

FQPA SF = 1x	rLOC for MOE < 100

oLOC for MOE < 100	Subchronic Feeding Study in Dogs (spinosad); LOAEL =
9.73 mg/kg/day based on microscopic changes in multiple organs, clinical
signs of toxicity, decreases in mean body weights and food consumption
and biochemical evidence of anemia and possible liver damage.

Inhalation Intermediate-Term (1-6 months)	NOAEL = 2.49 mg/kg/day 	UFA  =
10x

UFH  = 10x

FQPA SF = 1x	rLOC for MOE < 100

oLOC for MOE < 100	Chronic toxicity dog (spinetoram); LOAEL = 5.36
mg/kg/day in males/5.83 mg/kg/day in females based on arteritis and
necrosis of the arterial walls of the epididymides in males, and the
thymus, thyroid, larynx and urinary bladder in females.

Cancer (oral, dermal, inhalation)	Classification:  “Not likely to be
Carcinogenic to Humans” based on the spinosad carcinogenicity studies.
Based on the structural similarity of spinetoram and spinosad and the
similarity of the toxicological database for the currently-available
studies, HED concluded that in the interim, the conclusions concerning
the spinosad chronic oral carcinogenicity studies will be translated to
spinetoram (petitioner indicated they will be submitting spinetoram
carcinogenicity studies in the fall of 2007).  

1  NOAEL = no-observed adverse-effect level.  LOAEL = lowest-observed
adverse-effect level.  UF = uncertainty factor.  UFA = extrapolation
from animal to human (intraspecies).  UFH = potential variation in
sensitivity among members of the human population (interspecies).  FQPA
SF = FQPA Safety Factor.  PAD = population-adjusted dose (a = acute, c =
chronic).  RfD = reference dose (a = acute, c = chronic).  MOE = margin
of exposure.  LOC = level of concern (r = residential, o =
occupational).  N/A = not applicable.

3.2  Endocrine Disruption

EPA is required under the Federal Food Drug and Cosmetic Act (FFDCA), as
amended by FQPA, to develop a screening program to determine whether
certain substances (including all pesticide active and other
ingredients) "may have an effect in humans that is similar to an effect
produced by a naturally occurring estrogen, or other such endocrine
effects as the Administrator may designate."  Following the
recommendations of its Endocrine Disruptor Screening and Testing
Advisory Committee (EDSTAC), EPA determined that there were scientific
bases for including, as part of the program, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system.  EPA also
adopted EDSTAC’s recommendation that the Program include evaluations
of potential effects in wildlife.  For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA authority to
require the wildlife evaluations.  As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).  When the appropriate
screening and/or testing protocols being considered under the Agency’s
EDSP have been developed, there may be additional screening and/or
testing required to better characterize effects related to endocrine
disruption.  

4.0  EXPOSURE ASSESSMENT AND CHARACTERIZATION

residue chemistry summary - D335084, B. Hanson, 11-Sep-2007

dietary exposure analysis - D337531, T. Bloem, 12-Sep-2007

drinking water summary (EFED Memo) - D331271, R. Parker, 28-July-2002

spinosad   SEQ CHAPTER \h \r 1 residential exposure analysis - D284802,
M. Dow and D. Vogel, 15-Aug-2002

spinetoram residential exposure analysis – D325865, K. Lowe,
10-Jul-2007

4.1  Summary of Registered Uses

Spinosad and spinetoram are registered for application to numerous crops
with tolerances for the combined residues of spinosyn A and D (spinosad)
or XDE-175-J, XDE-175-L, ND-J, and NF-J (spinetoram) ranging from
0.01-200 ppm (spinosad - 40 CFR 180.495; spinetoram 40 CFR 180.*** (just
recently registered)).  Spinosad is also registered for homeowner
application to turf/ornamentals and spinetoram is registered for
homeowner application to gardens, lawns/ ornamentals, and turfgrass.

4.2  Summary of Proposed Uses

The petitioner proposed the application of Entrust® (WP; 80% ai; EPA
Reg. No. 62719-282), SpinTor® 2SC (2 lbs ai/gal; EPA Reg. No.
62719-294), and Success® (SC; 2 lb ai/gal; EPA Reg. No. 62719-292) to
the spice subgroup (19B, except black pepper) and pineapple.  For
resistance management, the labels indicate that spinosad should not be
applied more than 3 times in any 30-day period or applied less than 10
days apart.  When applied up to 3 times in succession, spinosad should
be rotated with other insect control products with a different mode of
action.  Table 5 is a detailed summary of the proposed application
scenarios.  

Table 5:  Summary of Directions for Use of Spinosad.

Applic. Timing, Type, and Equip.1	Formulation2

[EPA Reg. No.]	Applic. Rate (lb ai/acre)	Max. No. Applic. per Season
Max. Seasonal Applic. Rate (lb ai/acre)	PHI (days)4	Use Directions and
Limitations3

Spice, Subgroup 19B, Except Black Pepper

Foliar applications during fruiting; ground or aerial equipment; when
pests appear	80% WP [62719-282] 22.8% 2SC [62719-294]   22.8% SC
[62719-292]	0.063-0.156	5	0.45	14	The minimum RTI4 is 10 days.

Pineapple

Foliar applications during fruiting; ground or aerial equipment; when
pests appear	80% WP [62719-282] 	0.063 -0.100	6	0.45	7	The minimum RTI
is 7 days.

	22.8% 2SC [62719-294]   22.8% SC [62719-292]	0.062-0.093	6	0.45	7	The
minimum RTI is 7 days.

1  Ground application may be made through the following types of
irrigation systems:  center pivot, lateral move, end tow, side wheel
roll, traveler, solid set, micro sprinkler or hand mover.

2  Unless otherwise specified, the use directions are from the most
recent labels of the respective formulations.

3  Use directions allow for the use of spray adjuvants. 

4  PHI = preharvest interval; RTI = retreatment interval

4.3  Dietary Exposure/Risk Pathway

Nature of the Residue – Plants, Livestock, and Fish/Shellfish:  Table
6 is a summary of the conclusion made by HED concerning the residues of
concern in plants, livestock, and fish/shellfish following application
of spinosad.  For further information concerning these decisions, see
below and/or refer to the following memorandums:  plants and livestock -
D243816 (G. Herndon, 3-Mar-1998) and D264984 (W. Donovan, 14-Jun-2002);
fish/shellfish - D316078 (T. Bloem, 2-Aug-2006); and water - D316077 (T.
Bloem et al., 2-Aug-2006).  

Plants/Livestock:  The nature of spinosad residues in plants and
livestock is adequately understood based on metabolism studies conducted
with apples, cabbage, cotton, tomatoes, turnips, ruminants (oral and
dermal), and poultry (oral).  HED concluded that the residue of concern
in plants and livestock for risk assessment and tolerance enforcement
purposes are spinosyns A and D (D243816, G. Herndon, 3-Mar-1998;
D264984, W. Donovan, 14-Jun-2002).  For plants, residue levels of
spinosyns A and D declined significantly with increasing PHI (decreased
40-89% as the PHI increased from 0 to 3 days; decreased 86% to
nondetectable as the PHI increased from 0 to 10-48 days).  This decline
was accompanied by incremental increases in nonextractable and polar
14C-residues.  Extensive fractionation and characterization of
nonextractable and polar 14C-residues in selected crops indicated that
most of the radioactivity was degraded to multicomponent residues of low
molecular weight which are subsequently incorporated into natural plant
constituents (D228434, S. Willett, 23-Jan-1997; D243816, J. Herndon,
3-Mar-1998).  The livestock metabolism studies resulted in parent being
the major residue and indicated that metabolism in livestock involved
either the loss of a single methyl group from the N-methyl moiety on the
forosamine sugar and/or the hydroxylation of the macrolide at several
different positions.

Rotational Crops:  Based on the results of the spinosad confined
rotational crop study, the HED Metabolism Assessment Review Committee
(MARC) concluded that the residues of concern in rotational crops are
spinosyn A and D (D243816, G. Herndon, 3-Mar-1998; field rotational crop
data have not been submitted).  The confined study indicated that
residues are incorporated into the general carbon pool.  Spinosyns A and
D were not detected in the rotated crops (wheat, lettuce, and radish;
plant-back intervals (PBIs) of 30, 120, and 365 days).  

Fish/Shellfish:  EFED reviewed a spinosad radiolabeled fish
bioconcentration study which included information concerning the nature
of the residue in fish.  Based on these data, HED concluded that the
residues of concern in fish/shellfish for tolerance setting purposes are
spinosyn A and D; for purposes of risk assessment, HED concludes that
adjustment of the TRRs in the edible tissues from the 19 ppb spinosyn A
bioconcentration study for the EFED water concentration resulting from
the mosquito larvicide use was appropriate (see D316078, T. Bloem,
2-August-2006).  HED notes that these conclusions are appropriate for
the current petitions only and will be reevaluated if the petitioner
alters the aquatic application scenario.



Table 6:  Residues for Tolerance Expression and Risk Assessment.

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

plants	Spinosyn A and D	spinosyn A and D

livestock	Spinosyn A and D	spinosyn A and D

rotational crops	Spinosyn A and D	spinosyn A and D

fish/shellfish1	adjustment of the TRRs in the edible tissues from the 19
ppb spinosyn A bioconcentration study for the EFED water concentration
resulting from the mosquito larvicide use	spinosyn A and D

1  HED notes that these conclusions are appropriate for this mosquito
larvicide petition only and will be reevaluated if the petitioner alters
the aquatic application scenario.

Magnitude of the Residue – Spice Subgroup 19B (except black pepper)
and Pineapple:  The petitioner submitted adequate dill seed (U.S.; n=3)
and pineapple (U.S. n=3; Mexico n=3; South America n=3) field trial
data.  The field trials were conducted using the requested application
scenario and the collected samples were analyzed using an adequate
method (storage intervals/conditions have also been validated).  The
number and locations of the field trials for both dill seed and
pineapple are in accordance with OPPTS Guideline 860.1500 (with some
acceptable deviations).  Combined residues of spinosyn A and D in/on
dill seed and pineapple were ≤0.57 ppm and <0.02 ppm, respectively.  
The petitioner also submitted a pineapple processing study which
indicated that residues do not concentrate in juice.  The processing
study did not monitor for residues in pineapple processed residue.  The
petitioner proposed and it was agreeded that the theoretical
concentration factor be used to set the pineapple process residue
tolerance (3.8x).  However, if a new use on pineapple is requested which
results in finite pineapple residues, then a new processing study
monitoring for residues in juice and processes residues would be
required.  

The following tolerances for the combined residues of spinosyn A and D
are appropriate (maximum residue limit spreadsheet was used to calculate
the spice tolerances; for pineapple, limit of quantitation (LOQ)
tolerances were recommended since residues were <LOQ):

Spice subgroup (19B), except black pepper	1.7 ppm

Pineapple	0.02 ppm

Pineapple, process residue	0.08 ppm

Analytical Enforcement Method - Plants:  Method RES 94025 (GRM 94.02;
cottonseed) has been successfully subjected to an independent laboratory
validation (ILV) as well as an EPA laboratory validation.  It has been
forwarded to the Food and Drug Administration (FDA) for inclusion in the
Pesticide Analytical Manual (PAM) Volume II (G. Herndon, 2-Mar-1998). 
The following methods have also been submitted to the FDA for inclusion
in PAM II:  GRM 95.17 (leafy vegetables); GRM 96.09 (citrus); GRM 96.14
(tree nuts); GRM 95.04 (fruiting vegetables); GRM 94.02.S1 (cotton gin
byproducts), and an immunoassay method which was validated on 17
different crop matrices (G. Herndon, 18-Feb-1998).  HED concludes that
these methods are sufficient to enforce the plant tolerances associated
with the current actions.

Analytical Enforcement Method - Livestock:  Methods are available to
enforce the currently established livestock tolerances (Method GRM 95.03
- G. Herndon, 6-Apr-1999; Method GRM 95.15 - D249374, M. Doherty,
24-Jun-1999; Method RES 95114 (immunoassay method) - G. Herndon,
5-Jan-1999).  

4.4  Water Exposure and Risk Pathway

The environmental fate data indicates that the spinosad and spinetoram
transformation products maintain the basic ring structure for these
compounds and that these transformation products are stable.  Therefore,
EFED and HED concluded that a total residue method should be used when
estimating residues in water for purposes of dietary exposure assessment
for both spinosad and spinetoram.  Summarized below are the general fate
properties for spinosyns A and D (D331271, R. Parker, 28-July-2006). 

Environmental Fate Assessment:  Spinosyns A and D converted in an
aerobic soil metabolism study to transformation products very similar to
the parent with half-lives of approximately 9-17 days.  Similar
transformation products are formed under photolytic conditions with a
half-life of less than one day at pH 7 in sterile water and about 10
days in soil.  The photodegradation half-life is assumed to be stable
because the study was not conducted long enough to provide formation and
decline information on the transformation products.  Spinosyn A has a
low to moderate water solubility and a low to slight mobility in sandy
soils, and is immobile in silt loam and clay loam soils.  Although no
mobility data are available for spinosyn D, it is 180x less soluble than
spinosyn A and therefore would be expected to be less likely to leach in
the soil.  In terrestrial field dissipation studies with spinosyn A on
bareground plots, the half-life was <1 day, no leaching was observed,
and 3.1% of the applied test material was recovered in runoff.

Spinosad has a high affinity for sediment and moves rapidly from the
water to the sediment phases where it is highly persistent.  In
anaerobic aquatic metabolism studies, spinosad had a half-life of
161-250 days.  In an aquatic microcosm dissipation outdoor study,
spinosad residues in the sediment peaked at 8 days and had an observed
half-life of >>25 days.  Spinosad has a relatively low bio-concentration
factor (BCF’s of the parent 7.5X, 28.8X, and 21.1X for muscle,
viscera, and whole fish, respectively), and a relatively rapid rate of
depuration (half-life of about one day).  These factors generally would
prevent substantial bio-concentration of the material in the food web.

Ground and Surface Water Estimates:  EFED provided surface and ground
water estimates for estimates for spinosad (D331271, R. Parker,
28-July-2006) and spinetoram (D325409, L. Liu, 14-May-2007).  EFED
generated the surface and ground water estimates using the FQPA Index
Reservoir Screening Tool (FIRST) and Screening Concentration In Ground
Water (SCIGROW) models, respectively (for models and a description go to
  HYPERLINK "http://www.epa.gov/ oppefed1/models/water/" 
http://www.epa.gov/ oppefed1/models/water/ ).  Table 7 is a summary of
the modeled water concentrations.  Based on these estimates, the chronic
analysis assumed a water residue estimate of 10.5 ppb (note that the
pineapple and spice application rates are significantly lower than the
turf rate).  



Table 7:  Estimated Drinking Water Concentrations for
Spinosad/Spinetoram (ppb).

	Acute	Chronic	Long-term average

spinosad (turf application scenario; 4 x 0.4 lb ai/acre; RTI = 7 days;
87% of the watershed is treated)

Surface	34.5	10.5	--

Ground	1.1	1.1	1.1

spinetoram (turf and fire ant mound application; 1 x 0.454 lb ai/acre;
100% of the watershed is treated)

Surface	14.419	6.171	--

Ground	0.072	0.072	0.072

4.5  Dietary-Exposure Analysis

As previously stated, HED concluded that spinosad and spinetoram are
toxicologically equivalent; therefore, dietary exposure to these
compounds were aggregated.  Since both products control the same pest
species, HED concludes that it is unlikely that spinetoram and spinosad
will be applied to the same crop.  Therefore, the dietary exposure
analysis did not calculate a combined spinetoram and spinosad residue
for crops.  Based on the side-by-side spinetoram and spinosad residue
data which indicated that spinetoram residues were less than or equal to
spinosad residues (see D325387, T. Bloem, 12-Sep-2007), HED concludes
that the spinosad residue data was an adequate surrogate for spinosad or
spinetoram in/on crops.   HED notes that the currently established
spinetoram crop tolerances are based on translation of the spinosad
tolerances to spinetoram.   

exposure estimates are not of concern to HED (≤81% cPAD; children 1-2
years old were the most highly exposed population).  Table 8 is a
summary of the chronic dietary exposure and risk estimates.

Table 8:  Summary of Chronic Dietary (food and water) Exposure and
Risk.

Population Subgroup	cPAD (mg/kg/day)	Chronic

Exposure (mg/kg/day)	%cPAD

General U.S. Population	0.0249	0.008700	35

All Infants (< 1 year old)

0.008613	35

Children 1-2 years old

0.020099	81

Children 3-5 years old

0.017392	70

Children 6-12 years old

0.011431	46

Youth 13-19 years old

0.007562	30

Adults 20-49 years old

0.007461	30

Adults 50+ years old

0.007215	29

Females 13-49 years old

0.006893	28

4.6  Residential Exposure and Risk Pathway

As previously stated, HED has concluded that spinosad and spinetoram are
toxicologically equivalent; therefore, residential exposure to both
spinosad and spinetoram is relevant to the current assessment.  Spinosad
is currently registered for homeowner application to turfgrass and
ornamentals to control a variety of worms, moths, flies, beetles,
midges, thrips, leafminers and fire ants (granular formulation). 
Spinetoram is proposed for homeowner applications to gardens, lawns/
ornamentals, and turfgrass for control of lepidopterous larvae (worms or
caterpillars), dipterous leafminers, thrips, sawfly larvae, certain
psyllids and leaf-feeding beetles, and red imported fire ants (mound
application is permitted).  Therefore, there is potential for
residential handler and post-application exposures to both spinosad and
spinetoram.  Since spinosad and spinetoram control the same pests, HED
concludes that these products will not be used in combination with each
other and combining the residential exposures is unnecessary.  The
following paragraphs are summaries of the spinosad and spinetoram
residential exposure estimates.  

Spinosad:  Since no dermal endpoints were identified and based on the
granular formulation and low vapor pressure for spinosad, residential
handler/applicator/post-application dermal and inhalation exposure
assessments were not conducted.  HED concluded that there is a potential
for toddler short-term non-dietary oral exposures (hand-to-mouth,
object-to-mouth, and soil ingestion).  The resulting combined short-term
incidental oral MOE was 640 and is, therefore, not of concern to HED. 
Since HIARC did not identify an acute dietary endpoint, episodic
ingestion of granulars was not assessed.  

HED notes that the registered fruit fly bait application scenario
permits application to non-crop vegetation and this use may result in
residential exposures.  Based on the application rates (fruit fly bait -
0.0003 lb ai/acre; turf/ornamental - 0.41 lbs ai/acre), HED concludes
that residential exposure resulting from the fruit fly application will
be insignificant when compared to the exposure resulting from the
turf/ornamental application.  Therefore, quantitative analysis of the
residential exposure resulting from the fruit fly bait application was
not performed.  HED concludes that all other registered/proposed
application scenarios will not result in residential exposures.  

Spinetoram:  Since no dermal endpoints were identified, only short-term
inhalation risks were assessed for the handlers (postapplication
inhalation exposure expected to be negligible).  The resulting MOEs
ranged from 4,300,000-8,400,000 and are, therefore, not of concern to
HED.  HED concluded that there is a potential for toddler short-term
non-dietary oral exposures (hand-to-mouth, object-to-mouth, and soil
ingestion).  The resulting combined short-term incidental oral MOEs was
970 and is, therefore, not of concern to HED.  Since HIARC did not
identify an acute dietary endpoint, episodic ingestion of granulars was
not assessed.  

4.7  Non-occupational Off-Target Exposure

Spray drift is always a potential source of exposure to residents nearby
to spraying operations.  This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from the ground application method employed for spinosad. 
The Agency has been working with the Spray Drift Task Force, EPA
Regional Offices and State Lead Agencies for pesticide regulation and
other parties to develop the best spray drift management practices.  On
a chemical by chemical basis, the Agency is now requiring interim
mitigation measures for aerial applications that must be placed on
product labels/labeling.  The Agency has completed its evaluation of the
new database submitted by the Spray Drift Task Force, a membership of
U.S. pesticide registrants, and is developing a policy on how to
appropriately apply the data and the AgDRIFT® computer model to its
risk assessments for pesticides applied by air, orchard airblast and
ground hydraulic methods.  After the policy is in place, the Agency may
impose further refinements in spray drift management practices to reduce
off-target drift with specific products with significant risks
associated with drift.

5.0  AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

In general, aggregate exposures are calculated by summing dietary (food
and water) and residential exposures (residential or other
non-occupational exposures).  Based on the anticipated residential
exposure scenarios and since acute and cancer risk assessments are not
required, only short-term (residential, food, and water) and chronic
(food and water) aggregate exposure assessments were conducted.  

Short-Term Aggregate Risk Assessment:  Currently, short-term incidental
oral exposures to toddlers are anticipated from the registered turf and
ornamental application scenarios for spinosad and spinetoram and
short-term inhalation exposure to handler/applicators is anticipated for
the proposed home garden, turf, and ornamental application scenarios for
spinetoram (no handler/applicator exposure to spinosad is anticipated;
see Section 6.0).  Since spinosad and spinetoram control the same pests,
HED concludes that these products will not be used in combination with
each other and incidental oral exposure from spinosad and spinetoram do
not need to be added together.  For aggregate short-term assessment, HED
selected the incidental oral exposure resulting from application of
spinosad as this was greater than the incidental exposure resulting from
application of spinetoram. 

term aggregate exposures and risk estimates.  Since the aggregate MOEs
are ≥180, short-term aggregate exposure to spinosad is not of concern
to HED. 

Table 9:  Short-Term Aggregate Risk Calculations.

Population	NOAEL1

(mg/kg/day)	Target

MOE	Chronic Food and Water Exposure

(mg/kg/day)	Residential Oral Exposure

(mg/kg/day)2	Residential Inhalation Exposure

(mg/kg/day)3	Aggregate MOE 

(food, water, and residential)1

All Infants (< 1 year old)	4.9	100	0.008613	0.00762	--	300

Children 1-2 years old

	0.020099	0.00762	--	180

Children 3-5 years old

	0.017392	0.00762	--	200

Children 6-12 years old

	0.011431	0.00762	--	260

Youth 13-19 years old

	0.007562	--	0.000001	650

Adults 20-49 years old

	0.007461	--	0.000001	660

Adults 50+ years old

	0.007215	--	0.000001	680

Females 13-49 years old

	0.006893	--	0.000001	710

1  Since the short-term inhalation and incidental oral endpoints are
based on the same study and since the level of concern for incidental
oral and inhalation assessments are both 100, chronic dietary exposure
may be added to short-term inhalation or short-term incidental oral
exposure and this total exposure can then be compared to the selected
endpoints for aggregate risk assessment; aggregate MOE = NOAEL ÷
(Chronic Food and Water Exposure + Residential Exposure)

2  residential oral exposure = 0.00762; see D2848802

2  residential inhalation exposure = 0.000001; see D325865

Chronic Aggregate Risk:  Since there are no registered/proposed uses
which result in chronic residential exposures, the chronic aggregate
exposure assessment consists of exposure from food and water. 
Therefore, the dietary exposure estimates presented in Section 4.5
represent aggregate chronic exposure. 

6.0  CUMULATIVE RISK

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to spinetoram/spinosad and any
other substance and spinetoram/spinosad do not appear to produce a toxic
metabolite produced by other substances.  For the purposes of this
tolerance action, therefore, EPA has not assumed that
spinetoram/spinosad does not have a common mechanism of toxicity with
other substances.  For information regarding EPA’s efforts to
determine which chemicals have a common mechanism of toxicity and to
evaluate the cumulative effects of such chemicals, see the policy
statements released by EPA’s Office of Pesticide Programs concerning
common mechanism determinations and procedures for cumulating effects
from substances found to have a common mechanism on EPA’s website at  
HYPERLINK http://www.epa.gov/pesticides/cumulative/.
http://www.epa.gov/pesticides/cumulative/. 

7.0  OCCUPATIONAL EXPOSURE

D335169, M. Dow, 30-Jan-2007

7.1  Handler Exposure 

Based upon the proposed use patterns, the most likely methods of
application will be by ground-boom spray machinery for the lower
(shorter)  crops such as celery, fennel or dill and some form of air
assisted spray (i.e., airblast) for those crops that are taller such as
allspice, annatto, cassia, cloves, juniper or nutmeg.   

For the proposed new uses, the most highly exposed occupational
pesticide handlers will be mixer/loaders using open-pour loading of
liquid formulations and open-pour loading of water-dispersible granules,
and applicators using open-cab, ground-boom sprayers and open-cab
air-blast sprayers.  

Since the treatment blocks (i.e., areas treated) are expected to be
rather small for the proposed new crop uses (as compared to typical
field crops such as cotton, corn, soybeans or wheat), pesticide handlers
will be exposed to short-term duration (1 - 30 days) exposures, but not
to intermediate-term (1 - 6 months) duration exposures.  Although
multiple applications are possible, they are separated by  7 - 10 day
retreatment intervals.  It is unlikely that pesticide handlers would be
exposed continuously for 30 days or more.  

Private (grower) applicators may perform all functions, that is, mix,
load and apply the material.  The HED Exposure Science Advisory Council
(ExpoSAC) Standard Operating Procedure (SOP) #12 (29-Mar-2000) directs
that although the same individual may perform all those tasks, they
shall be assessed separately.  The available exposure data for combined
mixer/loader/applicator scenarios are limited in comparison to the
monitoring of these two activities separately.  These exposure scenarios
are outlined in the PHED Surrogate Exposure Guide (August 1998).   HED
has adopted a methodology to present the exposure and risk estimates
separately for the job functions in some scenarios and to present them
as combined in other cases.  Most exposure scenarios for hand-held
equipment (such as hand wands, backpack sprayers, and push-type granular
spreaders) are assessed as a combined job function.  With these types of
hand-held operations, all handling activities are assumed to be
conducted by the same individual.  The available monitoring data support
this and HED presents them in this way.  Conversely, for equipment types
such as fixed-wing aircraft, groundboom tractors, or air-blast sprayers,
the applicator exposures are assessed and presented separately from
those of the mixers and loaders.  By separating the two job functions,
HED determines the most appropriate levels of personal protective
equipment (PPE) for each aspect of the job without requiring an
applicator to wear unnecessary PPE that might be required for a
mixer/loader (e.g., chemical-resistant gloves may only be necessary
during the pouring of a liquid formulation).  

No chemical-specific data were available with which to assess potential
exposure to pesticide handlers.  The estimates of exposure to pesticide
handlers are based upon surrogate study data available in the PHED (v.
1.1, 1998).   For pesticide handlers, it is HED standard practice  to
present estimates of dermal exposure for “baseline”; that is, for
workers wearing a single layer of work clothing consisting of a
long-sleeved shirt, long pants, shoes plus socks and no protective
gloves as well as for “baseline” and the use of protective gloves or
other PPE as might be necessary.   According to the three product labels
in this case, PPE consists of long-sleeved shirt, long pants and shoes
plus socks.  

A MOE of 100 is adequate to protect occupational pesticide handlers from
exposures to spinosad from the inhalation route as might result from the
proposed new uses.  Therefore, the proposed uses are not of concern to
HED (MOEs ≥ 1900).  Table 10 is a summary of the occupational exposure
assessment.

Table 10:  Summary of Exposure & Risk for Occupational Handlers Applying
Spinosad to Spices and Pineapple.

Unit Exposure1

mg ai/lb handled	Applic. Rate2	Units Treated3	Avg. Daily Exposure4

mg ai/kg bw/day	Inhalation MOE5

Mixer/Loader Using Open Pour Loading of Liquids

Inhal.                 0.0012 HC	1.5 lb ai/acre	40 acre/day	Inhal.      
        0.001	4,900

Mixer/Loader Using Open Pour Loading of Water Dispersible Granules**

Inhal.                0.0017 HC	1.5 lb ai/acre	40 acre/day	Inhal.       
       0.0015	3,300

Applicator Using Open-Cab Ground-boom

Inhal.               0.00074 HC	1.5 lb ai/acre	40 acre/day	Inhal.       
       0.00063	7,800

Applicator Using Open-Cab Air-blast (Spices)

Inhal.               0.0045 HC	1.0 lb ai/acre	40 acre/day	Inhal.        
       0.0026	1,900

1  Unit Exposures are taken from the PHED (Ver. 1.1, August 1998).  
Inhal. = Inhalation.  Units = mg ai/pound of active ingredient handled. 
Data Confidence: LC = Low Confidence, MC = Medium Confidence, HC = High
Confidence.

2  Applic. Rate. = Taken from the  

3  Units Treated are taken from “Standard Values for Daily Acres
Treated in Agriculture”; SOP  No. 9.1.  ExpoSAC;  Revised 5 July 2000.

4  Average Daily Dose (ADD) = Unit Exposure * Applic. Rate * Units
Treated ( Body Weight (70 kg ).

5  MOE = NOAEL  ( ADD.  

**  PHED data for loading 'granules' used for exposure and risk
calculations.

7.2  Post-Application Worker Exposure

There is often the potential for agricultural workers to experience
post-application exposure to pesticides during the course of typical
agricultural activities such as crop scouting, hand-weeding or thinning
or during irrigation activities.  However, in this case, the HIARC did
not identify dermal toxicological endpoints.  Post-application
inhalation exposure for agricultural workers is considered negligible,
therefore a post-application risk assessment is not necessary.

7.3  Restricted Entry Interval (REI)

The REI listed on the proposed labels is 4 hours. PR Notice 95-03 on the
Reduced REI policy 

(3-May-1995) does not list spinosad as an active ingredient approved for
a 4-hour REI.  PR 95-03 requires that end-use products meet the reduced
risk criteria listed below.  Based on the toxicity criteria listed
below, spinosad meets the criteria for a reduced (4 hour) REI;
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●The end-use product is in Toxicity Category III or IV for all of the
following acute toxicity studies:  acute dermal toxicity, acute
inhalation toxicity, primary skin irritation, and primary eye
irritation.

●Based on the required sensitization or hypersensitivity studies, the
end use product is not a sensitizer, and there have been no reports of
hypersensitivity.

●The registrant has no data indicating, and is not aware of, adverse
health effects associated with the end use product, e.g.,
carcinogenicity, neurotoxicity, developmental effects, or reproductive
effects.

●The registrant is not aware and has not been informed of incident
information (illness or injury reports) that are “definitely” or
“probably”' (as defined by the California Incident Reporting System)
related to post-application exposures to the product.  

8.0  DEFICIENCIES / DATA NEEDS

8.1  Toxicology

●28-day inhalation toxicity study in rat waived  for the proposed uses
based on the inhalation MOEs (≥1900) and since spinosad is toxicity
category IV for acute inhalation and has low volatility (see HED SOP
2002.01; HED Standard Operating Procedure: Guidance: Waiver Criteria for
Multiple-Exposure Inhalation Toxicity Studies) 

8.2  Chemistry

●none

8.3  Occupational/Residential

●none

Attachment 1: Chemical Structures

T. Bloem:S10945:PY1:(703)605-0217:7509P

Attachment 1: Chemical Names and Structures

Common Name Chemical Name	Structure

Spinosad Compounds

Spinosyn A

(Factor A)

2-[(6-deoxy-2,3,4-tri-O-methyl-α-L-manno-pyranosyl)oxy]-13-[[5-(dimethy
lamino)-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-14-methyl-1H-as-Indaceno[3,2-d]oxa
cyclododecin-7,15-dione

Spinosyn D

(Factor D)

2-[(6-deoxy-2,3,4-tri-O-methyl-α-L-manno-pyranosyl)oxy]-13-[[5-(dimethy
lamino)-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]o
xacyclododecin-7,15-dione	

	N-Demethyl Spinosyn D

(Factor B of D)

2-[(6-deoxy-2,3,4-tri-O-methyl-α-L-manno-pyranosyl)oxy]-9-ethyl-2,3,3a,
5a,5b,6,9,-10,11,12,13,14,16a,16b-tetradecahydro-4,14-dimethyl-13-[[tetr
ahydro-6-methyl-5-(methylamino)-2H-pyran-2-yl]oxy]-1H-as-Indaceno[3,2-d]
oxacyclododecin-7,15-dione	spinosyn D with N-demethylation of the
forosamine ring

Spinosyn J	structure was not provided; based on MS analysis, structure
is similar to spinosyn A

Spinosyn L and Spinosyn O	structure was not provided; based on MS
analysis, structure is similar to spinosyn D with loss of methyl from
the rhamnose sugar

15-pk4 and 15-pk6	structure was not provided; based on MS analysis,
structure is similar to spinosyn D with loss of methyl from the
forosamine sugar dimethylamino group and loss of a methyl from rhamnose
sugar

Spinetoram Compounds

Spinetoram (XDE-175-J)

 

Spinetoram (XDE-175-L)

 

Spinetoram metabolite – ND-J (N-demethyl-175-J)

Spinetoram metabolite – NF-J (N-formyl-175-J)

Spinosad (110003)	Human Health Risk Assessment	D335084

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