Document ID: EPA-HQ-OPP-2008-0810-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-09-23T04:00Z

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

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

Date:		05-JUN-2009

Subject:	Spinosad and Spinetoram.  Human-Health Risk Assessment for
Application of Spinosad to Date and Pomegranate and Spinetoram to
Pineapple, Date, Pomegranate, Hops, and Spices (Crop Subgroup 19B,
except black pepper).  

PC Code:  	Spinosad:  110003

Spinetoram:  110008 and 110009	DP Barcode:	Spinosad:  D357855

Spinetoram:  D357837

Decision No.:	Spinosad:  400738

Spinetoram:  401004	Registration No.:	Spinosad: 62719-282, 62719-292

Spinetoram: 62719-541, 62719-545

Petition No.:	Spinosad:  8E7445

Spinetoram:  8E7450	Regulatory Action:	Section 3

Assessment Type:	Single Chemical Aggregate	Registration Case No.:	None

TXR No.:	None	CAS No.:	Spinosad:  131929-60-7, 131929-63-0

Spinetoram:  187166-40, 187166-15-0

MRID No.:	None	40 CFR:	Spinosad:  180.495

Spinetoram:  180.635

From:		Mary Clock-Rust, Risk Assessor

			Tom Bloem, Chemist

			Lata Venkateshwara, Environmental Scientist

			Risk Assessment Branch 1/Health Effects Division (RAB1/HED; 7509P)

			Whang Phang, Toxicologist

		Risk Assessment Branch 3 (RAB3)

Through:	Dana M. Vogel, Branch Chief

		George F. Kramer, Ph.D., Senior Chemist

		RAB1/HED (7509P)

To:		Laura Nollen, RM 05

			Registration Division (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 and spinetoram.  A summary of these findings is provided in
this document.  The risk assessment was conducted by Mary Clock-Rust,
the residue chemistry review and dietary exposure assessment were
provided by Tom Bloem of RAB1; the toxicological review was provided by
Whang Phang of RAB3; the occupational/ residential exposure and risk
assessment was provided by Lata Venkateshwara 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 "_Toc231960500"  1.0  EXECUTIVE
SUMMARY	  PAGEREF _Toc231960500 \h  4  

  HYPERLINK \l "_Toc231960501"  2.0  Ingredient Profile	  PAGEREF
_Toc231960501 \h  12  

  HYPERLINK \l "_Toc231960502"  2.1  Summary of Registered Uses	 
PAGEREF _Toc231960502 \h  12  

  HYPERLINK \l "_Toc231960503"  2.2  Summary of Proposed Uses	  PAGEREF
_Toc231960503 \h  13  

  HYPERLINK \l "_Toc231960504"  2.3  Structure and Nomenclature	 
PAGEREF _Toc231960504 \h  14  

  HYPERLINK \l "_Toc231960505"  3.0  HAZARD CHARACTERIZATION	  PAGEREF
_Toc231960505 \h  16  

  HYPERLINK \l "_Toc231960506"  3.1  FQPA Assessment	  PAGEREF
_Toc231960506 \h  19  

  HYPERLINK \l "_Toc231960507"  3.2  Endocrine Disruption	  PAGEREF
_Toc231960507 \h  22  

  HYPERLINK \l "_Toc231960508"  4.0  DIETARY EXPOSURE/RISK
CHARACTERIZATION	  PAGEREF _Toc231960508 \h  22  

  HYPERLINK \l "_Toc231960509"  4.1  Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc231960509 \h  22  

  HYPERLINK \l "_Toc231960510"  4.2  Spinosad Analytical Methodology	 
PAGEREF _Toc231960510 \h  23  

  HYPERLINK \l "_Toc231960511"  4.3 Spinetoram Analytical Methodology	 
PAGEREF _Toc231960511 \h  23  

  HYPERLINK \l "_Toc231960512"  4.4  Toxicity Profile of Major
Metabolites and Degradates	  PAGEREF _Toc231960512 \h  24  

  HYPERLINK \l "_Toc231960513"  4.5  Drinking Water Residue Profile	 
PAGEREF _Toc231960513 \h  24  

  HYPERLINK \l "_Toc231960514"  4.6  Food Residue Profile	  PAGEREF
_Toc231960514 \h  25  

  HYPERLINK \l "_Toc231960515"  4.7  International Residue Limits	 
PAGEREF _Toc231960515 \h  27  

  HYPERLINK \l "_Toc231960516"  4.8  Dietary Exposure and Risk	  PAGEREF
_Toc231960516 \h  28  

  HYPERLINK \l "_Toc231960517"  4.9  Residential Exposure and Risk
Pathway	  PAGEREF _Toc231960517 \h  29  

  HYPERLINK \l "_Toc231960518"  4.10  Non-occupational Off-Target
Exposure	  PAGEREF _Toc231960518 \h  30  

  HYPERLINK \l "_Toc231960519"  5.0  AGGREGATE RISK ASSESSMENT	  PAGEREF
_Toc231960519 \h  31  

  HYPERLINK \l "_Toc231960520"  6.0  CUMULATIVE RISK	  PAGEREF
_Toc231960520 \h  32  

  HYPERLINK \l "_Toc231960521"  7.0  OCCUPATIONAL EXPOSURE	  PAGEREF
_Toc231960521 \h  32  

  HYPERLINK \l "_Toc231960522"  7.1  Handler Exposure	  PAGEREF
_Toc231960522 \h  34  

  HYPERLINK \l "_Toc231960523"  7.1.1  Spinosad Handler Exposure	 
PAGEREF _Toc231960523 \h  36  

  HYPERLINK \l "_Toc231960524"  7.1.2  Spinetoram Handler Exposure	 
PAGEREF _Toc231960524 \h  37  

  HYPERLINK \l "_Toc231960525"  7.2  Occupational Post-Application
Exposure and Risk	  PAGEREF _Toc231960525 \h  40  

  HYPERLINK \l "_Toc231960526"  7.2.1  Spinosad Occupational
Post-Application	  PAGEREF _Toc231960526 \h  40  

  HYPERLINK \l "_Toc231960527"  7.2.2  Spinetoram Occupational
Post-Application	  PAGEREF _Toc231960527 \h  41  

  HYPERLINK \l "_Toc231960528"  8.0  DEFICIENCIES / DATA NEEDS	  PAGEREF
_Toc231960528 \h  41  

  HYPERLINK \l "_Toc231960529"  8.1  Toxicology	  PAGEREF _Toc231960529
\h  41  

  HYPERLINK \l "_Toc231960530"  8.2  Residue Chemistry	  PAGEREF
_Toc231960530 \h  41  

  HYPERLINK \l "_Toc231960531"  Attachment 1:  Chemical Names and
Structures	  PAGEREF _Toc231960531 \h  42  

  HYPERLINK \l "_Toc231960532"  Attachment 2:  Toxicity Profile for
Spinosad	  PAGEREF _Toc231960532 \h  44  

  HYPERLINK \l "_Toc231960533"  Attachment 3:  Toxicity Profile for
Spinetoram	  PAGEREF _Toc231960533 \h  49  

 1.0  EXECUTIVE SUMMARY

Background

Spinosad and spinetoram are fermentation products of Saccharopolyspora
spinosa developed for the control of lepidopterous larvae, leafminers,
and thrips on a variety of crops.  Spinosad 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).  Spinetoram, a
recently registered active ingredient, is a structural analogue to
spinosad (similar structures).  Spinosad and spinetoram are both
currently registered for use on agricultural crops, aquatic plants,
ornamentals, tree farms/plantations, turfgrass, home gardens, and lawns
(residential use).  

The mode of action in insects for both spinosad and spinetoram is
thought to be disruption of nicotinic/gamma amino butyric acid
(GABA)-gated chloride channels.  

The toxicity data of both spinosad and spinetoram were evaluated by HED
Hazard Science Policy Council (HASPOC, memo, W. Greear, D340521,
18-June-2007), and the members of HASPOC concluded that spinosad and
spinetoram should be considered toxicologically identical.  Therefore,
the toxicity data of these pesticides can be used interchangeably or in
combination in establishing the toxicity endpoints for risk assessment. 
Since spinosad and spinetoram control the same pests, HED concludes that
these products will not be used in combination with each other and
combining residential exposures is unnecessary.  The dietary exposure
analysis also assumed that both products will not be applied to the same
crop.  

Requested Action

For spinetoram, the registrant, Dow AgroSciences, LLC has requested
registration of spinetoram for use on dates, pomegranate, pineapple,
spices, hops, dried cones, tree nuts and pistachios.  For spinosad, the
same registrant, Dow, has requested registration on dates, pomegranate,
tree nuts, and pistachios.

Hazard Assessment

As stated above, spinosad and spinetoram should be considered
toxicologically identical.  Therefore, the toxicity data of these
pesticides can be used interchangeably or in combination in establishing
the toxicity endpoints for risk assessment.  

Spinosad 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.  The primary effects seen in the
subchronic toxicity study 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 2-gereation reproductive toxicity study in rats (MRID No.
43701506), 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.  

There were no treatment-related gross or microscopic changes in the
reproductive organs, and the sexual maturation of weanlings.  Parental
toxicity was expressed as cytoplasmic vacuolation of the follicular
epithelial cells of the thyroid with increased levels of
thyroid-stimulating hormone (TSH) and decreased levels of T4.  

The concern for endocrine-related effects is low since there are clear
well-defined no-observed adverse-effect levels (NOAELs)/lowest-observed
adverse-effect levels (LOAELs) established for parental and offspring
toxicity, the dose-response is well characterized, and the point of
departure (PoD) used for overall risk assessment will provide adequate
protection for these effects (NOAEL for risk assessment:  2.49
mg/kg/day; NOAEL for reproductive effects:  10 mg/kg/day).

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.  

Spinetoram Hazard Assessment

Spinetoram has low acute toxicity via the oral, dermal and inhalation
routes of exposure (acute Toxicity Category IV).  It is a dermal
sensitizer but not an eye or dermal irritant.  In subchronic toxicity
studies conducted in rats, mice and dogs, spinetoram produced
multi-organ toxicity.  Treatment had no adverse effects on survival but
decreases in body weight, body weight gain and/or food consumption was
observed in all three species.  Treatment-related findings include
anemia in multiple species (rats, mice and dogs) with the presence of
histiocytic aggregates of macrophages in various organs and tissues
(lymph nodes, spleen, thymus, and bone morrow). Aggregation of
macrophages was indicative of immune stimulation in response to insults
of the chemical exposure and was considered secondary effects of the
toxic effect to the hematopoetic system. 

Dogs appear to be the most toxicologically sensitive species to
spinetoram exposure.  In the subchronic study with dogs, lower thymus
weights, atrophy of the thymic cortex, arteritis and/or perivascular
inflammation in numerous organs with necrosis of the bone marrow leading
to regenerative anemia was seen.  These effects were seen in the
presence of general systemic toxicity. In the chronic study with dogs,
there were no treatment-related effects on survival, body weight,
hematology, clinical chemistry or gross pathology.  Treatment-related
changes were limited to areteritis and necrosis of the areterial walls
of the epididymides in one male dog and thymus, thyroid, larynx, and
urinary bladder in one female at the high dose.  It is postulated that
chronic treatment exacerbated the spontaneous arteritis in genetically
predisposed Beagle dogs (“Beagle Pain Syndrome”).  In developmental
toxicity studies, there is no evidence of increased susceptibility
following in utero exposures in rats and rabbits. 

Spinetoram produced reproductive effects in the female rat in the
2-generation reproductive toxicity study (NOAEL=10 mg/kg/day).  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, no adverse effects were
observed on the offspring at dose levels that produced parental toxicity
in the 2-generation reproductive toxicity study.  

No indication of neurotoxicity was observed in the acute neurotoxicity
screening battery in rats, or in the subchronic and chronic toxicity
studies conducted on spinetoram. All the mutagenicity studies conducted
on spinetoram were negative. The NOAEL derived from the chronic dog
study (2.49 mg/kg/day) is well characterized, and together with the
traditional uncertainty/safety factors will provide adequate protection
for effects observed in laboratory animals.

Cancer

EPA has concluded that spinetoram is toxicologically identical to
spinosad.  Spinosad is classified as “not likely to be carcinogenic to
humans” based on lack of evidence for carcinogenicity in mice and
rats.  Since the last risk assessment, the petitioner has submitted an
acceptable rat chronic/carcinogenicity study in spinetoram (MRID
47212901 and 47212902), which shows no evidence of carcinogenicity. 
Based on the structural similarity of spinosad and spinetoram, and the
similarity of the toxicological database for the currently-available
studies, spinetoram is classified as “not likely to be carcinogenic to
humans.”  

Dose-Response Assessment and Food Quality Protection Act (FQPA) Decision

The HED HASPOC concluded that spinosad and spinetoram should be
considered toxicologically identical.  This conclusion was based on the
following:  (1) spinosad and spinetoram 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.  Thus, the
toxicity data of these pesticides could be used interchangeably or in
combination in establishing the toxicity endpoints for risk assessment. 

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 spinosad and spinetoram
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.  

In 2007, 40 CFR Part 158 was revised to require an immunotoxicity test
for registration of a pesticide (food and non-food uses).  The
immunotoxicity study guideline (OPPTS 870.7800) prescribes functional
immunotoxicity testing designed to evaluate the potential of a repeated
chemical exposure to produce adverse effects (i.e., suppression) on the
immune system.  These immunotoxicity data have not been submitted and
are required for either spinosad or spinetoram, since they are
considered toxicologically identical and since the toxicity data of
these pesticides can be used interchangeably.  At this time a database
uncertainty factor (UF) is not required. 

Table 1.0.1.  Toxicological Endpoints for Spinosad and Spinetoram.

Exposure Scenario	Dose Used for Risk Assessment – 

PoD	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 necessary.

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 carcinogenicity studies in spinosad
and spinetoram. 

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.

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, dermal assessments
are not necessary.  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 HED did not identify an acute dietary
endpoint, episodic ingestion of granules 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), residential
exposure resulting from the fruit fly application is expected to 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:  MOEs for handler’s inhalation risk ranged from 4,300,000
to 8,400,000 and are not of concern to HED.  An assessment was performed
for short-term non-dietary oral exposures to toddlers (hand-to-mouth,
object-to-mouth, and soil ingestion).  The combined short-term
incidental oral MOEs for toddlers was 970 and is not of concern to HED. 
Since HED did not identify an acute dietary endpoint, episodic ingestion
of granules was not assessed.  

Dietary (food and water) Exposure and Risk Assessment

HED concluded that spinosad and spinetoram are toxicologically
equivalent (D331741, P. Shah et al., 20-Sep-2007); therefore, as part of
the current assessment, exposures to these compounds were combined.  The
chronic dietary risk assessment was conducted using Dietary Exposure
Evaluation Model software with the Food Commodity Intake Database
(DEEM-FCID(, Version 2.03).  DEEM-FCID( incorporates the United States
Department of Agriculture (USDA) Continuing Surveys of Food Intakes by
Individuals (CSFII,1994-1996 and 1998).  Acute and cancer analyses were
not conducted as toxicological effects attributable to a single dose
were not identified and spinosad and spinetoram are classified as not
likely to be carcinogens (cancer risk assessment is not required). 
Since both products control the same pest species, the dietary exposure
analysis assumed that both that both spinosad and spinetoram will not be
applied to the same crop.    

≤95% cPAD; children 1-2 years old were the most highly exposed
subpopulation).

Aggregate Exposure and Risk Assessment

 ≥160 and aggregate chronic (food and water) exposures were ≤95% of
the cPAD; therefore, aggregate exposure to spinosad and spinetoram, as a
result of all registered/proposed uses, is not of concern to HED.  

Occupational Exposure and Risk Assessment

Occupational exposure and risk assessments were performed for spinosad
and spinetoram separately due to their different use sites and
formulated products.  For both chemicals, dermal risk assessments are
unnecessary due to a lack of concern for toxicity through the dermal
route.  Since post-application inhalation exposure for agricultural
workers is considered negligible, HED evaluated only occupational
handler inhalation exposure.  Based on the proposed use pattern,
exposure is expected to be short-term in duration (1-30 days).  

Based on the proposed uses, aerial and airblast sprayer application
methods will be used to apply spinosad and spinetoram.  No
chemical-specific handler exposure data were submitted in support of
this Section 3 registration.  It is the policy of the HED to use data
from the Pesticide Handlers Exposure Database (PHED) Version 1.1 as
presented in PHED Surrogate Exposure Guide (8/98) to assess handler
exposures for regulatory actions when chemical-specific monitoring data
are not available [HED Science Advisory Council for Exposure (ExpoSAC)
Draft SOP # 7, dated 1/28/99]. 

Occupational Handler Risk for Spinosad

All risk estimates for occupational handlers are not of concern (i.e.,
MOEs>100), assuming handlers wear the recommended National Institute for
Occupational Safety and Health (NIOSH)-approved quarter-face, cup-style
dust/mist filtering respirator.  

Occupational Handler Risk for Spinetoram

MOE ≥ 100) with baseline clothing protection, and, therefore, do not
exceed HED's LOC. 

Occupational Post-Application Risk for Spinosad

Spinosad has a low vapor pressure (spinosad A:  3.0 x10-11 kPa at 25°C
and spinosad D:  2.0 x 10-11 kPa at 25°C); therefore, short-term
post-application inhalation exposures are expected to be minimal and
less than the application exposures.  A quantitative post-application
inhalation exposure assessment was not performed.

Occupational Post-Application Risk for Spinetoram

Spinetoram has a low vapor pressure (XDE-175-J: 5.3 x10-5 Pa at 20°C
and XDE-175-L: 2.1 x10-5 Pa at 20°C); therefore, short-term
post-application inhalation exposures are expected to be minimal and
less than the application exposures.  A quantitative post-application
inhalation exposure assessment was not performed.

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,"
(http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pd
f).  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 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

Provided revised Sections B and F are submitted, HED concludes that the
toxicological, residue chemistry, and occupational/residential databases
support an unconditional registration and establishment of the following
permanent tolerances: 

Table 1.0.2.  HED-Recommend Tolerances

Commodity Definition	Tolerance (ppm)

Spinetoram (combined XDE-175-J, XDE-175-L, ND-J, and NF-J)

almond, hulls	19

nut, tree, group 14	0.10

pistachio	0.10

date	0.10

pomegranate	0.30

pineapple	0.04

pineapple, process residue	0.15

spice, subgroup 19B, except black pepper	1.7

hop, dried cones	22

citrus, oil	23

vegetable, leafy, except Brassica, group 4	10

Spinosad (combined spinosyn A and spinosyn D)

almond, hulls	19

nut, tree, group 14	0.10

pistachio	0.10

date	0.10

pomegranate	0.30

citrus, oil	23

vegetable, leafy, except Brassica, group 4	10

1  The citrus oil and leafy vegetable (except Brassica) tolerances are
being recommended as a result of spinetoram data submitted in response
to a previous condition registration (D357703, T. Bloem, 28-Apr-2009).  

2.0  Ingredient Profile

Spinetoram (XDE-175) and spinosad are multicomponent tetracyclic
macrolide developed for the control of a variety of insects.  Spinetoram
(XDE-175-J:XDE-175-L; 3:1) and spinosad (spinosyn A:spinosyn D; 85:15)
are fermentation products of Saccharopolyspora spinosa whose mode of
action is disruption of nicotinic/GABA-gated chloride channels to
insects.  

2.1  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 180.635. 
Spinosad is also registered for homeowner application to
turf/ornamentals and spinetoram is registered for homeowner application
to gardens, lawns/ ornamentals, and turfgrass.

2.2  Summary of Proposed Uses

The petitioner submitted supplemental labeling for Delegate WG™
(water-dispersible granule; 25% spinetoram; EPA Reg. No. 62719-541);
Radiant™ SC (soluble concentrate; 1 lb spinetoram/gal; EPA Reg. No.
62719-545); Entrust™ [WP (wettable powder); 80% spinosad; EPA Reg. No.
62719-282] and Success™ (SC; 2 lb spinosad/gal; EPA Reg. No.
62719-292).  Table 2.1.1 is a summary of the proposed application
scenarios.  The petitioner should submit a revised Section B with the
following changes:  (1) spinosad Entrust® (EPA Reg. No. 62719-282)
label should specify a 7-day retreatment interval (RTI) for dates and
(2) the spinetoram Radiant™ SC (EPA Reg. No. 62719-545) label should
specify a 30-day plant-back interval (PBI) for all non-labeled crops
following application to spices (subgroup 19B, except black pepper).  

Table 2.2.  Proposed Application Scenarios for Spinosad and Spinetoram.

Formulation	Rate

Delegate WG™ (25% ai; EPA Reg. No. 62719-541)	0.023-0.109	4	0.438	1
-7-day RTI

-crop oils may be added to the spray solution

Pomegranate

Delegate WG™ (25% ai; EPA Reg. No. 62719-541)	0.062-0.109	3	0.219	1
-4-7-day RTI

Date

Delegate WG™ (25% ai; EPA Reg. No. 62719-541)	0.109	4	0.305	7	-7-day
RTI

Hop

Delegate WG™ (25% ai; EPA Reg. No. 62719-541)	0.039-0.063	5	0.305	1
-4-day RTI

Spices (Subgroup 19B; Except Black Pepper)

Radiant™ SC (1 lb ai/gal; EPA Reg. No. 62719-545)	0.039-0.062	5	0.305
14	-10-day RTI

Pineapple

Radiant™ SC (1 lb ai/gal; EPA Reg. No. 62719-545)	0.031-0.062	6	0.305
7	-7-day RTI

Spinosad

Tree Nuts and Pistachio

Entrust® (WP; 80% ai; EPA Reg. No. 62719-282) Success® (SC; 2 lb
ai/gal; EPA Reg. No. 62719-292)	0.062-0.156	

32	0.45	1	-7-day RTI

-dilute and concentrate sprays are permitted

-crop oils may be added to the spray solution

Pomegranate

Entrust® (WP; 80% ai; EPA Reg. No. 62719-282)	0.062-0.125	32	0.45	7
-10-14-day RTI

-dilute and concentrate sprays are permitted

-spray adjuvants may be adder to the spray solution

Date

Entrust® (WP; 80% ai; EPA Reg. No. 62719-282)	0.125	32	0.45	7	-RTI not
indicated

-dilute and concentrate sprays are permitted

-crop oils may be added to the spray solution

1  PHI = preharvest interval; RTI = retreatment interval.  

2 According to label, do not make more than 3 consecutive applications
per year.

2.3  Structure and Nomenclature

Tables 2.3.1 and 2.3.2 are summaries of the spinetoram nomenclature and
physical/chemical properties; Tables 2.3.3 and 2.3.4 are summaries of
the spinosad nomenclature and physical/chemical properties.  

 

                               XDE-175-J                                
                        XDE-175-L

Common name	Spinetoram (mixture of XDE-175-J and XDE-175-L)

Company experimental name	XDE-175-J (TSN104472; 3’-O-ethyl 5,6-dihydro
spinosyn J; 175-J)

XDE-175-L (TSN104480; 3’-O-ethyl spinosyn L; 175-L)

IUPAC name	XDE-175-J  SEQ CHAPTER \h \r 1 : 
(2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR)-13-{[(2R,5S,6R)-5-(dimethylamino)-
6-methyltetrahydro-2H-pyran-2-yl]oxy}-9-ethyl-14-methyl-7,15-dioxo-2,3,3
a,4,5,5a,5b,6,7,9,10,
11,12,13,14,15,16a,16b-octadecahydro-1H-as-indaceno[3,2-d]oxacyclododeci
n-2-yl 6-deoxy-3-O-ethyl-2,4-di-O-methyl-alpha-L-mannopyranoside;
XDE-175-L:  (2S,3aR,5aS,5bS,9S,13S,14R,
16aS,16bS)-13-{[(2R,5S,6R)-5-(dimethylamino)-6-methyltetrahydro-2H-pyran
-2-yl]oxy}-9-ethyl-4,14-dimethyl-7,15-dioxo-2,3,3a,5a,5b,6,7,9,10,11,12,
13,14,15,16a,16b-hexadecahydro-1H-as-indaceno[3,2-d]oxacyclododecin-2-yl
6-deoxy-3-O-ethyl-2,4-di-O-methyl-alpha-L-mannopyranoside

CAS name	  SEQ CHAPTER \h \r 1 XDE-175-J: 
1H-as-indaceno[3,2-d]oxacyclododecin-7,15-dione,
2-[(6-deoxy-3-O-ethyl-2,4-di-O-methyl-a-L-mannopyranosyl)oxy]-13-[[(2R,5
S,6R)-5-(dimethylamino)tetrahydro-6-methyl
2H-pyran-2-yl]oxy]-9-ethyl-2,3,3a,4,5,5a,5b,6,9,10,11,12,13,14,16a,16b-h
exadecahydro 14-methyl- (2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR) 
XDE-175-L: 
1H-as-indaceno[3,2-d]oxacyclododecin-7,15-dione,2-[(6-deoxy-3-O-ethyl-2,
4-di-O-methyl-a-L-mannopyranosyl)oxy]-13-[[(2R,5S,6R)-5-(dimethylamino)t
etrahydro-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-dimethyl-
(2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS)	

CAS #	XDE-175-J: 187166-40-1; XDE-175-L: 187166-15-0

Table 2.3.2.  Spinetoram Physicochemical Properties.

Melting points	XDE-175-J:  143.4°C; XDE-175-L:  70.8°C

pH	6.46 at 23.1°C for 1% w/w aqueous solution

Density	1.1485 g/cm3 at 20°C

Water solubility (20°C)	  SEQ CHAPTER \h \r 1 XDE-175-J:  10.0 mg/L
(purified water); 423 mg/L (pH 5 buffer); 11.3 mg/L (pH 7 buffer); ~8
mg/L (pH 9 buffer); 6.27 mg/L (pH 10 buffer)

XDE-175-L:  31.9 mg/L (purified water); 1630 mg/L (pH 5 buffer); 46.7
mg/L (pH 7 buffer); 1.98 mg/L (pH 9 buffer); 0.706 mg/L (pH 10 buffer)

Solvent solubility (20°C)	  SEQ CHAPTER \h \r 1 Methanol - >250 g/L;
Acetone - >250 g/L; n-Octanol - 132 g/L; Ethyl Acetate - >250g/L;
1,2-dichloromethane - >250 g/L; Xylene - >250 g/L; Heptane - 61.0 g/L

Vapor pressure 	XDE-175-J:    SEQ CHAPTER \h \r 1 5.3 x10-5 Pa  at
20°C,     SEQ CHAPTER \h \r 1 6.0 x10-5 Pa  at 25°C

XDE-175-L:  2.1 x10-5 Pa at 20°C,     SEQ CHAPTER \h \r 1 4.2 x10-5 Pa 
at 25°C

Dissociation constant (pKa)	XDE-175-J:  pKa = 7.86; XDE-175-L:  pKa =
7.59

Octanol/water partition coefficient (20°C)	  SEQ CHAPTER \h \r 1
XDE-175-J:  2.44 (pH 5); 4.09 (pH 7); 4.22 (pH 9)

XDE-175-L:  2.94 (pH 5); 4.49 (pH 7); 4.82 (pH 9)

UV/visible absorption spectrum	XDE-175-J:

		         Wavelength       Extinction coefficient

Solution		         (max, nm	       (, L/(mol*cm)

Neutral			   245	            	12200

Basic (pH 12.6)		   246	    	11700	

Acidic (pH 1.04)         	   247	             	12400

XDE-175-L:

		     Wavelength           Extinction coefficient

Solution		      (max, nm	      (, L/(mol*cm)

Neutral 			243	          	11100

Basic (pH 12.6)  		244	  	11200

Acidic (pH 1.04)    		202	            	9800

			245	          	11400

Table 2.3.3.  Spinosad Nomenclature.

Chemical Structure	

-methyl-αa-L-mannopyranosyloxy)-13-(4-dimethylamino-2,3,4,6-tetradeoxy-
βß-D-erythropyranosyloxy)-9-ethyl-2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15
,16a,16b-hexadecahydro-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-αa-L-mannopyranosyloxy)-13-(4-dimet
hylamino-2,3,4,6-tetradeoxy-βß-D-erythropyranosyloxy)-9-ethyl-2,3,3a,5
a,5b,6,7,9,10,11,12,13,14,
15,16a,16b-hexadecahydro-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]oxacyclod
odecin-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]oxac
yclododecin-7,15-dione

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

Table 2.3.4.  Spinosad Physicochemical Properties.

Melting points	Spinosyn A: 84-99.5°C; Spinosyn 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)	Spinosyn A: 89.4; Spinosyn D: 0.495

	Vapor pressure at 25°C (kPa)	Spinosyn A: 3.0 x 10-11; Spinosyn D: 2.0
x 10-11

	Dissociation constant (pKa)	not available

	Octanol/water partition coefficient Log(KOW)	Spinosyn A:  2.8 (pH 5);
4.0 (pH 7); 5.2 (pH 9)

Spinosyn D:  3.2 (pH 5); 4.5 (pH 7); 5.2 (pH 9)

	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
the toxicological profile for spinosad is provided in the executive
summary of this document.  The HASPOC concluded that spinosad and
spinetoram should be considered toxicologically identical.  This
conclusion was based on the following:  (1) spinosad and spinetoram 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 toxicological profiles of these two chemicals are
presented in Attachment A.  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. Therefore,
the toxicity data of these pesticides could be used interchangeably or
in combination in establishing the toxicity endpoints and points of
departure for risk assessment.  Except the recently required
immunotoxicity tests, the combined toxicology database for spinosad and
spinetoram is complete (Attachment A contains the toxicity profiles for
spinosad and spinetoram).   

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.  The
toxicity endpoints and points of departures for spinosad/spinetoram risk
assessments are presented in Table 3.1.  However, due to variations in
dosing levels used in the spinosad and spinetoram 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.  

Spinosad 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.  The primary effects seen in the
subchronic toxicity study 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 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 2-generation reproductive toxicity study in rats (MRID No.
43701506), 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.  

There were no treatment-related gross or microscopic changes in the
reproductive organs, and the sexual maturation of weanlings.  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 concern for endocrine-related effects is low since there are clear
well-defined NOAELs/LOAELs established for parental and offspring
toxicity, the dose-response is well characterized, and the PoD used for
overall risk assessment will provide adequate protection for these
effects (NOAEL for risk assessment: 2.49 mg/kg/day; NOAEL for
reproductive effects: 10 mg/kg/day).

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.  

Spinetoram Hazard Assessment

Spinetoram has low acute toxicity via the oral, dermal and inhalation
routes of exposure (acute Toxicity Category IV).  It is a dermal
sensitizer but not an eye or dermal irritant.  In subchronic toxicity
studies conducted in rats, mice and dogs, spinetoram produced
multi-organ toxicity.  Treatment had no adverse effects on survival but
decreases in body weight, body weight gain and/or food consumption was
observed in all three species.  Treatment-related findings include
anemia in multiple species (rats, mice and dogs) with the presence of
histiocytic aggregates of macrophages in various organs and tissues
(lymph nodes, spleen, thymus, and bone morrow).  Aggregation of
macrophages was indicative of immune stimulation in response to insults
of the chemical exposure and was considered secondary effects of the
toxic effect to the hematopoetic system. 

Dogs appear to be the most toxicologically sensitive species to
spinetoram exposure.  In the subchronic study with dogs, lower thymus
weights, atrophy of the thymic cortex, arteritis and/or perivascular
inflammation in numerous organs with necrosis of the bone marrow leading
to regenerative anemia was seen.  These effects were seen in the
presence of general systemic toxicity. In the chronic study with dogs,
there were no treatment-related effects on survival, body weight,
hematology, clinical chemistry or gross pathology.  Treatment-related
changes were limited to areteritis and necrosis of the areterial walls
of the epididymides in one male dog and thymus, thyroid, larynx, and
urinary bladder in one female at the high dose.  It is postulated that
chronic treatment exacerbated the spontaneous arteritis in genetically
predisposed Beagle dogs (“Beagle Pain Syndrome”).  In developmental
toxicity studies, there is no evidence of increased susceptibility
following in utero exposures in rats and rabbits. 

Spinetoram produced reproductive effects in the female rat in the
2-generation reproductive toxicity study (NOAEL=10 mg/kg/day).  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, no adverse effects were
observed on the offspring at dose levels that produced parental toxicity
in the 2-generation reproductive toxicity study.  

Cancer

EPA has concluded that spinetoram is toxicologically identical to
spinosad.  Spinosad is classified as “not likely to be carcinogenic to
humans” based on lack of evidence for carcinogenicity in mice and
rats.  Since the last risk assessment, the petitioner has submitted an
acceptable rat chronic/carcinogenicity study in spinetoram (MRID
47212901 and 47212902), which shows no evidence of carcinogenicity. 
Based on the structural similarity of spinosad and spinetoram, and the
similarity of the toxicological database for the currently-available
studies, spinetoram is classified as “not likely to be carcinogenic to
humans.”  

3.1  FQPA Assessment

Spinosad and spinetoram were assessed in a complete battery of
subchronic, chronic, carcinogenicity, developmental, and reproductive
studies as well as acute and subchronic neurotoxicity screen studies
(spinosad).  There was some evidence of adverse effects on the organs of
the immune system at the LOAEL in three short-term studies with spinosad
or spinetoram.  For example, in the 90-day oral toxicity study of
spinosad in the rat, lymph node histiocytosis (abnormal multiplication
of macrophages) was observed.  Histiocytic aggregates of macrophages
were also observed in several organs of the immune system in the 90-day
oral toxicity in the rat with spinetoram.  In the 90-day oral toxicity
study of spinetoram in the dog, necrosis of the bone marrow leading to
regenerative anemia, as well as histopathology of the thymus were
observed in males.  However, a clear NOAEL was attained in each of these
studies, and the observed histopathologies were generally observed in
the presence of other organ toxicity.  Finally, spinosad does not belong
to a class of chemicals (e.g., the organotins, heavy metals, or
halogenated aromatic hydrocarbons) that would be expected to be
immunotoxic.  Based on the above considerations, HED does not believe
that conducting a special series 870.7800 immunotoxicity study will
result in a PoD less than the NOAEL of 2.49 mg/kg/day already set for
spinosad and spinetoram, and therefore, a database UF is not needed. 

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 was 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
effects.  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.  

In the subchronic studies, anemia was observed in multiple species
(rats, mice and dogs) with the presence of histiocytic aggregates of
macrophages in various organs and tissues (lymph nodes, spleen, thymus,
and bone morrow).  Aggregation of macrophages was indicative of immune
stimulation in response to insults of the chemical exposure and was
considered secondary effects of the toxic effect to the hematopoetic
system.  Therefore, these effects are not considered to be indicative of
frank immunotoxicity.  In the chronic study with dogs, areteritis and
necrosis of the areterial walls of the thymus was seen in one female dog
at the HDT.  This finding is attributed to the exacerbation of the
spontaneous arteritis present in genetically predisposed Beagle dogs
(“Beagle Pain Syndrome”).  

An acute neurotoxicity study (MRID No. 46995113) with spinetoram showed
no treatment-related changes at the Limit Dose (2000 mg/kg/day).  There
is no evidence of clinical signs of neurotoxicity or neuropathology
observed in adult animals in any of the available studies with
spinetoram.  In addition, spinosad, which is considered toxicologically
identical to spinetoram, was negative in both acute and subchronic
neurotoxicity studies.  Based on these observations and since these
compounds do not belong to the class of compounds (e.g.,
organophospates, synthetic pyrethroids) that would be expected to be
toxic to the nervous system, a waiver can be granted for the subchronic
neurotoxicity study for spinetoram, as required by the revised CFR 40
Part 158 data requirements.  

In accordance with the revised 40 CFR Part 158 data requirements, an
immunotoxicity study is required for all food and non-food use
chemicals.  Since spinosad and spinetoram are considered toxicologically
identical, and since the toxicity data of these pesticides can be used
interchangeably, the immunotoxicity study is required on only one of the
compounds.  The available studies do not indicate potential
immunotoxicity.  Further, these compounds do not belong to the class of
compounds (e.g., the organotins, heavy metals, or halogenated aromatic
hydrocarbons) that would be expected to be toxic to the immune system. 
Based on the available data, the immunotoxicity is not expected to
provide a PoD lower than that currently used for overall risk
assessment.  Therefore, at this time, a database uncertainty factor is
not needed for the lack of these 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 3.1 is a summary of the doses
and endpoints used in the current risk assessment.   

Table 3.1.  Summary of Toxicological Doses and Endpoints for Spinosad
and spinetoram 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 in dogs (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 toxicity 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 in dogs (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 carcinogenicity studies in spinosad
and spinetoram.

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  DIETARY EXPOSURE/RISK CHARACTERIZATION

References: 

Residue chemistry summaries - D358163, T. Bloem, 27-May-2009; D358160,
T. Bloem, 27-May-2009; D357703, T. Bloem, 28-April-2009.

Dietary exposure summary - D358161, T. Bloem, 27-May-2009.

Drinking water assessment (EFED memoranda) - D325409, L. Liu,
14-May-2007 (spinetoram); D331271, R. Parker, 28-July-2006 (spinosad).

4.1  Pesticide Metabolism and Environmental Degradation

The spinosad and spinetoram residues of concern, for tolerance
expression and risk assessment purposes, are as defined in Tables 4.1.1
and 4.1.2, respectively.  For further information refer to the documents
referenced in Table 4.1.1 and 4.1.2.  

Table 4.1.1. Residues for Tolerance Expression and Risk Assessment for
Spinetoram (see D331741, P. Shah et al., 20-Sep-2007 for more
information).

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants1	XDE-175-J, XDE-175-L, ND-J, and NF-J	XDE-175-J, XDE-175-L, ND-J,
and NF-J

Ruminant1,2	XDE-175-J, XDE-175-L, ND-J, and NF-J	XDE-175-J, XDE-175-L,
ND-J, and NF-J

Hen1,3	XDE-175-J, XDE-175-L, ND-J, NF-J, 3'-O-deethyl-175-J,
3'-O-deethyl-175-L, and O-demethyl-175-L3	XDE-175-J, XDE-175-L, ND-J,
and NF-J

Rotational Crops1	Cannot be determined from the available data.

Drinking Water1	Since identified or partially identified degradates in
the fate studies contained the major ring structures of the parent
compound, a total residue method was used in modeling.	--

1  See D331741 (P. Shah et al., 20-Sep-2007) for more information.  

2  HED notes that feeding studies should employ dosing with parent only
(XDE-175-J and XDE-175-L) and should monitor for the residues of concern
for risk assessment.

3  O-demethyl-175-L is either 2’-O-demethyl-175-L or
4’-O-demethyl-175-L or a mixture of both.

Table 4.1.2.  Residues for Tolerance Expression and Risk Assessment for
Spinosad.

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants1	spinosyn A and D	spinosyn A and D

Livestock1	spinosyn A and D	spinosyn A and D

Rotational Crops1	spinosyn A and D	spinosyn A and D

Drinking Water2	total spinosad	--

Fish/Shellfish3	adjustment of the TRRs in the edible tissues from the
spinosyn A bioconcentration study (19 ppb data) for the EFED water
concentration resulting from the mosquito larvicide use	spinosyn A and D

1  See D243816 (G. Herndon, 03-Mar-1998) and D264984 (W. Donovan,
14-Jun-2002) for more information.

2  See D316077 (T. Bloem et al., 02-Aug-2006) for more information.  

3  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; see D316077 (T. Bloem et al,
02-Aug-2006) for more information.

4.2  Spinosad Analytical Methodology

Plants:  Adequate plant methods are available for enforcement of the
tolerance associated with the current petition.  Method RES 94025 (GRM
94.02; high-performance liquid chromatography (HPLC)/ultraviolet (UV)]
has been forwarded to the Food and Drug Administration (FDA) for
inclusion in Pesticide Analytical Methods Volume II (PAM II) (D243795,
G. Herndon, 02-Mar-1998).  The following additional methods have been
submitted for other crop matrices:  GRM 95.17 for leafy vegetables; GRM
96.09 for citrus; GRM 96.14 for tree nuts; GRM 95.04 for fruiting
vegetables; and GRM 94.02.S1 for cotton gin byproducts.  All of these
methods are essentially similar to GRM 94.02 and have been submitted to
FDA for inclusion in PAM II (D242940, G. Herndon, 18-Feb-1998).  The
immunochemical methods GRM 96.10.S1 (cereal grain commodities,
cucurbits, and legumes), GRM 96.11.S1 (stone fruits), and GRM 97.05
(sorghum fodder) were also proposed for tolerance enforcement and GRM
96.11.S1 and GRM 97.05 have undergone successful independent laboratory
validation.  A number of HPLC/UV and HPLC/MS (mass spectrometry) methods
are available for confirmation (e.g., GRM 96.09, GRM 97.06).

Livestock, Fish, and Shellfish:  Adequate methods are available for
tolerance enforcement.  Method RES 94094 (GRM 95.03; ruminants) and GRM
95.15 (poultry) are HPLC/UV methods forwarded to the FDA for inclusion
in PAM II (D254677, G. Herndon, 06-Apr- 1999; D249374, M. Doherty,
24-Jun-1999).  The ruminant immunochemical method RES 95114, has also
been submitted to FDA for inclusion in PAM (D245211, G. Herndon,
5-Jan-1999).  HED previously recommended for the establishment of fish
and shellfish tolerances and assumed that the ruminant and poultry
enforcement methods were suitable for fish and shellfish.  

FDA Multiresidue Methods (MRMs):  Data pertaining to multiresidue
methods testing of spinosyns A, D, B, and K and N-demethyl spinosyn D
were forwarded to the Food and Drug Administration (FDA) for review (S.
Willett, 23-Jan-1997; G. Herndon, 01-May-1996).  

4.3 Spinetoram Analytical Methodology

Plants:  Adequate plant methods are available for enforcement of the
tolerance associated with the current petition.  Methods GRM 05.03
(HPLC/MS/MS) has been determined to be an acceptable method for the
determination of spinetoram residues in a variety of crops and was
forwarded to the FDA for inclusion in PAM II (D343662, T. Bloem,
12-Sep-2007).  

Livestock:  Adequate methods are available for tolerance enforcement. 
Method GRM 05.15 [HPLC/mass spectrometry (MS)] has been determined to be
an acceptable for determination of spinetoram residues in bovine and
poultry tissues, milk, cream, and eggs and was forwarded to the FDA for
inclusion in PAM (D343662, T. Bloem, 12-Sep-2007). 

FDA MRMs:  XDE-175-J, XDE-175-L, ND-J, NF-J, ND-L, and NF-L were
screened through the FDA PAM I MRMs.  None of the test substances were
found to be fluorescent using procedures outlined in Protocol A.  All
test substances were subjected to Protocol C, modules DG1, DG5, DG13,
DG17, and DG18.  Test substances were determined to be
non-chromatographable by the chosen gas chromatography modules described
in Protocol C.  Due to the poor sensitivity of the test substances to
detection by methods described in Protocol C, no further analyses were
performed by Protocols D, E, or F.  Since the test substances are not
acids, phenols, or substituted ureas, analyses were not performed using
Protocols B or G.  The test substances were not detectable through FDA
PAM I Protocols A and C; therefore, these methods are unsuitable for
enforcement.  The MRM results were forwarded to the FDA (D335229, T.
Bloem, 18-Jan-2007).  

4.4  Toxicity Profile of Major Metabolites and Degradates

No toxicological data are available on the metabolites of spinosad and
spinetoram.  The identified metabolites for spinosad/spinetoram are
structurally similar.  Since the metabolites (identified and
unidentified) were found to be more polar than parent and, therefore,
are likely to be rapidly excreted, it is unlikely that the metabolites
will be more toxic than the parent.  

4.5  Drinking Water Residue Profile

Estimated drinking water concentrations (EDWCs) were provided by the
EFED.  EFED concluded that the previously provided spinetoram (D325409,
L. Liu, 14-May-2007) and spinosad (D331271, R. Parker, 28-Jul-2006)
estimates were acceptable for the current use.  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.  Table 4.5 is a summary of the modeled
water concentrations.  Based on these estimates, the chronic analysis
assumed a water residue estimate of 10.5 ppb.  The models and
descriptions are available at the EPA internet site:   HYPERLINK
"http://www.epa.gov/oppefed1/models/water/" 
http://www.epa.gov/oppefed1/models/water/ .

Table 4.5.  EDWCs for Spinosad/Spinetoram (ppb).

Water Source	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

4.6  Food Residue Profile

Spinosad:  The petitioner proposed new registration for application of
spinosad to pomegranate and date and reduction in the tree nut (group
14) and pistachio PHI from 14 days to 1 day.  Date and pomegranate
residues data were not submitted; rather the petitioner proposed
translating the spinosad plum residue data to dates and the spinosad
avocado tolerance to pomegranate.  The HED Chemistry Science Advisory
Council (ChemSAC) reviewed and approved these translations (see minutes
of 16-Jul-2008 and 27-Aug-2008); based on this, HED concludes that the
spinosad pomegranate and date tolerance listed in Table 4.7 are
appropriate.  In support of the proposed reduction in the tree nut
(group 14) and pistachio PHI from 14 days to 1 day, the petitioner
submitted almond (nutmeat and hull; n=5) residue data conducted using
the proposed application scenario.  Combined residues of spinosyn A and
D were as follows:  almond nutmeat - <0.040-0.067 ppm and almond hull -
0.292-5.11 ppm.  HED generally requests the submission of 5 almond
(nutmeat and hull) and 5 pecan field trials for establishment of a tree
nut crop group tolerance.  The petitioner has fulfilled the almond field
trial requirements but has not fulfilled the pecan residue trial
requirements.  Due to the low toxicity of spinosad and since the
previously submitted almond and pecan field trail data indicated that
residues in the nutmeat were similar (14-day PHI), HED concludes that
additional pecan residue data were unnecessary.  Based on the almond
field trial data and the North American Free Trade Act (NAFTA) Maximum
Residue Limit (MRL) Spreadsheet, the tree nut crop group and the almond
hull tolerances listed in Table 4.7 are appropriate.  HED notes that
pistachio residue data have not been submitted and concludes that the
tree nut crop group tolerance may be translated to pistachio [see
Reviewer's Guide and Summary of HED ChemSAC Approvals for Amending
Commodity Definitions (40 CFR 180.1(h)) and Crop Group/Subgroups (40 CFR
180.41)].  A revised Section F is requested.  

In addition, the petitioner submitted residue data in response to
residue chemistry deficiencies identified in a previous spinetoram
action.  Based on these data, HED concluded that the citrus oil and
leafy vegetable (except Brassica) spinetoram tolerance should be
increased to 23 ppm and 10 ppm, respectively.  For further information
concerning this, refer to D357703 (T. Bloem, 28-Apr-2009).  Since HED
has concluded that residues of spinosad and spinetoram are likely to be
similar provided the application rates are similar (see below), HED
concludes that the spinosad citrus oil and leafy vegetable (except
Brassica) tolerances should also be increased to 23 ppm and 10 ppm,
respectively.  A revised Section F is requested.

Based on the revised Table 1 feedstuffs (OPPTS 860.1000), the only feed
item associated with the current petition is almond hulls which are fed
to only dairy cattle (roughage; 10% of the diet; 90% dry matter).  The
previously-calculated dairy cattle maximum dietary burden was 46.354 ppm
(D347514, T. Bloem, 24-Apr-2008) with the roughage component of this
diet consisting of nongrass forage (21 ppm; 22% dry matter; 40% of the
diet).  Based on the roughage component of the previously calculated
diary cattle diet, HED concludes that the increase in the almond hull
tolerance from 2.0 ppm to 19 ppm will not necessitate an increase in the
ruminant tolerances.  

Spinetoram:  The petitioner proposed new registration for application of
spinetoram to hop, pineapple, spice (subgroup 19B, except black pepper),
pomegranate, and date and reduction in the tree nut (group 14) and
pistachio PHI from 14 days to 1 day.  No spinetoram residue data were
provided in support of the current request; rather the petitioner is
requesting translation of spinosad residue data to spinetoram.  HED
previously concluded that translation of spinosad residue data to
spinetoram for numerous crops was acceptable for the following reasons
(D325387, T. Bloem, 12-Sep-2007):  (1) spinosad and spinetoram are
structurally similar; (2) the spinetoram plant metabolism studies
resulted in the incorporation of radioactivity into numerous peaks with
each representing ≤3% TRR (PHI = 0-30 days); (3) the proposed
spinetoram application rates were less than or equal to the application
rates used in the spinosad field trial studies; and (4) the spinosad and
spinetoram side-by-side residue data indicated that, in general,
residues of spinetoram (combined XDE-175-J, XDE-175-L, ND-J, and NF-J)
were comparable to residues of spinosad (combined spinosyn A and D)
provided the application scenarios were similar.  HED also concluded
that translation of the spinosad processing factors to spinetoram was
acceptable (D357703, T. Bloem, 28-Apr-2009).  Based on these
conclusions, and since the proposed spinetoram application scenarios are
similar to that of spinosad (spinetoram application rates ≤ to
spinosad; similar RTIs and PHIs), HED concludes that translation of the
spinosad residue data to spinetoram is acceptable and the spinetoram
tolerances listed in Table 4.7 are appropriate.  A revised Section F is
requested.

In addition, the petitioner submitted residue data in response to
residue chemistry deficiencies identified in a previous action.  Based
on these data, HED concluded that the citrus oil and leafy vegetable
(except Brassica) tolerances should be increased to 23 ppm and 10 ppm,
respectively (tolerance for the combined residues of XDE-175-J,
XDE-175-L, ND-J, and NF-J).  For further information concerning this,
refer to D357703 (T. Bloem, 28-Apr-2009).  A revised Section F is
requested.

The only proposed crop which is rotated is spices.  Based on the
submitted confined rotational crop data and the proposed application
rates (≤0.46 lb ai/acre), HED previously concluded that a 30-day
plant-back interval for all non-labeled crops was appropriate (D325387,
T. Bloem, 12-Sep-2007; D353933, T. Bloem, 28-Aug-2008).  Since the
proposed spice rate is 0.305 lb ai/acre, HED concludes that the spice
label should indicate that a 30-day PBI for all nonlabeled crops.  A
revised Section B is requested.

Based on the revised Table 1 feedstuffs (OPPTS 860.1000), the only feed
item associated with the current petition is almond hulls which are fed
to only dairy cattle (roughage; 10% of the diet; 90% dry matter).  The
previously calculated dairy cattle maximum reasonable dietary burden
(MRDB) was 7.64 ppm (D325387, T. Bloem, 12-Sep-2007) with the roughage
component consisting of wheat forage (3.50 ppm; 25% dry matter; 25% of
the diet), soybean forage (2.29 ppm; 35% dry matter; 10% of the diet),
and leaves of root and tuber vegetable (1.33 ppm; 30% dry matter; 10% of
the diet).  Therefore, inclusion of almond hulls in the dietary burden
calculation instead of leaves of root and tuber vegetables results in
and increase in the dietary burden to 8.42 ppm.  HED previously reviewed
a ruminant feeding study (47030801.der.wpd).  The study employed dosing
with spinetoram (XDE-175-J:XDE-175-L; 3:1) at a dietary burden of 37.85
ppm or a mixture of XDE-175-J:XDE-175-L:ND-J:NF-J (1:0.25:1.1:1.2) at
dietary burdens of 1.18 ppm, 3.69 ppm, 11.46 ppm, and 38.59 ppm.  Since
the nature of the residue in ruminants following dosing with ND-J and
NF-J has not been demonstrated, HED concludes that the results from the
feeding study which employed dosing with only parent will be used for
determination of the magnitude of the residue in ruminants.  Using these
data, the estimate residues in ruminants at the current MRDB are less
than the currently-established tolerances; therefore, the
currently-established tolerances remain appropriate.  

4.7  International Residue Limits

Spinosad:  Table 4.7 is a summary of the proposed and HED-recommended
tolerances for the combined residues of spinosyn A and D (a revised
Section F is requested).  There are currently-established Codex almond
hull (2 ppm) and nutmeat (0.01 ppm) MRLs (spinosyn A and D) and a
Mexican walnut (2 ppm) MRL (spinosad).  HED concludes that harmonization
with these tolerance is not possible as the HED recommended tolerance
are either significantly greater or lower than those currently
established by Codex and in Mexico.  HED notes that the commodity
definitions for all of the proposed tolerances are correct; however,
based on the field trial data, HED is recommending for different
tolerance levels than those proposed by the petitioner.  

Spinetoram:  Table 4.7 is a summary of the proposed and HED-recommended
tolerances for the combined residues of XDE-175-J, XDE-175-L, ND-J, and
NF-J (a revised Section F is requested).  Codex, Canada, and Mexico do
not have spinetoram MRLs for the requested crops; therefore,
harmonization is not an issue.  HED notes that the commodity definitions
for all of the proposed tolerances are correct; however, based on the
field trial data, HED is recommending for different tolerance levels
than those proposed by the petitioner.  

Table 4.7.  Tolerance Summary.

Proposed	HED-Recommended 

Commodity Definition	Tolerance (ppm)	Commodity Definition	Tolerance
(ppm)

Spinetoram (combined XDE 175 J, XDE 175, NF-J, ND-J)

almond, hulls	9.0	almond, hulls	19

nut, tree, group 14	0.08	nut, tree, group 14	0.10

pistachio	0.08	pistachio	0.10

date	0.1	date	0.10

pomegranate	0.3	pomegranate	0.30

pineapple

ee	0.02	pineapple	0.04

pineapple, process residue	0.08	pineapple, process residue	0.15

spice, subgroup 19B, except black pepper	1.7	spice, subgroup 19B, except
black pepper	1.7

hop, dried cones	22	hop, dried cones	22

--	--	citrus, oil1	23

--	--	vegetable, leafy, except Brassica, group 41	10

Spinosad (combined spinosyn A and spinosyn D)

almond, hulls	9.0	almond, hulls	19

nut, tree, group 14	0.08	nut, tree, group 14	0.10

pistachio	0.08	pistachio	0.10

date	0.1	date	0.10

pomegranate	0.3	pomegranate	0.30

--	--	citrus, oil1	23

--	--	vegetable, leafy, except Brassica, group 41	10

1  The citrus oil and leafy vegetable (except Brassica) tolerances are
being recommended as a result of spinetoram data submitted in response
to a previous condition registration (D357703, T. Bloem, 28-Apr-2009).  

4.8  Dietary Exposure and Risk

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

 exposure estimates are not of concern to HED (≤95% cPAD; children 1-2
years old were the most highly exposed population).  Table 4.8 is a
summary of the chronic exposure and risk estimates.

Table 4.8.  Summary of Chronic Dietary (food and water) Exposure and
Risk for Spinosad/Spinetoram.

Population Subgroup	cPAD (mg/kg/day)	Chronic

Exposure (mg/kg/day)	%cPAD

General U.S. Population	0.0249	0.011873	48

All Infants (< 1 year old)

0.010256	41

Children 1-2 years old

0.023616	95

Children 3-5 years old

0.020963	84

Children 6-12 years old

0.014588	59

Youth 13-19 years old

0.010210	41

Adults 20-49 years old

0.010755	43

Adults 50+ years old

0.010356	42

Females 13-49 years old

0.010246	41

The chronic analysis is conservative in that it assumed DEEM™ (ver.
7.81) default processing factors for the majority of the food
commodities, 100% CT for all food crop commodities, and modeled drinking
water estimates which assumed 87% of the watershed is treated.  HED
notes that residues in livestock were refined through the incorporation
of a refined dietary burden (average feed-crop residues and projected
percent crop or percent CT estimates for some feed commodities) and
through the incorporation of average milk residues from the ruminant
dermal magnitude of the residue study.  The following additional
refinements are possible:  

(1) Incorporation of combined spinosad and spinetoram percent CT
estimates for the food crop commodities (100% CT currently assumed for
all food crop commodities). 

(2) Refinement in the fish/shellfish residue estimates.  Fish/shellfish
are included as spinosad is currently registered for application as a
mosquito larvicide (direct application to water); the current
fish/shellfish residue estimates are based on a 489 ppb water
concentration which assumed an entire water body is treated, uniform 10
cm depth, and no inflow/outflow.

(3) Refinement in the poultry residue estimates (tolerance-level
residues are currently assumed). 

4.9  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 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
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 HED did not identify an acute dietary endpoint, episodic ingestion
of granules 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 (post-application
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 HED did not
identify an acute dietary endpoint, episodic ingestion of granules was
not assessed.

  

4.10  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 ASSESSMENT

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. 

For toddlers, short-term aggregate includes dietary (food plus water)
and incidental oral exposure resulting from the spinosad use on turf. 
For adults, short-term aggregate includes dietary exposure (food plus
water) and inhalation exposure for homeowners applying spinetoram turf
products.  

The incidental oral or inhalation exposures were combined with chronic
dietary (food and water) exposure for determination of aggregate
short-term exposure.  HED uses chronic dietary exposure when conducting
short-term aggregate assessments as it has been determined that this
will more accurately reflect exposure from food over the HED defined
short-term interval (1-30 days) than will acute exposure.  Since the
short-term inhalation and incidental oral endpoints are based on the
same study and since the LOC 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.  Table 5 is a summary of the short-term
aggregate exposures and risk estimates.  Since the aggregate MOEs are
≥160, short-term aggregate exposure to spinosad is not of concern to
HED. 

Table 5.  Short-Term Aggregate Risk Calculations.

Population	NOAEL1

(mg/kg/day)	Target

MOE	Chronic Food 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	0.010256	0.00762	--	270

Children 1-2 years old

	0.023616	0.00762	--	160

Children 3-5 years old

	0.020963	0.00762	--	170

Children 6-12 years old

	0.014588	0.00762	--	220

Youth 13-19 years old

	0.010210	--	0.000001	480

Adults 20-49 years old

	0.010755	--	0.000001	460

Adults 50+ years old

	0.010356	--	0.000001	470

Females 13-49 years old

	0.010246	--	0.000001	480

1  Since the short-term inhalation and incidental oral endpoints are
based on the same study and since the LOC 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.

3  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 4.8
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

References:  

Spinosad occupational assessment - Memo, L. Venketashwara, D358165,
6-MAY-2009.

Spinetoram occupational assessment - Memo, L. Venketashwara, D358162,
18-FEB-2009

Proposed Uses

Spinosad and spinetoram are formulated into different end use products. 
Spinosad is available as a wettable powder product (Entrust TM, Reg. No.
62718-282), containing 80% spinosad, and as a liquid product (Success
TM, Reg. No. 62719-292) containing 2 lb spinosad per gallon. 

Spinetoram is available as a wettable powder product (Delegate TM, Reg.
No. 62719-541), containing 25% spinetoram and as a soluble concentrate
product (Radiant TM, Reg. No. 62719-545) containing 1 lb spinetoram per
gallon.

A summary of the use pattern for each pesticide follows in Tables 7.1
and 7.2.  

Table 7.1.  Proposed Occupational Use Pattern for Spinosad.

Crop Type/Use Site	Max Single Application Rate (lb ai/A)	Application
Equipment	Application Interval	Maximum lb ai per crop, season or year
Max # applications 	Pre-harvest Interval 	Additional Notes

Entrust TM  (EPA Reg#62719-282: 80% ai; wettable powder;
Restricted-Entry Interval (REI) = 4 hours

Tree Nuts and Pistachios1 	0.15  	aerial, airblast	7 days 	0.45 lb
ai/A/crop	3 apps per crop season3	1 day2	Toxic to bees exposed to
treatment for 3 hours following treatment and toxic to aquatic
invertebrates.

Pomegranate	0.125	aerial, airblast	A 10 to 14-day retreatment schedule
may be necessary to maintain control if crop is growing rapidly or if
there is heavy pest pressure	0.45 lb ai/A/yr	3 apps per crop season3	7
days 

	Dates	0.125	aerial, airblast	Not provided	0.45 lb ai/A/yr	3 apps per
crop season3	7 days 

	Success TM  (EPA Reg#62719-292): 2 lb ai/gal, liquid; REI=4 hours

Tree Nuts and Pistachios1	0.156	aerial, airblast	7 days	0.45 lb
ai/A/crop	3 apps per acre per year3	1 day2	Toxic to bees exposed to
treatment for 3 hours following treatment and toxic to aquatic
invertebrates.

1  Crops include almond, cashew, chestnut, filbert (hazelnut), macadamia
nut, pecan, pistachios, and walnuts.

2  According to the label, the 1-day PHI for tree nuts and pistachios
supersedes the previous PHI of 14 days.

3  According to the label, do not make more than 3 consecutive
applications per year.



Table 7.2.  Proposed Occupational Use Pattern for Spinetoram.

Crop Type/Use Site	Max Single Application Rate	Application Equipment
Application Interval	Maximum lb ai per crop, season or year	Max
applications per crop or year	Pre-harvest Interval (days)	Additional
Notes

Delegate WG TM  (EPA Reg#62719-541): 25% ai; dry flowable; REI  = 4
hours

Dates	0.1094 lb ai/A  

	aerial, airblast	7 days 	0.305 lb ai /A/yr	4 apps per acre per year3	7
days of harvest	3, 4

Pomegranate	0.1094 lb ai/A	aerial, airblast	4 days apart for thrips, 7
days apart for other listed pests	0.219 lb ai/A/yr	3 apps per acre per
year	1 day of harvest	3, 4

Hops, Dried Cones	0.063 lb ai/A	airblast	4 days 	0.305 lb ai/A/crop	5 
apps per acre  per crop	1 day of harvest	3, 4

Tree Nuts and Pistachios	0.1094 lb ai/A	aerial, airblast	7 days	0.438 lb
ai/A/crop 	4 apps per acre per crop	1 day of harvest2	Amount of Delegate
WG per acre will depend upon tree size, volume of foliage present and
pest pressure.  Do not make more than 3 consecutive applications per
year.   

RadiantTM SC (EPA Reg#62719-545): 1 lb ai/gal, liquid; REI=4 hours

Pineapple	0.063 lb ai/A	aerial, groundboom	7 days	0.305 lb ai /A/yr	6
apps per acre per year	7 days of harvest	3, 4  For distribution and  use
 in the State of Hawaii

Spices (Except Black Pepper)1	0.0469 lb ai/A	airblast, groundboom	10
days	0.305 lb ai/A/crop	5  apps per year	14 days of harvest	3, 4

1  Spices, including allspice, anise (seed), annatto (seed), black
caraway, caper (buds), caraway, cardamom, cassia (buds), celery (seed),
cinnamon, clove (buds), common fennel, coriander (seed), cilantro
(seed), cumin, dill (seed), Florence fennel (seed), fenugreek, grains of
paradise, juniper (berry), lovage (seed), mace, mustard (seed), nutmeg,
poppy (seed), saffron, star anise, vanilla, and white pepper.

2  The 1-day PHI for tree nuts and pistachios supersedes the previous
PHI of 7 days.

3  Do not make more than 2 consecutive applications per year.

4  Highly toxic to bees exposed to direct treatment on blooming crops or
weeds.

7.1  Handler Exposure 

Based upon the proposed use patterns, the most likely methods of
application for spinosad/spinetoram will be airblast spray machinery and
aerial sprayers.  Both spinosad and spinetoram have been assessed
previously for ground application to agricultural crops.  For the
current assessment, airblast and aerial application are assessed.

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
are expected to be exposed to short-term duration (1-30 days) exposures,
and intermediate-term (1-6 months) duration exposures.  However, it is
unlikely that pesticide handlers would be exposed continuously for 30
days or more (intermediate-term exposure).  However, as a conservative
measure, risk estimates for intermediate-term durations are presented.  

Private (grower) applicators may perform all functions, that is, mix,
load, and apply the material.  The ExpoSAC 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.   

The average adult body weight of 70 kg was used for estimating
inhalation dose. 

Daily inhalation handler exposures are estimated for each applicable
handler task with the application rate, the area treated in a day using
the following formula:

Daily Exposure (mg ai/day) = 

Unit Exposure (mg ai/lb ai handled) x Application Rate (lbs ai/area) x
Daily Area Treated (area/day)

Where:  

Daily Exposure		=	Amount (mg ai/day) inhaled that is available for
inhalation absorption;

Unit Exposure 		=	Unit exposure value (mg ai/lb ai) derived from August
1998 PHED data;

Application Rate		=	Normalized application rate based on a logical unit
treatment, such as acres; and

	Daily Area Treated 	=	Normalized application area based on a logical
unit treatment such as acres (A/day). 

The daily inhalation dose is calculated by normalizing the daily
exposure by body weight and adjusting, if necessary, with an appropriate
inhalation absorption factor using the following formula:

Average Daily Dose (mg/kg/day) = Daily Exposure (mg ai/day) x
(Absorption Factor (%/100)) / Body Weight (kg)

Where:

Average Daily Dose 	= 	Absorbed dose received from exposure to a
pesticide in a given scenario (mg ai/kg body weight/day);

Daily Exposure 		=	Amount (mg ai/day) inhaled that is available for
inhalation absorption;

Absorption Factor 	=	A measure of the amount of chemical that crosses a
biological boundary such as lungs (100% of the total available
absorbed); and

Body Weight 		= 	Body weight determined to represent the population of
interest in a risk assessment (kg).

Inhalation risks for each applicable handler scenario are calculated
using a MOE, which is a ratio of the NOAEL to the daily dose.  All MOE
values were calculated using the formula below:

MOE = NOAEL or LOAEL (mg/kg/day) / Average Daily Dose (mg/kg/day)

7.1.1  Spinosad Handler Exposure

Exposure of spinosad handlers may occur from applications to the
proposed agricultural crops.  Handler’s exposure and risk were
estimated for the following scenarios: 

Mixer/Loader:

(1a) Open mixing/loading liquids for aerial application;

(1b) Open mixing/loading liquids for airblast application;

(1c) Open mixing/loading wettable powders for aerial application;

(1d) Open mixing/loading wettable powders for airblast application;

Applicator:

(2) Applying sprays via aerial applications;

(3) Applying sprays via airblast applications; and

Flagger:

(5) Flagging to support aerial applications.

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.  HED has determined that risks are not of concern
(i.e., MOEs>100), assuming handlers wear the recommended NIOSH-approved
quarter-face, cup-style dust/mist filtering respirator.  Table 7.1.1 is
a summary of occupational exposure and risk to handlers from spinosad.

Table 7.1.1.  Occupational Inhalation Exposures and Risks for Proposed
Uses of Spinosad. 

Exposure Scenario	App Rate (lb ai/acre)1	Area Treated Daily (acres)2
Inhalation Unit Exposures

(mg/lb ai)	Inhalation Doses (mg/kg/day)3	Short-term Inhalation MOEs4
Intermediate-term Inhalation MOEs4

Mixer/Loader

Mixing/Loading Liquids for Aerial Applications (PHED)	0.156	350
Baseline5: 0.0012 (High confidence)	Baseline: 0.00094	Baseline: 5,200
Baseline: 2,700

Mixing/Loading Liquids for Airblast (PHED)	0.156	40

Baseline: 0.00011	Baseline: 46,000	Baseline: 23,000

Mixing/Loading Wettable Powders for Aerial Applications (PHED)	0.15	350
Baseline: 0.043 (High confidence)

PF5 R6:  0.0086	Baseline: 0.032

PF5 R: 0.0065 	Baseline: 150	Baseline: 77

PF5 R: 390

Mixing/Loading Wettable Powders for Airblast Applications (PHED)	0.15	40

Baseline:

0.0037	Baseline: 1,300	Baseline: 680

Applicator

Applying Sprays via Airblast Equipment (PHED)	0.156	40	Baseline: 0.0045

(High confidence)	Baseline: 0.0004	Baseline: 12,000	Baseline: 6,200

Applying Sprays via Aerial Equipment (PHED)	0.156	350	Eng control7:
0.000068

(High confidence)	Eng control:0.000053	Eng control: 92,000	Eng control:
47,000

Flagger

Aerial Application (PHED)	0.156	350	Baseline: 0.00035

(Low confidence)	Baseline: 0.00027	Baseline: 18,000	Baseline: 9,100

1.	Application rate = maximum application rate from labels.

2.	Amount handled per day values are HED estimates of acres treated per
day based on ExpoSAC SOP #9 “Standard Values for Daily Acres Treated
in Agriculture,” industry sources, and HED estimates.

3.	Dose (mg/kg/day) = Unit exposure (mg/lb ai) x App Rate (lb ai/acre) x
Area Treated (acres/day) x %Absorption (100% inhalation) / Body weight
(70 kg).  

4.	  SEQ CHAPTER \h \r 1 MOE = NOAEL (mg/kg/day) / Dose (mg/kg/day);
where the short-term NOAEL = 4.9 mg/kg/day and the intermediate-

	term NOAEL= 2.49 mg/kg/day.

5.	Baseline Inhalation: no respirator.

6.	PF5 R respirator is a NIOSH-approved respirator with a dust-mist
filter with MSHA/NIOSH approval number prefix TC-21 or any N, R, P, or
HE filter, that provides 80% protection factor.

7.	Only engineering control data are available to assess dermal and
inhalation risks to handlers operating aircraft (enclosed cockpit).

7.1.2  Spinetoram Handler Exposure

Individuals handling spinetoram are exposed through mixing, loading and
application to agricultural crops and non-crop use sites.  Handler’s
exposure and risk were estimated for the following scenarios: 

	

Mixer/Loader:

(1a) Open mixing/loading liquids for aerial application;

(1b) Open mixing/loading liquids for airblast application;

(1c) Open mixing/loading liquids for groundboom application;

(1e) Open mixing/loading dry flowables for aerial application;

(1f) Open mixing/loading dry flowables for airblast application;

Applicator:

(2) Applying sprays via aerial applications;

(3) Applying sprays via airblast applications;

(4) Applying sprays via groundboom applications; and

Flagger:

(5) Flagging to support aerial applications.

The spinetoram product labels direct applicators and other handlers to
wear a long-sleeve shirt, long pants, and shoes plus socks. 

Table 7.1.2 presents the estimated risks for workers based on the short
and intermediate-term inhalation exposures at baseline.  HED has
determined that risks are not of concern (i.e., MOEs >100).



Table 7.1.2:  Spinetoram Occupational Inhalation Exposures and Risks.

Exposure Scenario	App Rate (lb ai/acre)a	Area Treated Daily (acres)b
Inhalation Unit Exposures

 (mg/lb ai)	Inhalation Doses (mg/kg/day)c	Short-term Inhalation MOEsd
Intermediate-term Inhalation MOEsd

Mixer/Loader

Mixing/Loading Liquids for Aerial Applications (PHED) 	0.063	350
Baselinee: 0.0012 (High confidence)	Baseline: 0.00038	Baseline: 13,000
Baseline: 6,600

Mixing/Loading Liquids for Groundboom (PHED)	0.063	80

Baseline: 0.000064	Baseline: 57,000	Baseline: 39,000

Mixing/Loading Liquids for Airblast (PHED)	0.063	40

Baseline: 0.000043

	Baseline: 110,000

	Baseline: 60,000

Mixing/Loading Dry Flowables for Aerial Applications (PHED)	0.1094	350
Baselinee: 0.00077 (High confidence)	Baseline: 0.00042	Baseline: 12,000
Baseline: 5,900

Mixing/Loading Dry Flowables for Airblast Applications (PHED)	0.1094	40

Baseline: 

0.000048	Baseline: 100,000

	Baseline: 52,000

Applicator

Applying Sprays via Groundboom Equipment (PHED)	0.063	80	Baseline:
0.00074 (High confidence)	Baseline: 0.000053	Baseline: 92,000	Baseline:
47,000

Applying Sprays via Airblast Equipment (PHED)	0.1094	40	Baseline: 0.0045

(High confidence)	Baseline: 0.00028	Baseline: 17,000	Baseline: 8,900

Applying Sprays via Aerial Equipment (PHED)	0.1094	350	Baseline:
0.000068

(High confidence)	Baseline:0.000037	Baseline: 130,000	Baseline: 67,000

Flagger

Aerial Application (PHED)	0.1094	350	Baseline: 0.00035

(Low confidence)	Baseline: 0.00019	Baseline: 26,000	Baseline: 13,000

a	Application rate = maximum application rate from labels.

b	Amount handled per day values are HED estimates of acres treated per
day based on ExpoSAC SOP #9 “Standard Values for Daily Acres Treated
in Agriculture,” industry sources, and HED estimates.

c	Dose (mg/kg/day) = Unit exposure(mg/lb ai) x App Rate (lb ai/acre) x
Area Treated (acres/day) x %Absorption (100% inhalation) / Body weight
(70 kg).  

d	  SEQ CHAPTER \h \r 1 MOE = NOAEL (mg/kg/day) / Dose (mg/kg/day);
where the short-term NOAEL = 4.9 mg/kg/day and the intermediate-

	term NOAEL= 2.49 mg/kg/day.

e	Baseline Inhalation:  no respirator.

7.2  Occupational Post-Application Exposure and Risk

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 the case of
spinosad/spinetoram, HED 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.

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
lis整⁤敢潬ⱷ猠楰潮慳⁤敭瑥⁳桴⁥牣瑩牥慩映牯愠爠
摥捵摥⠠ⴴ潨牵 䕒㭉琠敨敲潦敲‬桴⁥ⴴ潨牵删䥅椠
⁳捡散瑰扡敬മ

●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.  

7.2.1  Spinosad Occupational Post-Application

Spinosad has a low vapor pressure (spinosad A:  3.0 x10-11 kPa at 25°C
and spinosad D:  2.0 x 10-11 kPa at 25°C); therefore, short-term
post-application inhalation exposures are expected to be minimal and
less than the application exposures.  A quantitative post-application
inhalation exposure assessment was not performed.

No dermal occupational post-application risk assessment was performed
because a dermal endpoint was not selected for spinosad.  In lieu of a
post-application risk assessment, an REI of 12 hours is assumed based on
the default of 12 hours in the Worker Protection Standard for
Agricultural Pesticides for active ingredients classified as Category
III or IV for acute dermal toxicity, skin irritation potential, and eye
irritation potential.   However, the product labels for spinosad propose
an REI of 4 hours.  Based on review of the toxicological database,
spinosad is a candidate for a reduced risk active ingredient and a
4-hour REI.  However, end-use products must meet the criteria of PR
Notice 95-3 to qualify for an REI of 4 hours.

7.2.2  Spinetoram Occupational Post-Application

Spinetoram has a low vapor pressure (XDE-175-J:  5.3 x10-5 Pa at 20°C
and XDE-175-L:  2.1 x 10-5 Pa at 20°C); therefore, short-term
post-application inhalation exposures are expected to be minimal and
less than the application exposures.  A quantitative post-application
inhalation exposure assessment was not performed.

No dermal occupational post-application risk assessment was performed
because a dermal endpoint was not selected for spinetoram.  In lieu of a
post-application risk assessment, an REI of 12 hours is assumed based on
the default of 12 hours in the Worker Protection Standard for
Agricultural Pesticides for active ingredients classified as Category
III or IV for acute dermal toxicity, skin irritation potential, and eye
irritation potential.  However, the product labels for spinetoram carry
an REI of 4 hours.  Based on review of the toxicological database,
spinetoram is a candidate for a reduced risk active ingredient and a
4-hour REI.  However, end-use products must meet the criteria of PR
Notice 95-3 to qualify for an REI of 4-hours.	

8.0  DEFICIENCIES / DATA NEEDS

8.1  Toxicology

In accordance with the revised 40 CFR Part 158 data requirements, an
immunotoxicity study is required for all food and non-food use
chemicals. Since spinosad and spinetoram are considered toxicologically
identical and since the toxicity data of these pesticides can be used
interchangeably the immunotoxicity study is required on only one of the
compounds. 

28-day inhalation toxicity study in rat is waived  for the proposed uses
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  Residue Chemistry

Spinosad:

(Revised Section B.

(Revised Section F.

Spinetoram:

(Revised Section B.

(Revised Section F.

Attachment 1: Chemical Structures.

Attachment 2: Toxicity Profile for Spinosad.

Attachment 3: Toxicity Profile for Spinetoram.

M. Clock-Rust: S10947:PY1: (703)308-2718:7509P

Attachment 1:  Chemical Names and
瑓畲瑣牵獥഍潃浭湯丠浡⁥桃浥捩污丠浡ݥ瑓畲瑣牵ݥ
匇楰潮慳⁤潃灭畯摮ݳ匇楰潮祳⁮ു䘨捡潴⁲⥁

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)

 



metabolite – ND-J (N-demethyl-175-J)

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

Attachment 2:  Toxicity Profile for Spinosad

Spinosad: Acute Toxicity.

Guideline No.	Study Type	MRID No.	Results	Tox. Category

81-1	Acute Oral-Rat	43770701; 43414515	LD50 = >2000 mg/kg	III

81-2	Acute Dermal-Rabbit	43414516	LD50 = >2000 mg/kg	III

81-3	Acute Inhalation-Rat	43414517	LC50 = >5.18 m/L	IV

81-4	Primary Eye Irritation	43414518	not an eye irritant	IV

81-5 	Primary Skin Irritation	43414519	not a skin irritant	IV

81-6	Dermal Sensitization	43414520	not a skin sensitizer	n/a

Spinosad: Subchronic, Chronic, and Other Toxicity Studies.

Guideline No./Study Type	MRID No. (year)/

Classification/Doses	Results

870.3100

90-Day oral toxicity rodents-Mouse	43566602 (1992)

Acceptable/guideline 

0, 0.005, 0.015, 0.045, or 0.12% 

0, 7.5, 22.5, 67.5, or 180 mg/kg/day	NOAEL = 7.5 mg/kg/day in males and
females.

LOAEL = 22.5 mg/kg/day in males and females; based on cytoplasmic
vacuolation of lymphoid organs, liver, kidney, stomach, female
reproductive tract, and epididymis.  Other tissues less severely
affected are heart, lung, pancreas, adrenal cortex, bone marrow, tongue,
and pituitary gland. 

870.3100

90-Day oral toxicity rodents-Rat	43566601 (1992)

Acceptable/guideline

0, 0.05, 0.1, 0.2, or 0.4%

0/0, 33.9/38.8, 68.5/78.1, 133.5/151.6, or 273.1/308.2 mg/kg/day; M/F
NOAEL = 33.9 mg/kg/day in males; 38.8 mg/kg/day in females.

LOAEL = 68.5 mg/kg/day in males; 78.1 mg/kg/day in females based on
adrenal cortical vacuolation in males, lymph node histiocytosis in both
sexes.

870.3100

90-Day oral toxicity rodents-Rat	43557502 (1994)

Acceptable/guideline

0, 0.003, 0.006, 0.012, or 0.06%

0/0, 2.2/2.6, 4.3/5.2, 8.6/10.4, or 42.7/52.1 mg/kg/day; M/F	NOAEL =
42.7 mg/kg/day in males; 52.1 mg/kg/day in females (HDT).

LOAEL= Not observed in males and females.

870.3150

90-Day oral toxicity nonrodents-Dog	43444102 (1994)

Acceptable/guideline

0, 150, 300, or 1350/900 (males)  900 (females) ppm

0/0, 4.89/5.38, 9.73/10.47, or 33.4/29.9 mg/kg/day; M/F	NOAEL = 4.89
mg/kg/day in males; 5.38 mg/kg/day in females.

LOAEL = 9.73 mg/kg/day in males; 10.47 mg/kg/day in females based on
microscopic changes in a variety of tissues, clinical signs of toxicity,
decreases in mean body weights and food consumption, and biochemical
evidence of anemia and possible liver damage.

870.3200

Repeated Dose Dermal Toxicity- Rabbit (21 days)	43557503 (1984)

Acceptable/guideline

0, 100, 500, or 1000 mg/kg/day	NOAEL = 1000 mg/kg/day in males and
females (HDT).

LOAEL = Not observed.

870.3700a 

Prenatal developmental in rodents- Rat	43557505 (1993)

43770702 (1992; range finding)

Acceptable/guideline

0, 10, 50, or 200 mg/kg/day	Maternal:  NOAEL = 200 mg/kg/day (HDT).

LOAEL = Not observed.

Developmental:  NOAEL = 200 mg/kg/day (HDT).

LOAEL = Not observed.

870.3700b 

Prenatal developmental in nonrodents- Rabbit	43414521 (1994)

43770703 (1992; range finding)

Acceptable/guideline

0, 2.5, 10.0, or 50.0 mg/kg/day	Maternal:  NOAEL = 50 mg/kg/day (HDT).

LOAEL = Not observed.

Developmental:  NOAEL = 50 mg/kg/day (HDT).

LOAEL = Not observed.

870.3800 Reproduction and fertility effects- Rat	43701506 (1994)

Acceptable/guideline

0, 0.005, 0.02, or 0.2%

0, 3, 10, or 100 mg/kg/day	Parental/Systemic NOAEL = 10 mg/kg/day.

LOAEL = 100 mg/kg/day based on increases in heart, kidney, liver,
spleen, and thyroid weights (both sexes), corroborative histopathology
in the spleen and thyroid (both sexes), heart and kidney (males only),
and histopathologic lesions in the lungs and mesenteric lymph nodes
(both sexes), stomach (females only), and prostate.  

Reproductive NOAEL = 10 mg/kg/day.

LOAEL = 100 mg/kg/day based on increased incidence of dystocia and/or
vaginal bleeding after parturition with associated increases in
mortality in the dams.

Offspring NOAEL = 10 mg/kg/day. 

LOAEL = 100 mg/kg/day based on decreases in litter size, survival and
body weights.

870.4100b 

Chronic toxicity- Dog	43701504 (1995)

Acceptable/guideline

0, 50/60, 100/120, or 300/360 ppm

0/, 1.44/1.33, 2.68/2.72, or 8.46/8.22 mg/kg/day; M/F	NOAEL = 2.68
mg/kg/day in males, 2.72 mg/kg/day in females. 

LOAEL = 8.46 mg/kg/day in males; 8.22 mg/kg/day in females based on
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).

870.4200 Carcinogenicity-Mouse	43701505 (1995)

Acceptable/guideline

0, 0.0025, 0.008, or 0.036%

0, 25, 80, or 360 ppm

0/0, 3.4/4.2, 11.4/13.8, or 50.9/67.0 mg/kg/day; M/F	NOAEL = 11.4
mg/kg/day in males, 13.8 mg/kg/day in females. 

LOAEL = 50.9 mg/kg/day in males; 67.0 mg/kg/day in females based on
decreased weight gains, increased mortality, the hematologic effects,
and the gross finding of increased thickening of the gastric mucosa in
females and the histologic changes in the stomach of males.  No evidence
of carcinogenicity.

870.4200 Carcinogenicity-Mouse	44123601 (1996)

Acceptable/guideline

0, 0.0008, or 0.024%

0/0, 1.1/1.3, or 32.7/41.5 mg/kg/day; M/F	NOAEL not established.  

LOAEL = 1.1 mg/kg/day in males; 1.3 mg/kg/day in females.  No evidence
of carcinogenicity.

870.4300 Chronic/

Carcinogenicity- Rat	43701507, 43710503 (1995)

0, 0.005, 0.02, 0.05, or 0.1%

0/0, 2.4/3.0, 9.5/12.0, 24.1/30.3, or 49.4/62.8 mg/kg/day; M/F	NOAEL =
9.5 mg/kg/day in males, 12.0 mg/kg/day in females. 

LOAEL = 24.1 mg/kg/day in males; 30.3 mg/kg/day in females based on
vacuolation of the epithelial follicular cells of the thyroid in both
sexes.  No evidence of carcinogenicity.

870.5265

Reverse Mutation Assay	43414522 (1992)

Unacceptable/guideline	In the Ames Test, the mutation rates observed
after treatment of Salmonella typhimurium strains (TA1535, TA1537, TA98,
and TA100) and one strain of Escherichia coli (WP2/uvrA) with XDE105
increased in a dose-related manner when compared to the vehicle control.
 The colonies were shown in a replica plate assay to be predominately
auxotrophs and not revertants.  No growth of auxotrophs is expected in
the Ames assay, but their presence an this assay suggests that XDE-105
supported their growth.  The investigators noted that trace amounts of
histidine and other amino acids were present in the test substance,
which is a fermentation product.  Therefore, an Ames assay with XDE-105
may not be appropriate, and this assay is considered to be unacceptable.

870.5300

Mouse lymphoma cell/mammalian activation gene forward mutation assay
43414523 (1992)

Acceptable/guideline

0, 1, 5, 10, 15, 20, or 35 µg/ml

15 through 50 µg/ml with metabolic activation.	In a forward mutation
assay using mouse lymphoma cells, spinosad did not induce forward
mutations in mouse lymphoma L5178Y Tk+/- cells at concentrations of 0,
1, 5, 10, 15, 20, or 35 µg/ml without metabolic activation or at
concentrations of 15 through 50 µg/ml with metabolic activation.

870.5375

In Vitro mammalian cytogenetic assay	43414524 (1992)

Acceptable/guideline

20, 26, or 35 µg/ml

100, 250, or 500 µg/ml with metabolic activation.	In a chromosomal
aberrations assay, spinosad did not increase the number of CHO cells
with chromosome aberrations at concentrations of 20, 26, or 35 µg/ml
without metabolic activation or at concentrations of 100, 250 or 500
µg/ml with metabolic activation.

870.5385

Micronucleus Assay	43414525 (1992)

Acceptable/guideline

0, 500, 1000, or 2000 mg/kg/day	In a mouse micronucleus test, spinosad
did not increase the frequency of micronuclei in replicate assays with
bone marrow cells from ICR mice treated with doses of 0, 500, 1000, or
2000 mg/kg/day for two consecutive days.

870.5550

Unscheduled DNA Synthesis	43414526 (1992)

Acceptable/guideline

0.01 to 5 µg/ml

10 to 1000 µg/ml	In the unscheduled DNA synthesis assay using primary
rat hepatocytes, spinosad did not induce unscheduled DNA synthesis (UDS)
in adult rat hepatocytes in vitro at concentrations of 0.01 to 5 µg/ml.
 Concentrations from 10 to 1000 µg/ml of XDE-105 were cytotoxic.

870.6200

Acute Neurotoxicity -Rat	43557501 (1994)

Acceptable/nonguideline

0, 200, 630, or 2000 mg/kg	NOAEL = 2000 mg/kg in males and females
(HDT).

LOAEL = Not established in both sexes.

870.6200b Repeat Dose Neurotoxicity-Rat	43557504 (1993)

Acceptable/nonguideline

0, 0.003, 0.006, 0.012 or 0.06%

0/0, 2.2/2.6, 4.3/5.2, 8.6/10.4, or 42.7/52.1 mg/kg/day; M/F	NOAEL =
42.7 mg/kg/day in males; 52.1 mg/kg /day in females (HDT).

LOAEL = Not established in both sexes.

870.6200b 

Repeat Dose Neurotoxicity-Rat	43701507, 43701503 (1995)

Acceptable/guideline

0 or 0.1%

0/0 or 46.0/57.0 mg/kg/day, M/F	NOAEL = 46.0 mg/kg/day in males; 57.0
mg/kg/day in females (HDT).

LOAEL = Not established in both sexes.

870.7485 Metabolism and pharmacokinetics - Rat	43701508 (1995)

Acceptable/guideline

10 or 100 mg/kg (single oral dose)

10 mg/kg (repeated dose 14 days)	At high (100 mg/kg) and single or
multiple low (10 mg/kg) doses, there are no major differences in the
bioavailability, routes or rates of excretion or metabolism of
14C-XDE-105 (Factor A) following oral administration.  The feces were
the major route of excretion (82 to 87% of the doses at 168 hours after
dosing), and ~7-10% of the dose was excreted in the urine. 
Approximately 70-80% of the dose was absorbed with ~20% of the dose
eliminated unabsorbed in the feces.  Blood levels of 14C after the
single and multiple 10 mg/kg doses were highest at 1 hour in both sexes.
 These levels were reduced by half 6 hours (males) and 12 hours
(females) after dosing indicating that blood levels remain high for
longer periods of time in female rats than in male rats.  Blood levels
of 14C after the 100 mg/kg dose were highest at 6 and 2 hours in males
and females, respectively. Concentrations of 14C-XDE-105 at the time
plasma concentrations were half the maximum value, suggested that the
test material was still undergoing distribution.

At 168 hr after administration of the low dose, the kidney, liver and
fat of males and females had higher levels than other tissues.  In the
high dose group however, the adrenals (females only), kidney, lymph
nodes, fat, and thyroids had higher levels than other tissues.  The
total radioactivity remaining in the tissues and carcass of the low and
high dose animals was <0.6% and <3% of the administered dose,
respectively.  Also, at 7 days after the 100 mg/kg dose of XDE-105
(Factor A), the radioactivity observed in fat was 3-fold higher in
female rats (40.978 μg equivalents/g tissue) than male rats (13.227
μg/g of tissue).

The primary metabolites excreted were identified as the glutathione
conjugates of the parent and O-demethylated XDE-105 (Factor A). 
Metabolites in the tissues were characterized as the – and
O-demethylated (Factor A).  The absorption, disposition, and elimination
of 14C-XDE-105 (Factor A) demonstrated no appreciable differences based
on, dose or repeated dosing.

870.7485 Metabolism and pharmacokinetics - Rat	43701509 (1995)

Acceptable/guideline

ic with the α and ß excretion halftimes (t½) of approximately 6 and
30 hours, respectively.

The primary metabolites excreted were identified as the glutathione
conjugates of the parent and O-demethylated XDE-105 (Factor D). 
Metabolites in the tissues were characterized as the – and
O-demethylated (Factor D).  The absorption, disposition, and elimination
of 14C-XDE-105 (Factor D) demonstrated no appreciable differences based
on, dose or repeated dosing.

870.7485 Metabolism and pharmacokinetics - Rat	43701510 (1995)

Acceptable/guideline

excretion rate.  The maximum rate of bile excretion was ~644 μg
equivalents per hour at 2-4 hr; then the rate decreased to ~123 μg
equivalents per hour at the 12-24 hr interval.

The results of the study suggested that metabolites in the bile included
the glutathione conjugates of the unchanged form, as well as – and
O-demethylated forms of XDE-105 (Factor D).

Attachment 3:  Toxicity Profile for Spinetoram

 ≥ 5000 mg/kg	IV

870.1300	Acute inhalation rat	46695037	LC50 > 5.50 mg/L	IV

870.2400	Acute eye irritation rabbit	46695040	slight eye irritant	IV

870.2500	Acute dermal irritation rabbit	46695043	not a dermal irritant
IV

870.2600	Skin sensitization mouse	46695046	positive	--

Spinetoram: Subchronic, Chronic, and Other Toxicity Studies.

Guideline No.

Study Type	MRID No. (year)/ Classification/dose	Results

870.3100

90-Day oral toxicity 

Rat	46695104 (2005)

Acceptable/guideline

0, 120, 500, 1000, or 2000 ppm

M: 0, 7.9, 32.4, 65.8, and 128 mg/kg/d

F: 0, 9.5, 39.6, 79.3, 159, and 311 mg/kg/d	NOAEL (F) = 120 ppm (9.5
mg/kg/day).

LOAEL (F) = 500 ppm (39.6 mg/kg/day) based on an increased incidence of
very slight to slight kidney tubular vacuolization, very slight
vacuolization of the follicular epithelial cells of the thyroid, and
increased incidence of histiocytic aggregates of macrophages in the bone
marrow, spleen and mesenteric lymph node.

NOAEL (M) = 500 ppm (32.4 mg/kg/day).

LOAEL (M) = 1000 ppm (65.8 mg/kg/day) based on an increased incidence of
histiocytic aggregates of macrophages in lymph nodes, spleen, thymus,
and ileum and jejunum (Peyer’s patches), and follicular epithelial
cell vacuolization of the thyroid with colloid depletion.  

870.3100

90-Day oral toxicity Mouse	46695105 (2005)

Acceptable/guideline

0, 50, 150, or 450 ppm 

M: 0, 7.5, 22.8, and 70.8 mg/kg/d

F: 0, 10.2, 29.6, and 89.9 mg/kg/d 11 mg/kg/d	NOAEL (M) was not
observed.

LOAEL (M) = 50 ppm (7.5 mg/kg/day) based histopathology degeneration
with regeneration of the tubules of the kidney.

NOAEL (F) = 50 ppm (10.2 mg/kg/day).

LOAEL (F) = 150 ppm (29.6 mg/kg/day) based histopathology
(extramedullary hematopoiesis in the spleen) and the steepness of the
dose-response curve.  

870.3150

90-Day oral toxicity Dog	46568501 (2005)         Acceptable/guideline

0, 150, 300 or 900 ppm

M: 0, 5.73, 9.82, and 27.1 mg/kg/d

F: 0, 4.97, 10.2, and 31.0 mg/kg/d 	NOAEL (M) = 150 ppm [(4.975.73
(females/males)] mg/kg/day).

LOAEL (M) = 300 ppm [9.8/10.2 (males/females) mg/kg bw/day in
males/females, respectively], based on decreased body weight gain
(males), generalized vacuolization of macrophages within lymphoid
tissue, arteritis and/or perivascular inflammation in numerous organs
with necrosis of the bone marrow leading to regenerative anemia, and a
decrease in thymus weights (males) with slight atrophy of the thymic
cortex (males).

870.3200

21/28-Day dermal toxicity Rat	46675106 (2005)

Acceptable/ guideline

0, 100, 500, and 1000 mg/kg/d	NOAEL = 1000 mg/kg/day.

LOAEL was not observed.

870.3700a

Prenatal developmental in Rat	46695108 (2005)

Acceptable/ guideline

0, 30, 100, and 300 mg/kg/d from GD 6-20

	Maternal NOAEL = 100 mg/kg/day.

LOAEL = 300 mg/kg/day based on decreased body-weight gain and food
consumption during gestation .

Developmental NOAEL = 300 mg/kg/day.

LOAEL was not determined.

870.3700b

Prenatal developmental in Rabbit	46695107 (2005)

Acceptable/ guideline

0, 2.5, 10, and 60 mg/kg/d from GD 7-27

	Maternal NOAEL = 10 mg/kg/day.

LOAEL = 60 mg/kg/day based on decreased body-weight gains, fecal output,
and food consumption, and increased absolute and relative liver weights.
 

Developmental NOAEL = 60 mg/kg/day.

LOAEL was not observed.

870.3800

Reproduction and fertility effects

Rat	46887501 (2006)

Acceptable/ guideline

0, 3, 10, or 75 mg/kg/d

	Parental/Systemic NOAEL = 10.46 mg/kg/day (M) and 9.87 mg/kg/day (F).

LOAEL = 78.97 mg/kg/day (M) and 74.87 mg/kg/day (F) based on thyroid
histopathology (cytoplasmic vacuolation of follicular epithelial cells)
in F0 and F1 animals of both sexes and decreased serum T4 and/or
increased serum TSH in F0 females and F1 animals of both sexes.  

Reproductive NOAEL (F) = 9.87 mg/kg/day

LOAEL = 74.87 mg/kg/day based on dystocia/other parturition
abnormalities and late resorptions/retained fetuses and increased
postimplantation loss in F0 and F1 dams. 

Reproductive NOAEL (M) ( 78.87 mg/kg/day

LOAEL (M) was not identified. 

Offspring NOAEL ( 78.97 mg/kg/day (M) and 74.87 mg/kg/day (F).

LOAEL was not identified.

870.4100b

Chronic toxicity

Dog	47011901 (2006)

Acceptable/ guideline

0, 50, 100, or 200 ppm

M: 0, 1.57, 2.96, and 5.36 mg/kg/d

F: 0, 1.31, 2.49, and 5.83 mg/kg/d	NOAEL = 100 ppm (2.49 mg/kg/day in
females/2.96 mg/kg/day in males).

LOAEL = 200 ppm (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.

870.4300

Chronic/carcinogenicity Rat	47212901 & 47212902 (2007)

0, 50, 250, or 750 ppm 

M. 0, 2.12, 10.8, 21.6, & 32.9 mg/kg/day

F: 0, 2.63, 13.2, 26.6, & 40 mg/kg/day	NOAEL = 250 ppm (10.8 mg/kg/day
in males/ 13.2 mg/kg/day in females).

LOAEL = 500 ppm (21.6 mg/kg/day in males/26.6 mg/kg/day in females). 
Based on increased incidences of thyroid follicular cell vacuolation and
of aggregates of marcrophages/histiocytes inpeyer’s patches in the
ileum and mediastinals lymph nodes and an increased severity of
aggregates of marcrophages/histiocytes in mesenteric lymph nodes.

870.5100

In vitro Bacterial Gene Mutation (Salmonella typhimurium/ E. coli)/
mammalian activation gene mutation assay	466951109 (2005)

Acceptable/ guideline

0, 33, 100, 333, 1000, 2500, or 5000 (g/plate (+/- S9-activation) in the
E. coli strain ; or 0, 1, 3.33, 10, 33.3, 100, 333, and 1000 (g/plate
(-S9) and 0, 3.33, 10, 33.3, 100, 333, 1000, and 5000 (g/plate (+S9) in
the Salmonella strains	There was no evidence of induced mutant colonies
over background.

(Negative)

870.5300

In Vitro Gene Mutation assay in Chinese Hamster Ovary cells	4669510
(2005)

Acceptable/ guideline

0, 10, 20, 30, 40, 50, 60, 70, 80, 100, 120, 140, 160, 180, 200, 260,
and 320 (g/mL (-S9),

0, 10, 20, 40, 80, 160, 200, 240, 280, and 320 (g/mL (+S9)	There was no
evidence of induced mutant colonies over background in the presence or
absence of S9-activation.

(Negative)

870.5395 

In Vivo Mammalian Cytogenetics - Erythrocyte Micronucleus Assay in Mice
46695112 (2005)

Acceptable/guideline

0, 500, 1000, or 2000 mg/kg	No statistically significant increases in
the micronucleated polychromatic erythrocytes (MPCE) frequency or % of
polychromatic erythrocytes (PCE) were observed in any treatment group
when compared to controls.  

(Negative)

870.5375

In vitro Mammalian Cytogenetics (Chromosomal Aberration Assay in Rat 

Lymphocytes)	46695111 (2005)

Acceptable/guideline

0, 2.5, 5, 10, 20, 30, 40, 50, or 100 µg/mL (-S9),

0, 5, 10, 20, 30, 40, 50, 60, 80, or 100 µg/mL (+S9).	There were no
significant increases in the frequency of aberrant cells (excluding
gaps) noted in the presence or absence of S9 at any exposure period.  

(Negative)

870.6200

Subchronic Neurotoxicity screening battery	46995113 (2005)

Acceptable/guideline

0, 200, 630, and 2000 mg/kg

	NOAEL = 2000 mg/kg.

LOAEL was not observed.

870.7485

hZ

ࠀ

0

4

5

6

?

C

M

W

p

q

}

~

”

•

–

 

¤

µ

·

¸

¿

Ê

Ì

Ô

Õ

Ö

똆

똆

똆

0

5

6

?

D

M

q

•

똆

똆

똆

摧䨇2ЀÖ

×

Ü

Þ

ÿ

h

  h

h

  h

  h

*

+

,

/

H

I

^

_

c

g

h

q

“

–

—

h

j³

j6

j§

j*

hÁ

hþ

hs

 hs

hs

  hs

hs

  hs

hs

  hþ

  hþ

  hþ

hþ

hþ

&

hþ

  h

&

@

&

摧䇜H

&

&

&

&

&

&

&

&

&

&

&

&

&

&

&

&

&

&

&

&

&

&

&

he

he

he

&

&

&

&

&

&

&

&

&

&

&

&

&

 hî

&

 hî

b	@

$

b	@

b	@

$

$

$

$

$

$

$

b	@

$

&

&

$

b	@

f4ytd

kd

&

&

&

&

¶

¶

&

&

¶

¶

¶

¶

¶

¶

&

&

¶

¶

¶

¶

&

&

¶

¶

¶

¶

&

&

 hs

  hs

hd

h^

  he

  he

he

  he

 he

 he

  he

@

gd

gd

h

@

$

@

@

@

@

@

h

@

$

$

$

$

!

Õ

Ù

Ú

Û

è

ë

ì

ì

ï

Ÿ

 hî

㄀Ĥ摧ᖕO

kd

&

hš

hš

&

@

&

&

&

&

&

&

&

&

h«

h«

&

&

h«

h«

h«

h«

h«

h«

h«

há

 há

 há

há

@

&

$

há

há

há

há

há

há

há

há

há

há

há

há

Ff]

há

há

há

há

há

há

há

há

há

há

há

há

há

há

há

há

há

há

há

há

há

 h“j

há

há

há

&

ഀ׆Ā褐฀ㇾĤ葝ﻲ摧ᇱÃ

ഀ׆Ā褐฀ㇾĤ葝ﻲ摧ᇱÃ

'

@

&

@

ô

ô

ô

ô

ô

ô

ô

ô

ô

ô

ô

 

!

R

T

Ã

Å

ô

ô

ô

ô

ô

ô

ô

ԀÅ

hï1

hï1

hï1

ô

gdï1

hï1

hï1

hï1

hï1

hï1

$

a$gdï1

gdï1

$

hï1

etabolism and pharmacokinetics

Rat	46695114 (2005)

Acceptable/ guideline

single p.o. dose 10 or 100 mg/kg

14 daily doses 10 mg/kg

single i.v. dose 10 mg/kg

	The orally administered doses were rapidly absorbed.  The absorbed dose
was 70% or greater.  After 168 h, total recoveries ranged from
88.1-97.1% of the administered doses, with no differences observed
between dose levels, single or multiple doses, or route of exposure. 
The majority of the radioactivity was recovered in the feces (77.4-89.6%
of the administered dose), while urine (3.3-9.6%) was a minor route of
elimination. The majority of the radioactivity in the feces was
recovered during the first 24 h, while the majority of radioactivity
recovered in the urine was recovered during the first 12 h.  Animals
given an i.v. dose of the test compound eliminated a larger proportion
of radioactivity in the urine (9.0-9.6% vs 3.3-4.7%), and elimination of
radioactivity in the feces was prolonged compared to orally-dosed
animals.  However the total amount of radioactivity excreted in the
feces was similar regardless of route of administration, suggesting that
a large percentage of orally-administered XDE-175-J would be eliminated
in the feces via biliary excretion.  The carcass contained the highest
levels of radioactivity (0.2-1.3% administered dose); no other tissue
exceeded 0.4% of the administered dose.  The highest concentrations of
radioactivity were generally detected in fat, kidneys, liver, and lymph
nodes, and in the ovaries in females.  There was no evidence of
bioaccumulation.  The test compound was extensively metabolized
regardless of the route of administration.  The majority of
radioactivity recovered from urine and fecal extract samples was present
as parent and a total of seven metabolites, the largest proportion of
which were found in the fecal extracts. Metabolic profiles were
qualitatively similar for all of the experimental groups. The major
route of metabolism was found to be glutathione conjugation with the
parent compound, as well as glutathione conjugation with N-demethylated,
O-deethylated, and hydroxylated forms of the parent compound.  Parent
and identified compounds accounted for 70.9-83.4% of the administered
dose, while unidentified metabolites accounted for 9.6-17.1% of the
administered dose.  The total administered dose accounted for in the
excreta was 86.4-94.7%. Parent compound accounted for 7.0-22.2% (40.0%
in the 100 mg/kg males) of the total radioactivity eliminated, and was
found almost exclusively in the fecal extracts.  The majority of
radioactivity (31.4-61.0% of the administered dose) was identified as
the glutathione conjugate of D5-XDE-175-J, the glutathione conjugate of
XDE-175-J, and the glutathione conjugate of N-demethyl-XDE-175-J in the
urine, and the glutathione conjugate of XDE-175-J and the cysteine
conjugate of XDE-175-J (tentatively identified) in the feces.  The other
major identified metabolites were identified as the glutathione
conjugate of 3’-O-deethyl-XDE-175-J and the glutathione conjugate of
hydroxy-XDE-175-J (tentatively identified) in the urine, and the
cysteine conjugate of 3’-O-deethyl-XDE-175-J (tentatively identified)
and the cysteine conjugate of hydroxyl-XDE-175-J (tentatively
identified) in the feces (2.3-20.0% total).  An additional major
metabolite was identified as 3’-O-deethyl-XDE-175-J (3.9-14.4%) and
was found almost exclusively in the feces. In animals dosed with
[14C]N-formyl-XDE-175-J (the plant metabolite), the majority of
radioactivity was recovered in the feces (89-2-91.7%), while urine
(3.4-4.4%) was a minor route of elimination.  The radioactivity was
rapidly excreted during the first 24 h, similar to the other groups.  It
was stated that the N-formyl plant metabolite was also highly
metabolized, and that the major metabolites were tentatively identified
as the parent N-formyl test material and cysteine conjugates of the
N-formyl parent and N-demethyl-XDE-175-J.  Based on the fecal metabolite
profile, it was estimated that 21-28% of this test material was
converted to metabolites that may be common with those formed from the
parent compound.

Parent compound accounted for 7.0-22.2% (40.0% in the 100 mg/kg males)
of the total radioactivity eliminated, and was found almost exclusively
in the fecal extracts.  The majority of radioactivity (31.4-61.0% of the
administered dose) was identified as the glutathione conjugate of
D5-XDE-175-J, the glutathione conjugate of XDE-175-J, and the
glutathione conjugate of N-demethyl-XDE-175-J in the urine, and the
glutathione conjugate of XDE-175-J and the cysteine conjugate of
XDE-175-J (tentatively identified) in the feces.  The other major
identified metabolites were identified as the glutathione conjugate of
3’-O-deethyl-XDE-175-J and the glutathione conjugate of
hydroxy-XDE-175-J (tentatively identified) in the urine, and the
cysteine conjugate of 3’-O-deethyl-XDE-175-J (tentatively identified)
and the cysteine conjugate of hydroxyl-XDE-175-J (tentatively
identified) in the feces (2.3-20.0% total).  An additional major
metabolite was identified as 3’-O-deethyl-XDE-175-J (3.9-14.4%) and
was found almost exclusively in the feces.

In animals dosed with [14C]N-formyl-XDE-175-J (the plant metabolite),
the majority of radioactivity was recovered in the feces (89-2-91.7%),
while urine (3.4-4.4%) was a minor route of elimination.  The
radioactivity was rapidly excreted during the first 24 h, similar to the
other groups.  It was stated that the N-formyl plant metabolite was also
highly metabolized, and that the major metabolites were tentatively
identified as the parent N-formyl test material and cysteine conjugates
of the N-formyl parent and N-demethyl-XDE-175-J.  Based on the fecal
metabolite profile, it was estimated that 21-28% of this test material
was converted to metabolites that may be common with those formed from
the parent compound.

870.7485

Metabolism and pharmacokinetics

Rat	46695115 (2005)

Acceptable/ guideline

single p.o. dose 10 or 100 mg/kg

14 daily doses 10 mg/kg

single i.v. dose 10 mg/kg

	The orally administered doses were rapidly absorbed, as radioactivity
was detected in the plasma at 15 minutes post-dosing.  The calculated
systemic oral bioavailable absorbed dose was 39-57% for the low dose and
73-92% for the high dose.  However, the percent of the administered dose
recovered as metabolite(s) in the urine and feces was much higher at
both doses.  Therefore, it was considered likely that the fraction of
the orally administered dose absorbed was 70% or greater in both the low
and high oral dose groups.  After 168 h, total recoveries ranged from
90.4-94.9% of the administered doses, with no differences observed
between dose levels, single or multiple doses, or route of exposure. 
The majority of the radioactivity was recovered in the feces (78.5-86.7%
of the administered dose), while urine (2.3-3.8%) was a minor route of
elimination. The majority of the radioactivity in the feces was
recovered during the first 24 h, while the majority of radioactivity
recovered in the urine was recovered during the first 12 h. Generally,
tissues, carcass, and cage wash accounted for <8%, except for the
i.v.-dosed females (13%). At 168 h, the carcass (1.3-5.8% of the
administered dose) and skin (0.4-5.9%) contained the highest mean levels
of radioactivity; no other tissue (excluding the gastrointestinal tract)
exceeded 0.6% of the administered dose.  In general, the highest
concentrations of radioactivity were detected in fat, lymph nodes, skin,
and adrenals in the males, and in the fat, ovaries, lymph nodes, uterus,
skin, and adrenals in females.  Radioactivity was detected at low levels
in other tissues.  Radioactivity did not partition into the RBC.  Time
courses of radioactivity distribution in tissues was not performed;
however, relatively little radioactivity remained in the tissues or
carcass at 168 h post-dosing.  Therefore, there was no evidence of
bioaccumulation. The test compound was extensively metabolized
regardless of the route of administration.  The majority of
radioactivity in urine and fecal extract samples was present as parent
and a total of nine metabolites.  Metabolic profiles were qualitatively
similar across dose levels and route of exposure, and no major
differences were noted between sexes.  The major route of metabolism was
found to be glutathione conjugation with the parent compound, as well as
glutathione conjugation with N-demethylated and O-deethylated forms of
the parent compound.  In excreta, parent and identified compounds
accounted for 70.7-85.8% of the administered dose, while unidentified
metabolites accounted for 0.8-16.1% of the administered dose.  The total
administered dose accounted for in the excreta was 82.0-89.1%.  Parent
compound accounted for 6.5-26.1% of the total radioactivity eliminated,
and was found almost exclusively in the fecal extracts.  The majority of
the radioactivity was contained in Peak 5 (50.7-66.4% of the
administered dose), which consisted of the glutathione conjugate of
D5-XDE-175-L, the glutathione conjugate of XDE-175-L and the glutathione
conjugate of N-demethyl-XDE-175-L in the urine, and the cysteine
conjugate of XDE-175-L (tentatively identified) in the feces.  Peak 9
(3.9-7.7%) was identified as N-demethyl-XDE-175-L and was found in the
feces.  The only other identified metabolite was contained in Peak 3
(0.1-1.2%), and was tentatively identified as the cysteine conjugate of
3’-O-deethyl-XDE-175-L.

Spinosad and Spinetoram 	Human Health Risk Assessment	D357837, D357855

Page   PAGE  2  of   NUMPAGES  54