Document ID: EPA-HQ-OPP-2007-0349-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-08-29T04:00Z

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

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

Date:		2-August-2006

Subject:	Application of Spinosad to Hops and as a Mosquito Larvicide. 
Human Health Risk Assessment.  Registration Nos.  6E7068 (hops) and
62719-LGN-GF-1578, -1592, and -1593 (mosquito larvicide).  DP Nos.: 
316077, 316155, and 329520.  Decision Nos.:  355532, 355533, 355534, and
367510.  PC Code:  110003.  40 CFR 180.495.

From:		Tom Bloem, Chemist

	PV Shah, Ph.D., Toxicologist

			Mark I. Dow, Ph.D., Biologist

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

Through:	Felicia Fort, RAB1 Branch Chief

			PV Shah, Ph.D., Toxicologist

			RAB1/HED (7509P)

To:			Daniel Rosenblatt/Sidney Jackson; RM 05

			George LaRocca/Bonaventure Akinlosotu; RM 13

		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.  A summary of these findings is provided in this document. 
The risk assessment, residue chemistry review, and dietary exposure
assessment were provided by Tom Bloem of RAB1; the hazard
characterization was provided by PV Shah of RAB1; the
occupational/residential exposure and risk assessment was provided by
Mark Dow of RAB1; and the drinking water assessment was provided by
Ronald Parker of the Environmental Fate and Effects Division (EFED). 

NOTE:  In 2002, HED completed a Section 3 risk assessment for the
application of spinosad to herbs, peanut, caneberry, grape, fig, and
root and tuber vegetables (D284803, D. Vogel et al., 15-Aug-2002).  The
current document contains only those aspects of the risk assessment
which are affected by the addition of the proposed spinosad uses.

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc142352783"  1.0  EXECUTIVE
SUMMARY	  PAGEREF _Toc142352783 \h  3  

  HYPERLINK \l "_Toc142352784"  2.0  PHYSICAL/CHEMICAL PROPERTIES	 
PAGEREF _Toc142352784 \h  7  

  HYPERLINK \l "_Toc142352785"  3.0  HAZARD CHARACTERIZATION	  PAGEREF
_Toc142352785 \h  8  

  HYPERLINK \l "_Toc142352786"  3.1  Endocrine Disruption	  PAGEREF
_Toc142352786 \h  9  

  HYPERLINK \l "_Toc142352787"  3.2  Residues of Concern for Dietary
Risk Assessment	  PAGEREF _Toc142352787 \h  9  

  HYPERLINK \l "_Toc142352788"  4.0  EXPOSURE ASSESSMENT AND
CHARACTERIZATION	  PAGEREF _Toc142352788 \h  11  

  HYPERLINK \l "_Toc142352789"  4.1  Summary of Registered Uses	 
PAGEREF _Toc142352789 \h  11  

  HYPERLINK \l "_Toc142352790"  4.2  Summary of Proposed Uses	  PAGEREF
_Toc142352790 \h  11  

  HYPERLINK \l "_Toc142352791"  4.3  Dietary Exposure/Risk Pathway	 
PAGEREF _Toc142352791 \h  13  

  HYPERLINK \l "_Toc142352792"  4.5  Dietary-Exposure Analysis	  PAGEREF
_Toc142352792 \h  16  

  HYPERLINK \l "_Toc142352793"  4.6  Residential Exposure and Risk
Pathway	  PAGEREF _Toc142352793 \h  17  

  HYPERLINK \l "_Toc142352794"  5.0  AGGREGATE RISK ASSESSMENTS AND RISK
CHARACTERIZATION	  PAGEREF _Toc142352794 \h  18  

  HYPERLINK \l "_Toc142352795"  6.0  CUMULATIVE RISK	  PAGEREF
_Toc142352795 \h  18  

  HYPERLINK \l "_Toc142352796"  7.0  OCCUPATIONAL EXPOSURE	  PAGEREF
_Toc142352796 \h  19  

  HYPERLINK \l "_Toc142352797"  7.1  Handler Exposure	  PAGEREF
_Toc142352797 \h  19  

  HYPERLINK \l "_Toc142352798"  7.2  Post-Application Worker Exposure	 
PAGEREF _Toc142352798 \h  22  

  HYPERLINK \l "_Toc142352799"  7.3  Restricted Entry Interval (REI)	 
PAGEREF _Toc142352799 \h  22  

  HYPERLINK \l "_Toc142352800"  8.0  DEFICIENCIES / DATA NEEDS	  PAGEREF
_Toc142352800 \h  23  

  HYPERLINK \l "_Toc142352801"  8.1  Toxicology	  PAGEREF _Toc142352801
\h  23  

  HYPERLINK \l "_Toc142352802"  8.2  Chemistry	  PAGEREF _Toc142352802
\h  23  

  HYPERLINK \l "_Toc142352803"  8.3  Occupational/Residential	  PAGEREF
_Toc142352803 \h  23  

 

1.0  EXECUTIVE SUMMARY

Background:  Spinosad is a fermentation product of Saccharopolyspora
spinosa, a naturally occurring soil organism.  The product consists of
two related active ingredients:  spinosyn A and spinosyn D.  The two
active ingredients differ by one methyl group and are typically present
at an 85:15 ratio (A:D).  The registrant indicated that the exact mode
of action is not known but is characterized by excitation of the insect
nervous system, leading to involuntary muscle contractions, prostration
with tremors, and paralysis (effects are consistent with excitation of
the nicotinic acetylcholine receptors).  Spinosad is currently
registered for application to numerous crops with tolerances for the
combined residues of spinosyn A and D ranging from 0.01-200 ppm (40 CFR
180.495).  Spinosad is also registered for dermal application to cattle.
 

The Interregional Research Project No. 4 (IR-4) requested the
registration for application of spinosad to hops and Dow AgroSciences
requested application of spinosad as a mosquito larvicide.  In
conjunction with the hop request, IR-4 proposed the establishment of the
following tolerance for the combined residues of spinosyn A and D (no
tolerances were proposed in conjunction with the mosquito larvicide
application):    

hops	22 ppm

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

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

Residue of Concern for Dietary Risk Assessment:  Based on acceptable
metabolism studies conducted with apples, cabbage, cotton, tomatoes,
turnips, ruminants (oral and dermal), and poultry (oral), HED concluded
that the residues of concern in plants and livestock are spinosyns A and
D.  These studies indicated the primary metabolism/degradation routes
for spinosad proceeds via o-demethylation of the rhamnose ring,
n-demethylation of the forosamine ring, and/or hydroxylation of the
macrolide.  

HED previously concluded that the residues of concern in drinking water
are spinosad A and D (D243816, G. Herndon, 3-Mar-1998).  This was based
on the conclusion that spinosad is not persistent.  EFED has since
reassessed the environmental fate data; this reassessment indicated that
the spinosad transformation products maintain the basic ring structure
of spinosad and that combined spinosad and its transformation products
are stable.  Based on this reassessment, it was concluded that residues
in water should be estimated using a total spinosad residue method. 
Since the EFED review of the environmental fate studies indicated that
the basic spinosad structure remains intact, HED concludes that these
compounds are not likely to more toxic than spinosad.  

As part of the current mosquito larvicide petition, HED reviewed a fish
bioconcentration study.  Based on these data, HED concludes that the
residues of concern in fish/shellfish for tolerance enforcement are
spinosyn A and D; for purposes of risk assessment, HED concludes that
adjustment of the total radioactive residues (TRRs) in the edible
tissues from the 19 ppb spinosyn A bioconcentration study for the EFED
water concentration resulting from the mosquito larvicide use is
acceptable for the following reasons (fish/shellfish residue study is
unnecessary):  (1) spinosyn A is the major residue in spinosad (spinosyn
A:spinosyn D = 85:15); (2) the fish bioconcentration study indicated
that the metabolic pathway in fish proceeds via demethylation of the
foroasamine ring which is similar to the metabolic pathway observed in
apple, cabbage, cotton, tomato, turnip, ruminants (oral and dermal), and
poultry (oral); based on this similar metabolic pathway, HED does not
anticipate the presence of metabolites in fish/shellfish which are more
toxic than parent; (3) study demonstrated rapid clearance of TRRs when
the fish were moved to untreated water indicating that spinosad is
metabolized and incorporated into nature products; (4) the
bioconcentration study employed a sufficient dosing interval (28 days);
(5) the 489 ppb water concentration provide by EFED is conservative in
that it assumes that the entire water body is treated, the water depth
is 10 cm, and static conditions (no inflow, outflow, or dilution); and
(6) low toxicity of spinosad (no acute or cancer assessments required). 

Dose Response:  The HED Hazard Identification Assessment Review
Committee (HIARC) met on 22-January-1998 (TXR No.012500) and
11-July-2002 (TXR No. 0050928) to select endpoints for risk assessment
and to evaluate the potential for increased susceptibility of infants
and children from exposure to spinosad (evaluated according to the
February 2002 OPP 10X guidance document).  HED’s Food Quality
Protection Act (FQPA) Safety Factor Committee (SFC) met on 29-July-2002
and determined that based on reliable toxicological data no additional
safety factor is necessary to protect the safety of infants and children
(TXR No. 0051038); therefore, based on toxicological considerations and
the residue assumptions used in the dietary and residential exposure
analyses, the risk assessment team concluded that the FQPA Safety Factor
may be reduced to 1x.  Table 1 is a summary the endpoints used in the
current risk assessment.   

Table 1.  Summary of Toxicological Doses used in the Current Risk
Assessment

Exposure Scenario	Dose	Endpoint

acute dietary (all populations)	no endpoint attributable to a single
exposure was identified; this risk assessment is not required

chronic dietary	NOAEL = 2.7 mg/kg/day	chronic RfD and cPAD = 0.027
mg/kg/day

short-term incidental oral	oral NOAEL = 4.9 mg/kg/day	level of concern
(LOC) for margins of exposure (MOEs) < 100 (residential)

dermal (all intervals)	dermal risk assessments are not required

short-term inhalation	oral NOAEL = 4.9 mg/kg/day	LOC for MOEs < 100
(occupational)

intermediate-term inhalation	oral NOAEL = 2.7 mg/kg/day	LOC for MOEs <
100 (occupational)

cancer (oral, dermal, inhalation)	not likely to be carcinogen; cancer
risk assessments are not required

Occupational Exposure and Risk Assessment:  Since HIARC did not identify
dermal toxicological endpoints and since post-application spinosad
inhalation exposure for agricultural workers is considered negligible,
HED evaluated only occupational handler exposure.  No chemical-specific
data are available with which to assess potential exposure to pesticide
handlers.  Therefore, pesticide handler exposures were calculated based
upon surrogate study data available in the Pesticide Handler’s
Exposure Database (PHED; v. 1.1, 1998).  For pesticide handlers, it is
HED policy to present estimates of exposure for “baseline;” that is,
with a single layer of work clothing consisting of a long-sleeved shirt,
long pants, shoes plus socks, and no protective gloves as well as for
“baseline” plus the use of protective gloves or other
personal-protective equipment (PPE) as might be necessary.  Since the
HIARC only identified inhalation endpoints (no dermal endpoints were
identified), only inhalation exposure assessments were conducted.  All
hop handler MOEs are >100 and all mosquito larvicide MOEs are >100
except the mixer-loader using open pour loading of the WP (wettable
powder) in support of aerial application and an applicator using
high-pressure hand-wand (all formulations).  The PHED contains data
which indicate that a dust/mist filtering respirator will reduce
exposure to dusts and mists by 80%.  An 80% reduction in inhalation
exposure would result in MOEs which are greater than 100.  Therefore,
for the mosquito larvicide petition, HED request revised labels which
indicate that a dust/mist filtering respirator is required for
mixer/loaders supporting aerial application of the WP and for hand-wand
applicators (all formulations).

Residential and Non-Occupational Exposure and Risk Assessment:  Spinosad
is currently registered for use on turf and ornamentals to control a
variety of worms, moths, flies, beetles, midges, thrips, leafminers and
fire ants.  Granular (homeowner) and emulsifiable concentrate (EC;
commercial applicators) formulations are registered.  Since no dermal
endpoints were identified and based on the granular formulation and low
vapor pressure for spinosad, residential handler/applicator and
post-application dermal/inhalation exposure assessments were not
conducted.  HED concluded that there is potential toddler short-term
non-dietary oral exposures (hand-to-mouth, object-to-mouth, ingestion of
granulars, and soil ingestion).  Since HIARC did not identify an acute
dietary endpoint, episodic ingestion of granulars was not assessed.  The
resulting combined short-term incidental oral MOEs were 640 and are
therefore less than HED’s level of concern.  HED concludes that all
other registered/proposed application scenarios will not result in
residential exposures.  

Dietary (food and water) Exposure and Risk Assessment:  Chronic dietary
risk assessments were conducted using the Dietary Exposure Evaluation
Model - Food Consumption Intake Database (DEEM-FCID™, ver. 2.03; acute
and cancer endpoints were not identified) which incorporates the food
consumption data from the USDA’s Continuing Surveys of Food Intakes by
Individuals (CSFII; 1994-1996 and 1998).  The chronic dietary analyses
assumed average/projected percent crop treated estimates, projected
percent head treated resulting from the dermal and premise treatments to
ruminants, average field trial residues, experimentally determined
processing factors, and anticipated livestock residues.  For drinking
water, the chronic analyses assumed the modeled tier 1 FQPA Index
Reservoir Screening Tool (FIRST) chronic surface water estimate
resulting from the application of spinosad to turf.  The resulting
exposure estimates were ≤86% the cPAD and are therefore less than
HED’s level of concern (children 1-2 years old were the most highly
exposed subpopulation). 

 ≥160 and aggregate chronic (food and water) exposures were ≤91% the
cPAD; therefore, aggregate exposure to spinsoad, as a result of all
registered/proposed uses, is less than HED’s level of concern.  

Recommendations for Tolerances/Registration:  Separate recommendations
are written for the hop and mosquito larvicide requests.

Hops (6E7068):  Provided the petitioner submits Revised Sections B and
F, HED concludes that the toxicological, residue chemistry, and
occupational/residential databases support an unconditional registration
and establishment of the following permanent tolerances for the combined
residues of spinosyn A and D: 

hop, dried cones	22 ppm

Mosquito Larvicide (62719-LGN-GF1578, -1592, and -1593):  Provided a
petition is submitted which indicates the tolerances listed below and
the labels are revised to prohibit the application to water intended for
irrigation and to indicate that a dust/mist filtering respirator is
required for mixer-loaders using open pour loading of the WP in support
of aerial application and for applicators using a high pressure
hand-wand (all formulations), HED concludes that the toxicological,
residue chemistry, and occupational/residential databases support the
establishment of a conditional registration and the following permanent
tolerances for the combined residues of spinosyn A and D: 

fish	4.0 ppm

fish, shellfish, crustacean	4.0 ppm

fish, shellfish, mollusc	4.0 ppm

Unconditional registration may be established upon submission of data
which addresses the following deficiency.  

●28-day inhalation toxicity study in rat



2.0  PHYSICAL/CHEMICAL PROPERTIES

Common name	Spinosad

Company experimental name	XDE-105

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

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

CAS name	Spinosyn A: 
2-[(6-deoxy-2,3,4-tri-O-methyl-α-L-manno-pyranosyl)oxy]-13-[[5-(dimethy
lamino)-tetrahydro-6-methyl-2H-pyran-2-yl]oxy]-9-ethyl-2,3,3a,5a,5b,6,9,
10,11,12,13,14,16a,16b-tetradecahydro-14-methyl-1H-as-Indaceno[3,2-d]oxa
cyclododecin-7,15-dione

Spinosyn D: 
2-[(6-deoxy-2,3,4-tri-O-methyl-α-L-manno-pyranosyl)oxy]-13-[[5-(dimethy
lamino)-tetrahydro-6-methyl-2H-pyran-2-yl]oxy]-9-ethyl-2,3,3a,5a,5b,6,9,
10,11,12,13,14,16a,16b-tetradecahydro-4,14-methyl-1H-as-Indaceno[3,2-d]o
xacyclododecin-7,15-dione

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

Table 3.  Physicochemical Properties of the Technical Grade Test
Compound

Melting range	Spinosad A: 84-99.5°C

Spinosad D: 161.5-170°C	EPA Fact Sheet

pH (10% slurry of spinosad in water)	7.74

	Density at 20°C	0.512

	Water solubility (ppm)	Spinosad A: 89.4

Spinosad D: 0.495	

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

Spinosad D: 2.0 x 10-11

	Dissociation constant (pKa)	not available

	Octanol/water partition coefficient Log(KOW)	

pH 5

pH 7

pH 9	Spinosad A 2.8

4.0

5.2	Spinosad D 3.2

4.5

5.2

	UV/visible absorption spectrum	not available

	

3.0  HAZARD CHARACTERIZATION

A detailed hazard characterization for spinosad is presented in a
previous HED risk assessment (D284803, D. Vogel et al., 15-Aug-2002) and
a summary of the spinosad toxicological profile is provided in the
executive summary.  

The HIARC met on 22-January-1998 (TXR No.012500) and 11-July-2002 (TXR
No. 0050928) to select endpoints for risk assessment and to evaluate the
potential for increased susceptibility of infants and children from
exposure to spinosad (evaluated according to the February 2002 OPP 10X
guidance document).  The FQPA SFC met on 29-July-2002 and determined
that based on reliable toxicological data no additional safety factor is
necessary to protect the safety of infants and children (TXR No.
0051038); therefore, based on toxicological considerations and the
residue assumptions used in the dietary (D319957, T. Bloem, 24-Aug-2005)
and residential (D284802, M.Dow and D.Vogel,15-Aug-2002) exposure
analyses, the risk assessment team concluded that the FQPA Safety Factor
may be reduced to 1x when assessing chronic dietary and short-term
incidental oral exposures (these are the only nonoccupational exposure
scenarios assessed for spinosad).  Table 4 is a summary of the endpoints
used in the current assessment.   

Table 4.  Summary of Toxicological Doses and Toxicological Endpoints for
Spinosad

Exposure

Scenario	Dose Used in Risk

Assessment, UF	FQPA SF and Endpoint for Risk Assessment	Study and
Toxicological Effects

Acute Dietary -  

all populations	No endpoint attributable to a single exposure was
identified.  This risk assessment is not required.

Chronic Dietary -

all populations	NOAEL= 2.7 mg/kg/day  

UF = 100

cRfD = 0.027 mg/kg/day	FQPA SF = 1x

cPAD = 0.027 mg/kg/day	Chronic Toxicity Study in Dogs;  LOAEL = 8.22
mg/kg/day; based on vacuolation in glandular cells (parathyroid) and
lymphatic tissues, arteritis, and  increases in serum alanine
aminotransferase, aspartate aminotransferase, and triglycerides levels 

Short-term Incidental Oral 

(1 - 30 Days)	NOAEL= 4.9 mg/kg/day

UF = 100

	FQPA SF = 1x

LOC for MOEs < 100	Subchronic Feeding Study in Dogs; 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

Dermal (Any Time Period)	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 dermal toxicity study in rats
which indicates poor dermal absorption; and 3) the lack of long-term
exposure based on the current use pattern. 

Short-term Inhalation 

(1 - 30 days)	Oral NOAEL= 4.9 mg/kg/day (inhalation absorption rate =
100%)

UF = 100	LOC for MOEs < 100

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

Intermediate-term Inhalation 

(1 - 6 Months)	Oral NOAEL= 2.7 mg/kg/day

(inhalation absorption rate = 100%)

UF = 100	LOC for MOEs < 100

(occupational)	Chronic Toxicity Study in Dogs;  LOAEL = 8.22 mg/kg/day;
based on vacuolation in glandular cells (parathyroid) and lymphatic
tissues, arteritis, and increases in serum alanine aminotransferase,
aspartate aminotransferase, and triglycerides levels 

Cancer 	Classification: Not likely to be carcinogen; cancer risk
assessment is not required

1	UF= Uncertainty Factor; RfD= Reference Dose; FQPA SF = Food Quality
Protection Act Safety Factor; PAD = Population Adjusted Dose= RfD/FQPA
SF; LOC = level of concern; MOE = margin of exposure

3.1  Endocrine Disruption

	

EPA is required under the 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 recommendations of its Endocrine Disruptor and Testing
Advisory Committee (EDSTAC), EPA determined that there was a scientific
basis 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).  In the available spinosad
toxicity studies, there was no estrogen or thyroid mediated toxicity.

3.2  Residues of Concern for Dietary Risk Assessment  

Table 5 is a summary of the conclusion made by HED concerning the
residues of concern in plants, livestock, fish/shellfish, and drinking
water.  Based on acceptable metabolism studies conducted with apples,
cabbage, cotton, tomatoes, turnips, ruminants (oral and dermal), and
poultry (oral), HED concluded that the residues of concern in plants and
livestock are spinosyns A and D (D243816, G. Herndon, 3-Mar-1998;
D264984, W. Donovan, 14-Jun-2002).  These studies indicated the primary
metabolism/degradation routes for spinosad proceeds via o-demethylation
of the rhamnose ring, n-demethylation of the forosamine ring, and/or
hydroxylation of the macrolide.  

HED previously concluded that the residues of concern in drinking water
are spinosad A and D (D243816, G. Herndon, 3-Mar-1998).  This was based
on the conclusion that spinosad is not persistent.  EFED has since
reassessed the environmental fate data; this reassessment indicated that
the spinosad transformation products maintain the basic ring structure
of spinosad and that combined spinosad and its transformation products
are stable.  Based on this reassessment, it was concluded that residues
in water should be estimated using a total spinosad residue method. 
Since the EFED review of the environmental fate studies indicated that
the basic spinosad structure remains intact, HED concludes that these
compounds are not likely to more toxic than spinosad.  

As part of the current mosquito larvicide petition, HED reviewed a fish
bioconcentration study.  Based on these data, HED concludes that the
residues of concern in fish/shellfish for tolerance enforcement are
spinosyn A and D; for purposes of risk assessment, HED concludes that
adjustment of the TRRs in the edible tissues from the 19 ppb spinosyn A
bioconcentration study for the EFED water concentration resulting from
the mosquito larvicide use is acceptable for the following reasons
(fish/shellfish residue study is unnecessary):  (1) spinosyn A is the
major residue in spinosad (spinosyn A:spinosyn D = 85:15); (2) the fish
bioconcentration study indicated that the metabolic pathway in fish
proceeds via demethylation of the foroasamine ring which is similar to
the metabolic pathway observed in apple, cabbage, cotton, tomato,
turnip, ruminants (oral and dermal), and poultry (oral); based on this
similar metabolic pathway, HED does not anticipate the presence of
metabolites in fish/shellfish which are more toxic than parent; (3)
study demonstrated rapid clearance of TRRs when the fish were moved to
untreated water indicating that spinosad is metabolized and incorporated
into nature products; (4) the bioconcentration study employed a
sufficient dosing interval (28 days); (5) the 489 ppb water
concentration provide by EFED is conservative in that it assumes that
the entire water body is treated, the water depth is 10 cm, and static
conditions (no inflow, outflow, or dilution); and (6) low toxicity of
spinosad (no acute or cancer assessments required).  

Table 5.  Residues for Tolerance Expression and Risk Assessment

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants	spinosyn A and D	spinosyn A and D

Livestock	spinosyn A and D	spinosyn A and D

Rotational Crops	spinosyn A and D	spinosyn A and D

Drinking Water	total spinosad	total spinosad

Fish/Shellfish1	adjustment of the TRRs in the edible tissues from the 19
ppb spinosyn A bioconcentration study for the EFED water concentration
resulting from the mosquito larvicide use	spinosyn A and D

1	HED notes that these conclusions are appropriate for this mosquito
larvicide petition only and will be reevaluated if the petitioner alters
the aquatic application scenario; for discussion concerning the residues
of concern in fish/shellfish see D316078 (T. Bloem, 2-Aug-2006) 



4.0  EXPOSURE ASSESSMENT AND CHARACTERIZATION

residue chemistry summary (hop) - D330231, T. Bloem, 19-July-2006

residue chemistry summary (mosquito larvicide) - D316078, T. Bloem,
2-August-2006

dietary exposure analysis - D319959, T. Bloem, 2-August-2006

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

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

4.1  Summary of Registered Uses

Spinosad is currently-registered for application to numerous crops with
tolerances for the combined residues of spinosyn A and D ranging from
0.01-200 ppm (40 CFR 180.495).  Spinosad is also registered for
homeowner application to turf/ornamentals.

4.2  Summary of Proposed Uses

Hop Application Scenario:  The petitioner requested registration for
application of Entrust® (WP; 80% ai; EPA Reg. No. 62719-282), SpinTor®
2SC (suspension conecetrate (SC: 2 lbs ai/gal); EPA Reg. No. 62719-294),
and Success® (SC; 2 lb ai/gal; EPA Reg. No. 62719-292) to hops.  For
resistance management, the labels indicate that spinosad should be
rotated with other insect control products with a different mode of
action.  Table 6 is a summary of the proposed application scenarios. 
The Entrust® label states the following:  “do not apply more than 7.5
oz of Entrust® (0.47 lb ai of spinosad) per acre per crop.”  Since
Entrust® is a 80% by weight ai, this should read as follows: “do not
apply more than 9.5 oz of Entrust® (0.47 lb ai) per acre per crop.” 
Rotational crop restrictions are not included on the labels.  A revised
Section B is requested.  

Table 6.  Proposed Hop Application Scenario

Formulation	Rate

(lb ai/acre)	No. Apps.	Retreatment Interval 

(RTI; days)	Preharvest Interval 

(PHI; days)	Comments

Entrust® (WP; 80% ai) SpinTor® 2SC (2 lbs ai/gal) Success® (SC; 2 lb
ai/gal)	0.062-0.100	5	5	1	do not apply more than 0.47 lb ai/acre

 

Mosquito Larvicide Application Scenario:  Aquatic application of GF-1578
Naturalyte® Insect Control (0.5% spinosad; granular; EPA Reg. No.
62719-xxx), GF-1592 Naturalyte® Insect Control (2 lb ai/gallon;
emulsifiable concentrate (EC); EPA Reg. No. 62719-xxx), and GF-1593
Naturalyte® Insect Control (1 lb ai/gallon; EC; EPA Reg. No. 62719-xxx)
for control of mosquito and midge larvae is requested.  For resistance
management, the labels indicate that spinosad should be rotated with
other mosquito larvicides with a different mode of action.  Table 7 is a
summary of the proposed application scenarios.  HED concludes that the
labels should be amended to prohibit the application of water intended
for irrigation. Table 7.  Summary of Proposed Application Scenarios

Formulation	Site	Single Application Rate 

(lb ai/acre)	Comments

GF-1578 Naturalyte® Insect Control 

(0.5% spinosad; granular; EPA Reg. No. 62719-xxx) 

GF-1592 Naturalyte® Insect Control 

(2 lb ai/gallon; EC; EPA Reg. No. 62719-xxx)

GF-1593 Naturalyte® Insect Control 

(1 lb ai/gallon; EC; EPA Reg. No. 62719-xxx)	temporary standing water: 
woodland pools, snow pools, roadside ditches, retention ponds,
freshwater dredge spoils, tire racks and other nature manmade
depressions, rock holes, pot holes, and similar areas subject to holding
water	0.018-0.031	•single application rates of up to 0.10 lb ai/acre
are permitted in waters high in organic content, deep-water mosquito
habits, or those with dense surface cover, and where monitoring
indicates a lack of control at typical rates

•no more than 20 applications per year are permitted in dormant rice
fields, standing water within agricultural sites, and permanent marine
and freshwater sites

•retreatment intervals (RTIs) of 7 days are specified unless
monitoring indicates that larval populations have reestablished or
weather conditions have rendered initial treatments ineffective. 

	other freshwater sites:  natural and manmade aquatic sites and edges of
lakes, ponds, canals, stream eddies, creek edges, and retention ponds

	freshwater swamps and marshes:  mixed hardwood swamps cattail marsh,
common reed wetland, water hycinth ponds, and similar freshwater areas
with emergent vegetation	0.045

marine coastal areas:  intertidal areas above the mean high water mark,
mangroves, brackish swamps and marshes, coastal impoundments, and
similar areas

	stormwater/drainage systems:  storm sewers, catch basins, drainage
ditches, and similar areas	0.031-0.045

wastewater:  sewage effluent, sewers, sewage lagoons, cesspools,
oxidation ponds, septic ditches and tanks, animal waste lagoons and
settling ponds, livestock runoff lagoons, wastewater impoundments
associated with fruit and vegetable processing, and similar areas

	dormant rice fields:  impounded water in dormant rice fields (for
application only during the interval between harvest and preparation of
the field for the next cropping cycle)	0.017-0.033

natural and artificial containers:  tree holes, bromeliads, leaf axils,
and other similar natural water holding containers

cemetery urns, bird baths, flower pots, rain barrels, buckets, single
tires, tires stockpiled in dumps, landfills, recycling plants, and other
similar areas

abandoned swimming pool, ornamental ponds, flooded roof tops, and
similar water holding sites

landfill containers, salvage yards, and abandoned vehicles	0.017-0.045

For control of mosquito larvae species in standing water within
agricultural/crop sites where mosquito breeding occurs:  pastures/hay
fields, rangeland, orchards, and citrus groves	0.017-0.045

	

4.3  Dietary Exposure/Risk Pathway

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

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

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

Magnitude of the Residue - Hops:  The petitioner proposed translating
the dried basil residue data to hops.  The Chemistry Science Advisory
Council (ChemSAC) reviewed the proposal and determined the following
(ChemSAC minutes min_293.9-28-05.doc):  “…hops are large plants,
growing to heights in excess of 18 ft.  Thus, biomass considerations
imply that residue levels in hops should be significantly lower than in
basil.  Given that identical use patterns are intended for basil and
hops, the basil tolerance should be adequate for hops.  The ChemSAC
agreed that the proposed data translation is reasonable….”

Based on fresh basil field trial data which resulted in combined
residues of spinosyn A and D of 0.43-1.9 ppm (5 x 0.094 lb ai/acre; RTI
= 4-6days; PHI = 1 day) and the basil processing study which indicated a
11.6x processing factor for dried basil, HED established a 22 ppm
tolerance for the combined residues of spinosyn A and D in/on dried
basil (D278777, W. Donovan, 10-Jul-2002).  Therefore, based on these
data, HED concludes that a hop, dried cone tolerance of 22 ppm is
appropriate (revised Section F is requested).  HED notes that hops are
not fed to livestock, therefore a discussion concerning the
nature/magnitude of the residue in livestock resulting from the
application to spinosad is unnecessary.  

Based on the results of a confined rotational crop study, the MARC
concluded that the residues of concern in rotational crops are spinosyn
A and D (D243816, G. Herndon, 3-Mar-1998; field rotational crop data
have not been submitted).  The confined study was conducted at 0.98 lb
ai/acre (2.0x) and indicated that residues are incorporated into the
general carbon pool.  Spinosyns A and D were not detected in the rotated
crops (wheat, lettuce, and radish; PBIs of 30, 120, and 365 days). 
Since the confined study was conducted at 2.0x the maximum proposed rate
and since spinosyns A and D were not detected, HED concludes that no
rotational crops restrictions are required for the currently- proposed
crops.

Magnitude of the Residue - Mosquito Larvicide:  EFED provided HED with
the following total spinosad water concentrations resulting from the
mosquito larvicide application of spinosad (20 x 0.10 lb ai/acre; RTI =
7 days; D331271, Ronald Parker, 28-July-2006):  peak - 489 ppb; annual
average - 472 ppb.  The water numbers were generated using the Pesticide
Root Zone Model (PRZM 3.12) and Exposure Analysis Modeling System (EXAMS
2.98.04) models and assumed a 10 cm water column and static conditions
(no flow through or dilution).  HED concludes that these estimates are
conservative for the following reasons:  (1) mosquito larvae predominate
in areas sheltered from wind and wave action; therefore treatment of an
entire body of water is unlikely and dilution of treated with untreated
water will likely occur; (2) static conditions (no inflow or dilution);
and (3) uniform 10 cm water depth.  

Crops, Livestock, Drinking Water, and Rotational Crops:  Based on the
proposed application scenario, the results of the plant metabolism
studies, and the currently-registered applications scenarios, HED
concludes that the magnitude of the residue resulting from the treatment
of impounded water in crop fields, the magnitude of the residue in
livestock resulting from the consumption of treated water, and the
magnitude of the residue in rotational crops will be insignificant when
compared to the currently-established tolerances.  In addition, EFED
indicated that, based on the range of application sites listed on the
mosquito larvicide label, the mosquito larvicide use is not likely to
cause exposure through drinking water that would exceed other crops
already assessed.  Therefore, exposure to spinosad via consumption of
treated water will be adequately considered.  However, assuming the
theoretical 489 ppb water concentration and assuming that this water is
used to provide 1 inch of irrigation, a spinosad application rate of
0.11 lb ai/acre is calculated (one acre-inch of water = 27,154 gallons).
 HED has previously reviewed a petition for application of spinosad as a
fruit fly bait to all food crops (0.0003 lb ai/acre; 7-14 day RTI;
D319956, T. Bloem, 10-Aug-2005).  In support of this request, mustard
green, spinach, cowpea forage, and snap bean forage field trial residue
data were submitted.  Each of these crops were treated with spinosad at
0.001x the theoretical irrigation rate (residues of <0.005-0.0076),
0.004x the theoretical irrigation rate (residues of <0.005-0.0094 ppm),
or 0.014x the theoretical irrigation rate (residues of 0.011-0.110 ppm)
and were harvested on the same day as application.  Based on the residue
data, significant spinosad residues in irrigated crops are possible. 
HED notes that the 489 ppb water concentration is conservative in that
it assumes a 10 cm depth and static conditions (no inflow or dilution). 
However, the theoretical spinosad water concentration resulting from the
mosquito larvicide use would have to drop by >200x to yield
insignificant residues in/on irrigated crops.  Therefore, HED requests
that the petitioner revise the labels to prohibit application to water
intended for irrigation.  

Fish/Shellfish:  HED concluded that the residues of concern in
fish/shellfish for tolerance enforcement are spinosyn A and D; for
purposes of risk assessment, HED concluded that adjustment of the TRRs
in the edible tissues from the 19 ppb spinosyn A bioconcentration study
for the EFED water concentration resulting from the mosquito larvicide
use is acceptable (see Section 3.2).  

Based on TRRs of ~0.50 ppm in the edible tissue from the spinosyn A
19-ppb bioconcentration study, the identification of spinosyn A or D at
~30% of the TRRs on the last day of dosing, and the 489 ppb water
concentration estimation provided by EFED, HED concludes that the
following tolerances for the combined residues of spinosyn A and
spinosyn D are appropriate (0.50 ppm x 0.30 x (489 ppb ÷ 19 ppb) = 3.9
ppm): fish - 4.0 ppm; fish, shellfish, crustacean - 4.0 ppm; and fish,
shellfish, mollusc - 4.0 ppm.  Based on the 489 ppb water concentration
provided by EFED and the TRRs of ~0.50 ppm in the edible tissue from the
spinosyn A 19-ppb bioconcentration study, the dietary risk assessment
should assume a residue of 12.5 ppb in fish and shellfish (0.50 ppm x
489 ppb ÷ 19 ppb = 12.5 ppm). 

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

Analytical Enforcement Method - Livestock:  HED is recommending for the
establishment of fish and shellfish tolerances and will assume that the
current livestock enforcement methods are suitable for enforcing these
tolerances (Method GRM 95.03 - G. Herndon, 6-Apr-1999; Method GRM 95.15
- D249374, M. Doherty, 24-Jun-1999; Method RES 95114 (immunoassay
method) - G. Herndon, 5-Jan-1999).  

4.4  Water Exposure and Risk Pathway

Environmental Fate Assessment:  Environmental fate data indicates that
the spinosad transformation products maintain the basic ring structure
of spinosad and that combined spinosad and its transformation products
are stable.  Therefore, EFED and HED concluded that a total residue
method should be used when estimating residues in water.  Summarized
below are the general fate properties for spinosyns A and D (D331271, R.
Parker, 28-July-2006). 

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

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

Ground and Surface Water Estimates:  Based on the fate of spinosad
discussed in the above paragraphs, EFED provided HED with water
estimates using a total residue method (assumes spinosad and its
transformation products are stable under the aqueous photolysis, aerobic
soil metabolism, and anaerobic aquatic metabolism conditions).  Total
spinosad water concentrations resulting from the mosquito larvicide
application of spinosad were as follows (20 x 0.033 lb ai/acre; RTI = 7
days; highest registered/proposed rate):  peak - 489 ppb; annual average
472 ppb.  The water numbers were generated using the Pesticide Root Zone
Model (PRZM 3.12) and Exposure Analysis Modeling System (EXAMS 2.98.04)
models and assumed a 10 cm water column and static conditions (no flow
through or dilution).  The peak estimate was used for determination of
residues in fish/shellfish.  EFED noted that based on the range of
application sites listed on the mosquito larvicide label, the mosquito
larvicide use is not likely to result in exposure through drinking water
that would exceed other crops already assessed.  Therefore, EFED
provided HED with the following surface water (FIRST) and ground water
(Screening Concentration in Ground Water (SCIGROW)) drinking water
concentrations resulting from application of spinosad to turf (4 x 0.4
lb ai/acre; RTI = 7 days; highest registered/proposed rate excluding the
mosquito larvicide use):  surface water - acute 34.5 ppb and chronic
10.5 ppb; ground water - 1.1 ppb.  Therefore, the dietary exposure
assessment assumed a water concentration of 10.5 ppb for all water
sources (direct and indirect).  The models and their description are
available at the EPA internet site:   HYPERLINK "http://www.epa.gov/
oppefed1/models/water/"  http://www.epa.gov/ oppefed1/models/water/ .  

4.5  Dietary-Exposure Analysis

The resulting exposure estimates were ≤86% the cPAD and are therefore
less than HED’s level of concern.  Table 8 is a summary of the chronic
dietary risk assessment.  



Table 8.  Summary of Chronic Dietary Exposure and Risk (drinking water
included)

Population	cPAD (mg/kg/day)	Exposure (mg/kg/day)	%cPAD

General U.S. Population	0.027	0.009881	37

All Infants (< 1 year old)

0.008751	32

Children 1-2 years old

0.023254	86

Children 3-5 years old

0.019551	72

Children 6-12 years old

0.012974	48

Youth 13-19 years old

0.008480	31

Adults 20-49 years old

0.008523	32

Adults 50+ years old

0.008195	30

Females 13-49 years old

0.007971	30



4.6  Residential Exposure and Risk Pathway

Spinosad is currently registered for use on turf and ornamentals to
control a variety of worms, moths, flies, beetles, midges, thrips,
leafminers and fire ants.  Granular (homeowner) and EC (commercial
applicators) formulations are registered.  Since no dermal endpoints
were identified and based on the granular formulation and low vapor
pressure for spinosad, residential handler/applicator and
post-application dermal/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,
ingestion of granulars, and soil ingestion).  Since HIARC did not
identify an acute dietary endpoint, episodic ingestion of granulars was
not assessed.  The resulting combined short-term incidental oral MOEs
were 640 and are therefore less than HED’s level of concern. 

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.  

4.7  Non-occupational Off-Target Exposure

Spray drift is always a potential source of exposure to residents nearby
to spraying operations.  This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from ground application.  The Agency has been working with
the Spray Drift Task Force, EPA Regional Offices, 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 data base submitted by the Spray
Drift Task Force, a membership of U.S. pesticide registrants, and is
developing a policy on how to appropriately apply the data and the
AgDRIFT® computer model to its risk assessments for pesticides applied
by air, orchard airblast and ground hydraulic methods.  After the policy
is in place, the Agency may impose further refinements in spray drift
management practices to reduce off-target drift with specific products
with significant risks associated with drift.



5.0  AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

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

Short-Term Aggregate Risk Assessment:  Currently, only short-term
incidental oral exposures to toddlers are anticipated from the
registered turf and ornamental application.  This incidental oral
exposure is 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.  Table 9 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 less than HED’s level of
concern. 

Table 9.  Short-Term Aggregate Risk and DWLOC Calculations.

Population	 NOAEL

(mg/kg/day)	Target

MOE	Chronic Food and Water Exposure

(mg/kg/day)	Residential Oral Exposure1

(mg/kg/day)	Aggregate MOE 

(food, water, and residential)2

All infants (< 1 year old)	4.9	100	0.008751	0.0077	300

Children (1-2 years old)	4.9	100	0.023254	0.0077	160

Children (3-5 years old)	4.9	100	0.019551	0.0077	180

Children (6-12 years old)	4.9	100	0.012974	0.0077	240

1	residential exposure = sum of hand-to-mouth, object-to-mouth, and soil
ingestion residue estimates; see D284802, M.Dow and D.Vogel, 15-Aug-2002

2	Aggregate MOE = NOAEL ÷ (Chronic Food Exposure + Residential
Exposure)

Chronic Aggregate Risk Assessment:  Since there are no
registered/proposed uses which result in chronic residential exposures,
the chronic aggregate exposure assessment is concerned only with
exposure from food and water.  Since the dietary exposure analysis
included drinking water, the discussion and exposure estimates presented
in Section 4.5 represent aggregate chronic exposure. 

6.0  CUMULATIVE RISK

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding for spinosad and any other
substances, and spinosad does not appear to produce a toxic metabolite
produced by other substances.  For the purposes of this tolerance
action, therefore, EPA has assumed that 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 OPP 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

D316077, M. Dow, 22-Aug-2005 (mosquito larvicide)

D329918, M. Dow, 29-Jun-2006 (hops)

7.1  Handler Exposure 

No chemical-specific data were available with which to assess potential
exposure to occupational 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 proposed product labels involved
in this assessment directs applicators and other handlers to wear the
following PPE:  long-sleeved shirt, long pants and shoes plus socks
(GF-1592 Naturalyte® Insect Control label (mosquito larvicide label)
also instructs handlers to wear protective eyewear).  No other statement
of PPE is listed on the label.  Based on the toxicological data, HED
concludes that only inhalation assessments are necessary (dermal and
cancer assessment are unnecessary; see Section 3.0).   

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-wand, backpack sprayer, and push-type granular spreader) are
assessed as a combined job function.  With these types of hand held
operations, all handling activities are assumed to be effected 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 PPE for each aspect of the job
without requiring an applicator to wear unnecessary PPE that may be
required for a mixer/loader (e.g., chemical resistant gloves may only be
necessary during the pouring of a liquid formulation).  

Mosquito Larvicde:    SEQ CHAPTER \h \r 1 Based upon the proposed
labels, HED believes most occupational pesticide handlers (i.e., mixers,
loaders, applicators) will probably be “commercial” handlers. 
Private, “grower” handlers are
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●mixer/loaders supporting aerial operations

●aerial applicator

●applicator using open-cab airblast machinery (HED does not have unit
exposure for mist-     blower applicators; therefore, airblast is used
as a conservative surrogate)

●applicator using open cab ground boom machinery

●applicator using high-pressure hand-wand sprayer.

Other methods of application might be utilized such as backpack sprayer
for spot treatments (etc).  Based on data in the PHED, HED believes
exposures and risks from other methods of application will be lower than
those noted above.   The methods listed above involve much larger
volumes of material to be handled per work day than could possibly be
handled with smaller sprayers or methods of delivery.  

Typically, private (i.e.,  grower) pesticide handlers are expected to
experience short-term duration exposures (1 - 30 days).   However,
“commercial” (i.e., state employed or contracted) handlers might
experience intermediate-term duration exposures (1 - 6 months).  The
Science Advisory Council for Exposure (ExpoSAC) Standard Operating
Procedure (SOP) 9.1 (Revised 25 September 2001), “Standard Values for
Daily Acres Treated in Agriculture” indicates that up to 1,200 acres
per day may be treated by aerial applications.  Ground-boom machinery
and mist-blower machinery are believed to treat a maximum of 200 acres
per day and a high-pressure hand-wand sprayer to spray  a maximum of
1,000 gallons of spray per day.   

A MOE of 100 is adequate to protect occupational pesticide handlers. 
All MOEs are >100 except for a mixer loader using open pour loading of a
WP in support of aerial application and an applicator using
high-pressure hand-wand (all formulations).  The PHED contains data
which indicate that a dust/mist filtering respirator will reduce
exposure to dusts and mists by 80%.  An 80% reduction in inhalation
exposure would result in MOEs which are > than 100.  For a mixer/loader
supporting aerial operations at 1200 acres per day and for an applicator
using 1000 gallons per day using a high-pressure hand-wand, a dust/mist
filtering respirator is required to obtain a MOE that does not exceed
HED’s level of concern (revised Section B).  Table 10 is a summary of
exposures and risks to pesticide handlers.

Hops:  Based upon the proposed use patterns,  HED believes that the most
highly-exposed occupational pesticide handler exposures are for a
mixer/loader open-pour loading the WP formulation, a mixer/loader using
open-pour of liquids, and an applicator using open-cab air-blast
machinery.  Further, HED believes exposure durations will be short-term
(1 - 30 days).   Intermediate-term (1-6 months) and long-term (>6
months) exposures are not expected.

It is expected that some private applicators may perform all tasks, that
is, mix, load and apply the material.  However, HED ExpoSAC draft
Standard Operating Procedure (SOP) (29 March 2000) directs that although
the same individual may perform all tasks, in some cases they shall be
assessed separately.  A MOE of 100 is adequate to protect occupational
pesticide handlers.  Since the calculated MOEs are >100, the proposed
use pattern does not exceed HED's level of concern.  Table 10 is a
summary of exposures and risks to pesticide handlers.



Table 10.  Estimated Handler Exposure and Risk from the Proposed Use of 
Spinosad as a Mosquito/Midge Larvicide and to Hops.

Unit Exposure1

(mg ai/lb handled)	Applic. Rate2	Units Treated3

Per Day	Average Daily

Dose4 (mg/kg/day)	MOE5

ST	IT

Mosquito Larvicde

Mixer/Loader - Liquid - Open Pour - Supporting Aerial Operation

Inhal	0.0012 HC	0.1  lb ai/acre	1,200 acres	Inhal	0.0021	2,300	1,300

Mixer/Loader - WP - Open Pour - Supporting Aerial Operation

Inhal	0.043 MC

Protected	0.0086	0.1  lb ai/acre	1,200 acres	Inhal	0.074         

          	0.015	66

326	36

180

Aerial Applicator

Inhal	0.000068 MC	0.1  lb ai/acre	1,200 acres	Inhal	0.00012	40,800
23,000

Applicator - Open Cab - Airblast surrogate for mist blower

Inhal	0.0045 HC	0.1 lb  ai/acre	40 acres	Inhal	0.00026	18,850	10,400

Applicator - Ground-boom - Open Cab

Inhal	0.00074 HC	0.1  lb ai/acre	200 acres	Inhal	0.00021	23,300	13,000

Applicator - High Pressure Hand-wand6

Inhal	0.079 LC

Protected	0.016	2.0 lb ai/gal formulation

(0.1 lb ai/acre)	1,000 gal/day

@ 2 gal/acre = 500 acres/day

0.1 lb ai/acre * 500 acre/day =

50 lb ai/day	Inhal	0.056

          	0.011	88

450	50

245

Hops

Mixer/Loader - WP with Water Soluble Bags

Inhal.	0.00024 LC	0.1 lb ai/acre	40 acres	Inhal	0.000014	350,000	--

Mixer/Loader - Liquid Open-Pour

Inhal	0.0012 HC	0.1 lb ai/acre	40 acres	Inhal	0.000069	71,000	--

Applicator - Airblast - Open Cab

Inhal	0.0045 HC	0.1 lb ai/acre	40 acres	Inhal	0.00026	19,000	--

1	Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”,
Estimates of Worker Exposure from The 	PHED (ver. 1.1, August 1998). 
Inhal. = Inhalation.  Data Confidence: LC, MC, and HC = low, medium, and
high confidence.

2	Applic. Rate. = Taken from proposed labeling for GF-1592 Naturalyte
Insect Control.

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

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

5	MOE  = NOAEL  ÷ ADD.   Short-term  inhalation NOAEL = 4.9 mg/kg/day;
intermediate-term inhalation NOAEL = 2.7 mg 	ai/kg/day; ST = Short-term
MOE; IT= Intermediate-term MOE

6	At one point the proposed label provides mixing instructions for the
rate 2 gal/acre finish spray  (the only indication of 	volume/acre). 
HED has assumed that volume per acre to estimate total ai/day for an
applicator using high pressure spray wand.

7.2  Post-Application Worker Exposure

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

7.3  Restricted Entry Interval (REI)

  SEQ CHAPTER \h \r 1 On spinosad agricultural use labels, the suggested
REI is 4 hours.  Most of the use sites on the proposed label evidently
do not fall under the protections of the Worker Protection Standard
(WPS) and therefore the label does not list a REI.  However, there is a
header “Agricultural/Crop Site” in which pastures/hay fields,
rangeland, orchards and citrus groves are listed.  HED suggests that the
RD confirm whether or not a REI is necessary for the agricultural uses. 

Mosquito Larvicide:    SEQ CHAPTER \h \r 1 On spinosad agricultural use
labels, the suggested REI is 4 hours.  Most of the use sites on the
proposed label evidently do not fall under the protections of the Worker
Protection Standard (WPS) and therefore the label does not list a REI. 
However, there is a header “Agricultural/Crop Site” in which
pastures/hay fields, rangeland, orchards and citrus groves are listed. 
HED suggests that the RD confirm whether or not a REI is necessary for
the agricultural uses.  

Hops:  The REI listed on the 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
following reduced risk criteria:

●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.

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●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.

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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. 

Based on the toxicity criteria listed above, spinosad meets the criteria
for a reduced (4 hour) REI.

8.0  DEFICIENCIES / DATA NEEDS

8.1  Toxicology

Mosquito larvicide

●28-day inhalation toxicity study in rat (MOEs less than HED’s level
of concern calculated but since <1000, this study is required)

Hops

●28-day inhalation toxicity study in rat waived due to inhalation MOEs
>1000

8.2  Chemistry

Mosquito Larvicide

●Section F

Hops

●Revised Section B - do not apply more than 9.5 oz of Entrust® (0.47
lb ai) per acre per crop

●Revised Section F

8.3  Occupational/Residential

Mosquito Larvicide

●Revised Section B - dust/mist filtering respirator is required for
mixer/loaders supporting aerial application of the WP and for hand-wand
applicators (all formulations).

● On spinosad agricultural use labels, the suggested REI is 4 hours. 
Most of the use sites on the proposed label evidently do not fall under
the protections of the Worker Protection Standard (WPS) and therefore
the label does not list a REI.  However, there is a header
“Agricultural/Crop Site” in which pastures/hay fields, rangeland,
orchards and citrus groves are listed.  HED suggests that the RD confirm
whether or not a REI is necessary for the agricultural uses.  

Hops

●none

Attachment 1: Chemical Structures

RDI: RAB1 Branch (12-Jul-2006)

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

Attachment 1: Chemical Names and Structures

Common Name

Chemical Name	Structure

Spinosyn A

(Factor A)

&

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摧巕<଀2-[(6-deoxy-2,3,4-tri-O-methyl-α-L-manno-pyranosyl)oxy]-13-[[
5-(dimethylamino)-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]oxacyclododecin-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	sturcutue 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

Spinosad (110003)	Human Health Risk Assessment	D316077

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Spinosad (110003)	Human Health Risk Assessment	D316077

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