![](media/image1.wmf){width="0.93125in"
height="0.7284722222222222in"}Number range CHAPTER**UNITED STATES
ENVIRONMENTAL PROTECTION AGENCY**

WASHINGTON, D.C. 20460

OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

**[MEMORANDUM]{.underline}**

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**

[**1.0 EXECUTIVE SUMMARY** 3](#__RefHeading___Toc142352783)

[**2.0 PHYSICAL/CHEMICAL PROPERTIES** 7](#__RefHeading___Toc142352784)

[**3.0 HAZARD CHARACTERIZATION** 8](#__RefHeading___Toc142352785)

[3.1 Endocrine Disruption 9](#__RefHeading___Toc142352786)

[3.2 Residues of Concern for Dietary Risk Assessment
9](#__RefHeading___Toc142352787)

[**4.0 EXPOSURE ASSESSMENT AND CHARACTERIZATION**
11](#__RefHeading___Toc142352788)

[4.1 Summary of Registered Uses 11](#__RefHeading___Toc142352789)

[4.2 Summary of Proposed Uses 11](#__RefHeading___Toc142352790)

[4.3 Dietary Exposure/Risk Pathway 13](#__RefHeading___Toc142352791)

[4.5 Dietary-Exposure Analysis 16](#__RefHeading___Toc142352792)

[4.6 Residential Exposure and Risk Pathway
17](#__RefHeading___Toc142352793)

[**5.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION**
18](#__RefHeading___Toc142352794)

[**6.0 CUMULATIVE RISK** 18](#__RefHeading___Toc142352795)

[**7.0 OCCUPATIONAL EXPOSURE** 19](#__RefHeading___Toc142352796)

[7.1 Handler Exposure 19](#__RefHeading___Toc142352797)

[7.2 Post-Application Worker Exposure 22](#__RefHeading___Toc142352798)

[7.3 Restricted Entry Interval (REI) 22](#__RefHeading___Toc142352799)

[**8.0 DEFICIENCIES / DATA NEEDS** 23](#__RefHeading___Toc142352800)

[8.1 Toxicology 23](#__RefHeading___Toc142352801)

[8.2 Chemistry 23](#__RefHeading___Toc142352802)

[8.3 Occupational/Residential 23](#__RefHeading___Toc142352803)

[]{#__RefHeading___Toc142352783 .anchor}**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  no endpoint             
  populations)        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          oral NOAEL = 4.9        level of concern (LOC) for
  incidental oral     mg/kg/day               margins of exposure (MOEs) \<
                                              100 (residential)

  dermal (all         dermal risk assessments 
  intervals)          are not required        

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

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

  cancer (oral,       not likely to be        
  dermal, inhalation) 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).

***Aggregate Exposure and 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. Aggregate short-term (food, water,
and residential) exposures resulted in MOEs ≥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

[]{#__RefHeading___Toc142352784 .anchor}**2.0 PHYSICAL/CHEMICAL
PROPERTIES**

+-----------+----------------------------------------------------------+
| **Table   |                                                          |
| 2. Test   |                                                          |
| Compound  |                                                          |
| Nomen     |                                                          |
| clature** |                                                          |
+===========+==========================================================+
| Chemical  | ![](media/image2.wmf){width="3.522222222222222in"        |
| Structure | height="2.078472222222222in"}                            |
+-----------+----------------------------------------------------------+
| Common    | Spinosad                                                 |
| name      |                                                          |
+-----------+----------------------------------------------------------+
| Company   | XDE-105                                                  |
| exp       |                                                          |
| erimental |                                                          |
| name      |                                                          |
+-----------+----------------------------------------------------------+
| IUPAC     | **Spinosyn A:**                                          |
| name      | (2*R*,3a*S*,5a*R*,5b*S*,                                 |
|           | 9*S*,13*S*,14*R*,16a*S*,16b*R*)-2-(6-deoxy-2,3,4-tri-*O* |
|           | -methyl-α-L-mannopyranosyloxy)-13-(4-dimethylamino-2,3,4 |
|           | ,6-tetradeoxy-β-D-erythropyranosyloxy)-9-ethyl-2,3,3a,5a |
|           | ,5b,6,7,9,10,11,12,13,14,15,16a,16b-hexadecahydro-14-met |
|           | hyl-1*H*-8-oxacyclododeca\[*b*\]*as*-indacene-7,15-dione |
|           |                                                          |
|           | **Spinosyn D:**                                          |
|           | (2*S*,3a*R*,5a*S*,5b*S*,9*S*                             |
|           | ,13*S*,14*R*,16a*S*,16b*R*)-2-(6-deoxy-2,3,4-tri-*O*-met |
|           | hyl-α-L-mannopyranosyloxy)-13-(4-dimethylamino-2,3,4,6-t |
|           | etradeoxy-β-D-erythropyranosyloxy)-9-ethyl-2,3,3a,5a,5b, |
|           | 6,7,9,10,11,12,13,14,15,16a,16b-hexadecahydro-4,14-dimet |
|           | hyl-1*H*-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-\[\[5-(dimethylamin |
|           | o)-tetrahydro-6-methyl-2*H*-pyran-2-yl\]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:**                                          |
|           | 2-\[(6-deoxy-2,3,4-tri-O-m                               |
|           | ethyl-α-L-manno-pyranosyl)oxy\]-13-\[\[5-(dimethylamino) |
|           | -tetrahydro-6-methyl-2*H*-pyran-2-yl\]oxy\]-9-ethyl-2,3, |
|           | 3a,5a,5b,6,9,10,11,12,13,14,16a,16b-tetradecahydro-4,14- |
|           | methyl-1H-as-Indaceno\[3,2-d\]oxacyclododecin-7,15-dione |
+-----------+----------------------------------------------------------+
| CAS \#    | **Spinosyn A:** 131929-60-7; **Spinosyn D:** 131929-63-0 |
+-----------+----------------------------------------------------------+

+--------------------------+--------+--------+--------+-----------------+
| **Table 3.               |        |        |        |                 |
| Physicochemical          |        |        |        |                 |
| Properties of the        |        |        |        |                 |
| Technical Grade Test     |        |        |        |                 |
| Compound**               |        |        |        |                 |
+==========================+========+========+========+=================+
| Melting range            | Sp     |        |        | EPA Fact Sheet  |
|                          | inosad |        |        |                 |
|                          | A:     |        |        |                 |
|                          | 84-    |        |        |                 |
|                          | 99.5°C |        |        |                 |
|                          |        |        |        |                 |
|                          | Sp     |        |        |                 |
|                          | inosad |        |        |                 |
|                          | D:     |        |        |                 |
|                          | 161.5  |        |        |                 |
|                          | -170°C |        |        |                 |
+--------------------------+--------+--------+--------+-----------------+
| pH (10% slurry of        | 7.74   |        |        |                 |
| spinosad in water)       |        |        |        |                 |
+--------------------------+--------+--------+--------+-----------------+
| Density at 20°C          | 0.512  |        |        |                 |
+--------------------------+--------+--------+--------+-----------------+
| Water solubility (ppm)   | Sp     |        |        |                 |
|                          | inosad |        |        |                 |
|                          | A:     |        |        |                 |
|                          | 89.4   |        |        |                 |
|                          |        |        |        |                 |
|                          | Sp     |        |        |                 |
|                          | inosad |        |        |                 |
|                          | D:     |        |        |                 |
|                          | 0.495  |        |        |                 |
+--------------------------+--------+--------+--------+-----------------+
| Vapor pressure at 25°C   | Sp     |        |        |                 |
| (kPa)                    | inosad |        |        |                 |
|                          | A: 3.0 |        |        |                 |
|                          | x      |        |        |                 |
|                          | 1      |        |        |                 |
|                          | 0^-11^ |        |        |                 |
|                          |        |        |        |                 |
|                          | Sp     |        |        |                 |
|                          | inosad |        |        |                 |
|                          | D: 2.0 |        |        |                 |
|                          | x      |        |        |                 |
|                          | 1      |        |        |                 |
|                          | 0^-11^ |        |        |                 |
+--------------------------+--------+--------+--------+-----------------+
| Dissociation constant    | not    |        |        |                 |
| (pK~a~)                  | ava    |        |        |                 |
|                          | ilable |        |        |                 |
+--------------------------+--------+--------+--------+-----------------+
| Octanol/water partition  | pH 5   | **Sp   | **Sp   |                 |
| coefficient Log(K~OW~)   |        | inosad | inosad |                 |
|                          | pH 7   | A**    | D**    |                 |
|                          |        | 2.8    | 3.2    |                 |
|                          | pH 9   |        |        |                 |
|                          |        | 4.0    | 4.5    |                 |
|                          |        |        |        |                 |
|                          |        | 5.2    | 5.2    |                 |
+--------------------------+--------+--------+--------+-----------------+
| UV/visible absorption    | not    |        |        |                 |
| spectrum                 | ava    |        |        |                 |
|                          | ilable |        |        |                 |
+--------------------------+--------+--------+--------+-----------------+

[]{#__RefHeading___Toc142352785 .anchor}**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       |               |               |                           |
| Toxic    |               |               |                           |
| ological |               |               |                           |
| Doses    |               |               |                           |
| and      |               |               |                           |
| Toxic    |               |               |                           |
| ological |               |               |                           |
| E        |               |               |                           |
| ndpoints |               |               |                           |
| for      |               |               |                           |
| Sp       |               |               |                           |
| inosad** |               |               |                           |
+==========+===============+===============+===========================+
| Exposure | Dose Used in  | FQPA SF and   | Study and Toxicological   |
|          | Risk          | Endpoint for  | Effects                   |
| Scenario |               | Risk          |                           |
|          | Assessment,   | Assessment    |                           |
|          | UF            |               |                           |
+----------+---------------+---------------+---------------------------+
| Acute    | No endpoint   |               |                           |
| Dietary  | attributable  |               |                           |
| -        | to a single   |               |                           |
|          | exposure was  |               |                           |
| all      | identified.   |               |                           |
| pop      | This risk     |               |                           |
| ulations | assessment is |               |                           |
|          | not required. |               |                           |
+----------+---------------+---------------+---------------------------+
| Chronic  | NOAEL= 2.7    | FQPA SF = 1x  | Chronic Toxicity Study in |
| Dietary  | mg/kg/day     |               | Dogs; LOAEL = 8.22        |
| -        |               | cPAD = 0.027  | mg/kg/day; based on       |
|          | UF = 100      | mg/kg/day     | vacuolation in glandular  |
| all      |               |               | cells (parathyroid) and   |
| pop      | cRfD = 0.027  |               | lymphatic tissues,        |
| ulations | mg/kg/day     |               | arteritis, and increases  |
|          |               |               | in serum alanine          |
|          |               |               | aminotransferase,         |
|          |               |               | aspartate                 |
|          |               |               | aminotransferase, and     |
|          |               |               | triglycerides levels      |
+----------+---------------+---------------+---------------------------+
| Sh       | NOAEL= 4.9    | FQPA SF = 1x  | Subchronic Feeding Study  |
| ort-term | mg/kg/day     |               | in Dogs; LOAEL = 9.73     |
| In       |               | LOC for MOEs  | mg/kg/day based on        |
| cidental | UF = 100      | \< 100        | microscopic changes in    |
| Oral     |               |               | multiple organs, clinical |
|          |               |               | signs of toxicity,        |
| (1 - 30  |               |               | decreases in mean body    |
| Days)    |               |               | weights and food          |
|          |               |               | consumption and           |
|          |               |               | biochemical evidence of   |
|          |               |               | anemia and possible liver |
|          |               |               | damage                    |
+----------+---------------+---------------+---------------------------+
| Dermal   | Short-,Int    |               |                           |
| (Any     | ermediate-and |               |                           |
| Time     | Long-Term     |               |                           |
| Period)  | 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.      |               |                           |
+----------+---------------+---------------+---------------------------+
| Sh       | Oral NOAEL=   | LOC for MOEs  | Subchronic Feeding Study  |
| ort-term | 4.9 mg/kg/day | \< 100        | in Dogs; LOAEL = 9.73     |
| In       | (inhalation   |               | mg/kg/day based on        |
| halation | absorption    | (             | microscopic changes in a  |
|          | rate = 100%)  | occupational) | multiple organs, clinical |
| (1 - 30  |               |               | signs of toxicity,        |
| days)    | UF = 100      |               | decreases in mean body    |
|          |               |               | weights and food          |
|          |               |               | consumption and           |
|          |               |               | biochemical evidence of   |
|          |               |               | anemia and possible liver |
|          |               |               | damage                    |
+----------+---------------+---------------+---------------------------+

+----------+---------------+---------------+---------------------------+
| I        | Oral NOAEL=   | LOC for MOEs  | Chronic Toxicity Study in |
| ntermedi | 2.7 mg/kg/day | \< 100        | Dogs; LOAEL = 8.22        |
| ate-term |               |               | mg/kg/day; based on       |
| In       | (inhalation   | (             | vacuolation in glandular  |
| halation | absorption    | occupational) | cells (parathyroid) and   |
|          | rate = 100%)  |               | lymphatic tissues,        |
| (1 - 6   |               |               | arteritis, and increases  |
| Months)  | UF = 100      |               | in serum alanine          |
|          |               |               | aminotransferase,         |
|          |               |               | aspartate                 |
|          |               |               | aminotransferase, and     |
|          |               |               | triglycerides levels      |
+----------+---------------+---------------+---------------------------+
| Cancer   | Cl            |               |                           |
|          | assification: |               |                           |
|          | 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

[]{#__RefHeading___Toc142352786 .anchor}**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.

[]{#__RefHeading___Toc142352787 .anchor}**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/Shellfish^1^   adjustment of the TRRs in the edible  spinosyn A and D
                      tissues from the 19 ppb spinosyn A    
                      bioconcentration study for the EFED   
                      water concentration resulting from    
                      the mosquito larvicide use            
  ---------------------------------------------------------------------------------

^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)

[]{#__RefHeading___Toc142352788 .anchor}**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

Number range CHAPTERresidential exposure analysis - D284802, M.Dow and
D.Vogel, 15-Aug-2002

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

[]{#__RefHeading___Toc142352789 .anchor}**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.

[]{#__RefHeading___Toc142352790 .anchor}**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  | N  | Retre  | Preha | Comments             |
|                |       | o. | atment | rvest |                      |
|                | (lb   | A  | In     | Int   |                      |
|                | ai/   | pp | terval | erval |                      |
|                | acre) | s. |        |       |                      |
|                |       |    | (RTI;  | (PHI; |                      |
|                |       |    | days)  | days) |                      |
+----------------+-------+----+--------+-------+----------------------+
| Entrust® (WP;  | 0     | 5  | 5      | 1     | do not apply more    |
| 80% ai)        | .062- |    |        |       | than 0.47 lb ai/acre |
| SpinTor® 2SC   | 0.100 |    |        |       |                      |
| (2 lbs ai/gal) |       |    |        |       |                      |
| Success® (SC;  |       |    |        |       |                      |
| 2 lb ai/gal)   |       |    |        |       |                      |
+----------------+-------+----+--------+-------+----------------------+

***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                      | Si   | Comments      |
|                   |                           | ngle |               |
|                   |                           | App  |               |
|                   |                           | lica |               |
|                   |                           | tion |               |
|                   |                           | Rate |               |
|                   |                           |      |               |
|                   |                           | (lb  |               |
|                   |                           | ai/a |               |
|                   |                           | cre) |               |
+-------------------+---------------------------+------+---------------+
| GF-1578           | **temporary standing      | 0.0  | •**single     |
| Naturalyte®       | water:** woodland pools,  | 18-0 | application   |
| Insect Control    | snow pools, roadside      | .031 | rates of up   |
|                   | ditches, retention ponds, |      | to 0.10 lb    |
| (0.5% spinosad;   | freshwater dredge spoils, |      | ai/acre are   |
| granular; EPA     | tire racks and other      |      | permitted in  |
| Reg. No.          | nature manmade            |      | waters high   |
| 62719-xxx)        | depressions, rock holes,  |      | in organic    |
|                   | pot holes, and similar    |      | content,      |
| GF-1592           | areas subject to holding  |      | deep-water    |
| Naturalyte®       | water                     |      | mosquito      |
| Insect Control    |                           |      | habits, or    |
|                   |                           |      | those with    |
| (2 lb ai/gallon;  |                           |      | dense surface |
| EC; EPA Reg. No.  |                           |      | cover, and    |
| 62719-xxx)        |                           |      | where         |
|                   |                           |      | monitoring    |
| GF-1593           |                           |      | indicates a   |
| Naturalyte®       |                           |      | lack of       |
| Insect Control    |                           |      | control at    |
|                   |                           |      | typical       |
| (1 lb ai/gallon;  |                           |      | rates**       |
| EC; EPA Reg. No.  |                           |      |               |
| 62719-xxx)        |                           |      | •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   | 0    |               |
|                   | marshes:** mixed hardwood | .045 |               |
|                   | swamps cattail marsh,     |      |               |
|                   | common reed wetland,      |      |               |
|                   | water hycinth ponds, and  |      |               |
|                   | similar freshwater areas  |      |               |
|                   | with emergent vegetation  |      |               |
+-------------------+---------------------------+------+---------------+
|                   | **marine coastal areas:** |      |               |
|                   | intertidal areas above    |      |               |
|                   | the mean high water mark, |      |               |
|                   | mangroves, brackish       |      |               |
|                   | swamps and marshes,       |      |               |
|                   | coastal impoundments, and |      |               |
|                   | similar areas             |      |               |
+-------------------+---------------------------+------+---------------+
|                   | **stormwater/drainage     | 0.0  |               |
|                   | systems:** storm sewers,  | 31-0 |               |
|                   | catch basins, drainage    | .045 |               |
|                   | ditches, and similar      |      |               |
|                   | areas                     |      |               |
+-------------------+---------------------------+------+---------------+
|                   | **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:**  | 0.0  |               |
|                   | impounded water in        | 17-0 |               |
|                   | dormant rice fields (for  | .033 |               |
|                   | application only during   |      |               |
|                   | the interval between      |      |               |
|                   | harvest and preparation   |      |               |
|                   | of the field for the next |      |               |
|                   | cropping cycle)           |      |               |
+-------------------+---------------------------+------+---------------+
|                   | **natural and artificial  | 0.0  |               |
|                   | containers:** tree holes, | 17-0 |               |
|                   | bromeliads, leaf axils,   | .045 |               |
|                   | 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        |      |               |
+-------------------+---------------------------+------+---------------+
|                   | **For control of mosquito | 0.0  |               |
|                   | larvae species in         | 17-0 |               |
|                   | standing water within     | .045 |               |
|                   | agricultural/crop sites   |      |               |
|                   | where mosquito breeding   |      |               |
|                   | occurs:** pastures/hay    |      |               |
|                   | fields, rangeland,        |      |               |
|                   | orchards, and citrus      |      |               |
|                   | groves                    |      |               |
+-------------------+---------------------------+------+---------------+

[]{#__RefHeading___Toc142352791 .anchor}**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 ^14^C-residues. Extensive fractionation and
characterization of nonextractable and polar ^14^C-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: [http://www.epa.gov/
oppefed1/models/water/](http://www.epa.gov/ oppefed1/models/water/).

[]{#__RefHeading___Toc142352792 .anchor}**4.5 Dietary-Exposure
Analysis**

Chronic dietary risk assessments were conducted using the DEEM-FCID™
(ver. 2.03; acute and cancer endpoints were not identified) which
incorporates the food consumption data from the USDA's 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 chronic surface water estimate resulting from application
of spinosad to turf (4 x 0.4 lb ai/acre; RTI = 7 days). 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          Exposure            %cPAD
                     (mg/kg/day)   (mg/kg/day)         

  General U.S.       0.027         0.009881            37
  Population                                           

  All Infants (\< 1                0.008751            32
  year old)                                            

  Children 1-2 years               0.023254            86
  old                                                  

  Children 3-5 years               0.019551            72
  old                                                  

  Children 6-12                    0.012974            48
  years old                                            

  Youth 13-19 years                0.008480            31
  old                                                  

  Adults 20-49 years               0.008523            32
  old                                                  

  Adults 50+ years                 0.008195            30
  old                                                  

  Females 13-49                    0.007971            30
  years old                                            
  -------------------------------------------------------------------------

[]{#__RefHeading___Toc142352793 .anchor}**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.

[]{#__RefHeading___Toc142352794 .anchor}**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         |       |     |            |           |             |
| Ca            |       |     |            |           |             |
| lculations.** |       |     |            |           |             |
+---------------+-------+-----+------------+-----------+-------------+
| Population    | NOAEL | Tar | Chronic    | Re        | Aggregate   |
|               |       | get | Food and   | sidential | MOE         |
|               | (     |     | Water      | Oral      |             |
|               | mg/kg | MOE | Exposure   | Ex        | (food,      |
|               | /day) |     |            | posure^1^ | water, and  |
|               |       |     | (          |           | resi        |
|               |       |     | mg/kg/day) | (m        | dential)^2^ |
|               |       |     |            | g/kg/day) |             |
+---------------+-------+-----+------------+-----------+-------------+
| All infants   | 4.9   | 100 | 0.008751   | 0.0077    | 300         |
| (\< 1 year    |       |     |            |           |             |
| old)          |       |     |            |           |             |
+---------------+-------+-----+------------+-----------+-------------+
| Children (1-2 | 4.9   | 100 | 0.023254   | 0.0077    | 160         |
| years old)    |       |     |            |           |             |
+---------------+-------+-----+------------+-----------+-------------+
| Children (3-5 | 4.9   | 100 | 0.019551   | 0.0077    | 180         |
| years old)    |       |     |            |           |             |
+---------------+-------+-----+------------+-----------+-------------+
| Children      | 4.9   | 100 | 0.012974   | 0.0077    | 240         |
| (6-12 years   |       |     |            |           |             |
| old)          |       |     |            |           |             |
+---------------+-------+-----+------------+-----------+-------------+

^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.

[]{#__RefHeading___Toc142352795 .anchor}**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
<http://www.epa.gov/pesticides/cumulative/.>

[]{#__RefHeading___Toc142352796 .anchor}**7.0 OCCUPATIONAL EXPOSURE**

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

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

[]{#__RefHeading___Toc142352797 .anchor}**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:*** Number range CHAPTERBased upon the proposed
labels, HED believes most occupational pesticide handlers (*i.e.*,
mixers, loaders, applicators) will probably be "commercial" handlers.
Private, "grower" handlers are also likely to apply the material.
Typically, handlers involved in "area wide" control efforts are
"commercial," *i.e.*, professional handlers. HED believes the most
highly exposed handlers are the following:

●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>
<colgroup>
<col style="width: 20%" />
<col style="width: 0%" />
<col style="width: 15%" />
<col style="width: 0%" />
<col style="width: 25%" />
<col style="width: 15%" />
<col style="width: 0%" />
<col style="width: 11%" />
<col style="width: 0%" />
<col style="width: 10%" />
<col style="width: 0%" />
</colgroup>
<thead>
<tr class="header">
<th colspan="10"><strong>Table 10. Estimated Handler Exposure and Risk
from the Proposed Use of Spinosad as a Mosquito/Midge Larvicide and to
Hops.</strong></th>
<th></th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td rowspan="2"><p>Unit Exposure<sup>1</sup></p>
<p>(mg ai/lb handled)</p></td>
<td colspan="2" rowspan="2">Applic. Rate<sup>2</sup></td>
<td colspan="2" rowspan="2"><p>Units Treated<sup>3</sup></p>
<p>Per Day</p></td>
<td colspan="2" rowspan="2"><p>Average Daily</p>
<p>Dose<sup>4</sup> (mg/kg/day)</p></td>
<td colspan="3">MOE<sup>5</sup></td>
<td></td>
</tr>
<tr class="even">
<td>ST</td>
<td colspan="2">IT</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="10"><em><strong>Mosquito Larvicde</strong></em></td>
<td></td>
</tr>
<tr class="even">
<td colspan="10">Mixer/Loader - Liquid - Open Pour - Supporting Aerial
Operation</td>
<td></td>
</tr>
<tr class="odd">
<td>Inhal 0.0012 HC</td>
<td colspan="2">0.1 lb ai/acre</td>
<td colspan="2">1,200 acres</td>
<td colspan="2">Inhal 0.0021</td>
<td>2,300</td>
<td colspan="2">1,300</td>
<td></td>
</tr>
<tr class="even">
<td colspan="10">Mixer/Loader - WP - Open Pour - Supporting Aerial
Operation</td>
<td></td>
</tr>
<tr class="odd">
<td><p>Inhal 0.043 MC</p>
<p>Protected 0.0086</p></td>
<td colspan="2">0.1 lb ai/acre</td>
<td colspan="2">1,200 acres</td>
<td colspan="2"><p>Inhal 0.074</p>
<p>0.015</p></td>
<td><p>66</p>
<p>326</p></td>
<td colspan="2"><p>36</p>
<p>180</p></td>
<td></td>
</tr>
<tr class="even">
<td colspan="10">Aerial Applicator</td>
<td></td>
</tr>
<tr class="odd">
<td>Inhal 0.000068 MC</td>
<td colspan="2">0.1 lb ai/acre</td>
<td colspan="2">1,200 acres</td>
<td colspan="2">Inhal 0.00012</td>
<td>40,800</td>
<td colspan="2">23,000</td>
<td></td>
</tr>
<tr class="even">
<td colspan="10">Applicator - Open Cab - Airblast surrogate for mist
blower</td>
<td></td>
</tr>
<tr class="odd">
<td>Inhal 0.0045 HC</td>
<td colspan="2">0.1 lb ai/acre</td>
<td colspan="2">40 acres</td>
<td colspan="2">Inhal 0.00026</td>
<td>18,850</td>
<td colspan="2">10,400</td>
<td></td>
</tr>
<tr class="even">
<td colspan="10">Applicator - Ground-boom - Open Cab</td>
<td></td>
</tr>
<tr class="odd">
<td>Inhal 0.00074 HC</td>
<td colspan="2">0.1 lb ai/acre</td>
<td colspan="2">200 acres</td>
<td colspan="2">Inhal 0.00021</td>
<td>23,300</td>
<td colspan="2">13,000</td>
<td></td>
</tr>
<tr class="even">
<td colspan="10">Applicator - High Pressure Hand-wand6</td>
<td></td>
</tr>
<tr class="odd">
<td><p>Inhal 0.079 LC</p>
<p>Protected 0.016</p></td>
<td colspan="2"><p>2.0 lb ai/gal formulation</p>
<p>(0.1 lb ai/acre)</p></td>
<td colspan="2"><p>1,000 gal/day</p>
<p>@ 2 gal/acre = 500 acres/day</p>
<p>0.1 lb ai/acre * 500 acre/day =</p>
<p>50 lb ai/day</p></td>
<td><p>Inhal 0.056</p>
<p>0.011</p></td>
<td colspan="2"><p>88</p>
<p>450</p></td>
<td colspan="2"><p>50</p>
<p>245</p></td>
<td></td>
</tr>
<tr class="even">
<td colspan="10"><em><strong>Hops</strong></em></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="11">Mixer/Loader - WP with Water Soluble Bags</td>
</tr>
<tr class="even">
<td>Inhal. 0.00024 LC</td>
<td colspan="3">0.1 lb ai/acre</td>
<td>40 acres</td>
<td>Inhal 0.000014</td>
<td colspan="3">350,000</td>
<td colspan="2">--</td>
</tr>
<tr class="odd">
<td colspan="11">Mixer/Loader - Liquid Open-Pour</td>
</tr>
<tr class="even">
<td colspan="2">Inhal 0.0012 HC</td>
<td colspan="2">0.1 lb ai/acre</td>
<td>40 acres</td>
<td>Inhal 0.000069</td>
<td colspan="3">71,000</td>
<td colspan="2">--</td>
</tr>
<tr class="odd">
<td colspan="11">Applicator - Airblast - Open Cab</td>
</tr>
<tr class="even">
<td colspan="2">Inhal 0.0045 HC</td>
<td colspan="2">0.1 lb ai/acre</td>
<td>40 acres</td>
<td>Inhal 0.00026</td>
<td colspan="3">19,000</td>
<td colspan="2">--</td>
</tr>
</tbody>
</table>

^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.

[]{#__RefHeading___Toc142352798 .anchor}**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.

[]{#__RefHeading___Toc142352799 .anchor}**7.3 Restricted Entry Interval
(REI)**

Number range CHAPTEROn 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:*** Number range CHAPTEROn 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.

●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.

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

[]{#__RefHeading___Toc142352800 .anchor}**8.0 DEFICIENCIES / DATA
NEEDS**

[]{#__RefHeading___Toc142352801 .anchor}**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

[]{#__RefHeading___Toc142352802 .anchor}**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

[]{#__RefHeading___Toc142352803 .anchor}**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**              | Structure                             |
|                              |                                       |
| Chemical Name                |                                       |
+==============================+=======================================+
| **Spinosyn A**               | ![](media/im                          |
|                              | age2.wmf){width="3.522222222222222in" |
| **(Factor A)**               | height="2.078472222222222in"}         |
|                              |                                       |
| 2-\[(6-deoxy-2,3,4-tri       |                                       |
| -O-methyl-α-L-manno-pyranosy |                                       |
| l)oxy\]-13-\[\[5-(dimethylam |                                       |
| ino)-tetrahydro-6-methyl-2H- |                                       |
| pyran-2-yl\]oxy\]-9-ethyl-2, |                                       |
| 3,3a,5a,5b,6,9,10,11,12,13,1 |                                       |
| 4,16a,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-\[\[5-(dimethylamin |                                       |
| o)-tetrahydro-6-methyl-2H-py |                                       |
| ran-2-yl\]oxy\]-9-ethyl-2,3, |                                       |
| 3a,5a,5b,6,9,10,11,12,13,14, |                                       |
| 16a,16b-tetradecahydro-4,14- |                                       |
| methyl-1H-as-Indaceno\[3,2-d |                                       |
| \]oxacyclododecin-7,15-dione |                                       |
+------------------------------+---------------------------------------+
|                              |                                       |
+------------------------------+---------------------------------------+
| **N-Demethyl Spinosyn D**    | spinosyn D with N-demethylation of    |
|                              | the forosamine ring                   |
| **(Factor B of D)**          |                                       |
|                              |                                       |
| 2-\[(6-deoxy-2,3,4-tri-O-    |                                       |
| methyl-α-L-manno-pyranosyl)o |                                       |
| xy\]-9-ethyl-2,3,3a,5a,5b,6, |                                       |
| 9,-10,11,12,13,14,16a,16b-te |                                       |
| tradecahydro-4,14-dimethyl-1 |                                       |
| 3-\[\[tetrahydro-6-methyl-5- |                                       |
| (methylamino)-2H-pyran-2-yl\ |                                       |
| ]oxy\]-1H-as-Indaceno\[3,2-d |                                       |
| \]oxacyclododecin-7,15-dione |                                       |
+------------------------------+---------------------------------------+
| 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                        |
+------------------------------+---------------------------------------+