Document ID: EPA-HQ-OPP-2008-0272-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-04-16T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

 PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

Date:		18-DEC-2008

SUBJECT:	Spiromesifen:  Human-Health Risk Assessment for Proposed
Section 3 Uses on Pop Corn, Sweet Corn, Low-Growing Berry Subgroup; and
Section 18 Emergency Exemption Use on Soybean.  

PC Code:  024875	DP Barcodes:  358892, 358894, and 358914

Decision Nos.:  391027, 391287, and 396698	Registration No.:  264-719
and 264-850

Petition Nos.:  8F7338, 8E7340, and 08DE03	Regulatory Action:  Section 3
Registration and Section 18 Registration

Risk Assessment Type:  Single Chemical Aggregate	Case No.:  NA

TXR No.:  NA	CAS No.:  283594-90-1

MRID No.:  NA	40 CFR:  180.607

FROM:	Jennifer R. Tyler, Chemist

Robert Mitkus, Ph.D., Toxicologist

		Registration Action Branch 1 (RAB1)

		Health Effects Division (HED; 7509P)

THROUGH:	Dana M. Vogel, Branch Chief 

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

		RAB1/HED (7509P)

TO:		Jennifer Gaines/John Hebert (RM Team 07)

Insecticide Branch/Registration Division (RD) (7505P)

Introduction

Bayer CropScience has submitted a petition (PP# 8F7338) to register the
end use products Oberon® 2 Suspension Concentrate (SC)
Insecticide/Miticide [a 2 pound (lb) active ingredient (ai)/gallon (gal)
SC formulation of spiromesifen
(2-oxo-3-(2,4,6-trimethylphenyl)-1-oxaspiro[4.4]non-3-en-4-yl
3,3-dimethylbutanoate) and Oberon® 4 SC Insecticide/Miticide [a 4 pound
(lb) active ingredient (ai)/gallon (gal) SC formulation of spiromesifen]
for use on pop corn.  Bayer requests the establishment of permanent
tolerances for the combined residues of spiromesifen and its enol
metabolite
(4-hydroxy-3-(2,4,6-trimethylphenyl)-1-oxaspiro[4,4]non-3-en-2-one),
calculated as the parent compound equivalents, in/on pop corn grain
(0.02 ppm) and pop corn stover (1.5 ppm).

The Interregional Research Project No. 4 (IR-4), on behalf of the
Agricultural Experiment Stations of Washington (WA), has submitted a
petition (PP# 8E7340) to register the end use products Oberon® 2 SC
Insecticide/Miticide and Oberon® 4 SC Insecticide/Miticide for use on
sweet corn and lowbush berry subgroup.  IR-4 requests the establishment
of permanent tolerances for the combined residues of spiromesifen and
its enol metabolite, calculated as the parent compound equivalents,
in/on corn, sweet, kernel plus cob with husks removed (0.02 ppm); corn,
sweet, forage (6.0 ppm); corn, sweet, stover (7.0 ppm); and berry and
small fruit, low-growing berry, subgroup 13-07G (2.0 ppm).

In accordance with 40 CFR 166.20, the Delaware Department of Agriculture
has submitted a Section 18 Specific Emergency Exemption request for the
use of spiromesifen on soybeans to control two spotted spider mites
(Tetranychus urticae).

The most recent human-health risk assessment was conducted in
conjunction with a request for use of spiromesifen on field corn and
tomatoes (Memo, J. Tyler et al., 5/21/08; D352921).  A human-health risk
assessment was also recently conducted in conjunction with a request for
use of spiromesifen on beans (Memo, B. Hanson, 12/20/07; D338832).  The
following information from the 12/20/07 risk assessment can be applied
directly to this action:

Identification of Active Ingredient and Physical and Chemical Properties
(Sections 2.2 and 2.3; pp. 13-14).

Hazard Characterization and Dose-Response Characterization (Section 3.1;
pp. 15-19).

Hazard Identification and Toxicity Endpoint Selection (Section 3.5; pp.
21-27).  See Appendix A for pertinent toxicology tables.

Endocrine Disruption (Section 3.6; p. 28).

Pesticide Metabolism and Environmental Degradation (Sections
5.1.1-5.1.9; pp. 28-33).

Cumulative Risk Assessment (Section 8.0; pp. 38-39).

This document contains only those aspects of the risk assessment which
are affected by the proposed Section 3 requests for use of spiromesifen
on pop corn, sweet corn, low-growing berry subgroup, and Section 18
Emergency Exemption request for use on soybeans.

1.0	Executive Summary

Spiromesifen is a tetronic acid insecticide/miticide used for control of
a broad spectrum of mites and whiteflies in corn, cotton, strawberries,
and various vegetable crops.  The mode of action is through inhibition
of lipid synthesis.  Permanent tolerances are currently established for
the combined residues of spiromesifen and its enol metabolite,
calculated as the parent compound equivalents, in/on a variety of
commodities (40 CFR §180.607).  There are currently no registered or
proposed residential uses for spiromesifen.

Food Quality Protection Act (FQPA) Considerations:  Based on the
available hazard and exposure data, HED recommends that the FQPA Safety
Factor (SF) be reduced to 1X (see Section 3.0 of this risk assessment
for the basis of this recommendation).

™, Version 2.03).  DEEM™ 7.81 default processing factors and 100%
crop treated (CT) was assumed for all commodities; and tolerance-level
residues were assumed for all commodities except for the leafy-green and
leafy-Brassica vegetable subgroups (4A and 5B).  For these subgroups,
the residue values were adjusted to account for the metabolite BSN
2060-4-hydroxymethyl (free and conjugated), which is a residue of
concern in leafy vegetables for risk assessment purposes only.  Drinking
water was incorporated directly into the dietary exposure assessment
using the chronic estimated drinking water concentration (EDWC) of 188
ppb for groundwater generated by the Provisional Cranberry Model.  The
chronic dietary risk assessment shows that the chronic dietary risk
estimates do not exceed HED’s level of concern [i.e., <100% of the
chronic population-adjusted dose (cPAD)].  For the general U.S.
population the exposure for food and water utilized 49% of the cPAD. 
The chronic dietary risk estimate for the highest exposed population
subgroup, children 3-5 years old, is 77% of the cPAD.

Aggregate-Risk Estimates:  A chronic aggregate exposure risk assessment
was assessed by incorporating the drinking water directly into the
dietary-exposure assessment.  As the chronic dietary exposure estimates
are not of concern to HED for the general U.S. population or any
population subgroup, the chronic aggregate risk is not of concern for
these populations.  Short-, intermediate-, and long-term aggregate-risk
assessments were not performed because there are no registered or
proposed uses of spiromesifen which result in residential exposures. 
Acute and cancer aggregate-risk assessments were not performed because
no appropriate endpoint was available to determine the acute reference
dose (aRfD) for the general population or any population subgroup and
spiromesifen is not carcinogenic, respectively.

Occupational Exposure and Risk Assessment:  Since there were no
compound-specific data available with which to assess pesticide handler
exposure, the exposure estimates are based upon surrogate exposure data
in the Pesticide Handler Exposure Database (PHED) Surrogate Exposure
Guide (AUG-1998).  Since no dermal endpoints were identified, only
short- and intermediate-term inhalation exposures and risks are
estimated.  Margins of exposure (MOEs) ≥100 are adequate to protect
occupational pesticide handlers.  The calculated MOEs are >100;
therefore, the proposed uses are not of concern to HED.

There is a potential for post-application exposure to agricultural
workers during the course of typical agricultural activities.  However,
in this case, the Hazard Identification Assessment Review Committee
(HIARC) did not identify short- or intermediate-term dermal endpoints
and there is a 12-hour post-application restricted-entry interval (REI).
 In addition, due to the vapor pressure of spiromesifen, HED believes
post-application inhalation exposure to be negligible.  Therefore, a
post-application exposure assessment was not performed.

Environmental Justice Considerations:  Potential areas of environmental
justice concerns, to the extent possible, were considered in the
human-health risk assessment, in accordance with U.S. Executive Order
12898, "Federal Actions to Address Environmental Justice in Minority
Populations and Low-Income Populations,"
http://www.eh.doe.gov/nepa/tools/guidance/
Volume1/2-6-EO_12898envjustice.pdf).  The Office of Pesticide Programs
(OPP) typically considers the highest potential exposures from the legal
use of a pesticide when conducting human health risk assessments,
including, but not limited to, people who obtain drinking water from
sources near agricultural areas, the variability of diets within the
U.S., and people who may be exposed when harvesting crops.  Should these
highest exposures indicate potential risks of concern, OPP further
refines the risk assessments to ensure that the risk estimates are based
on the best available information.

Review of Human Research:  This risk assessment relies in part on data
from PHED studies in which adult human subjects were intentionally
exposed to a pesticide or other chemical.  These studies have been
determined to require a review of their ethical conduct, and have
received that review.

Recommendations for Tolerances:

Pop Corn (PP# 8F7338):  Provided revised Sections B and F are submitted,
there are no residue chemistry, toxicology or occupational exposure
issues that would preclude granting an unconditional registration and
permanent tolerances for residues of spiromesifen and its enol
metabolite, calculated as the parent compound equivalents, in/on corn,
pop, stover at 4.0 ppm; and corn, pop, grain at 0.02 ppm.

Sweet Corn (PP# 8E7340):  Provided revised Sections B and F are
submitted, there are no residue chemistry, toxicology or occupational
exposure issues that would preclude granting an unconditional
registration and permanent tolerance for residues of spiromesifen and
its enol metabolite, calculated as the parent compound equivalents,
in/on corn, sweet, kernel plus cob with husks removed at 0.02 ppm; corn,
sweet, forage at 17 ppm; and corn, sweet, stover at 12 ppm.

Low-Growing Berries (PP# 8E7340):  There are no residue chemistry,
toxicology or occupational exposure issues that would preclude granting
the permanent tolerance for residues of spiromesifen and its enol
metabolite, calculated as the parent compound equivalents, in/on berry,
lowgrowing, subgroup 13G at 2.0 ppm.

In addition, the available residue chemistry, toxicology or occupational
exposure databases supports the following tolerances for residues of
spiromesifen and its enol metabolite, calculated as the parent compound
equivalents, in/on milk, fat at 0.25 ppm, and meat, byproducts of
cattle, goats, horses, and sheep at 0.20 ppm  SEQ CHAPTER \h \r 1 .

Soybean (PP#08DE03):  There are no residue chemistry, toxicology or
occupational exposure issues that would preclude granting the
time-limited tolerance for residues of spiromesifen and its enol
metabolite, calculated as the parent compound equivalents, in/on soybean
at 0.02 ppm; soybean, forage at 30 ppm; and soybean, hay at 86 ppm.

  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 

2.0	PROPOSED USE PATTERN

Pop Corn (PP# 8F7338):  Bayer submitted proposed labels for Oberon® 2
SC Insecticide/Miticide (2 lb ai/gal; EPA Reg. No. 264-719) and Oberon®
4 SC Insecticide/Miticide (4 lb ai/gal; EPA Reg. No. 264-850) for use on
pop corn.

Sweet Corn and Low-Growing Berries (PP# 8E7340):  IR-4 submitted
proposed labels for Oberon® 2 SC Insecticide/Miticide (2 lb ai/gal; EPA
Reg. No. 264-719) and Oberon® 4 SC Insecticide/Miticide (4 lb ai/gal;
EPA Reg. No. 264-850) for use on sweet corn and Oberon® 2 SC
Insecticide/Miticide (2 lb ai/gal; EPA Reg. No. 264-719) for use on
low-growing berries.

Soybeans (PP# 08DE03):  The Delaware Department of Agriculture has
submitted a proposed Section 18 label for Oberon® 2 SC
Insecticide/Miticide (2 lb ai/gal; EPA Reg. No. 264-719) for use on
soybeans.

A summary of the proposed use patterns is provided in Table 2.1.

Table 2.1.  Summary of Proposed Directions for Use of Spiromesifen.

Crop	Trade Name (EPA Reg. No.)	Application Timing, Type, Equipment
Applic. Rate 

(lb ai/A)	Maximum Number Applications 

Per Season	Maximum Seasonal Application Rate 

(lb ai/A) 	PHI1 

(days)	Use Directions and Limitations1

PP# 8F7338

Pop corn	Oberon® 2 SC

(264-719)	Ground & aerial	0.27	2	0.27	30 (grain, stover);

5 (forage)	RTI:  14 days.2  Min. spray volume:  10 GPA ground, 5 GPA
aerial.

	Oberon® 4 SC (264-850)

PP# 7E7340

Sweet corn	Oberon® 2 SC

(264-719)	Ground & aerial	0.27	2	0.27	5 (forage, silage sweet corn for
fresh consumption); 30 (grain or stover).	RTI:  14 days.2  Min. spray
volume:  10 GPA ground, 5 GPA aerial.

	Oberon® 4 SC (264-850)

Low-growing berry (crop group 13-07-G)	Oberon® 2 SC (264-719)	Ground &
aerial	0.25	3	0.75	3	RTI:  7 days.  Min. spray volume:  100.0 GPA
ground.

PP# 08DE03

Soybean	Oberon® 2 SC (264-719)	Ground & aerial	0.1875	1	0.1875	21	-

RTI = retreatment interval.  PHI = preharvest interval.  NA = not
applicable.  NS = not specified.  GPA = gallons per acre. 

The desired RTI is unclear on both labels.  Under the general directions
for Crop Uses, a RTI of 7-10 days is specified.  However, under the
specific directions for each crop, a RTI of 14 days is specified.

Additional Restrictions for all Crops:

RESTRICTED ENTRY INTERVAL (REI): Do not enter or allow worker entry into
treated areas during the REI of 12 hours following application.  

ROTATIONAL PLANT-BACK INTERVALS (PBIs):  Immediate plant-back:  Cotton,
Field Corn, Fruiting Vegetables, Leafy Vegetables, Cucurbits, Tuber
Vegetables (Potatoes), Strawberry.  30-day PBI:  Alfalfa, Barley,
Sugarbeets, Wheat.

12-month PBI:  All other crops

HED Conclusions:  HED concludes that the use directions provided in the
submitted labels are sufficient with the exception of the RTI for pop
corn and sweet corn on both the Oberon® 2 SC and Oberon® 4 SC labels. 
For both labels, a RTI of 7-10 days is specified under the general
directions for Field Crops.  However, under the specific use directions,
a RTI of 14 days is specified.  The Oberon® 2 SC and Oberon® 4 SC
labels should be revised to specify the appropriate RTI for both pop
corn and sweet corn.  The crop field trial data support a RTI of 12-14
days.

3.0	HAZARD CHARACTERIZATION/FQPA CONSIDERATIONS

Spiromesifen is believed to exert its effects through the inhibition of
lipid biosynthesis.  The critical effects observed are loss of body
weight, adrenal effects (discoloration, decrease in fine vesiculation,
and the presence of cytoplasmic eosinophilia in zona fasciculata cells),
thyroid effects (increased thyroid stimulating hormone, increased
thyroxine binding capacity, decreased T3 and T4 levels, colloidal
alteration and thyroid follicular cell hypertrophy), liver effects
(increased alkaline phosphatase, ALT and decreased cholesterol,
triglycerides), and spleen effects (atrophy, decreased spleen cell
count, and increased macrophages).  Because the spleen effects were seen
in several toxicity studies, the registrant pursued specialized
immunotoxicity studies in rats and mice that were both negative. 
Although these studies were classified as unacceptable/guideline due to
lack of positive control data, the endpoints selected for the risk
assessment are considered protective of any possible immunotoxic
effects.  In addition, although the acute and subchronic neurotoxicity
studies were classified as unacceptable/guideline due to lack of
positive control data, the studies can still be used for risk assessment
and assessment of FQPA.

Based on the hazard and exposure data, the HED spiromesifen risk
assessment team recommends that the FQPA SF be reduced to 1X.  The
recommendation is based on the following:

There is no evidence of increased susceptibility of rats or rabbits to
in utero and/or postnatal exposure to spiromesifen.  In the prenatal
developmental toxicity studies in rats and rabbits and in the
two-generation reproduction study in rats, developmental toxicity to the
offspring occurred at equivalent or higher doses than parental toxicity.

There are no neurotoxicity concerns based on acute and subchronic
neurotoxicity studies.

The dietary food exposure assessment uses tolerance-level or higher
residues and 100% CT information for all commodities.  By using these
screening-level assessments, chronic exposures and risks will not be
underestimated.  The “higher residues” are those that were
calculated using a modifying factor to account for the lack of residue
data for the metabolite BSN 2060-4-hydroxymethyl. 

The dietary drinking-water assessment uses values generated by model and
associated modeling parameters which are designed to provide
conservative, health-protective and high-end estimates of water
concentrations.

Residential exposure is not expected - spiromesifen will be registered
for agricultural and greenhouse/ornamental uses only.  

4.0	DIETARY EXPOSURE/RISK CHARACTERIZATION

The exposure pathways resulting from use of this chemical are dietary
(food and drinking water) and occupational; there are no residential
uses.  The residue chemistry data submitted in support of the proposed
uses were summarized in the HED memorandum by J. Tyler (Memo, 12/18/08;
DP# 351034).  The chronic dietary exposure assessment was completed in a
HED memorandum by J. Tyler (Memo, 12/18/08; DP# 358893).

4.1	Food Residue Profile

The nature of the residue in plants and livestock is adequately
understood based on acceptable metabolism studies conducted on lactating
goats, laying hens, lettuce, cotton, tomato, and confined rotational
crops.  Residues in crops with late-season applications are mostly on
surfaces.  The residues of concern are as follows:  

Primary crops:		spiromesifen and its enol metabolite.  BSN
2060-4-hydroxymethyl (free and conjugated) is a residue of concern in
leafy vegetables (risk assessment only);

Rotational crops:		spiromesifen, its enol metabolite, and its
metabolites containing the 4-hydroxymethyl moiety;

Livestock:		spiromesifen and its metabolites containing the enol and
4-hydroxymethyl moieties.

Residues of spiromesifen, BSN 2060-enol, and BSN 2060 4-hydroxymethyl
were quantitated by an adequately validated high-performance liquid
chromatography (HPLC)/triple-stage quadruple mass spectrometry (MS/MS). 
The current tolerance enforcement method is also adequate for enforcing
the proposed tolerances.  Method 00631 was forwarded to the Analytical
Chemistry Branch (ACB) for Agency petition method validation (PMVs;
memos, J. Tyler, 6/17/03; D290912 and D290914).  ACB reviewed the
proposed enforcement method data without a laboratory validation (Memo,
E. Kolbe, 11/15/07; DP# 305721).  The ACB determined that Method 00631
appears to meet the guidelines for an acceptable enforcement method,
provided it is modified as detailed in the 11/17/07 memo.  Once the
method has been modified, the results of the PMV will be forwarded to
the Food and Drug Administration’s (FDA) for inclusion in Pesticide
Analytical Methods (PAM) Volume II.

Pop Corn (PP# 8F7338):    SEQ CHAPTER \h \r 1 The crop field trial
residue data on pop corn are classified as scientifically acceptable. 
The residue data reflect the use of either one foliar spray application
of Oberon® 240 SC at 0.250 lb ai/A (0.9x the maximum proposed single
and seasonal application rates), or 2 foliar spray applications of
Oberon® 240 SC at 0.135 lb ai/A/application (0.5x the maximum proposed
single application rate) for a total application rate of 0.270 lb ai/A
(1x the maximum proposed seasonal application rate) (RTI of 12-14 days;
PHI of 28-29 days).  The highest-average field trial (HAFT) total
residues of spiromesifen were 1.95 ppm in/on stover (1 application;
adjusted from 38% dry matter to 85% dry matter), and 0.8435 ppm (2
applications; adjusted from 33% dry matter to 85% dry matter), and less
than the limit of detection (<LOD) in/on grain (1 or 2 applications). 
Using the North American Free Trade Agreement (NAFTA) Maximum Residue
Limit (MRL)/Tolerance Harmonization Workgroup methodology for stover,
the available crop field trial data indicate that the following
tolerance of 4.0 ppm for total residues of spiromesifen in/on corn, pop,
stover.  A tolerance of 0.02 ppm [sum of limits of quantitation (LOQs)
for each analyte] for residues in/on corn, pop, grain is adequate. 
However, a revised Section F to include the HED-recommended tolerance
for residues in/on corn, pop, stover (4.0 ppm) should be submitted.

Sweet Corn and Low-Growing Berries (PP# 8E7340):  The sweet corn crop
field trial residue data are classified as scientifically acceptable. 
The residue data reflect the use of either one foliar spray application
of Oberon® 240 SC at 0.250 lb ai/A (0.9x the maximum proposed single
application rate), or 2 foliar spray applications of Oberon® 240 SC at
0.135 lb ai/A/application (0.5x the maximum proposed single application
rate) for a total application rate of 0.270 lb ai/A (~1x the maximum
proposed seasonal application rate) [RTI of 12-14 days; PHIs of 30 days
(stover) and 5-10 days (forage and kernels plus cob with husks removed
(K+CWHR)].  The HAFT total spiromesifen residues in corn stover were
4.14 ppm (1 application), and 2.51 ppm (2 applications).  Following a
single application, the HAFT total spiromesifen residues in corn forage
were 10.83 ppm (5-day PHI), and 6.26 ppm (10-day PHI).  Following a
total of two applications, the HAFT total spiromesifen residues on corn
forage were 6.37 ppm (5-day PHI).  In corn K+CWHR, the combined residue
was <LOQ in all samples following both 1 application and 2 applications.
 Using the NAFTA MRL/Tolerance Harmonization Workgroup methodology for
sweet corn stover (30-day PHI) and forage (5-day PHI), the available
crop field trial data indicate that the following tolerances for total
residues of spiromesifen are appropriate:  12 ppm in/on corn, sweet,
stover; and 17 ppm in/on corn, sweet, forage (see Section 860.1550
Proposed Tolerances).  A tolerance of 0.02 ppm (sum of LOQs for each
analyte) for residues in/on corn, sweet, kernel plus cob with husks
removed is adequate.  A revised Section F to include the HED-recommended
tolerances for residues in/on corn, sweet, stover (12 ppm) and corn,
sweet, forage (17 ppm) should be submitted.

Although crop field trial data on low-growing berries (subgroup 13-07G)
were not submitted with the current petition, crop field trial data on
strawberries have been submitted and reviewed by HED (Memo, G. Kramer,
et al., 2/18/05; D308837).  Following a total of 3 foliar applications
at 0.24-0.26 lb ai/A/application (1x the proposed single application
rate) for a total rate of 0.75-0.77 lb ai/A (1x the proposed maximum
seasonal rate; RTI = 5-8 days), the maximum total spiromesifen residues
were 1.64 ppm (2-4 days PHI).  There is currently a tolerance for
residues of spiromesifen in/on strawberries (2.0 ppm).  As strawberry is
the representative commodity for crop subgroup 13-07G, no additional
data are required to support a tolerance on the entire crop subgroup.

Soybean (PP# 08DE03):  No crop field trial data on soybean were
submitted with the proposed Section 18.  IR-4 requested the following
tolerances on beans based on previously reviewed data (Memo, D. Rate,
12/5/07; D345985) be translated to soybean for purposes of the proposed
Section 18:

Table 4.1.  Proposed Surrogate Crops to Support Section 18 Emergency
Exemption Request for Use on Soybean.

RAC	Surrogate Crop	Proposed Tolerance (ppm)

(based on current surrogate-crop tolerance)

soybean	bean, dry	0.02

soybean, forage	cowpea, forage	30

soybean, hay	cowpea, hay	86

soybean, vegetable	bean, edible-podded	0.8

In the previously submitted field trial studies, maximum residues of
spiromesifen and its metabolite BSN 2060-enol were each below the lowest
limit of method validation (LLMV; <0.01 ppm per analyte and <0.02 ppm
for combined residues) in/on dry shelled bean seed harvested 9-10 days
after the third, or for one trial, a fourth broadcast foliar application
of spiromesifen at total rates of 0.57-0.81 lb ai/A (3x-4x the maximum
proposed application rate for soybeans).  Maximum residues of
spiromesifen and BSN 2060-enol were each below the LLMV (<0.50 ppm per
analyte and <0.10 ppm for combined residues) in/on succulent shelled
bean seed harvested one day after a third broadcast foliar application
of spiromesifen at total rates of 0.57-0.58 lb ai/A (~4x the maximum
proposed application rate for soybeans).  Maximum residues of
spiromesifen and BSN 2060-enol in/on edible-podded bean harvested one
day after receiving a third or, for one trial, a fifth application of
spiromesifen at total rates of 0.57-0.95 lb ai/A (3x-5x the maximum
proposed application rate for soybeans) were 0.39 ppm and 0.08 ppm,
respectively and maximum total residues were 0.47 ppm.  Maximum residues
of spiromesifen and BSN 2060-enol were 14.9 ppm and 1.14 ppm,
respectively, in/on succulent shelled and edible-podded bean foliage
harvested one day after receiving a third or, for one trial, a fifth
application of spiromesifen at total rates of 0.57-0.95 lb ai/A (3x-5x
the maximum proposed application rate for soybeans); maximum total
residues were 15.99 ppm in/on bean foliage.

Additionally, the submitted data for succulent shelled bean foliage were
used to establish a tolerance in cowpea forage.  However, no residue
data were submitted for cowpea hay.  A tolerance was recommended for
cowpea hay of 86 ppm, which was calculated from the recommended
tolerance for cowpea forage and adjusting for percentages of dry matter
between cowpea hay and cowpea forage.

The available residue data on dry shelled, succulent shelled, and
edible-podded beans are adequate to support the following time-limited
tolerances for residues of spiromesifen and its enol metabolite,
calculated as the parent compound equivalents:  soybean (0.02 ppm);
soybean, forage (30 ppm); and soybean, hay (86 ppm).

There are adequate field rotational-crop data to support the established
tolerances for the inadvertant or indirect combined residues of
spiromesifen, its enol metabolite, and its metabolites containing the
4-hydroxymethyl moiety in/on the rotational crop commodities of alfalfa,
barley, sugar beet, oat, and wheat.  The proposed rotational crop
restrictions (a 30-day; and a 12-month PBI for all other crops) are
consistent with what were previously deemed acceptable and are supported
by adequate data.

The available field rotational crop data are adequate to support
conditional registrations and permanent tolerances for the combined
residues of spiromesifen, its enol metabolite, and its metabolites
containing the 4-hydroxymethyl moiety in/on sweet corn and pop corn. 
Conversion of conditional registration to unconditional registration may
be considered provided that additional storage stability data are
submitted for the commodities analyzed in the field accumulation in
rotational crops studies in order to validate the 22-month storage
intervals.  

Spiromesifen, BSN 2060-enol, and BSN 2060 4-hydroxymethyl were analyzed
according to the FDA Multiresidue Method (MRM) Testing guidelines in PAM
Volume I, Appendix II (January 1994) by ABC Laboratories, Inc.  Based on
the results of this study, the MRMs tested under Protocols D, E, and F
may be suitable for the analysis of spiromesifen in nonoily (cucumber)
and fatty (ground beef) commodities.  These methods are not suitable for
BSN 2060-enol or BSN 2060 4-hydroxymethyl.  The report has been
forwarded to FDA for inclusion in PAM I (Memo, J. Tyler, 4/16/08;
D351116).

Freezer storage stability data are available for a wide variety of crop
matrices for up to 14.5 months with no indication of residue decline
(Memo, G. Kramer, et al., 2/18/05; DP# 308837).  These data validate the
storage intervals for all commodities in the magnitude of the residue
studies (452 days for sweet corn, 392 days for pop corn, ~270 days for
strawberry, 346 days for dry shelled bean seed, 399 days for succulent
shelled bean seed, 497 days for edible podded bean, and 516 days for
bean foliage). 

Livestock feed commodities associated with the current actions are field
corn forage, stover, and grain.  Tolerances for meat, milk, poultry and
egg commodities have been established (40 CFR 180.607).  Based on the
newly calculated maximum reasonable dietary burden (MRDB) for dairy
cattle, and the residue data from an available ruminant feeding study,
the currently established tolerances for milk (0.01 ppm); and meat (0.02
ppm), and fat (0.10 ppm) of cattle, goats, horses, and sheep are
adequate.  However, tolerances of 0.25 ppm for milk, fat; and 0.20 ppm
for meat, byproducts of cattle, goats, horses, and sheep are n  SEQ
CHAPTER \h \r 1 ow needed.  A revised Section F is required for the
recommended tolerances for milk, fat; and meat, byproducts of cattle,
goats, horses and sheep.

  SEQ CHAPTER \h \r 1 

The petitioner did not submit a poultry feeding study with this
petition, but previously submitted a waiver request for magnitude of the
residue study in poultry and eggs.  Based on the results of a hen
metabolism study, HED previously concluded that there is no reasonable
expectation of finite residues (180.6(a)(3)) and that the requested
waiver is appropriate (Memo, G. Kramer, 2/18/05; D308837).  As the
current action does not affect the MRDB for poultry, the waiver is
appropriate for the proposed uses.  However, should additional uses
which increase the poultry dietary burden be proposed in the future,
this conclusion will be reevaluated.

As there are no established Canadian, Mexican, or Codex Maximum Residue
Limits (MRLs) for the proposed uses, harmonization is not an issue at
this time. 

Table 4.2.  Tolerance Summary for Spiromesifen.

Commodity	Proposed Tolerance (ppm)	HED Recommended Tolerance (ppm)
Comments

(correct commodity definition)

milk, fat	-	0.25	Current tolerance is 0.20 ppm

meat byproducts*

0.20	Current tolerance is 0.15 ppm

PP#  8E7340

corn, sweet, kernel plus cob with husks removed	0.02	0.02	-

corn, sweet, forage	6.0	17	-

corn, sweet, stover	7.0	12	-

Berry and small fruit, low growing berry, subgroup 13-07G	2.0	2.0	Berry,
lowgrowing, subgroup 13G

PP# 8F7338

Pop Corn grain	0.02	0.02	corn, pop, grain

Pop Corn, Stover	1.5	4.0	corn, pop, stover

* of cattle, goats, horses and sheep

4.2	Drinking Water Residue Profile

The Environmental Fate and Effects Division (EFED) provided ground and
surface water EDWCs for spiromesifen, BSN2060-enol, and BSN2060-carboxy
(Memo, J. Hebert, 10/1/08; DP#: 351035).  EDWCs of spiromesifen were
modeled for the proposed uses on popcorn, sweet corn, and low growing
berries using the maximum use patterns, which are for cranberries and
ornamentals.  The surface water EDWCs in Table 4.2 are greater than the
reported water solubility limit for spiromesifen parent (130 µg/L at
25°C).  However, they represent residues of concern, which include
degradates likely to be more soluble than the parent.  The surface water
EDWCs for use on cranberries were adjusted by a regional
percent-cropped-area (PCA) factor (77%) to reflect the maximum fraction
of agriculture found in any watershed where cranberries are grown. 
These surface water and ground water exposure estimates were modeled
with the screening models Provisional Cranberry Model and Screening
Concentration in Ground Water (SCIGROW), respectively.

Spiromesifen is not likely to persist in the environment as it readily
undergoes both biotic and abiotic degradation; however, its primary
degradate, BSN2060-enol, is expected to persist.  While spiromesifen
strongly sorbs to sediment and is not likely to be mobile, its major
degradates, BSN2060-enol and BSN2060-carboxy, do not sorb to sediment
and are expected to leach into ground water.  Spiromesifen has limited
solubility in water (130 µg/L at 25°C) and in some cases has been
reported to have a practical solubility limit of 40 to 50 µg/L.  The
pesticide degrades primarily through aerobic soil metabolism and
hydrolysis; however, in clear shallow water it will readily undergo
photolysis.  Field studies indicate that spiromesifen readily dissipates
with field dissipation half-lives ranging from two to ten days. 

Total residue EDWCs for the proposed uses of spiromesifen likely exceed
actual values that occur in drinking water reservoirs and ground water
due to the screening design of the exposure models and variability in
the submitted environmental fate data.  Environmental degradation
half-lives used in the models reflect high-end confidence bounds and,
therefore, are longer when the data are more variable.

Table 4.2.  Total Residue EDWCs in Surface Water and Ground Water for
the Proposed Spiromesifen Uses on Popcorn, Sweet Corn, and Low Growing
Berries, Based on the Maximum Use Patterns for Cranberries and
Ornamentals.

Source	Use (maximum rate)	1-in-10-year Peak Exposure (ppb)	1-in-10-year
Annual Mean Exposure (ppb)	30-year Mean Exposure (ppb)

Surface water	Cranberries (0.75 lbs ai/A/year)	199	188	<188

Ground water	Ornamentals (3.0 lbs ai/A/year)	86	86	<86

4.3	Chronic Dietary Exposure and Risk

™ (Version 2.03), which uses food consumption data from the United
States Department of Agriculture (USDA’s) Continuing Surveys of Food
Intakes by Individuals (CSFII) from 1994-1996 and 1998.

No toxic effects attributable to a single (i.e., acute) exposure to
spiromesifen have been identified.  Therefore, an aRfD has not been
established for spiromesifen and an acute dietary exposure assessment is
not required.  Also, there is no evidence that spiromesifen is
carcinogenic to humans; therefore, a dietary cancer assessment is not
required. 

The 1994-96, 98 CSFII data are based on the reported consumption of more
than 20,000 individuals over two non-consecutive survey days.  Foods
“as consumed” (e.g., apple pie) are linked to EPA-defined food
commodities (e.g., apples, peeled fruit - cooked; fresh or N/S; baked;
or wheat flour - cooked; fresh or N/S, baked) using publicly available
recipe translation files developed jointly by USDA/ARS and EPA.  For
chronic exposure assessment, consumption data are averaged for the
entire U.S. population and within population subgroups, but for acute
exposure assessment are retained as individual consumption events. 
Based on analysis of the 1994-96, 98 CSFII consumption data, which took
into account dietary patterns and survey respondents, HED concluded that
it is most appropriate to report risk for the following population
subgroups: the general U.S. population, all infants (<1 year old),
children 1-2, children 3-5, children 6-12, youth 13-19, adults 20-49,
females 13-49, and adults 50+ years old.

For chronic dietary-exposure assessments, an estimate of the residue
level in each food or food-form (e.g., orange or orange juice) on the
food commodity residue list is multiplied by the average daily
consumption estimate for that food/food form to produce a residue intake
estimate.  The resulting residue intake estimate for each food/food form
is summed with the residue intake estimates for all other food/food
forms on the commodity residue list to arrive at the total average
estimated exposure.  Exposure is expressed in mg/kg body weight/day and
as a percent of the cPAD.  This procedure is performed for each
population subgroup.

™ 7.81 default processing factors and 100% CT were assumed for all
commodities.  Drinking water was incorporated directly into the dietary
assessment using the chronic EDWC of 188 ppb for groundwater generated
by the Provisional Cranberry Model.  The chronic dietary risk assessment
shows that for all included commodities, the chronic dietary risk
estimates do not exceed HED’s level of concern (i.e., <100% cPAD). 
For the general U.S. population the exposure for food and water utilized
49% of the cPAD.  The chronic dietary risk estimate for the highest
reported exposed population subgroup, children 3-5 years old, is 77% of
the cPAD.

Table 4.3.  Summary of Dietary (Food and Drinking Water) Exposure Risk
for Spiromesifen.

Population Subgroup	Acute Dietary (95th Percentile)	Chronic Dietary

	Dietary Exposure mg/kg/day)	% aPAD	Dietary Exposure (mg/kg/day)	% cPAD

General U.S. Population	NA	0.010662	49

All Infants (<1 year old)

0.016886	77

Children 1-2 years old

0.014868	68

Children 3-5 years old

0.014437	66

Children 6-12 years old

0.010737	47

Youth 13-19 years old

0.008666	39

Adults 20-49 years old

0.010373	47

Adults 50+ years old

0.010360	47

Females 13-49 years old

0.010493	48

*The values for the highest exposed population for each type of risk
assessment are bolded.

5.0	AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

Aggregate exposure risk assessments were assessed by incorporating the
drinking water directly into the dietary-exposure assessment for the
chronic exposure scenario.  Short-, intermediate-, and long-term
aggregate-risk assessments were not performed because there are no
registered or proposed uses of spiromesifen which result in residential
exposures.  Acute and cancer aggregate-risk assessments were not
performed because no appropriate endpoint was available to determine the
aRfD for the general population or any population subgroup and
spiromesifen is not carcinogenic.

The chronic dietary exposure estimates are not of concern to HED for the
general U.S. population and all population subgroups (see Table 4.3). 
Therefore, the chronic aggregate risk for spiromesifen is not of concern
for HED for the general U.S. population or any population subgroups.

6.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY

An occupational exposure assessment for spiromesifen was prepared in an
HED memorandum dated 12/18/08 (J. Tyler, DP# 351323).  See Table 2.1 for
a summary of the proposed use patterns.  Both proposed labels require
mixers, loaders and other handlers to wear long-sleeved shirt and long
pants, chemical-resistant gloves, and shoes plus socks.

6.1	Occupational Pesticide Handler Exposure and Risk

Based upon the proposed use patterns, HED believes the most highly
exposed occupational pesticide handlers, (i.e., mixers, loaders,
applicators) are likely to be:  1) mixer/loader using open pouring of
liquids in support of aerial operations; 2) aerial applicators; 3)
applicators using open-cab ground boom equipment; and 4) flaggers.

Spiromesifen may be applied via “chemigation.”  HED believes that a
“loader” (i.e., applicator in this sense) for chemigation will not
likely be exposed more than a loader supporting aerial operations. 
Chemigation typically involves minibulk containers which have siphon
tubes attached to the irrigation equipment and that “mixing and
loading” in the typical sense of pouring liquids, does not occur. 
Therefore, a “chemigator” is not assessed, with the assumption that
the work activity is represented by the mixer/loader supporting aerial
operations.

Handler exposure is expected to be short- and intermediate-term based on
information provided on proposed labels.  The average adult body weight
of 70 kg was used for estimating inhalation and dermal dose.  Long-term
exposures are not expected, therefore, a long-term assessment was not
conducted.

No chemical-specific data are available with which to assess potential
exposure to pesticide handlers.  The estimates of exposure to pesticide
handlers are based upon surrogate study data available in PHED.  For
pesticide handlers, it is HED policy to present estimates of dermal
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 “baseline” and the use of
protective gloves or other PPE as might be necessary. 

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

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

Where:  

Daily Exposure		=	Amount (mg ai/day) deposited on the surface of the
skin that is available for dermal absorption or amount inhaled that is
available for inhalation absorption;

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

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

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

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

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

Where:

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

Daily Exposure 			=	Amount (mg ai/day) deposited on the surface of the
skin that is available for dermal absorption or amount inhaled that is
available for inhalation absorption;

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

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

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

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

See Table 6.1 for a summary of the estimated exposures and risks to
occupational pesticide handlers.  See Appendix A for a summary of the
toxicological endpoints for use in risk assessment.



Table 6.1.  Estimated Handler Exposure and Risk from the Proposed Uses
of Spiromesifen.

Unit Exposure1

(mg ai/lb handled)	Application Rate2	Units Treated3

Per Day (A)	Average Daily

Dose4 (mg ai/kg bw/day)	MOE5

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

Inhalation         

Baseline:  0.0012 HC	0.27 lb ai/A	1200	Inhal  0.0056	3,800

Applicator – Aerial

Inhalation         

Engineering control: 0.000068 MC	0.27 lb ai/A	1200	Inhal  0.00031	67,000

Applicator - Ground-boom - Open Cab

Inhalation

Baseline:         0.00074 HC	0.27  lb ai/A	200	Inhal  0.00057	37,000

Flagger

Inhalation

Baseline:         0.00035 HC	0.27 lb ai/A	350	Inhal  0.00047	45,000

1.  Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”,
Estimates of Worker Exposure from The Pesticide Handler Exposure
Database Version 1.1, August 1998.  SLNG = Dermal Single Layer Work
Clothing No Gloves; SLWG = Dermal Single Layer Work Clothing With
Gloves; Inhal. = Inhalation.  Units = mg ai/pound of active ingredient
handled.  Data Confidence: LC = Low Confidence, MC = Medium Confidence,
HC = High Confidence.

2.  Applic. Rate taken from the Oberon 2 SC and Oberon 4 SC labels.

3.  Units Treated are taken from “Standard Values for Daily Acres
Treated in Agriculture”; Policy No. 9.1. 

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

5.  MOE = Margin of Exposure = No Observable Adverse Effect Level
(NOAEL) ( ADD.  Short-term and intermediate-term inhalation NOAEL = 21.1
mg ai/kg bw/day and are identified from a subchronic inhalation toxicity
study in the rat.

A MOE (100 is adequate to protect occupational pesticide handlers. 
Since all the estimated MOEs are >100, the proposed uses are not of
concern for HED.

6.2	Occupational Post-Application Worker Exposure and Risk

There is the potential for agricultural workers to be exposed to
post-application residues of spiromesifen.  However, the spiromesifen
risk assessment team did not identify any dermal toxicological endpoints
noting that there were no dermal, systemic or developmental toxicity
concerns at the limit dose.  A long-term (>6 months) dermal endpoint was
identified; however, long-term exposures are not expected as a result of
the proposed use pattern.  Since the vapor pressure of spiromesifen is
7.5 x 10-8 mm Hg and since there is a 12-hour REI, HED expects
post-application inhalation exposure to be negligible.

REI:  Spiromesifen is classified in acute dermal Toxicity Category III
and in Category IV for acute inhalation, eye irritation and dermal
irritation.  Therefore, the interim WPS REI of 12 hours is adequate to
protect agricultural workers from post-application exposures to
spiromesifen.

7.0	DATA NEEDS AND LABEL RECOMMENDATIONS

7.1	Toxicology

None.

7.2	Residue Chemistry

Revised Section F to include the recommended tolerances for milk, fat
(0.25 ppm); meat, byproducts of cattle, goats, horses, and sheep (0.20
ppm).

Pop Corn (PP# 8F7338):

Revised Section B to specify the appropriate RTI for pop corn.

Revised Section F to include the recommended tolerances for corn, pop,
stover (4.0 ppm).

The proposed analytical enforcement methods [Method 00631 (plants),
Method 110333 (rotational crops), and Method 110878 (livestock)] should
be modified as detailed in the 11/15/07 PMV memo.

Sweet Corn (PP# 8E7340):

Revised Section B to specify the appropriate RTI for sweet corn.

Revised Section F to include the recommended tolerances for corn, sweet,
stover (12 ppm); and corn, sweet, forage (17 ppm).

The proposed analytical enforcement methods [Method 00631 (plants),
Method 110333 (rotational crops), and Method 110878 (livestock)] should
be modified as detailed in the 11/15/07 PMV memo.

Low-Growing Berries (PP# 8E7340):

Revised Section F to include the correct commodity definition for the
subgroup – berry, lowgrowing, subgroup 13G.

The proposed analytical enforcement methods [Method 00631 (plants),
Method 110333 (rotational crops), and Method 110878 (livestock)] should
be modified as detailed in the 11/15/07 PMV memo.

7.3		Occupational and Residential Exposure

None.

cc: J. Tyler, R. Mitkus

RDI: RAB1 Chemists (5/14/08); RAB1 Branch (12/10/09); G. Kramer
(12/10/08); D. Vogel (12/18/08)

J. Tyler: S-10943: Potomac Yard 1 (PY1): (703) 305-5564: 7509P: RAB1

Appendix A:  TOXICOLOGY ASSESSMENT

A.1	Acute Toxicity Profile

Table A.1  Acute Toxicity of Spiromesifen.

Guideline

 No.	Study Type	MRID #(S).	Results	Toxicity Category

81-1	Acute oral—rat	45819514 	LD50=2000 mg/kg	III

81-2	Acute dermal—rat	45819521 	LD50=2000 mg/kg	III

81-3	Acute inhalation–rat	45819522 	LC50=4.873 mg/l	IV

81-4	Acute eye irritation—rabbit	45819525 	Not an irritant	IV

81-5	Acute dermal irritation—rabbit	45819524 	Not an irritant	IV

81-6	Skin sensitization—guinea pig	45819518 	Potential moderate 

contact sensitizer	Not applicable

A.2	Toxicity Profiles

Table A.2.  Toxicity Profile

Guideline Number/

Study Type	MRID Number (year)/

Doses/Classification	Results

870.3050

28-day oral (mouse)	  SEQ CHAPTER \h \r 1 45819523 (1999)

0, 1000, 3500, or 7000 ppm

M:  0, 202.6, 720.0, and 1292.3 mg/kg/day

F:
〠‬㘲⸹ⰶ㘠㤹㈮‬湡⁤㜱㘰〮洠⽧杫搯祡഍捁散瑰扡
敬港湯畧摩汥湩ݥ低䕁⁌慷⁳潮⁴獥慴汢獩敨⹤

LOAEL (M/F)=202.6/269.6 mg/kg/day based on decreased body weight gain
(↓25% in M; ↓41%F)

Note:  In this study only three animals were used and some of 90- day
oral toxicity guideline parameters were not measured.

870.3050

28-day oral toxicity (mouse)	  SEQ CHAPTER \h \r 1 45854505 (1998)

0 or 5000 ppm

M:  0 and 444.3 mg/kg/day (males only tested)

Acceptable/nonguideline	NOAEL was not established.

LOAEL (M/F)=444.3 mg/kg/day based on decreased body weight gain (↓51%)
and increase in alkaline phosphatase.

Note:  In this study only one dose was used and some of 90-day oral
toxicity guideline parameters were not measured.

870.3100

90-day oral toxicity (mouse)	  SEQ CHAPTER \h \r 1 45819526 (1999)

0, 140, 700, or 3500 ppm 

M:  0, 21.7, 104.5, and 589.3 mg/kg/day

F:  0, 35.3, 190.5, and 1010.3 mg/kg/day

Unacceptable/guideline	NOAEL was not established.

LOAEL=  SEQ CHAPTER \h \r 1 21.7/35.3 mg/kg/day based on gross
(discolored) and microscopic (decrease in fine vesiculation, and the
presence of cytoplasmic eosinophilia in zona fasciculata cells) changes
in the adrenal glands in both sexes.  

Note:  Some of the guideline parameters were not measured.

870.3150

14-week oral toxicity (rat)	  SEQ CHAPTER \h \r 1 45819515 (2000)

0, 100, 500, or 3000 ppm

M:  0, 6.3, 31.7, and 204.0 mg/kg/day

F:  0, 7.7, 36.6, and 232.1 mg/kg/day

Acceptable/guideline	  SEQ CHAPTER \h \r 1 NOAEL (M/F):  31.7/7.7 mg/kg
bw/day.

The LOAEL (F):  36.6 mg/kg bw/day based on thyroid effects (increased
thyroid stimulating hormone, thyroxine binding capacity, and thyroid
follicular cell hypertrophy), kidney effects (mineralization), and liver
effect (increased ALP).  

LOAEL (M):  204.0 mg/kg bw/day based on thyroid effect (colloidal
alteration, thyroid folicular cell hypertrophy, decreased T3 and T4 and
increased TBC and TSH), kidney effects (Hyalin droplets), and liver
effects (increase in ALP and ALAT).

870.3100

14-week oral toxicity (mouse)	  SEQ CHAPTER \h \r 1 45819601 (2001)

0, 20 or 80 ppm

M:  0, 3.2, and 11.5 mg/kg/day

F:  0, 5.1, and 20.3 mg/kg/day

Unacceptable/nonguideline	NOAEL=(M/F)=11.5/20.3 mg/kg/day.

LOAEL was not established.

Note:  In this study only two doses were used and some of 90-day oral
toxicity guideline parameters were not measured.

870.3100

28-day oral toxicity (rat)	  SEQ CHAPTER \h \r 1 45854507 (2000)

0, 100, 500, or 5000 ppm

F:  0, 10.9, 53.4, and 536.3 mg/kg/day (only females tested)

Acceptable/nonguideline	NOAEL=53.4 mg/kg/day.

LOAEL=  SEQ CHAPTER \h \r 1 536.3 mg/kg/day based on clinical signs
(piloerection, reduced motility, spastic gait, discolored feces and
increased reactivity when touched), decrease in body weight gain (↓53%
of controls), and food consumption, hematology (thromboplastin time
increase), clinical chemistry (increased aspartate aminotransferase and
alanine aminotransferase), liver enzyme (increased aldrin epoxidase and
epoxide hydrolase), increased spleen and lymph node cell proliferation,
organ weights (increased brain, heart and kidneys, decrease in weights
in the ovaries, spleen and thymus), gross pathology (thin appearance,
discolored adrenal glands and white mucous in the duodenum and jejunum
), and microscopic findings (vacuolation of the superficial mucosal
cells in the jejunum and duodenum, increased follicular cell hypertrophy
in the thyroid, indistinct corticomedullary junction in the thymus and
cytoplasmic changes in the adrenal glands). 

Note:  some of 90-day oral toxicity guideline parameters were not
measured.

870.3150

90-day oral toxicity (dog)	  SEQ CHAPTER \h \r 1 45819614 (2001)

0, 20, 50, 250, or 2000ppm

0, 0.75, 1.85, 9.2, and 71 mg/kg/day

Acceptable/guideline	NOAEL=9.2 mg/kg/day.

LOAEL=71 mg/kg/day (the highest dose tested or HDT) based on clinical
chemistry (increased ALP) and liver histopathology.

Note:  This study is acceptable when combined with MRID 45819623.

870.3150

90-day oral toxicity (dog)	  SEQ CHAPTER \h \r 1 45819623 (2001)

0, 3000 or 5000 ppm

M:  0, 98.4, and 172.5 mg/kg/day

F:  0, 102.8, and 170.8 mg/kg/day

Acceptable/guideline	NOAEL was not established. 

LOAEL=98.4 mg/kg/day based on increase in alkaline phosphatase and liver
histopathology (cytoplasmic changes).

Note:  This study is acceptable when combined with MRID 45819614.

870.3200

21/28-day dermal toxicity (rat)

	  SEQ CHAPTER \h \r 1 45819603 (2001)

0, 100, 300, or 1000 mg/kg/day

Acceptable/guideline	NOAEL=1000 mg/kg/day (HDT).

LOAEL was not established.

870.3465

5-day inhalation toxicity (rat)	  SEQ CHAPTER \h \r 1 45819605 (2000)

0, 2.9, 20.7, and 134.2 mg/l/day

Acceptable/nonguideline	NOAEL=20.7 mg/kg/day (0.0794 mg/l/day).

LOAEL=  SEQ CHAPTER \h \r 1 134.2 mg/kg/day (0.5143 mg/l/day) based on
the clinical signs (tremors, clonic-tonic convulsions, reduced activity,
bradypnea, labored breathing, vocalization, avoidance reaction,
giddiness, piloerection, limp, emaciation, cyanosis, squatted posture,
apathy, and salivation) and gross pathology (dark red areas or foci in
the lungs, bloated stomachs and pale liver).

Note:  No histopathology

870.3465

30-day inhalation toxicity (rat)	  SEQ CHAPTER \h \r 1 45819622 (2001)

0, 0.0050, 0.0246, or 0.0809 mg/l/day;

0, 1.3, 6.4, or 21.1 mg/kg/day 

Acceptable/nonguideline	NOAEL>21.1mg/kg/day (0.0809 mg/l/day, HDT).

LOAEL was not established.

870.3700a

Prenatal developmental in (rat)	  SEQ CHAPTER \h \r 1 45819612 (2001)

0, 10, 70, or 500 mg/kg/day

Acceptable/guideline	Maternal NOAEL=10 mg/kg/day.

LOAEL=70 mg/kg/day based on decreased body weight gain (↓15%) and
reduced food consumption.

Developmental NOAEL (500 mg/kg/day (HDT).

LOAEL >500 mg/kg/day.

870.3700b

Prenatal developmental in (rabbit)	  SEQ CHAPTER \h \r 1 45819604 (2000)

0, 5, 35, or 250 mg/kg/day

Acceptable/guideline	Maternal NOAEL=5 mg/kg/day.

LOAEL=35 mg/kg/day based on body weight loss and reduced food
consumption.

Developmental NOAEL (250mg/kg/day.

LOAEL >250 mg/kg/day.

870.3800

Reproduction and fertility effects (rat)	  SEQ CHAPTER \h \r 1 45819619
(2002)

0, 30, 120, or 500 ppm

M (P0):  0, 2.2, 8.8, and 37 mg/kg/day

F (P0):  0, 3.3, 14.2, and 64 mg/kg/day

M (F1):  0,3.3, 13.2, and 76 mg/kg/day

F (F1):  0, 4.6, 18.0, and 91 mg/kg/day

Acceptable/guideline	Parental/Systemic NOAEL (M/F)=2.2/3.8 mg/kg/day.

LOAEL (M/F)=  SEQ CHAPTER \h \r 1 8.8/13.2 mg/kg bw/day based on
significantly decreased spleen weight (absolute and relative in parental
females and  F1 males) and significantly decreased growing ovarian
follicles in females.  

Reproductive NOAEL (M/F)=37/64 mg/kg/day (HDT).

LOAEL=Not established.

Offspring NOAEL=2.2 mg/kg/day.

LOAEL=8.8 mg/kg/day based on pup body weight decrements (↓13.6) during
lactation.

870.3800

Reproduction and fertility effects (rat)	  SEQ CHAPTER \h \r 1 45854511
(2001) invalid 

0, 30, 120, or 500 ppm

M (P0):  0, 2.6, 10.2, and 46 mg/kg/day

F (P0):  0, 3.3, 14.7, and 56 mg/kg/day

M (F1):  0,3.1, 13.6, and 58 mg/kg/day

F (F1):  0, 4.7, 20.5, and 86 mg/kg/day

Not graded due to flaws  

	  SEQ CHAPTER \h \r 1 Parental/Systemic NOAEL=13.6 (M) and 20.5 (F)
mg/kg/day 

Parental LOAEL=58 (male F1) and 86 mg/kg/day (female F1) based on body
weight decrements (as high as 9% in lactating P females, at 8% and 9% at
the end of the premating period at week 12 in 500 ppm F1 adult males and
females, respectively).  Additional findings in parent rats included
slight increases in incidences of histopathology in thyroid gland
(general increases, usually not statistically significant, of follicular
cell hyperplasia and colloidal alteration in both sexes of both
generations), adrenal cortex [increased incidence of “decreased
vacuolation” in the zona glomerulosa (highly significant, but limited
to P females only)], and possibly liver (decreased incidence of
“decreased periportal fat content,” only in P females).  Although
there was no consistent relative organ weight alteration across
generations, a 9% decreased relative kidney weight in P males was
consistent with findings of the replacement study, and might represent a
minor treatment effect.  The parental systemic NOAEL is 120 ppm (13.6
mg/kg/day in males and 20.5 mg/kg/day in females).

Reproductive NOAEL (M/F)=58/86 (F) mg/kg/day (HDT). 

LOAEL (M/F) >58/86 mg/kg/day (HDT).

Offspring NOAEL=20.5 mg/kg/day.

LOAEL=86 mg/kg/day based on pup body weight decrements during lactation
(decrements compared to concurrent controls at lactation day 21 for 500
ppm pups were:  21% for F1 males, 18% for F1 females, 13% for F2 males
and 24% for F2 females).  Sexual maturation criteria (preputial
separation or vaginal opening) were unaffected in this study, in
contrast to the results of the replacement study.  This may reflect the
comparatively small body weight decrements in pups in this study (about
two to three day body weight gain delays at 500 ppm in either generation
in this study, compared to about eight days in the replacement study). 

Note:  invalid study, cannot be used due to colony contamination

870.4100a

Chronic toxicity (rat)	  SEQ CHAPTER \h \r 1 45819621 (2001)

0, 50, 125, 300, or 800 ppm

M:  0, 2.6, 6.5, 15.9, and 42.4 mg/kg/day

F:  0, 3.0, 7.6, 19.3, and 51.7 mg/kg/day

Acceptable/guideline	  SEQ CHAPTER \h \r 1 NOAEL (M/F)=15.9/19.3
mg/kg/day. 

LOAEL (M/F)=42.4/51.7 mg/kg/day based on increase in T3 hormone in
males, gross pathology (enlarged liver in males, dilated uterus and
discolored adrenal gland in females) and histopathology (adrenal
cytoplasmic eosinophilia, metritise, thyroid colloidal alteration in
female and thyroid follicular cell hypertrophy in both males and
females).

870.4100b

Chronic toxicity (dog)	  SEQ CHAPTER \h \r 1 45819620 (2002)

0, 50, 400, or 4000 ppm

M:  0, 1.4, 11.5, and 109 mg/kg/day

F:  0, 1.4, 10.8, and 117 mg/kg/day

Acceptable/guideline	NOAEL (M/F)=11.5/10.8 mg/kg/day.

LOAEL (M/F)=109/117 mg/kg/day based on increase in alkaline phosphatase
and liver histopathology (cytoplasmic changes, inclusions and vacuoles).

870.4200

Carcinogenicity (rat)	  SEQ CHAPTER \h \r 1 45819624 (2001)

0, 50, 125, 300, or 800 ppm

M:  0, 2.5, 6.1, 14.8, and 40.0 mg/kg/day

F:  0, 3.3, 8.2, 19.5, and 53.5 mg/kg/day

Acceptable/guideline	NOAEL (M/F)=14.8/19.5 mg/kg bw/day.

LOAEL (M/F)=40.0/53.5 mg/kg bw/day based on clinical signs (palpable
masses, vaginal bleeding and pallor), gross necropsy (discolored area in
the lungs and nodules/dilation of uterus), hispathology (osseus
metaplasia and granulomatous inflammation of the lungs in the males,
liver necrosis, endometritis/metritis, endometrial hyperplasia of the
cervix uteri, and colloidal alteration of the thyroid gland in females),
and increased TSH in females.

 no evidence of carcinogenicity  

870.4200

Carcinogenicity (mouse)	  SEQ CHAPTER \h \r 1 45819625 (2001)

0, 20, 140, 1000, or 2000 ppm

M:  0, 3.3, 22, 157, and 335 mg/kg/day

F:  0, 3.8, 30, 200, and 401 mg/kg/day

Acceptable/guideline	NOAEL (M/F)=3.3/3.8 mg/kg/day.

LOAEL (M/F)=22/30 mg/kg/day based on gross (enlarged adrenal gland in
males) and microscopic changes (cytoplasmic eosinophilia, ceroid
deposits, and diffuse fatty changes of the adrenal cortex and pancreatic
amyloidosis in both sexes).

no evidence of carcinogenicity 

Gene Mutation

870.[5100] In Vitro bacteria gene mutation 	  SEQ CHAPTER \h \r 1
45819516 (1997)

0, 16, 50, 158, 500, 1581, or 5000 (g/plate

Acceptable/guideline	Negative

Cytogenetics 

870.5300 In Vitro mammalian gene mutation (V79)	  SEQ CHAPTER \h \r 1
45819520 (1999)

1, 2.5, 5, 10, 15, 20, or 25 (g/mL 

(- activation)

10, 20, 35, 50, 65, 80, or 95 (g/mL 

(+ activation)

Acceptable/guideline	Negative

870.5375 In Vitro mammalian cytogenetics (V79) 	  SEQ CHAPTER \h \r 1
45819517 (1997)

0, 40, 60, and 80 (g/mL (with metabolic activation)

0, 10, 20, and 40 (g/mL without metabolic activation)

Acceptable/guideline	Negative

870.5395 In Vivo mammalian cytogenetics micronucleus (mouse)	  SEQ
CHAPTER \h \r 1 45819519 (1999)

0, 100, 200, or 400 mg/kg

Acceptable/guideline	Negative

870.6200a

Acute neurotoxicity screening battery	  SEQ CHAPTER \h \r 1 45819606
(2001)

0, 200, 700, or 2000 mg/kg

Unacceptable/guideline	NOAEL=2000 mg/kg/day. 

LOAEL=Not established.

Note:  No Positive control data

870.6200b

Subchronic neurotoxicity screening battery	  SEQ CHAPTER \h \r 1
45819607 (2002)

0, 100, 500, or 2000 ppm

M:  0, 6.4, 31.8, and 122.7 mg/kg/day

F:  0, 7.9, 38.3, and 149.3 mg/kg/day

Unacceptable/guideline	NOAEL (M/F)=31.8/38.3 mg/kg/day.

LOAEL (M/F)=122.7/149.3 mg/kg/day based on decreased body weight gain
and food consumption. 

Note:  Unacceptable positive control data and dietary data & stability
data were not provided.

870.7485

Metabolism and pharmacokinetics (rat)	  SEQ CHAPTER \h \r 1 45819403
(2000)

2 and 500 mg/kg

Acceptable/guideline	For a single dose of 2 mg/kg, 39% of the
administered dose was excreted in the urine and 55 to 57% in the feces
with 88 to 90% of the dose being eliminated within the first 24 hours. 
Approximately 43% of the orally administered dose is absorbed. 
Treatment with multiple doses of 2 mg/kg did not affect the ratio of
radiolabel excreted in the urine and feces.  Concentrations of residual
radioactivity in the tissues were quite low at 72 hours post-dose. 
Treatment with 500 mg/kg of the test material resulted in a much lower
percentage of the administered dose being excreted in the urine (7 to
9%) with the remainder recovered in the feces.  Following a single dose
of 2 mg/kg, the test material was rapidly if incompletely absorbed with
the Cmax value in the blood achieved within one to two hours post-dose. 
Treatment with multiple doses of 2 mg/kg or a single dose of 500 mg/kg
delayed the Tmax to three to four hours and six hours, respectively. 
The Cmax values and the concentration versus time curves [AUC(t)]
indicated a disproportionately lower increase in the uptake of the
radiolabel into the blood between the 2 mg/kg and 500 mg/kg treatments. 
At 500 mg/kg, these values were approximately 80% less than would be
predicted by a proportionately linear increase.  The data confirmed the
reduced percentage of radiolabel which was absorbed at the 500 mg/kg
treatment level in the excretion-balance profile.  In the two 2 mg/kg
treatment regimens, the Cmax and AUC(t) values for the females were less
than those of the males with values ranging from 66 to 86% for Cmax and
43 to 55% for AUC(t) in comparison to the males.  This data indicated
that the females experienced less of an exposure to the test material
than did the males.  The whole-body autoradiograms qualitatively
demonstrated the distribution of the radioactivity throughout the body. 
The highest areas of concentration at one hour post-dose were the
gastrointestinal tract, bladder and blood within the heart.  Overall
tissue distribution appeared to be the highest at four hours post-dose
with a progressive decline over the time-course of the study.  At 48
hours post-dose, observable levels of radioactivity were present only in
the gastrointestinal tract, kidneys and bladder.  The test material was
initially metabolized to the keto-enol by loss of the dimethylbutyric
acid moiety.  Both the phenyl and cyclopentyl rings were hydroxylated
and the methyl groups on the phenyl ring were ultimately oxidized to a
carboxylic acid.  These metabolites were largely recovered in the bile
and urine.  The predominate moiety recovered in the feces was the
unmetabolized test material.  No conjugation with either glucuronic acid
or sulphate was observed.

870.7600

Dermal penetration (monkey)	  SEQ CHAPTER \h \r 1 45819828 (2002)

Acceptable/nonguideline	Intravenous injection resulted in excretion of
the radiolabel mainly via urine:  urine (54.32%), feces (13.08%), and
cage debris/rinse (26.57%).  Excretion was rapid in that 70% of the dose
was excreted within 24 hours.  Dermal application of spiromesifen
resulted in limited absorption after eight-hour exposure (3.3%), which a
large portion was recovered from urine and cage debris/rinse showing
that it is poorly absorbed through the skin layers.  

870.7800

4-week immunotoxicity (rat) 	  SEQ CHAPTER \h \r 1 45819608 (2001)

0, 100, 500, or 3000 ppm

M:  0, 9.6, 52.8, and 291.6 mg/kg/day

F:  0, 10.7, 45.7, and 288.6 mg/kg/day

Unacceptable/guideline	NOAEL (M/F)=52.8/45.7 mg/kg/day.

 (↓44%M, ↓53%F) and food consumption.

Under the conditions of this study, the test material did not suppress
the humoral response in a dose-dependent manner.

Immunotoxicity:  Inconclusive due to study deficiencies, however, any
potential immunotoxicity will be protected by dose (2.2 mg/kg/day), used
for risk assessment.

870.7800

Immunotoxicity (Plaque-forming cell assay) (mouse) 	  SEQ CHAPTER \h \r
1 45819615 (2001)

0, 100, 500, or 3500 ppm 

M:  0, 30.5, 162.5, and 1226.6 mg/kg/day

F:  0, 47.9, 278.7, and 1510.2 mg/kg/day 

Unacceptable/guideline	NOAEL=500 ppm (equivalent to 162.5/278.7
mg/kg/day M/F).

↓38%) in males and decreased water consumption and spleen weights in
both sexes.  

Under conditions of this study, no immunotoxicity (as detected by plaque
forming cells) was observed at 3500 ppm (equivalent to 1226.6/1510.2
mg/kg/day (M/F), exceeds limit dose).  The LOAEL for plaque forming
assay was not established. 

Immunotoxicity:  Inconclusive due to study deficiencies, however, any
potential immunotoxicity will be protected by dose (2.2 mg/kg/day) used
for risk assessment).

A3.	Summary of Toxicological Doses and Endpoints.

Table A.3.  Summary of Toxicological Doses and Endpoints for Use in
Spiromesifen Risk Assessments.

Exposure

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(females 13 to 49 years old)	Not applicable	None	An endpoint of concern
attributable to a single dose was not identified.  An aRfD was not
established.

Acute Dietary

(general population)

	Chronic Dietary

(all populations)	NOAEL = 2.2 mg/kg/day

UF = 100X

Chronic RfD = 0.022 mg/kg/day

cPAD = 0.022 mg/kg/day	FQPA SF = 1X	  SEQ CHAPTER \h \r 1 Two-generation
reproduction study in rats.

The parental systemic LOAEL:  

13.2 mg/kgbw/day based on significantly decreased spleen weight
(absolute and relative in parental females and F1 males) and
significantly decreased growing ovarian follicles in females.  

Incidental Oral Short (1to 30 days) and Intermediate-Term 

(1 to 6 months)	  SEQ CHAPTER \h \r 1 NOAEL = 5.0 mg/kg/day	  SEQ
CHAPTER \h \r 1 Residential LOC for MOE = 100

Occupational LOC for MOE = 100	  SEQ CHAPTER \h \r 1 Developmental
toxicity study in rabbits.

Maternal LOAEL:  35 mg/kg/day based on body weight loss and reduced food
consumption.

Dermal Short

(1 to 30 days) and Intermediate-Term 

(1 to 6 months)	  SEQ CHAPTER \h \r 1 Not applicable	None	No dermal,
systemic, or developmental toxicity concerns. 

Dermal Long-Term

(>6 months)	Oral   SEQ CHAPTER \h \r 1 NOAEL = 2.2 mg/kg/day

(dermal-absorption rate=3.3%)	Residential LOC for MOE = 100

Occupational LOC for MOE = 100 	Two-generation reproduction study in
rats.

The parental systemic LOAEL:  

13.2 mg/kg/day based on significantly decreased spleen weight (absolute
and relative in parental females and F1 males) and significantly
decreased growing ovarian follicles in females.  

Inhalation Short-Term (1 to 30 days) and Intermediate-Term (1to 6
months)	Inhalation   SEQ CHAPTER \h \r 1 NOAEL (21.1 mg/kg/day
Residential LOC for MOE = 100

Occupational LOC for MOE = 100 	Subchronic (30-day) inhalation toxicity
study in rats.

LOAEL = not established.

Inhalation Long-Term (>6 months)	Oral   SEQ CHAPTER \h \r 1 NOAEL = 2.2
mg/kg/day

(Inhalation absorption rate = 100%)	Residential LOC for MOE = 100

Occupational LOC for MOE = 100 	Two-generation reproduction study in
rats.

The parental systemic LOAEL:  

13.2 mg/kg/day based on significantly decreased spleen weight (absolute
and relative in parental females and F1 males) and significantly
decreased growing ovarian follicles in females.  

Cancer (oral, dermal, inhalation)	Classification:  ‘  SEQ CHAPTER \h
\r 1 Not likely to be carcinogenic to humans.’

*FQPA SF = FQPA safety factor; LOAEL = lowest-observed adverse-effect
level; LOC = level of concern; NA = Not Applicable; NOAEL = no-observed
adverse-effect level; PAD = population-adjusted dose (a = acute, c =
chronic); RfD = reference dose; MOE = margin of exposure; UF =
uncertainty factor 

NOTE:  The FQPA SF recommended by HED assumes that the exposure
databases (dietary food, drinking water, and residential) are complete
and that the risk assessment for each potential exposure scenario
includes all metabolites and/or degradates of concern and does not
underestimate the potential risk for infants and children.

Spiromesifen	                       Human-Health Risk Assessment		DP#
358892

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