Document ID: EPA-HQ-OPP-2007-0331-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-03-12T04:00Z

UNITED STAES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

 PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

DATE:		December 20, 2007 

SUBJECT:	Spiromesifen.  Human Health Risk Assessment for a Section 3
Registration on Beans.  

Petition #	7E7195	

PC Code:	024875

DP #:	338832	

Class:	Insecticide/Miticide

Decision #:	377056	40 CFR:	§180.607                                    
                                                        

FROM:	Breann Hanson, Biologist 

		Alternative Risk Integration and Assessment (ARIA) Team

		Risk Integration Minor Use and Emergency Response Branch 		
(RIMUERB)/Registration Division (RD) (7505P)

                                                

THROUGH:	William Cutchin, Branch Senior Scientist 

		ARIA Team

		RIMUERB/RD (7505P)

		AND

		

		George Kramer, Ph.D., Senior Chemist 

		Dana Vogel, Branch Chief

		Registration Action Branch 1 (RAB 1)

		Health Effects Division (HED) (7509P)

TO:		Shaja Brothers, RM Team 05

		Barbara Madden, RM Team 05

		RIMUERB/RD (7505P)

TABLE OF CONTENTS

  TOC \o "1-4" \h \z \u    HYPERLINK \l "_Toc185908175"  1.0	EXECUTIVE
SUMMARY	  PAGEREF _Toc185908175 \h  4  

  HYPERLINK \l "_Toc185908176"  2.0	INGREDIENT PROFILE	  PAGEREF
_Toc185908176 \h  12  

  HYPERLINK \l "_Toc185908177"  2.1	Proposed Use	  PAGEREF _Toc185908177
\h  12  

  HYPERLINK \l "_Toc185908178"  2.2	Identification of Active Ingredient	
 PAGEREF _Toc185908178 \h  13  

  HYPERLINK \l "_Toc185908179"  2.3	Physical and Chemical Properties	 
PAGEREF _Toc185908179 \h  14  

  HYPERLINK \l "_Toc185908180"  3.0	HAZARD CHARACTERIZATION	  PAGEREF
_Toc185908180 \h  14  

  HYPERLINK \l "_Toc185908181"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc185908181 \h  15  

  HYPERLINK \l "_Toc185908182"  3.1.1	Database Summary	  PAGEREF
_Toc185908182 \h  16  

  HYPERLINK \l "_Toc185908183"  3.1.1.1	Studies available and considered
(animal, human, general literature)	  PAGEREF _Toc185908183 \h  16  

  HYPERLINK \l "_Toc185908184"  3.1.1.2	Mode of action, metabolism,
toxicokinetic data	  PAGEREF _Toc185908184 \h  16  

  HYPERLINK \l "_Toc185908185"  3.1.1.3	Sufficiency of studies/data	 
PAGEREF _Toc185908185 \h  17  

  HYPERLINK \l "_Toc185908186"  3.1.2	Toxicological Effects	  PAGEREF
_Toc185908186 \h  17  

  HYPERLINK \l "_Toc185908187"  3.1.3	Dose-response	  PAGEREF
_Toc185908187 \h  18  

  HYPERLINK \l "_Toc185908188"  3.2	Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc185908188 \h  19  

  HYPERLINK \l "_Toc185908189"  3.3	FQPA Considerations	  PAGEREF
_Toc185908189 \h  19  

  HYPERLINK \l "_Toc185908190"  3.3.1	Adequacy of the Toxicity Database	
 PAGEREF _Toc185908190 \h  19  

  HYPERLINK \l "_Toc185908191"  3.3.2	Evidence of Neurotoxicity	 
PAGEREF _Toc185908191 \h  19  

  HYPERLINK \l "_Toc185908192"  3.3.3	Developmental Toxicity Studies	 
PAGEREF _Toc185908192 \h  20  

  HYPERLINK \l "_Toc185908193"  3.3.4	Reproductive Toxicity Study	 
PAGEREF _Toc185908193 \h  20  

  HYPERLINK \l "_Toc185908194"  3.3.5	Additional Information from
Literature Sources	  PAGEREF _Toc185908194 \h  20  

  HYPERLINK \l "_Toc185908195"  3.3.6	Pre-and/or Postnatal Toxicity	 
PAGEREF _Toc185908195 \h  20  

  HYPERLINK \l "_Toc185908196"  3.3.6.1	Determination of Susceptibility	
 PAGEREF _Toc185908196 \h  20  

  HYPERLINK \l "_Toc185908197"  3.3.6.2	Degree of Concern Analysis and
Residual Uncertainties for Pre- and/or Postnatal Susceptibility	 
PAGEREF _Toc185908197 \h  20  

  HYPERLINK \l "_Toc185908198"  3.3.7	Recommendation for a Developmental
Neurotoxicity (DNT) Study	  PAGEREF _Toc185908198 \h  20  

  HYPERLINK \l "_Toc185908199"  3.4	FQPA Safety Factor for Infants and
Children	  PAGEREF _Toc185908199 \h  21  

  HYPERLINK \l "_Toc185908200"  3.5	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc185908200 \h  21  

  HYPERLINK \l "_Toc185908201"  3.5.1	Acute Reference Dose (aRfD)	 
PAGEREF _Toc185908201 \h  21  

  HYPERLINK \l "_Toc185908202"  3.5.2	Chronic Reference Dose (cRfD)	 
PAGEREF _Toc185908202 \h  21  

  HYPERLINK \l "_Toc185908203"  3.5.3	Incidental Oral Exposure (Short-
and Intermediate-Term)	  PAGEREF _Toc185908203 \h  23  

  HYPERLINK \l "_Toc185908204"  3.5.4	Dermal Absorption	  PAGEREF
_Toc185908204 \h  24  

  HYPERLINK \l "_Toc185908205"  3.5.5	Dermal Exposure (Short-,
Intermediate- and Long-Term)	  PAGEREF _Toc185908205 \h  25  

  HYPERLINK \l "_Toc185908206"  3.5.6	Inhalation Exposure (Short-,
Intermediate- and Long-Term)	  PAGEREF _Toc185908206 \h  25  

  HYPERLINK \l "_Toc185908207"  3.5.7	Level of Concern for Margin of
Exposure	  PAGEREF _Toc185908207 \h  26  

  HYPERLINK \l "_Toc185908208"  3.5.8	Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc185908208 \h  27  

  HYPERLINK \l "_Toc185908209"  3.5.9	Classification of Carcinogenic
Potential	  PAGEREF _Toc185908209 \h  27  

  HYPERLINK \l "_Toc185908210"  3.6	Endocrine Disruption	  PAGEREF
_Toc185908210 \h  28  

  HYPERLINK \l "_Toc185908211"  4.0	PUBLIC HEALTH AND PESTICIDE
EPIDEMIOLOGY DATA	  PAGEREF _Toc185908211 \h  28  

  HYPERLINK \l "_Toc185908212"  4.1	Incident Reports	  PAGEREF
_Toc185908212 \h  28  

  HYPERLINK \l "_Toc185908213"  5.0	DIETARY EXPOSURE/RISK
CHARACTERIZATION	  PAGEREF _Toc185908213 \h  28  

  HYPERLINK \l "_Toc185908214"  5.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc185908214 \h  28  

  HYPERLINK \l "_Toc185908215"  5.1.1	Metabolism in Primary Crops	 
PAGEREF _Toc185908215 \h  28  

  HYPERLINK \l "_Toc185908216"  5.1.2	Metabolism in Rotational Crops	 
PAGEREF _Toc185908216 \h  29  

  HYPERLINK \l "_Toc185908217"  5.1.3	Metabolism in Livestock	  PAGEREF
_Toc185908217 \h  29  

  HYPERLINK \l "_Toc185908218"  5.1.4	Analytical Methodology	  PAGEREF
_Toc185908218 \h  30  

  HYPERLINK \l "_Toc185908219"  5.1.5	Environmental Degradation	 
PAGEREF _Toc185908219 \h  30  

  HYPERLINK \l "_Toc185908220"  5.1.6	Comparative Metabolic Profile	 
PAGEREF _Toc185908220 \h  31  

  HYPERLINK \l "_Toc185908221"  5.1.7	Toxicity Profile of Major
Metabolites and Degradates	  PAGEREF _Toc185908221 \h  31  

  HYPERLINK \l "_Toc185908222"  5.1.8	Pesticide Metabolites and
Degradates of Concern	  PAGEREF _Toc185908222 \h  31  

  HYPERLINK \l "_Toc185908223"  5.1.9	  Drinking Water Residue Profile	 
PAGEREF _Toc185908223 \h  33  

  HYPERLINK \l "_Toc185908224"  5.1.10	Food Residue Profile	  PAGEREF
_Toc185908224 \h  33  

  HYPERLINK \l "_Toc185908225"  5.1.11	International Residue Limits	 
PAGEREF _Toc185908225 \h  35  

  HYPERLINK \l "_Toc185908226"  5.2	Dietary Exposure and Risk	  PAGEREF
_Toc185908226 \h  36  

  HYPERLINK \l "_Toc185908227"  5.2.1	Acute Dietary Exposure/Risk	 
PAGEREF _Toc185908227 \h  36  

  HYPERLINK \l "_Toc185908228"  5.2.2	Chronic Dietary Exposure/Risk	 
PAGEREF _Toc185908228 \h  36  

  HYPERLINK \l "_Toc185908229"  5.2.3	Cancer Dietary Risk	  PAGEREF
_Toc185908229 \h  37  

  HYPERLINK \l "_Toc185908230"  5.3	Anticipated Residue and Percent Crop
Treated (%CT) Information	  PAGEREF _Toc185908230 \h  37  

  HYPERLINK \l "_Toc185908231"  6.0	RESIDENTIAL (NON-OCCUPATIONAL)
EXPOSURE/RISK CHARACTERIZATION	  PAGEREF _Toc185908231 \h  37  

  HYPERLINK \l "_Toc185908232"  6.1	Other (Spray Drift, etc.)	  PAGEREF
_Toc185908232 \h  38  

  HYPERLINK \l "_Toc185908233"  7.0	AGGREGATE RISK ASSESSMENTS AND RISK
CHARACTERIZATION	  PAGEREF _Toc185908233 \h  38  

  HYPERLINK \l "_Toc185908234"  8.0	CUMULATIVE RISK
CHARACTERIZATION/ASSESSMENT	  PAGEREF _Toc185908234 \h  38  

  HYPERLINK \l "_Toc185908235"  9.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY	 
PAGEREF _Toc185908235 \h  39  

  HYPERLINK \l "_Toc185908236"  9.1	Occupational Pesticide Handler
Exposure and Risk	  PAGEREF _Toc185908236 \h  39  

  HYPERLINK \l "_Toc185908237"  9.2	Occupational Post-Application Worker
Exposure and Risk	  PAGEREF _Toc185908237 \h  41  

  HYPERLINK \l "_Toc185908238"  10.0	DATA NEEDS AND LABEL
RECOMMENDATIONS	  PAGEREF _Toc185908238 \h  41  

  HYPERLINK \l "_Toc185908239"  10.1	Toxicology	  PAGEREF _Toc185908239
\h  41  

  HYPERLINK \l "_Toc185908240"  10.2	Residue Chemistry	  PAGEREF
_Toc185908240 \h  41  

  HYPERLINK \l "_Toc185908241"  10.3	Occupational and Residential
Exposure	  PAGEREF _Toc185908241 \h  41  

  HYPERLINK \l "_Toc185908242"  Appendix A:  TOXICOLOGY ASSSESSMENT	 
PAGEREF _Toc185908242 \h  43  

  HYPERLINK \l "_Toc185908243"  A.1	Toxicology Data Requirements	 
PAGEREF _Toc185908243 \h  43  

  HYPERLINK \l "_Toc185908244"  A.2	Acute Toxicity Profile	  PAGEREF
_Toc185908244 \h  44  

  HYPERLINK \l "_Toc185908245"  A.3	Toxicity Profiles	  PAGEREF
_Toc185908245 \h  44  

  HYPERLINK \l "_Toc185908246"  Appendix B:	REFERENCES (in MRID order)	 
PAGEREF _Toc185908246 \h  52  

  HYPERLINK \l "_Toc185908247"  Appendix C:	REVIEW OF HUMAN RESEARCH	 
PAGEREF _Toc185908247 \h  56  

 1.0	EXECUTIVE SUMMARY

The Interregional Research Project No. 4 (IR-4) has submitted a
petition, per the Agricultural Experiment Stations of California,
Georgia, Idaho, Texas, North Carolina and Delaware, for use of the
insecticide/miticide spiromesifen,
[2-oxo-3-(2,4,6-trimethylphenyl)-1-oxaspiro[4.4]non-3-en-4-yl
3,3-dimethylbutanoate], on beans (PP# 7E7195).  Spiromesifen is a
tetronic acid insecticide/miticide used for control of a broad spectrum
of mite pests and whiteflies in corn, cotton, strawberries, and various
vegetable crops.  Spiromesifen acts as a lipid biosynthesis inhibitor by
blocking the proper synthesis of fatty acids and their biochemical
derivatives.

Use Profile

The registered product proposed for use is Oberon® 2 SC
Insecticide/Miticide (EPA Reg. No. 264 - 719).  Oberon® contains 2.0 lb
active ingredient (23.1 %) per gallon.  The range of the application
rate is 7.0 - 12.2 fl oz product per acre (0.11 - 0.19 lb ai/A).  There
is a 1-day preharvest interval (PHI) for succulent and edible-podded
beans and a 10-day PHI for dry shelled beans.  The re-application
interval is 7 days.  There is a maximum of 36.6 fl oz/A/season (0.57 lb
ai/A/season).  The label lists a restricted entry interval (REI) of 12
hours.  

Current Tolerances

Tolerances have been established under 40 CFR §180.607(a)(1) for the
combined residues of spiromesifen and its enol metabolite, calculated as
parent compound equivalents, in/on field corn, cotton, strawberry, and
vegetable commodities.  The established tolerances for primary crop
commodities range from 0.02 ppm (field corn grain and tuberous and corm
vegetables, subgroup 1C) to 15 ppm (cotton gin byproducts).  

Tolerances have been established under 40 CFR §180.607(a)(2) for the
combined residues of spiromesifen and its metabolites containing the
enol and 4-hydroxymethyl
[4-hydroxy-3-[4-(hydroxymethyl)-2,6-dimethylphenyl]-1-oxaspiro[4.4]non-3
-en-2-one] moieties, expressed as parent equivalents, at 0.05 ppm for
the fat and meat byproducts of cattle, goat, horse, and sheep, and at
0.10 ppm for milk fat.

Under 40 CFR §180.607(d), tolerances for the inadvertent or indirect
combined residues of spiromesifen, its enol metabolite, and its
metabolites containing the 4-hydroxymethyl moiety, expressed as
spiromesifen, have been established for alfalfa, barley, sugar beet, and
wheat commodities at 0.03-3.0 ppm.  

Proposed Tolerances

IR-4 has proposed the establishment of permanent tolerances for the
combined residues of spiromesifen and its enol metabolite, calculated as
the parent compound equivalents, in/on the following raw agricultural
commodities (RACs):

	Bean, dry	0.02 ppm

	Bean, succulent	0.10 ppm

	Bean, edible podded	1.4 ppm

	Cowpea, forage	35 ppm

In addition, to account for the potential increase in dietary exposure
resulting from the proposed tolerance on cowpea forage which is a
livestock feedstuff, IR-4 has proposed the establishment of permanent
tolerances for the combined residues spiromesifen and its metabolites
containing the enol and 4-hydroxymethyl moieties, calculated as the
parent compound equivalents, in/on the following livestock commodities:

	Cattle, fat	0.20 ppm

	Cattle, meat	0.01 ppm

	Cattle, meat byproducts	0.30 ppm

	Goat, fat	0.20 ppm

	Goat, meat	0.01 ppm

	Goat, meat byproducts	0.30 ppm

	Hog, fat	0.20 ppm

	Hog, meat	0.01 ppm

	Hog, meat byproducts	0.30 ppm

	Horse, fat	0.20 ppm

	Horse, meat	0.01 ppm

	Horse, meat byproducts	0.30 ppm

	Milk	0.01 ppm

	Sheep, fat	0.20 ppm

	Sheep, meat	0.01 ppm

	Sheep, meat byproducts	0.30 ppm

The most recent human health risk assessment for spiromesifen was
conducted in conjunction with a request for the establishment of
permanent tolerances for residues of spiromesifen in/on greenhouse-grown
tomatoes and oats (DP #: 328204, G. Kramer, 8/4/2006).

Human Health Risk Assessment

	

Toxicology/Hazard

The toxicological database for spiromesifen is adequate to support the
requested tolerance according to the guideline requirements for a
food-use chemical. 

Technical spiromesifen shows low acute toxicity (Toxicity Category III,
IV) via the oral, dermal and inhalation routes of exposure.  It was
neither an eye nor dermal irritant (Toxicity Category IV), but showed
moderate potential as a contact sensitizer in a Magnusson and Kligman
maximization assay.  Acute dietary-exposure limits for all populations,
including infants and children, were not necessary because an endpoint
of concern attributable to a single exposure (dose) was not identified
from the oral toxicity studies.  In addition, there are no developmental
concerns based on rat and/or rabbit developmental toxicity studies.  The
rat two-generation reproduction study was selected for chronic dietary,
as well as long-term dermal- and inhalation-exposure risk assessments.

In the two-generation reproduction study in rat the following effects
were noted at the lowest observed adverse effect level (LOAEL):
significantly decreased spleen weight (absolute and relative in parental
females and F1 males) and significantly decreased growing ovarian
follicles in females.  Spiromesifen shows no significant developmental
or reproductive effects, is not likely to be carcinogenic based on
bioassays in rat and mouse, and lacks in vivo and in vitro mutagenic
effects.  Spiromesifen is not a neurotoxic chemical based on results of
acute and subchronic neurotoxicity studies. 

In a rat metabolism study, approximately 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 was absorbed from the gastrointestinal
tract.  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 predominate moiety
recovered in the feces was the unmetabolized parent compound (about 85%
of the total excretion in the feces).  Less than 5% of the keto-enol
metabolite (BSN 2060-enol) was detected in the feces.  No conjugation
with either glucuronic acid or sulfate was observed.

Dose Response Assessment

Acute dietary-exposure limits for all populations, including infants and
children, were not necessary because an endpoint of concern attributable
to a single exposure (dose) was not identified from the oral toxicity
studies.  In addition, there are no developmental concerns based on rat
and/or rabbit developmental toxicity studies.  The rat two-generation
reproduction study was selected for chronic dietary, as well as
long-term dermal- and inhalation-exposure risk assessments.  This study
provided the lowest no-observed adverse-effect level (NOAEL) and the
most-sensitive endpoints in the database.  It will provide the
most-protective limits for human exposure.

The chronic reference dose (cRfD) was calculated by dividing the NOAEL
by 100 (10X for interspecies extrapolation, 10X for intraspecies
variation).  Since the FQPA SF has been reduced to 1X, the chronic
population-adjusted dose (cPAD) is equal to the cRfD.  The short- and
intermediate-term dermal risk was not calculated since there are no
developmental concerns and no evidence of systemic toxicity at the limit
dose.  The risk assessment team did identify short- and
intermediate-term inhalation endpoints from a subchronic (30-day)
inhalation study in the rat.  The level of concern (LOC) for residential
dermal exposures and occupational dermal and inhalation exposures are
for margins of exposure (MOEs) <100.

Dietary Exposure (Food/Water)

Residue Chemistry and Risk

The nature of the residue in plant and livestock commodities is
adequately understood based on acceptable metabolism studies conducted
on lettuce, cotton, tomato, and confined rotational crops.  Spiromesifen
and BSN 2060-enol are the residues of concern in crops and livestock for
purposes of tolerance enforcement and risk assessment.  Additionally,
BSN 2060-4-hydroxymethyl (free and conjugated) is a residue of concern
in leafy vegetables (risk assessment only) and rotational crops
(tolerance enforcement and risk assessment).  Additionally, BSN
2060-4-hydroxymethyl (free and conjugated) is a residue of concern in
ruminant commodities (tolerance enforcement and risk assessment).

A high-performance liquid chromatography (HPLC)/mass-spectrometry
(MS/MS) method (Method 00631/M001) was submitted previously for the
enforcement of tolerances for residues of spiromesifen, BSN 2060-enol,
and BSN 2060 4-hydroxymethyl in/on plant commodities.  

An adequate cattle feeding study is available to support the livestock
dietary burdens resulting from the proposed uses.  Dietary burdens were
calculated for beef and dairy cattle, for poultry, and for swine.  Based
on these dietary exposure levels and the residue data from the ruminant
feeding study, the data indicate that a tolerance is needed in the meat
of cattle, goats, horses, and sheep; a tolerance increase is required
for meat byproducts of cattle, goats, horses, and sheep; a tolerance
increase is required for the fat of cattle, goats, horses and sheep; a
tolerance increase for milk, fat and a tolerance for milk.  Based on the
transfer coefficients for livestock tissues and the relatively low
dietary burden for swine, spiromesifen tolerances in hogs are not
required.  

The proposed use of spiromesifen on cowpea addressed in this document is
not expected to alter the Agency’s previous determination that there
is no reasonable expectation of finite residues in poultry commodities,
and therefore, no tolerances are needed in poultry and eggs.  

The submitted field trial data for dry-shelled, succulent-shelled and
edible-podded beans are adequate.  There is sufficient geographic
representation of residue data, and the field trials were conducted
according to the proposed use pattern.  Residues for dry bean and
succulent bean were all below the combined lower limit method validation
(LLMV) for both the parent and metabolite.  Recommended tolerances for
bean, edible podded and cowpea forage were calculated using the maximum
residue limit (MRL)/maximum likelihood estimation (MLE) tolerance
spreadsheets.  

The submitted data for succulent shelled bean foliage was used to
establish a tolerance in cowpea forage.  However, no residue data were
submitted for cowpea hay.  For the purpose of this petition, ARIA will
recommend a tolerance for cowpea hay calculated from the recommended
tolerance for cowpea forage and adjusting for percentages of dry matter
between cowpea hay and cowpea forage.  

Water Exposure and Risk

The Environmental Fate and Effects Division ( tc \l2 "4.3 Water
Exposure/Risk Pathway   EFED) provided Tier II Estimated Drinking Water
Concentrations (EDWCs) for use in drinking water assessments when
spiromesifen is used according to proposed labeling.  The models
Pesticide Root Zone Model (PRZM, version 3.12 beta) and Exposure
Analysis Modeling System (EXAMS, version 2.98.04) were used to conduct
surface water exposure assessments.  Screening Concentration in Ground
Water (SCIGROW) (version 2.3) was used for groundwater.  The highest
estimated surface water concentrations occurred with the NC sweet potato
scenario.  For chronic assessments the EDWC is 11 ppb.  The groundwater
estimate from SCIGROW is 28 ppb; this was the value used in this
assessment.

Acute and Chronic Dietary Exposure Results and Characterization

No toxic effects attributable to a single (i.e., acute) exposure to
spiromesifen have been identified; therefore, an acute RfD (aRfD) has
not been established for spiromesifen and an acute dietary exposure
assessment has not been conducted.  

A chronic dietary assessment was performed assuming tolerance-level
residues for all commodities with existing and recommended tolerances
except for the leafy-green and leafy-Brassica vegetable subgroups (4A
and 5B).  Based on the dietary exposure levels and the residue data from
an available ruminant feeding study, data indicate that tolerances are
now recommended or increased in milk, whole; milk, fat; in the meat of
cattle, goats, horses, and sheep; in meat, byproducts, of cattle, goats,
horses, and sheep; and in the fat of cattle, goats, horses, and sheep. 
For all commodities, 100 percent crop treated (%CT) as well as DEEM™
Version 7.81 default processing factors were used.  The highest drinking
water estimate of 28 ppb was directly incorporated into the chronic
assessment.  The chronic dietary risk assessment shows that for all
included commodities, the chronic dietary risk estimates are below
ARIA’s level of concern.

Non-Occupational and Residential Exposure/Risks

Currently, there are no registered or proposed uses of spiromesifen that
would result in residential exposures.

Aggregate Exposure/Risks

No acute, short/intermediate/long-term or cancer aggregate exposure is
expected.  

Chronic Aggregate Exposure

Chronic aggregate risk estimates do not exceed ARIA's level of concern. 
Since the chronic aggregate risk assessment includes only food and
water, and the chronic dietary analysis included both, no further
calculations are necessary.  Since the chronic dietary risk does not
exceed ARIA’s level of concern, the chronic aggregate risk does not
exceed ARIA’s level of concern.

Occupational Exposure/Risks

An occupational risk assessment was completed for spiromesifen for its
use on beans.  Based upon the proposed use pattern, RD believes that the
most highly exposed occupational pesticide handlers will be
mixer/loaders using open-pour loading of liquid formulations in support
of aerial operations, applicators using open-cab, ground-boom sprayers
and aerial applicators.  Handlers preparing for use in chemigation are
not expected to be more highly exposed than mixer/loaders since the
activities are believed to be similar.  

RD believes pesticide handlers will be exposed to short-term duration
(1-30 days) exposures but not to intermediate-term (1-6 months) duration
exposures.   Although multiple applications are possible, they are
separated by 7-day retreatment intervals.   It is unlikely that
pesticide handlers would be exposed continuously for 30 days or more.  

Short- and intermediate-term inhalation endpoints have been identified
(NOAEL = 21.1 mg ai/kg bw/day).  The short-term and intermediate-term
inhalation endpoints were identified from a subchronic (30 day)
inhalation study in the rat.   These same toxicological endpoints were
used in the previous spiromesifen risk assessment.  

Total MOEs for handlers (mixers and loaders) supporting applications to
beans are not of concern to ARIA (MOEs range from 19,200 to 325, 600). 
Therefore, no additional mitigation is necessary for mixers and loaders
for this proposed use from potential exposure to spiromesifen. 

Environmental Justice Consideration

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

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

Review of Human Research

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.  These studies (listed in Appendix C) have been determined to
require a review of their ethical conduct, and have received that
review.

 

Additional Data Needs

Residue Chemistry

The following is a list of the deficiencies noted in the residue
chemistry memo (DP#: 345985, D. Rate, 12/5/2007):

860.1340 Residue Analytical Methods

The petitioner should submit revised methods of enforcement to the
Agency, incorporating the recommendations by the analytical chemistry
branch (ACB)(DP Num: 305721, 15/NOV/2007, E. Kolbe).

860.1550 Proposed Tolerances

The petitioner should submit a revised Section F reflecting the
ARIA-recommended tolerances and commodity definitions.

Recommendations for Tolerances/Registration

Pending submission of a revised Section F, are no residue chemistry
issues that would preclude granting a conditional registration for the
requested uses of spiromesifen on dry-shelled, succulent-shelled, and
edible-podded beans, or establishment of permanent tolerances for
spiromesifen residues as specified in Table 1.  A revised analytical
method should be submitted before the conditional registration on
dry-shelled, succulent-shelled, and edible-podded beans may be converted
to an unconditional registration.

A summary of the recommended tolerances for the crop commodities
discussed in this Risk Assessment are presented in Table 1.0, below.

Table 1.0   Tolerance Summary for Spiromesifen.

Commodity	Established Tolerance

(ppm)	Proposed Tolerance (ppm)	Recommended Tolerance (ppm)	Comments;

Correct Commodity Definition

Amends 40 CFR §180.607(a)(1):  Primary Crops

Bean, dry	None	0.02	0.02

	Bean, succulent	None	0.10	0.10

	Bean, edible podded 1	None	1.4	0.80

	Cowpea, forage	None	35	30

	Additional Tolerance on Primary Crop Commodities That Needs to be
Proposed/Established

Cowpea, hay	None	None	86 2

	Amends 40 CFR §180.607(a)(2):  Livestock Commodities

Cattle, fat	0.05	0.20	0.10

	Cattle, meat	None	0.01	0.02

	Cattle, meat byproducts	0.05	0.30	0.15	.

Goat, fat	0.05	0.20	0.10

	Goat, meat	None	0.01	0.02

	Goat, meat byproducts	0.05	0.30	0.15

	Hog, fat	None	0.20	Not required	Based on the transfer coefficients for
livestock tissues and a relatively low dietary burden for swine of 0.04
ppm for spiromesifen, tolerances for swine are not needed

Hog, meat	None	0.01	Not required

	Hog, meat byproducts	None	0.30	Not required

	Horse, fat	0.05	0.20	0.10	.

Horse, meat	None	0.01	0.02

	Horse, meat byproducts	0.05	0.30	0.15

	Milk	None	0.01	0.01

	Milk, fat	0.10	None	0.20 

	Sheep, fat	0.05	0.20	0.10

	Sheep, meat	None	0.01	0.02

	Sheep, meat byproducts	0.05	0.30	0.15

	1  According to the Food Feed Commodity Vocabulary edible podded bean
is not listed as a preferred term, however, in an email correspondence
between B. Schneider and the petitioner, dated 09/JAN/2007, B. Schneider
indicated that bean, edible podded is the correct tolerance term.

2   Calculated from the recommended tolerance for cowpea forage (30 ppm)
multiplied by the conversion factor (2.9x) derived when percentages of
dry matter (86% for cowpea hay and 30% for cowpea forage) are taken into
consideration.

2.0	INGREDIENT PROFILE

2.1	Proposed Use

The registered product proposed for use is Oberon® 2 SC
Insecticide/Miticide (EPA Reg. No. 264-719).  Oberon® contains 2.0 lb
active ingredient (23.1 %) per gallon.  The range of the application
rate is 7.0-12.2 fl oz product per acre (0.11-0.19 lb ai/A).  There is a
1-day PHI for succulent and edible-podded beans and a 10-day PHI for dry
shelled beans.  The re-application interval is 7 days.  There is a
maximum of 36.6 fl oz/A/season (0.57 lb ai/A/season).  Aerial
applications should be made in a minimum of 5 gallons of spray/A and
ground applications in a minimum of 10 gallons/A.  It may be applied
through irrigation systems (i.e., chemigation).  The product label
directs mixers, loaders and other handlers to wear personal protective
equipment (PPE) consisting of a long-sleeved shirt, long pants, shoes
plus socks and chemical resistant gloves such as natural rubber,
selection Category A.  Applicators must wear long-sleeved shirt, long
pants and shoes plus socks.  The label lists a restricted entry interval
(REI) of 12 hours.  

Table 2.1  Summary of Directions for Use of Spiromesifen.

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate 

(lb ai/A)	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(lb ai/A)	PHI

(days)

Succulent Shelled, Edible-Podded, and Dry Shelled Beans

[Lupinus spp., includes grain lupin, sweet lupin, white lupin, and white
sweet lupin;

Haseolus spp., includes field bean, kidney bean, lima bean, navy bean,
pinto bean, runner bean, snap bean, tepary bean, wax bean;

Vigna spp., includes adzuki bean, asparagus bean, blackeyed pea,
catjang, Chinese longbean, cowpea, Crowder pea, moth bean, mung bean,
rice bean, southern pea, urd bean, yardlong bean, broad bean (fava),
chickpea (garbanzo bean), guar, jackbean, lablab bean (hyacinth bean),
lentil, soybean (immature seed), sword bean

Foliar spray

Ground or aerial	2 lb/gal FlC

[264-719]	0.11-0.19	3

(implied)	0.57	1 (for succulent and edible-podded beans)

10 (for dry shelled beans)

	Use Directions and Limitations:  Good coverage of the foliage is
necessary for optimal control; an adjuvant may be used.  A minimum 7-day
RTI is specified.  Applications may be made in a minimum of 10 gal/A
using ground equipment and 5 gal/A using aerial equipment.  Forage from
treated crops may be used for animal consumption.

The following rotational crop restrictions are specified:  (i) immediate
(0 day) PBI for cotton, field corn, fruiting vegetables, leafy
vegetables, cucurbits, tuber vegetables (potatoes), and strawberry; (ii)
30-day PBI for alfalfa, barley, oat, sugar beets, and wheat; (iii)
12-month PBI for all other crops.  Cover crops for soil building or
erosion control may be planted at any time, but do not graze or harvest
for food or feed.

2.2	Identification of Active Ingredient

4-hydroxy-3-(2,4,6-trimethylphenyl)-1-oxaspiro[4.4]non-3-en-2-one

2.3	Physical and Chemical Properties

TABLE 2.3	Physicochemical Properties of Spiromesifen.

Parameter	Value	Reference

Melting point/range	96.7 - 98.7°C	DP# 298191, 4/29/04, S. Malak; MRID
45854501

pH	5.19 (2% suspension in 0.1% NaCl)

	Density	1.13 g/mL

	Water solubility (20°C)	0.13 mg/L (constant from pH 4 to pH 9)

	Solvent solubility (20°C)	Acetone: >250 g/L 

Acetonitrile: >250 g/L 

Ethyl Acetate: >250 g/L 

Dichloromethane: >250 g/L 

n-Heptane: 23 g/L

1-Octanol: 60 g/L

2-Propanol: 110 g/L

Xylene: >250 g/L

	Vapor pressure at 25°C	1 x 10-5 Pa

	Dissociation constant, pKa	No acid or base properties between pH 2 and
pH 12

	Octanol/water partition coefficient, Log(KOW)	4.55 at 20°C

	UV/visible absorption spectrum	Molar absorption coefficient 23,360
L/mol cm at 214 nm (neutral)

	

3.0	HAZARD CHARACTERIZATION  TC \l1 "3.0  HAZARD CHARACTERIZATION 

The toxicology data requirements (40 CFR 158.607) for food uses of
spiromesifen are complete.  

3.1	Hazard and Dose-Response Characterization

Technical spiromesifen shows low acute toxicity (Toxicity Category III,
IV) via the oral, dermal and inhalation routes of exposure.  It was
neither an eye nor dermal irritant (Toxicity Category IV), but showed
moderate potential as a contact sensitizer in a Magnusson and Kligman
maximization assay.  

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 a specialized
immunotoxicity study in rat study that showed no effects on plaque
forming assays.  However, this study was classified as unacceptable
guideline study due to lack of positive control data.  Although the data
are indicative of potential immunotoxicity, the dose selected for the
risk assessment would be protective of immunotoxic effects.

In the two-generation reproduction study in rat the following effects
were noted at the lowest observed adverse effect level (LOAEL):
significantly decreased spleen weight (absolute and relative in parental
females and F1 males) and significantly decreased growing ovarian
follicles in females.  Spiromesifen shows no significant developmental
or reproductive effects, is not likely to be carcinogenic based on
bioassays in rat and mouse, and lacks in vivo and in vitro mutagenic
effects.  Spiromesifen is not a neurotoxic chemical based on results of
acute and subchronic neurotoxicity studies. 

In a rat metabolism study, approximately 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 was absorbed from the gastrointestinal
tract.  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.  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.  More than 18 metabolites were identified in the urine. 
These metabolites ranged from less than 0.1% to 4.8% of the total
excretion in the urine.  None of the unmetabolized parent compound was
detected in the urine.  The keto-enol metabolite (BSN 2060-enol)
constitutes approximately 4 to 9% of the total urinary excretion.  The
predominate moiety recovered in the feces was the unmetabolized parent
compound (about 85% of the total excretion in the feces).  Less than 5%
of the keto-enol metabolite (BSN 2060-enol) was detected in the feces. 
No conjugation with either glucuronic acid or sulfate was observed.

3.1.1	Database Summary

  TC \l3 "3.1.1	Database Summary 

3.1.1.1	Studies available and considered (animal, human, general
literature)

Acute, sub-chronic, chronic, reproductive and developmental studies were
available and considered when preparing this risk assessment.  This risk
assessment relies in part on data from studies in which adult human
subjects were intentionally exposed to a pesticide or other chemical.  

  TC \l4 "3.1.1.1	Studies available and considered (animal, human,
general literature) 

3.1.1.2	Mode of action, metabolism, toxicokinetic data

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 a specialized
immunotoxicity study in rat study that showed no effects on plaque
forming assays.  However, this study was classified as unacceptable
guideline study due to lack of positive control data.  Although the data
are indicative of potential immunotoxicity, the dose selected for the
risk assessment would be protective of immunotoxic effects.

In plants, the metabolic pathways in all RACs are very similar. 
Spiromesifen is metabolized by the loss of the dimethylbutyric acid
group to yield BSN 2060-enol followed by hydroxylation and conjugation. 
The reviewed studies also indicate that spiromesifen, when foliarly
applied during the vegetative growth stage, is not readily translocated.
 

In livestock, spiromesifen is metabolized by the loss of the
dimethylbutyric acid group to yield BSN 2060-enol.  Further metabolism
can include hydroxylation of BSN 2060-enol to yield BSN
2060-2-hydroxymethyl or BSN 2060-4-hydroxymethyl; hydroxylation of BSN
2060-enol to yield BSN 2060-3-pentanol; oxidation of BSN 2060-3-pentanol
or BSN 2060-2- or -4-hydroxymethyl to give BSN 2060-2- or
-4-hydroxymethyl-3-pentanol; oxidation of BSN 2060-4-hydroxymethyl to
give BSN 2060-pentanone or BSN 2060-4-aldehyde; oxidation of BSN 2060-2-
or 4-hydroxymethyl-3-pentanol to give BSN 2060-hydroxy-4-carboxy; and
further hydroxylation of BSN 2060-4-hydroxymethyl-3-pentanol or BSN
2060-hydroxy-4-carboxy to give BSN 2060-dihydroxy-4-carboxy.

  TC \l4 "3.1.1.2	Mode of action, metabolism, toxicokinetic data 

3.1.1.3	Sufficiency of studies/data

The scientific and regulatory quality of the toxicology data base for
spiromesifen is high and is considered sufficient to clearly define the
toxicity of this chemical.  

  TC \l4 "3.1.1.3	Sufficiency of studies/data 

3.1.2	Toxicological Effects

Acute dietary exposure limits for all populations, including infants and
children, were not necessary because an endpoint of concern attributable
to a single exposure (dose) was not identified from the oral toxicity
studies.  In addition, there are no developmental concerns based on rat
and/or rabbit developmental toxicity studies.  The rat two-generation
reproduction study was selected for chronic dietary, and long-term
dermal and inhalation exposure risk assessments.  This study provided
the most sensitive endpoint in the database, which in this case is
spleen-weight changes in both males and females and significantly
decreased growing ovarian follicles in females observed at the LOAEL; it
will provide the most protective limits for human exposure.  

Spiromesifen shows no significant developmental or reproductive effects,
is not neurotoxic, is not likely to be carcinogenic, and lacks in vivo
and in vitro mutagenic effects.  

  TC \l3 "3.1.2	Toxicological Effects 

3.1.3	Dose-response

Table 3.1.3  Summary of Toxicological Doses and Endpoints for Use in
Spiromesifen Risk Assessments

Exposure

Scenario		Dose Used in Risk Assessment, UF	FQPA SF* and LOC for Risk
Assessment	Study and Toxicological Effects

Acute Dietary 

(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.

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)

A metabolism study has been conducted in the rat.  Approximately 43% of
the orally-administered dose is absorbed.  The chemical 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
predominant moiety recovered in the feces was the unmetabolized test
material.  No conjugation with either glucuronic acid or sulfate was
observed.

3.3	FQPA Considerations

  TC \l2 "3.3	FQPA Considerations 

Adequacy of the Toxicity Database

The spiromesifen toxicology database for FQPA hazard considerations is
adequate.  

3.3.2	Evidence of Neurotoxicity

HED concludes that there is no concern for neurotoxicity resulting from
exposure to spiromesifen.  Neurotoxic effects such as reduced motility,
spastic gait, increased reactivity, tremors, clonic-tonic convulsions,
reduced activity, labored breathing, vocalization, avoidance reaction,
piloerection, limp, cyanosis, squatted posture, and salivation were
observed in two studies (five-day inhalation and subchronic oral rat) at
high doses (134 and 536 mg/kg/day, respectively).  These effects were
neither reflected in neurohistopathology nor in other studies.  Because
these effects were not observed in the acute and subchronic
neurotoxicity studies, they were not considered reproducible.  Thus,
based on the chemical’s mode of action and the available data from
multiple studies, the chemical is not considered neurotoxic. 

3.3.3	Developmental Toxicity Studies	

In the rat and rabbit developmental toxicity studies, no developmental
effects were seen even in the presence of maternal toxicity. 

 

3.3.4	Reproductive Toxicity Study

In a two-generation reproduction study, offspring effects were seen at
the same dose that produced parental toxicity.  

3.3.5	Additional Information from Literature Sources

None.

3.3.6	Pre-and/or Postnatal Toxicity

Based on the available data, HED concludes that there is not a concern
for pre- and/or postnatal toxicity resulting from exposure to
spiromesifen.  

3.3.6.1	Determination of Susceptibility

There was no evidence of increased susceptibility of rat or rabbit to in
utero exposure to spiromesifen.  In a rat developmental toxicity study,
no developmental toxicity was observed at doses up to 500 mg/kg/day
(HDT).  The rat maternal LOAEL was determined to be 70 mg/kg/day based
on decreased body weight gain and reduced food consumption.  In the
rabbit developmental toxicity study, there was no developmental toxicity
observed at doses up to 250 mg/kg/day (HDT); the maternal LOAEL was
determined to be 35 mg/kg/day based on body weight loss and reduced food
consumption. There is no qualitative and/or quantitative evidence of
increased susceptibility to spiromesifen following pre/postnatal
exposure in a two-generation reproduction study in rats.

3.3.6.2	Degree of Concern Analysis and Residual Uncertainties  TC \l4
"3.3.6.2	Degree of Concern Analysis and Residual Uncertainties  for Pre-
and/or Postnatal Susceptibility

As pointed out above, there are no concerns or residual uncertainties
for pre- and/or postnatal toxicity that indicate the need for a special
safety factor.

3.3.7	Recommendation for a Developmental Neurotoxicity (DNT) Study

A DNT study is not required for spiromesifen.

3.4	FQPA Safety Factor for Infants and Children

Based on the hazard and exposure data, HED recommends that the special
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 proposed 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 BSN
2060-4-hydroxymethyl residue data.  

(  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.  

3.5	Hazard Identification and Toxicity Endpoint Selection

3.5.1	Acute Reference Dose (aRfD) 

Acute dietary exposure limits for all populations, including infants and
children, were not necessary because an endpoint of concern attributable
to a single exposure (dose) was not identified from the oral toxicity
studies.  In addition, there are no developmental concerns based on rat
and/or rabbit developmental toxicity studies.

3.5.2	Chronic Reference Dose (cRfD) 

A cRfD was determined based on a reproduction and fertility effects
study in the rat.  The rat two-generation reproduction study was
selected for chronic dietary exposure risk assessment because this study
provided the lowest NOAEL in the database (i.e., most sensitive
endpoint).  These endpoints will provide the most protective limits for
human effects.  This study is of the appropriate duration and route of
exposure.

Study Selected:  Two-generation Reproduction Study - Rat.

Executive Summary:  In a two-generation reproduction study (MRID
45819619), spiromesifen, 97.3 % ai, Mixed batch No. 06957/0009 was
administered to 25 Wistar rats/sex/dose in their diet at dose levels of
0, 30, 120, or 500 ppm (equivalent to mean premating intakes of 0, 2.2,
8.8, or 37 mg/kg bw/day in P males or 0, 3.8, 14.2, or 64 mg/kg bw/day
in P females, or to premating intakes of 0, 3.3, 13.2, or 76 mg/kg/day
in F1 males and 0, 4.6, 18.0, or 91 mg/kg/day in F1 females).  There was
one mating period per generation.

Body weight was significantly reduced in females (P) in 500 ppm group
(10% of the control) during the premating phase.  The F1 high dose pups
of both sexes began the premating phase significantly behind other
groups in body weight and remained significantly behind throughout the
study.  Body weight was decreased to 94 and 83% of controls for F1 adult
males in the 120 ppm and 500 ppm, respectively, at sacrifice and 95 and
83% of controls for F1 adult females in the 120 and 500 ppm groups,
respectively, at sacrifice.  The decrease in body weight at 120 ppm in
males and females were not considered biologically significant. 
Absolute and relative spleen weights were significantly reduced (8 to
21% of the control) in the 120 and 500 ppm parental females.  Absolute
spleen weights were also significantly decreased (10 to 21% of the
control) in the F1 males at 120 and 500 ppm and females at 500 ppm. 
Histopathology findings due to treatment included liver hypertrophy and
periportal basophilia in 500 ppm F1 females, thyroid follicular
hypertrophy and colloidal alteration in P and F1 500 ppm rats, and
elevated atrophy of the zona glomerulosa of the adrenal cortex in 500
ppm females.  

Therefore the parental systemic LOAEL is 120 ppm (8.8 and 13.2 mg/kg
bw/day in males and females, respectively) based on significantly
decreased spleen weight (absolute and relative in parental females and
F1 males) and significantly decreased growing ovarian follicles in
females.  The parental systemic NOAEL is 30 ppm (2.2 and 3.8 mg/kg
bw/day) in males and females, respectively).

Pup body weight was decreased by 86.4 and 63.3% of controls in F1 males
and 86.0 and 62.3% of controls in F1 females in the 120 and 500 ppm
groups, respectively, at lactation day 21.  Pup body weight was also
decreased by 88.9 and 68.0% of controls for F2 males and 91.6 and 68.1%
in F2 females in the 120 and 500 ppm groups, respectively, at lactation
day 21.  Sexual maturation was delayed in F1 500 ppm pups by six days
for preputial separation and three days for vaginal opening.  However,
since body weights of 500 ppm males and females lagged behind
contemporary controls by about eight days, no primary reproductive
effects are inferred by the corresponding maturation delays.  

The offspring LOAEL is 13.2 mg/kg bw/day, based on pup body weight
decrements during lactation.  The offspring NOAEL is 4.6 mg/kg bw/day. 

No treatment related effects on reproduction was observed in this study.

The reproductive NOAEL is 500 ppm (37 and 64 mg/kg bw/day in males and
females, respectively).  The reproductive LOAEL was not established.

The submitted study is classified as acceptable/guideline and does
satisfy the guideline requirements for a two-generation reproductive
study (OPPTS 870.3800) in rats.

Dose and Endpoint for Establishing cRfD:  The parental systemic NOAEL is
2.2 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.  

Uncertainty Factor(s):  100 (10X for interspecies, 10X for
intraspecies).

3.5.3	Incidental Oral Exposure (Short- and Intermediate-Term) 

An incidental oral exposure endpoint for short- and intermediate-term
exposure was determined based on a prenatal developmental toxicity study
in the rabbit; it is summarized below.  The endpoints are based on body
weight loss, and food consumption seen in a developmental toxicity study
in rabbits.  This study is of the appropriate duration and route of
exposure for short and intermediate endpoints.

Study Selected:  Prenatal Developmental Toxicity Study - Rabbit.

Executive Summary:    SEQ CHAPTER \h \r 1 In a developmental toxicity
study (MRID 45819604) spiromesifen technical (purity:  97.4%, batch no.
06957/0009) was administered orally to 22 female CHBB:HM rabbits/dose by
gavage at dose levels of 0, 5, 35, or 250 mg/kg bw/day from days six
through 28 of gestation. 

Four females in the 250 mg/kg treatment group aborted between days 20
and 25 of gestation.  These animals exhibited cold ears, severely
decreased food consumption accompanied by body weight loss.  Gross
examination of these females revealed two of them having tightly filled
stomachs and one with a light discolored small intestine.  Microscopic
examination of the latter lesion indicated a marked vacuolation at the
villous tips.  Cold ears were noted for most of the other females in
this treatment group.  Two other females suffered total resorption of
fetuses.  Transient reduced food consumption and body weight losses were
noted for the 35 mg/kg treatment group as well.  Otherwise, no deaths
occurred during the study and no treatment-related lesions were noted in
the gross necropsy except for those which had aborted.  

The maternal LOAEL is 35 mg/kg bw/day, based on transient body weight
loss and reduced food consumption.  The maternal NOAEL is 5 mg/kg
bw/day.  

There was an increased number of late resorptions in the 250 mg/kg group
because two females in this group suffered total resorptions.  This
effect is likely due to maternal toxicity evident in this treatment
group.  Otherwise, there were no fetal deaths and a comparable number of
resorptions per litter for all of the study groups.  There was no
treatment-related incidence of malformations.  Among the skeletal
deviations observed specific bones either demonstrated greater or lesser
ossification in a dose-related manner.  However, the percentage of
affected fetuses at any dose level was within the range or was
comparable to the lower end of the range for the historical controls. 
The litter incidence for any of these effects in any treatment group
also was not statistically significant from that of the control group. 
Therefore, these results were not considered to be treatment-related.  

The developmental NOAEL is 250 mg/kg bw/day.  The developmental LOAEL is
>250 mg/kg bw/day. 

The study is classified acceptable/guideline and satisfies the guideline
requirement for a developmental toxicity study (OPPTS 870.3700) in the
rabbit. 

Dose and Endpoint for Risk Assessment.  The maternal NOAEL is 5 mg/kg
bw/day.    SEQ CHAPTER \h \r 1 The maternal LOAEL is 35 mg/kg bw/day,
based on transient body weight loss and reduced food consumption.  

3.5.4	Dermal Absorption  TC \l3 "3.5.5	Dermal Absorption 	

A dermal absorption factor of 3.3% was established based the results
obtained from the in vivo dermal absorption/kinetics study in the monkey
which demonstrated that dermal application of the test material results
in only limited absorption for the eight-hour exposure period (3.31%). 
The study is summarized below.

Study Selected:  Metabolism Study - Monkey.

Executive Summary:    SEQ CHAPTER \h \r 1 In a metabolism study (MRID
45819828), BSN 2060-Phenyl-UL-14C (batch no. not provided, radiochemical
purity: 100%, specific activity:  34.9 mCi/mmol) was administered
intravenously to one male rhesus monkey at a dose level of 0.231 mg/kg
(21.8 uCi/kg).  In a second part of the study, BSN 2060 SC480 (batch no.
K1 BRD (0037), ai 45.2%) containing BSN 2060-Phenyl-UL-14C, was applied
to the skin of one male rhesus monkey at a dose of 0.191 mg/kg or 18.3
ug/cm2 (18.0 uCi/kg) for eight hours.  Dosing via the intravenous route
resulted in the excretion of the radiolabel largely in the urine.  The
percentage of the administered dose which was recovered in the urine,
feces and cage debris/rinse samples was as follows:  urine (54.32%),
feces (13.08%), and cage debris/rinse (26.57%).  A significant fraction
of the dose was recovered in the cage debris/rinse.  Although it was not
definitive whether this radiolabel was from the urine or feces, a
greater part of that fraction was recovered prior to any radiolabel
being found in the feces.  The 13% of the dose which was definitively
recovered in the feces had likely passed through the biliary excretion
route.  Excretion was relatively rapid with greater than 70% of the
administered dose recovered within the first 24 hours.  Dermal
application of the test material resulted in only limited absorption for
the eight-hour exposure period, 3.31%.  A large fraction of that total
was recovered from the urine and cage debris/rinse showing that it is
poorly absorbed through the skin layers.

The study is classified as acceptable/nonguideline and does not satisfy
the guideline requirement for a metabolism study (OPPTS 870.7485) in the
monkey.  The study is exploratory in nature and does not comply with the
guideline requirements.

3.5.5	Dermal Exposure (Short-, Intermediate- and Long-Term) 

Short-, and Intermediate-Term

HED recommends not quantifying short- or intermediate-term dermal risk
as there was no systemic toxicity at the limit dose (1000 mg/kg/day) in
a 28-day dermal toxicity study in rats (MRID 45819603) and no
developmental toxicity concerns were identified.  

Long-Term

HED selected a long-term dermal exposure endpoint based on a
reproduction and fertility effects study in the rat (MRID 45819619). 
This endpoint would be appropriate for the duration of exposure
(long-term) and population of concern (infants and children).  Use 3.3%
dermal absorption factor for route-to-route extrapolation.  

Dose and Endpoint Selected for Risk Assessment.  The parental systemic
NOAEL is 2.2 mg/kg/day and the LOAEL is 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.  

3.5.6	Inhalation Exposure (Short-, Intermediate- and Long-Term) 

Short-, and Intermediate Term

HED established a short- and intermediate-term endpoint for inhalation
scenarios based on a subchronic (30-day) inhalation toxicity study in
the rat.  In this study, no systemic toxicity was observed at the
highest dose (LOAEL not established; however, the LOAEL has been
established in another five-day inhalation toxicity study).  The study
was an appropriate route-specific study.  The study is summarized below.
 

Study Selected:  Subchronic Inhalation Toxicity Study in the Rat. 

Executive Summary:  In a subchronic (30-day) inhalation toxicity study
(MRID 45819622), technical grade spiromesifen (purity: 97.4%, batch no.
06957/0009) was administered to 10 Wistar rats/sex/concentration by
dynamic nose-only exposure at concentrations of 0, 5.0, 24.6, or 80.9
mg/m3 for six hours per day, five days/week for up to a total of 22 days
over a 30 day period (0, 0.005, 0.0246, and 0.0809 mg/L).  The mean MMAD
(GSD) values were 2.70 (1.91), 2.71 (1.77), and 2.87 (1.81) µm for the
5.0, 24.6, and 80.9 mg/m3 exposure groups, respectively.  An additional
10 animals/sex/group were included in the control and high exposure
groups and maintained for a recovery period of approximately five weeks.
 

	

No deaths occurred during the study.  No treatment-related clinical
signs were noted over the course of the exposure or recovery periods. 
These data included an evaluation of breathing patterns, neurological
reflexes, foot splay, and colonic temperature.  In the hematology
evaluation, the blood clotting time was increased for the 24.9 and 80.9
mg/m3 females after four weeks of exposure (p<0.01 or 0.05).  This
effect was not evident after five weeks of recovery.  In the clinical
chemistry, the serum alkaline phosphatase activity was increased for the
80.9 mg/m3 females after four weeks of exposure (p<0.05).  Likewise,
this effect was not evident after the recovery period.  Among the liver
enzymes which were evaluated, N-demethylase and O-demethylase activities
were increased in the 24.9 and 80.9 mg/m3 after four weeks of exposure
p<0.01 or 0.05) with recovery five weeks later.  There were no
treatment-related lesions or effects on organ weights noted in the
necropsy or histopathological evaluations.  

The LOAEL is not established.  The NOAEL is 21.1 mg/kg/day (0.0809
mg/L/day, HDT).  

Dose and Endpoint Selected for Risk Assessment:  The NOAEL was
determined to be 21.1 mg/kg/day and the LOAEL was not established.

Long-Term   TC "4.4.8	Inhalation Exposure (Long-Term)" \f C \l "3"  

	

HED established a long-term endpoint for inhalation scenarios based on a
reproduction and fertility effects study in the rat (45819619).  This
endpoint would be appropriate for the duration of exposure (long-term). 
Because an oral dose was selected, absorption via inhalation is presumed
to be equivalent to oral absorption.

Dose and Endpoint Selected for Risk Assessment:  The parental systemic
NOAEL is 2.2 mg/kg/day based significantly decreased spleen weight
(absolute and relative in parental females and F1 males) and
significantly decreased growing ovarian follicles in females at 13.2
mg/kg bw/day (LOAEL).  

3.5.7	Level of Concern for Margin of Exposure

Summarized below are the target MOEs that HED has used in this risk
assessment.  

Table 3.5.8  Margins of Exposure Used in the Spiromesifen Risk
Assessment.

Route/Duration	Short-Term

(1 to 30 Days)	Intermediate-Term

(1to 6 Months)	Long-Term

(>6 Months)

Occupational (Worker) Exposurea

Dermal	N/A	N/A	100

Inhalation	100	100	100

Residential (Non-Dietary) Exposureb

Oral	100	100	100

Dermal	N/A	N/A	100

Inhalation	100	100	100

aOccupational Exposure:  These MOEs are based on the conventional
uncertainty factor of 100X (10X for intraspecies variation and 10X for
interspecies extrapolation).

bResidential Exposure:  The MOEs are not applicable for this risk
assessment as there are no residential uses.

3.5.8	Recommendation for Aggregate Exposure Risk Assessments	

HED has determined that an aRfD is not necessary because an endpoint of
concern attributable to a single dose was not identified; thus acute
aggregate exposure and risk is not required.  For chronic aggregate
risk, the exposure from food can be added to the exposure from drinking
water which can then be compared to the cRfD.  

For short- and intermediate-term durations, the incidental oral and
inhalation exposures cannot be combined with chronic food exposures
because the corresponding toxicity endpoints differ.  Long-term dermal
and inhalation exposure can be combined with chronic food exposure
because they all have a common endpoint (i.e., NOAEL=2.2 mg/kg/day,
two-generation study in rats).  Please note that residential exposure is
not expected as there are no residential uses.  

3.5.9	Classification of Carcinogenic Potential

Spiromesifen has been classified as “not likely to be carcinogenic to
humans.”

3.6	Endocrine Disruption

EPA is required under the Federal Food Drug and Cosmetic Act (FFDCA), as
amended by FQPA, to develop a screening program to determine whether
certain substances (including all pesticide active and other
ingredients) "may have an effect in humans that is similar to an effect
produced by a naturally occurring estrogen, or other such endocrine
effects as the Administrator may designate."  Following the
recommendations of its Endocrine Disruptor Screening and Testing
Advisory Committee (EDSTAC), EPA determined that there was 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 has authority to
require the wildlife evaluations.  As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).

When the appropriate screening and/or testing protocols being considered
under the Agency’s EDSP have been developed, spiromesifen may be
subjected to additional screening and/or testing to better characterize
effects related to endocrine disruption.

4.0	PUBLIC HEALTH AND PESTICIDE EPIDEMIOLOGY DATA

4.1	Incident Reports

There are no known incidents reported for spiromesifen.

5.0	DIETARY EXPOSURE/RISK CHARACTERIZATION  TC \l1 "5.0	Dietary
Exposure/Risk Characterization 

Residue chemistry data pertaining to this submission was submitted and
reviewed by ARIA (DP#: 345985, D. Rate, 12/5/2007).  

5.1	Pesticide Metabolism and Environmental Degradation

5.1.1	Metabolism in Primary Crops

Residue Chemistry Memo DP#: 308837, G. Kramer, et al., 2/18/2005 

Residue Chemistry Memo DP#: 300469, K. Martin, et al., 2/17/2005 

The nature of the residue in plant commodities is adequately understood
based on metabolism studies conducted with lettuce, cotton and tomato. 
The results of these studies showed that spiromesifen is metabolized in
all RACs by the loss of the dimethylbutyric acid group to yield BSN
2060-enol.  Further metabolism can include:  hydroxylation of BSN
2060-enol to yield BSN 2060-2-hydroxymethyl or BSN 2060-4-hydroxymethyl;
hydroxylation of BSN 2060-enol to yield BSN 2060-3-pentanol; oxidation
of BSN 2060-3-pentanol or BSN 2060-2- or -4-hydroxymethyl to give BSN
2060-2- or -4-hydroxymethyl-3-pentanol; oxidation of BSN
2060-4-hydroxymethyl to give BSN 2060-pentanone or BSN 2060-4-aldehyde;
oxidation of BSN 2060-2- or 4-hydroxymethyl-3-pentanol to give BSN
2060-hydroxy-4-carboxy; and further hydroxylation of BSN
2060-4-hydroxymethyl-3-pentanol or BSN 2060-hydroxy-4-carboxy to give
BSN 2060-dihydroxy-4-carboxy.  The reviewed plant studies also indicate
that spiromesifen, when foliarly applied during the vegetative growth
stage, is not readily translocated.  

Spiromesifen and BSN 2060-enol are the residues of concern in crop
commodities for purposes of tolerance enforcement and risk assessment. 
Additionally, BSN 2060-4-hydroxymethyl (free and conjugated) is a
residue of concern in leafy vegetables (risk assessment only).

5.1.2	Metabolism in Rotational Crops

DP#: 308837, G. Kramer, et al., 2/18/2005, 

DP#: 300469, K. Martin, et al., 2/17/2005, 

A confined accumulation study in rotational crops has previously been
submitted and reviewed by HED Spiromesifen is initially metabolized by
hydrolysis of the dimethylbutyl carboxylic ester group to form the
ketoenol, BSN 2060-enol.  BSN 2060-enol is then metabolized by
hydroxylation of the methyl groups or cyclopentyl ring.  BSN
2060-4-hydroxymethyl is the major residue that is conjugated with
glucose to form BSN 2060-4-hydroxymethyl-glucoside in varying
proportions, depending on the crop type.  Natural incorporation of
radioactivity into the starch and polymeric constituents of the plant
cell matrix is observed.

The residues of concern in rotational crops for purposes of tolerance
enforcement and risk assessment are parent plus BSN2060-enol and BSN
2060-4-hydroxymethyl. 

5.1.3	Metabolism in Livestock

	

DP#: 308837, G. Kramer, et al., 2/18/2005

DP#: 300469, K. Martin, et al., 2/17/2005 

The nature of the residue in livestock commodities is adequately
understood based on metabolism studies conducted with lactating goats
and laying hens.  Based on these studies, spiromesifen is metabolized in
all RACs by the loss of the dimethylbutyric acid group to yield BSN
2060-enol.  Further metabolism can include hydroxylation of BSN
2060-enol to yield BSN 2060-2-hydroxymethyl or BSN 2060-4-hydroxymethyl;
hydroxylation of BSN 2060-enol to yield BSN 2060-3-pentanol; oxidation
of BSN 2060-3-pentanol or BSN 2060-2- or -4-hydroxymethyl to give BSN
2060-2- or -4-hydroxymethyl-3-pentanol; oxidation of BSN
2060-4-hydroxymethyl to give BSN 2060-pentanone or BSN 2060-4-aldehyde;
oxidation of BSN 2060-2- or 4-hydroxymethyl-3-pentanol to give BSN
2060-hydroxy-4-carboxy; and further hydroxylation of BSN
2060-4-hydroxymethyl-3-pentanol or BSN 2060-hydroxy-4-carboxy to give
BSN 2060-dihydroxy-4-carboxy.  

Spiromesifen and BSN 2060-enol are residues of concern in livestock for
purposes of tolerance enforcement.  Additionally, BSN
2060-4-hydroxymethyl (free and conjugated) is a residue of concern in
ruminant commodities (tolerance enforcement and risk assessment).  See
Table 5.1.8, below.

5.1.4	Analytical Methodology	

DP#: 308837, G. Kramer, et al., 2/18/2005

DP#: 305152, J. Tyler, 7/14/2004

DP#: 305721, E. Kolbe, 11/15/2007, 

Enforcement methods:  An HPLC/MS/MS method, Method 00631/M001, was
submitted for the enforcement of tolerances for residues of
spiromesifen, BSN 2060-enol, and BSN 2060 4-hydroxymethyl in/on plant
commodities.  The validated LOQ is 0.01 ppm for each analyte.  An
LC/MS/MS Method 110878 was also submitted for determination of
spiromesifin residues of concern in livestock tissues and milk. 
Validation data, including an independent laboratory validation (ILV)
and radiovalidation studies have been submitted.  Both methods were
submitted for PMV by ACB.  ACB recommended that each of the methods
(Plant Commodity, Rotational Plant Commodity and Livestock Commodity) 1)
appear to meet OPPTS 860.1340 Residue Chemistry Test Guidelines for
acceptable enforcement methods; 2) do not need to be validated by an
Agency Laboratory; and 3) have been independently validated with
recommendations for modifications.

Data-collection method:  Samples of bean (dry shelled, succulent
shelled, and edible podded) seed and foliage from the submitted field
trials were analyzed for residues of spiromesifen and its enol
metabolite (BSN 2060-enol) using a variation of HPLC/MS/MS Method
00631/M001, which is essentially the same as the proposed enforcement
method for plants.  The LLMV for this method for each spiromesifen and
BSN 2060-enol was 0.01 ppm for dry shelled bean seed and 0.05 ppm for
succulent shelled bean seed, edible podded bean, and bean foliage. 
Acceptable method validation and concurrent method recoveries were
achieved with bean seed and foliage fortified with spiromesifen or BSN
2060-enol at 0.01-20 ppm.

Conclusions.  The modified HPLC/MS/MS Method 00631/M001 is adequate for
data collection.  The proposed enforcement methods, HPLC/MS/MS Method
00631/M001 for plants and LC/MS/MS Method 110878 for animals will be
forwarded to FDA for inclusion in PAM Vol. II, once the petitioner has
submitted a revised method incorporating the recommendations by ACB.

5.1.5	Environmental Degradation

Parent spiromesifen is not likely to persist in the environment as it
readily undergoes both biotic and abiotic degradation; however, its
primary degradate BSN2060 is expected to persist.  While parent
spiromensifen strongly sorbs to sediment and is not likely to be mobile,
its enol degradate does not sorb to sediment and is expected to leach
into groundwater.  Spiromesifen has limited solubility in water and is
some cases has been reported to have a practical solubility limit of 40
to 50 Ug/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 dissipation half lives ranging from 2 to 10
days.  The compound is not likely to bioconcentrate appreciably given
its relatively rapid degradation and depuration.  (DP#: 289953, D.
Young, 12/16/2004).

5.1.6	Comparative Metabolic Profile

The metabolic pathways for plants and animals are similar.  The parent
is hydrolyzed, forming the -enol metabolite, which is then hydroxylated,
forming hydroxymethyl pentanol metabolites.  

5.1.7	Toxicity Profile of Major Metabolites and Degradates

Toxicity data on the major metabolites are not available.  ARIA assumed
that the toxicity of BSN 2060-enol and the BSN 2060-4-hydroxy
metabolites is equivalent to that of the parent; both are found in the
rat.  

5.1.8	Pesticide Metabolites and Degradates of Concern

Provided in Table 5.1.8 is a summary of the metabolites that are
considered in the risk assessment and in the tolerance expression. 
Primary crops include:  Corn, Field; Cotton; Cucurbit Vegetables and
Melons; Fruiting Vegetables; Vegetable, tuberous and corm; Vegetable,
Brassica leafy subgroup; Vegetable, leafy greens subgroup (except
Brassica); Vegetable, Brassica, head and stem subgroup; and Strawberry. 
Rotational crops are:  Alfalfa; Barley; Sugar Beet; and Wheat. 
Livestock includes:  Cattle, fat; Cattle, meat byproducts; Milk; Milk,
fat; Goat, fat; Goat, meat byproducts; Sheep, fat; Sheep, meat
byproducts; Horse, fat; and Horse, meat byproducts.  

The tolerance expression for primary crops is:  “for the combined
residues of spiromesifen
(2-oxo-3-(2,4,6-trimethylphenyl)-1-oxaspiro[4.4]non-3-en-4-yl
3,3-dimethylbutanoate) 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.”  The  tolerance
expression for rotational crops is:  “the inadvertent or indirect
combined residues of spiromesifen
(2-oxo-3-(2,4,6-trimethylphenyl)-1-oxaspiro[4.4]non-3-en-4-yl
3,3-dimethylbutanoate), its enol metabolite
(4-hydroxy-3-(2,4,6-trimethylphenyl)-1-oxaspiro[4.4]non-3-en-2-one), and
its metabolites containing the 4-hydroxymethyl moiety
(4-hydroxy-3-[4-(hydroxymethyl)-2,6-dimethylphenyl]-1-oxaspiro[4.4]non-3
-en-2-one), calculated as the parent compound equivalents.”  And, the
tolerance expression for livestock commodities is:  “the combined
residues of spiromesifen
(2-oxo-3-(2,4,6-trimethylphenyl)-1-oxaspiro[4.4]non-3-en-4-yl
3,3-dimethylbutanoate), and its metabolites containing the enol
(4-hydroxy-3-(2,4,6-trimethylphenyl)-1-oxaspiro[4.4]non-3-en-2-one) and
4-hydroxymethyl
(4-hydroxy-3-[4-(hydroxymethyl)-2,6-dimethylphenyl]-1-oxaspiro[4.4]non-3
-en-2-one) moieties, calculated as the parent compound equivalents.”

The rationale for inclusion of the metabolites is described below.  

Table 5.1.8  Summary of Metabolites and Degradates to be included in the
Risk Assessment and Tolerance Expression

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants

	Primary Crop	parent*

BSN 2060-enol

BSN 2060-4-hydroxymethyl (free and conjugated)	parent

BSN 2060-enol

	Rotational Crop	parent*

BSN 2060-enol

BSN 2060-4-hydroxymethyl	parent

BSN 2060-enol

BSN 2060-4-hydroxymethyl

Livestock

	Ruminant	parent*

BSN 2060-enol (free and conjugated)

BSN 2060-4-hydroxymethyl	parent

BSN 2060-enol

BSN 2060-4-hydroxymethyl

	Poultry	parent*

BSN 2060-enol

BSN 2060-4-carboxy-3-pentanol

BSN 2060-hydroxy-4-carboxy	parent

BSN 2060-enol

Drinking Water

	parent*

BSN 2060-enol

BSN 2060-hydroxy-4-carboxy	Not Applicable

*Recovered by Multiresidue Methods (MRMs)

Plants

Spiromesifen and BSN 2060-enol are the predominant residues in crops. 
The toxicity of BSN 2060-enol is expected to be comparable to the parent
compound.  

BSN 2060-4-hydroxymethyl (free and conjugated) is the only other major
metabolite observed in any of the metabolism studies.  It was only
present in the lettuce study where it comprised 21% of the total toxic
residue.  As the toxicity of BSN 2060-4-hydroxymethyl is expected to be
comparable to the parent compound, this metabolite will be included in
the risk assessment for leafy crops.

Livestock  

Spiromesifen, BSN 2060-4-hydroxymethyl (free and conjugated) and BSN
2060-enol are the predominant residues in ruminants.  The toxicity of
BSN 2060-enol and BSN 2060-4-hydroxymethyl is expected to be comparable
to the parent compound.  Two additional compounds, BSN
2060-4-carboxy-3-pentanol and BSN 2060-hydroxy-4-carboxy, are major
residues in poultry commodities.  If future new uses result in a
significant increase in the exposure of poultry to spiromesifen
residues, then these metabolites will be included in the risk
assessment.  Poultry commodities are not included in the risk assessment
due to low potential for exposure (40 CFR 180.6(a)(3)).

Rotational Crops  

At the proposed PBIs, BSN 2060-4-hydroxymethyl (free and conjugated) and
BSN 2060-enol are the predominant residues.  Several other minor
metabolites were also observed; however, HED determined that they were
not significant to the risk assessment or tolerance expression.

Drinking Water  

Spiromesifen and BSN 2060-enol are the predominant residues in drinking
water.  BSN 2060-enol may account for 75% of the total acute exposure
and for over 90% for chronic exposure.

 TC \l3 "5.1.5	Environmental Degradation 

5.1.9	  Drinking Water Residue Profile

The drinking water residues used in the dietary risk assessment were
provided by EFED (DP#: 300469, K. Martin, e. al.; 2/17/2005) and
incorporated directly into this dietary assessment.  Water residues were
incorporated in the DEEM-FCID into the food categories “water, direct,
all sources” and “water, indirect, all sources.” 

Because monitoring data are unavailable, estimates for spiromesifen
concentrations were made only with mathematical models.  The models PRZM
(version 3.12 beta) and EXAMS (version 2.98.04) were used to conduct
surface water exposure assessments.  SCIGROW (version 2.3) was used for
groundwater.  EDWCs were generated for the total toxic residue which
includes spiromesifen, the -enol and -carboxy metabolites, and
unextracted material.  The highest estimated surface water
concentrations occurred with the NC sweet potato scenario.  For chronic
assessments the EDWC is 11 ppb.  The groundwater estimate from SCIGROW
is 28 ppb; this was the value used in this assessment.

5.1.10	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.  The metabolic pathways in all RACs are very similar:  the loss
of the dimethylbutyric acid group to yield BSN 2060-enol followed by
hydroxylation and conjugation.  The reviewed plant studies also indicate
that spiromesifen, when foliarly applied during the vegetative growth
stage, is not readily translocated.  Residues in crops with late-season
application are mostly on surfaces.  Spiromesifen and BSN 2060-enol are
residues of concern in crops and livestock for purposes of tolerance
enforcement and risk assessment.  Additionally, BSN 2060-4-hydroxymethyl
(free and conjugated) is a residue of concern in leafy vegetables (risk
assessment only), rotational crops (tolerance enforcement and risk
assessment) and ruminant commodities (tolerance enforcement and risk
assessment).

A HPLC/MS/MS method (Method 00631/M001) was submitted previously for the
enforcement of tolerances for residues of spiromesifen, BSN 2060-enol,
and BSN 2060 4-hydroxymethyl in/on plant commodities.  The proposed
enforcement methodology was submitted for a PMV by the ACL/BEAD.  The
proposed method was evaluated and accepted with recommendations (DP#:
305721, E. Kolbe, 11/15/2007).  Samples of beans (dry shelled, succulent
shelled, and edible podded) from the crop field trials submitted in
support of this petition were analyzed for residues of spiromesifen and
BSN 2060-enol using a variation of Method 00631/M001.  The concurrent
method recoveries demonstrated that the method is adequate for data
collection.  Liquid chromatography (LC)/MS/MS Method 110878 was also
submitted for determination of spiromesifin residues of concern in
livestock tissues and milk.  Validation data, including independent
laboratory validation and radiovalidation studies have been submitted. 
Method 110878 has been evaluated by ACL/BEAD for a PMV and accepted with
recommendations (DP#: 305721, E. Kolbe, 11/15/2007).

The submitted field trial data for dry shelled, succulent shelled and
edible-podded beans are adequate.  There is sufficient geographic
representation of residue data, and the field trials were conducted
according to the proposed use pattern.  Residues for dry bean and
succulent bean were all below the combined LLMV for both the parent and
metabolite; therefore, the recommended tolerances are 0.02 ppm in bean,
dry and 0.10 ppm in bean, succulent.  Recommended tolerances for bean,
edible podded and cowpea forage were calculated using the MRL/MLE
tolerance spreadsheets.  The calculated tolerances for bean, edible
podded and cowpea, forage are 0.80 ppm and 30 ppm, respectively.  A
revised Section F must be submitted to change the requested tolerance in
bean, edible podded to 0.80 ppm, and the requested tolerance in cowpea,
forage to 30 ppm.

The submitted data for succulent shelled bean foliage was used to
establish a tolerance in cowpea forage.  However, no residue data were
submitted for cowpea hay.  For the purpose of this petition, ARIA will
recommend a tolerance for cowpea hay calculated from the recommended
tolerance for cowpea forage and adjusting for percentages of dry matter
between cowpea hay and cowpea forage.  A revised Section F must be
submitted for the addition of cowpea, hay at a level of 86 ppm.  If the
petitioner does not agree with the magnitude of the recommended
tolerance for cowpea, hay, then cowpea, hay residue data would need to
be submitted.  A minimum of three trials are required. 

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 plantback interval (PBI); and a 12-month PBI for
all other crops) are consistent with what were previously deemed
acceptable and are supported by adequate data.

Adequate multiresidue method data for spiromesifen, BSN 2060-enol, and
BSN 2060 4-hydroxymethyl were previously submitted.  Spiromesifen was
completely recovered using multiresidue method Protocols D, E and F, for
the analysis of nonoily and fatty commodities.  The methods were not
found to be suitable for the determination of BSN 2060-enol and BSN 2060
4-hydroxymethyl. Thus, the MRM are not adequate for enforcement of
tolerances which include residues of spiromesifen and BSN 2060-enol.

There are adequate storage stability data to support the storage
conditions and durations of samples collected from the bean field
trials.  There are no storage stability issues or corrections that may
need to be applied to the submitted residue studies on beans.

An adequate cattle feeding study is available to support the livestock
dietary burdens resulting from the proposed uses.  Dietary burdens of
~22 ppm were calculated for beef and dairy cattle, and ~0.3 ppm for
poultry, and ~0.04 ppm for swine.  The calculations reflect the most
recent guidance from HED concerning revisions of feedstuff percentages
and constructing reasonably balanced livestock diets.  Based on these
dietary exposure levels and the residue data from the ruminant feeding
study, the data indicate that a tolerance is needed in the meat of
cattle, goats, horses, and sheep; a tolerance increase is required for
meat byproducts of cattle, goats, horses, and sheep; a tolerance
increase is required for the fat of cattle, goats, horses and sheep; a
tolerance increase for milk, fat and a tolerance for milk.  Based on the
transfer coefficients for livestock tissues and the relatively low
dietary burden for swine, spiromesifen tolerances in hogs are not
required.  A revised Section F will be required to request the tolerance
increase for milk, fat and to adjust the proposed tolerance levels to
match the ARIA recommended tolerances.

Based on a dietary burden of 0.3 ppm for poultry and the residues
identified in the poultry metabolism study, the proposed use of
spiromesifen on cowpea addressed in this document is not expected to
alter the Agency’s previous determination that there is no reasonable
expectation of finite residues [40CFR§180.6(a)(3)] in poultry
commodities, and therefore, no tolerances are needed in poultry and
eggs.  If in the future, the petitioner proposes a use which increases
the dietary burdens of poultry, then the Category 3 situation will be
re-evaluated. 

5.1.11	International Residue Limits

No Codex, Canadian, or Mexican MRLs have been established for residues
of spiromesifen and its metabolites.  

5.2	Dietary Exposure and Risk

™ Version 2.03, which incorporates consumption data from USDA’s
CSFII, 1994-1996 and 1998.  The 1994-96, 98 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.

The dietary exposure analysis was performed by ARIA (DP #: 342904, B.
Hanson, 12/17/2007).

 TC \l2 "5.2  Dietary Exposure and Risk 

5.2.1	Acute Dietary Exposure/Risk

No toxic effects attributable to a single (i.e., acute) exposure to
spiromesifen have been identified; therefore, an acute reference dose
(RfD) has not been established for spiromesifen and an acute dietary
exposure assessment has not been conducted.   

5.2.2	Chronic Dietary Exposure/Risk

™ Version 7.81 default processing factors were used.  The highest
chronic EDWC of 28 ppb was directly incorporated into the analysis.  The
chronic dietary risk assessment shows that for all included commodities,
the chronic dietary risk estimates are below ARIA’s level of concern
(i.e., <100% chronic population adjusted doses (cPAD).  For the U.S.
population, the exposure for food and water utilized 32% of the cPAD. 
The chronic dietary risk estimate for the highest reported exposed
population subgroup, children 3-5 years old, is 42% of the cPAD.

Table 5.2.2  Summary of Chronic Dietary (Food and Drinking Water)
Exposure Risk for Spiromesifen

Population Subgroup	Chronic Dietary

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

General U.S. Population	0.007103	32

All Infants (< 1 year old)	0.005623	26

Children 1-2 years old	0.009323	42

Children 3-5 years old	0.009338	42

Children 6-12 years old	0.007271	33

Youth 13-19 years old	0.006100	28

Adults 20-49 years old	0.007069	32

Adults 50+ years old	0.006888	31

Females 13-49 years old	0.007209	33

5.2.3	Cancer Dietary Risk

Spiromesifen has been classified as “not likely to be carcinogenic to
humans.”  Therefore, a cancer dietary risk assessment was not
performed.      

5.3	Anticipated Residue and Percent Crop Treated (%CT) Information

The chronic dietary exposure and risk estimates are conservative as they
assumed 100% CT and ARIA recommended/established tolerance-level
residues for all commodities except leafy vegetables.  A 1.3x correction
factor was applied to leafy vegetables to account for the additional
metabolite.  Conservative DEEM-FCIDTM default processing factors were
applied to all processed commodities in the analyses.  

6.0	RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK CHARACTERIZATION

Currently, there are no registered or proposed uses of spiromesifen that
would result in residential (non-occupational) exposures.  Therefore,
potential risk from such uses is not addressed in this risk assessment. 

6.1	Other (Spray Drift, etc.)

Spray drift is always a potential source of exposure to residents nearby
to spraying operations.  This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from the ground application method employed for
spiromesifen.  The Agency has been working with the Spray Drift Task
Force, EPA Regional Offices and State Lead Agencies for pesticide
regulation and other parties to develop the best spray drift management
practices.  On a chemical by chemical basis, the Agency is now requiring
interim mitigation measures for aerial applications that must be placed
on product 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.

7.0	AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

In accordance with the FQPA, ARIA must consider and aggregate pesticide
exposures and risks from non-occupational sources, including; food,
drinking water, and residential pathways.  In an aggregate assessment,
exposures from relevant sources are added together and compared to
quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks
themselves can be aggregated.  When aggregating exposures and risks from
various sources, ARIA considers both the route and duration of exposure.

No acute or short/intermediate/long-term or cancer aggregate exposure is
expected.   Acute exposure is not expected because no hazard has been
identified for this endpoint.

Short/intermediate/long-term exposures are not expected since there are
no residential/non-occupational uses of spiromesifen.  Cancer exposure
is not expected because spiromesifen has been classified as “not
likely to be carcinogenic to humans.”

Since the chronic aggregate risk assessment includes exposure from food
and water only, and the chronic dietary analysis that was performed
included both, no further calculations are necessary.  Since the chronic
dietary risk does not exceed ARIA’s level of concern, the chronic
aggregate risk does not exceed ARIA’s level of concern.

8.0	CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT

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

9.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY

ARIA provided an assessment for the post-harvest use of spiromesifen on
beans (M. Dow, DP #: 338884, 5/22/2007).   For more detailed information
on the occupational risks associated with this proposed use, please see
afore mentioned assessment.

Proposed Uses

The registered product proposed for use is Oberon® 2 SC
Insecticide/Miticide (EPA Reg. No. 264 - 719).  A summary of the
proposed use is presented in Table 9.0.  

Table 9.0  Summary of Proposed Use Pattern for Applying Spiromesifen to
Beans

Formulation	Oberon® 2 SC; 2.0 lb ai per gallon liquid; 23.1 %; Reg. No.
264 - 719.

Pest	broad mite, two-spotted spider mite and silverleaf, sweetpotato and
greenhouse whiteflies

Method of Applic.	aerial, ground-boom, chemigation

Max. Applic. Rate	0.19 lb ai/A

Max. No. Applications	3 per season at the high rate

Applic. Interval	7 days

Preharvest Interval	1 day for succulent and edible podded beans

10 days for dry shelled beans

Restricted Entry Interval	12 hrs

Manufacturer	Bayer

9.1	Occupational Pesticide Handler Exposure and Risk

Based upon the proposed use pattern, ARIA believes that the most highly
exposed occupational pesticide handlers will be mixer/loaders using
open-pour loading of liquid formulations in support of aerial
operations, applicators using open-cab, ground-boom sprayers and aerial
applicators.  Handlers preparing for use in chemigation are not expected
to be more highly exposed than mixer/loaders since the activities are
believed to be similar.  

ARIA believes pesticide handlers will be exposed to short-term duration
(1-30 days) exposures but not to intermediate-term (1-6 months) duration
exposures.  Although multiple applications are possible, they are
separated by 7 day retreatment intervals.   It is unlikely that
pesticide handlers would be exposed continuously for 30 days or more. 
Estimates of intermediate-term exposures are, however, presented.  

Short-term (1-30 days) or intermediate-term (1 - 6 months) dermal
toxicological endpoints have not been identified.  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.

Short- and intermediate-term inhalation endpoints have been identified
(NOAEL= 21.1 mg ai/kg bw/day).  The short-term and intermediate-term
inhalation endpoints were identified from a subchronic (30-day)
inhalation study in the rat.  These same toxicological endpoints were
used in the previous spiromesifen risk assessment.  Therefore, only
estimated exposures and risks for short- and intermediate-term
inhalation are presented in Table 9.1, below.  

Table 9.1    Estimated Handler Exposure and Risk from the Proposed Uses
of  Spiromesifen on Beans

Unit Exposure1

mg a.i./lb handled	

Applic. Rate2	

Units Treated3

Per Day	

Average Daily

Dose4

mg a.i./kg bw/day	

NOAEL5

mg a.i./kg bw/day	

MOE6

Mixer/Loader - Liquid - Open-pour

Inhal              0.0012 HC	0.19 lb ai/A	350 A/day	Inhal          
0.0011	21.1	19,180

Applicator - Ground-boom - Open Cab

Inhal              0.00074 HC	0.19 lb ai/A	200 A/day	Inhal         
0.0004	21.1	52,750

Applicator - Fixed-wing - Aerial (Pilots not required to wear gloves)

Inhal           0.000068 MC 	0.19 lb ai/A	350 A/day	Inhal       
0.000065	21.1	324,615

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.      Inhal. = Inhalation.  Units = mg
a.i./pound of active ingredient handled.  Data Confidence: LC = Low
Confidence, MC = Medium Confidence, HC = High Confidence.

2.  Applic. Rate. = Taken from Sections B  and proposed labeling in  the
IR-4 submission.

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.  NOAEL = No Observable Adverse Effect Level (21.1 mg a.i./kg bw/day)
for short-term duration inhalation exposures 

6.  MOE = Margin of Exposure = NOAEL  ( ADD.  

A MOE of 100 is adequate to protect occupational pesticide handlers from
short-term exposures to spiromesifen.  The proposed use patterns do not
exceed ARIA’s level of concern.

9.2	Occupational Post-Application Worker Exposure and Risk

Since there is a 12 hour REI, post-application inhalation exposure is
expected to be negligible and is not assessed.

Restricted Entry Interval

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.

10.0	DATA NEEDS AND LABEL RECOMMENDATIONS

10.1	Toxicology

None.

10.2	Residue Chemistry

The following are deficiencies noted in the residue chemistry review:

860.1340 Residue Analytical Methods

The petitioner should submit revised methods of enforcement to the
Agency, incorporating the recommendations by the analytical chemistry
branch (ACB)(DP#: 305721, E. Kolbe, 15/NOV/2007).

860.1550 Proposed Tolerances

The petitioner should submit a revised Section F reflecting the ARIA
recommended tolerances and commodity definitions. 

10.3	Occupational and Residential Exposure

None.

REFERENCES:

Dietary Exposure Memorandum

	Spiromesifen.  Chronic Dietary Exposure Assessment for the Petition
Proposing Tolerances for Residues of Spiromesifen on Beans.  PP# 7E7195,
DP#: 342904, B. Hanson, 12/17/2007.

Drinking Water Memorandum

	Memo, DP#: 300469, K. Martin, et. al.;, 2/17/2005  

Residue Chemistry Data Review Memorandum

	Spiromesifen.  Petition for the Establishment of Permanent Tolerances
on Beans (Dry Shelled, Succulent Shelled, and Edible Podded) and Cowpea
Forage and Reassessment of Existing Tolerances on Livestock Commodities
- PP#7E7195.  DP#: 345985, D. Rate, 12/5/2007. 

Occupational and Residential Exposure Memorandum

	Spiromesifen – Human, Non-Dietary Exposure/Risk Assessment for the
Use of Spiromesifen on Dry Shelled, Succulent Shelled and Edible Podded
beans. DP#: 338884; M. Dow; 5/22/2007.

Risk Assessment Document

	Spiromesifen on Greenhouse-Grown Tomatoes (PP#5E6901) and Oats
(PP#6F7039).  Health Effects Division (HED) Risk Assessment.  DP#:
328204; G. Kramer; 8/4/2006.  

Appendix A:  TOXICOLOGY ASSSESSMENT

A.1	Toxicology Data Requirements

The requirements (40 CFR 158.607) for food use of spiromesifen are in
Table A.1. Use of the new guideline numbers does not imply that the new
(1998) guideline protocols were used.

 TC \l2 "A.1  Toxicology Data Requirements  

Table A.1  Toxicology Data Requirements for Spiromesifen

Test 

	Technical

	Required	Satisfied

870.1100    Acute Oral Toxicity	

870.1200    Acute Dermal Toxicity	

870.1300    Acute Inhalation Toxicity	

870.2400    Primary Eye Irritation	

870.2500    Primary Dermal Irritation	

870.2600    Dermal Sensitization		yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

yes

870.3100    Oral Subchronic (rodent)	

870.3150    Oral Subchronic (nonrodent)	

870.3200    21-Day Dermal	

870.3250    90-Day Dermal	

870.3465    90-Day Inhalation		yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

870.3700a  Developmental Toxicity (rodent)	

870.3700b  Developmental Toxicity (nonrodent)	

870.3800    Reproduction		yes

yes

yes	yes

yes

yes

870.4100a  Chronic Toxicity (rodent)	

870.4100b  Chronic Toxicity (nonrodent)	

870.4200a  Oncogenicity (rat)	

870.4200b  Oncogenicity (mouse)	

870.4300    Chronic/Oncogenicity		yes

yes

yes

yes

no	yes

yes

yes

yes

-

870.5100    Mutagenicity—Gene Mutation - bacterial	

870.5xxx    Mutagenicity—Structural Chromosomal Aberrations	

870.5xxx    Mutagenicity—Other Genotoxic Effects		yes

yes

yes	yes

yes

yes

870.6100a  Acute Delayed Neurotox. (hen)	

870.6100b  90-Day Neurotoxicity (hen)	

870.6200a  Acute Neurotox. Screening Battery (rat)	

870.6200b  90-Day Neuro. Screening Battery (rat)	

870.6300    Develop. Neuro		no

no

no

no

no	-

-

-

-

-

870.7485    General Metabolism	

870.7600    Dermal Penetration		yes

no	yes

-

Special Studies for Ocular Effects

Acute Oral (rat)	

Subchronic Oral (rat)	

Six-month Oral (dog)		no

no

no

no	-

-

-

-

A.2	Acute Toxicity Profile

Table A.2  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

1 Unacceptable because the 5% concentration used for the challenge was
inadequate.

A.3	Toxicity Profiles

Table A.3.  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:  0, 269.6, 699.2, and 1706.0 mg/kg/day

Ac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

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

 (↓44%M, ↓53%F) and food consumption.

Immunotoxicity:  Inconclusive, however, 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, however, immunotoxicity will be protected
by dose (2.2 mg/kg/day) used for risk assessment).

Appendix B:	REFERENCES (in MRID order)

45819403	Shaw, D. (2000) BSN 2060: Metabolism in Rats: Lab Project
Number: BAG/294: 110331: BAG 294/993171. Unpublished study prepared by
Huntingdon Life Sciences. 158 p. {OPPTS 870.7485}

45819514	Krotlinger, F. (1997) BSN2060 Study for Acute Oral Toxicity in
Rats: Lab Project Number: 26309: T9061589: 109630. Unpublished study
prepared by Bayer AG. 29 p. {OPPTS 870.1100}

45819515	Leser, K.; Sander, E. (2000) BSN2060 Study on the Subchronic
Toxicity in Wistar Rats (Dietary Administration Over 3 Months with a
Subsequent Recovery Period Over 4 Months): Lab Project Number: PH 29546:
T1061969: 109632. Unpublished study prepared by Bayer AG. 594 p. {OPPTS
870.3100}

45819516	Herbold, B. (1997) BSN2060 Salmonella/Microsome Test Plate
Incorporation and Preincubation Method: Lab Project Number: 26714: T
7053865: 109633. Unpublished study prepared by Bayer AG. 55 p. {OPPTS
870.5100}

45819517	Herbold, B. (1997) BSN2060 In Vitro Mammalian Chromosome
Aberration Test with Chinese Hamster V79 Cells: Lab Project Number:
PH-26887: T 5053863: 109634. Unpublished study prepared by Bayer AG. 37
p. {OPPTS 870.5375}

45819518	Stropp, G. (1998) BSN2060 Study for the Skin Sensitization
Effect in Guinea Pigs (Guinea Pig Maximization Test According to
Magnusson and Kligman): Lab Project Number: 27298: T 9061949: 109635.
Unpublished study prepared by Bayer AG. 30 p. {OPPTS 870.2600}

45819519	Herbold, B. (1999) BSN2060 Micronucleus Test on the Male Mouse:
Lab Project Number: PH-28653: T 7059887: 109636. Unpublished study
prepared by Bayer AG. 40 p. {OPPTS 870.5395}

45819520	Herbold, B. (1999) BSN2060 V79-HPRT Test in Vitro for the
Detection of Induced Forward Mutations: Lab Project Number: PH-28679: T
1059890: 109637. Unpublished study prepared by Bayer AG. 35 p. {OPPTS
870.5300}

45819521	Krotlinger, F. (1999) BSN2060 Study for Acute Dermal Toxicity
in Rats: Lab Project Number: 28496: T7067554: 109638. Unpublished study
prepared by Bayer AG. 26 p. {OPPTS 870.1200}

45819522	Pauluhn, J. (1999) BSN2060 Study on Acute Inhalation Toxicity
in Rats According to OECD No. 403: Lab Project Number: 28889: T6067571:
109639. Unpublished study prepared by Bayer AG. 71 p.

45819523	Schladt, L. (1999) BSN2060 Range-Finding Subacute Toxicity
Study in CD-1 Mice (Administration in the Feed Over 28 Days): Lab
Project Number: 29041: T6062242: 109640. Unpublished study prepared by
Bayer AG. 63 p.

45819524	Leuschner, P. (1997) Acute Skin Irritation Test (Patch Test) of
BSN 2060 in Rabbits: Lab Project Number: R6967: T6061199: 109641.
Unpublished study prepared by LPT Laboratory of Pharmacology and
Toxicology. 20 p. {OPPTS 870.2500}

45819525	Leuschner, P. (1997) Acute Eye Irritation Study of BSN 2060 by
Installation into the Conjunctival Sac of Rabbits: Lab Project Number:
R6968: T6061199: 109642. Unpublished study prepared by LPT Laboratory of
Pharmacology and Toxicology. 22 p. {OPPTS 870.2400}

45819526	Schladt, L.; Sander, E. (1999) BSN 2060 Study on Subchronic
Toxicity in CD-1 Mice (Dietary Over 3 Months): Lab Project Number:
PH-29173: T9062245: 109643. Unpublished study prepared by Bayer AG. 251
p. {OPPTS 870.3100}

45819601	Schladt, L.; Sander, E. (2001) BSN 2060 Study on Subchronic
Toxicity in CD-1 Mice (Dietary Administration over 14 Weeks): Lab
Project Number: PH 30763; T8068473; 110800. Unpublished study prepared
by Bayer AG. 188 p.

45819603	Krotlinger, F.; Popp, A. (2001) BSN 2060 Study for Subacute
Dermal Toxicity in Rats (Four-Week Treatment Period): Lab Project
Number: PH 30857: T3069378: 110802. Unpublished study prepared by Bayer
AG. 257 p. {OPPTS 870.3200}

45819604	Holzum, B. (2001) BSN 2060 Developmental Toxicity Study in
Rabbits After Oral Administration (Amendment Attached): Lab Project
Number: PH-30220: PH-30220A: 110810. Unpublished study prepared by Bayer
AG. 555 p. {OPPTS 870.3700}

45819605	Pauluhn, J. (2000) BSN 2060 Pilot Study Inhalation Toxicity in
Rats (Exposure: 5 x 6 Hours): Lab Project Number: PH 29835: T7069246:
110811. Unpublished study prepared by Bayer AG. 203 p.

45819606	Hastings, T. (2001) An Acute Oral Neurotoxicity Screening Study
with Technical Grade BSN 2060 in Wistar Rats: Lab Project Number:
00-N12-AE: 110815. Unpublished study prepared by Bayer Corporation and
Experimental Pathology Laboratories Inc. 443 p. {OPPTS 870.6200}

45819607	Gilmore, R.; Sheets, L. (2002) A Subchronic Neurotoxicity
Screening Study with Technical Grade BSN 2060 in Wistar Rats: Lab
Project Number: 00-N72-AF: 110820. Unpublished study prepared by Bayer
Corporation and Experimental Pathology Laboratories Inc. 484 p. {OPPTS
870.6200}

45819608	Krotlinger, F.; Vohr, H. (2001) BSN 2060 Plaque-Forming-Cell
Assay in Rats (Feeding Study Over About 4 Weeks): Lab Project Number:
PH-31139: T9069400: 110821. Unpublished study prepared by Bayer AG. 81
p.

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㄀$摧欧ᜀAfter Oral Administration: Lab Project Number: PH 31340:
T9061318: 110844. Unpublished study prepared by Bayer AG. 706 p. {OPPTS
870.3700}

45819614	Detzer, K.; Sander, V. (2001) BSN 2060 Subchronic Oral Toxicity
Study in Dogs: Lab Project Number: 31039: T2067577: 110922. Unpublished
study prepared by Bayer AG. 494 p. {OPPTS 870.3150}

45819615	Krotlinger, F.; Vohr, H. (2001) BSN 2060 Plaque-Forming-Cell
Assay in Mice (Feeding Study for About 4 Weeks): Lab Project Number: PH
31344: T3069279: 110935. Unpublished study prepared by Bayer AG. 93 p.

45819619	Eiben, R.; Bach, U.; Rinke, M. (2002) BSN 2060 Two-Generation
Study in Wistar Rats: Lab Project Number: PH 31775: T507099: G200100.
Unpublished study prepared by Bayer AG. 976 p. {OPPTS 870.3800}

45819620	Ruf, J.; Sander, E. (2002) BSN 2060 Chronic Toxicity Study in
Beagle Dogs (53 Week Feeding Study): Lab Project Number: PH 31665: T
0069357: G200102. Unpublished study prepared by Bayer AG. 640 p. {OPPTS
870.4100}

45819621	Schladt, L.; Hartmann, E.; Popp, A. (2001) BSN 2060 Chronic
Toxicity Study in Wistar Rats (Dietary Administration Over 1 Year): Lab
Project Number: PH 31617: T8068185: G200104. Unpublished study prepared
by Bayer AG. 1032 p. {OPPTS 870.4100}

45819622	Pauluhn, J. (2001) BSN 2060 Subacute Inhalation Toxicity on
Rats (Exposure 5 x 6 Hours/Week for 4 Weeks): Lab Project Number: PH
31546: T5069343: G200121. Unpublished study prepared by Bayer AG. 423 p.

45819623	Ruff, J.; Ruhl-Fehlert, C. (2001) BSN 2060 Subchronic Toxicity
Study in Beagle Dogs (13 Week Feeding Study): Lab Project Number: PH
31585: T 2069016: G200127. Unpublished study prepared by Bayer AG. 338
p. {OPPTS 870.3150}

45819624	Schladt, L. (2001) BSN 2060 Carcinogenicity Study in Wistar
Rats (Dietary Administration Over 2 Years): Lab Project Number: PH
31628: T3067505: G200128. Unpublished study prepared by Bayer AG. 3396
p. {OPPTS 870.4200}

45819828	Sebesta, C. (2002) An Exploratory Study to Determine the Rate
and Route of Elimination of BSN 2060-Phenyl-UL-(Carbon 14) When
Administered Intravenously or Dermally to Male Rhesus Monkeys: Final
Report: Lab Project Number: QEAZ-160-02-97: G200207: QEAZ-160.
Unpublished study prepared by Charles River Laboratories. 101 p. {OPPTS
870.7600}

45854505	Krotlinger, F.; Sander, E. (1998) BSN 2060: Study for Subacute
Oral Toxicity in Rats (Feeding Study for 4 Weeks): Lab Project Number:
109631: 27940: T 1061590. Unpublished study prepared by Bayer Ag. 131 p.

45854507	Andrews, P.; Sander, E. (2000) BSN 2060: Study for Subacute
Oral Toxicity in Rats (Feeding Study for 4 Weeks): Lab Project Number:
PH 30530: T 4059037: 110804. Unpublished study prepared by Bayer Ag. 187
p.

45854511	Eiben, R.; Bach, U. (2001) BSN 2060: Two-Generation Study in
Wistar Rats: Lab Project Number: PH 31303: T1068962: 110918. Unpublished
study prepared by Bayer Ag. 1063 p. {OPPTS 870.3800}

Appendix C:	REVIEW OF HUMAN RESEARCH 

No MRID - PHED Surrogate Exposure Guide

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