 

EPA Registration Division contact: Sidney Jackson, (703) 305-7610

 

Interregional Research Project Number 4 (IR-4)

PP# 8E7340

	EPA has received a pesticide petition (PP)  (8E7340) from Interregional
Research Project Number 4 (IR-4), Rutgers, The State University of NJ,
500 College Road East, Suite 201 W Princeton, NJ 08540  proposing,
pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act
(FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.607 by establishing
a tolerance for residues of Spiromesifen; butanoic acid, 3,3-dimethyl-,
2-oxo-3-(2,4,6-trimethylphenyl)-1-oxaspiro[4.4]non-3-en-4-yl ester, and
its enol metabolite;
4-hydroxy-3-(2,4,6-trimethylphenyl)-1-oxaspiro[4.4]non-3-en-2-one,
calculated as parent compound equivalents in or on the raw agricultural
commodity corn, sweet, kernel plus cob with husks removed at 0.02 parts
per million (ppm), corn, sweet, forage at 6.0 ppm, corn, sweet, stover
at 7.0 ppm, berry and small fruit, low growing berry, subgroup 13-07G at
2.0 ppm and delete existing the tolerance for strawberry at 2.0 ppm
since residues of spiromesifn on strawberry will be covered by the
tolerance proposed for berry and small fruit, low growing berry,
subgroup.  EPA has determined that the petition contains data or
information regarding the elements set forth in section 408 (d)(2) of
the FDDCA; however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data supports granting of the
petition. Additional data may be needed before EPA rules on the
petition.

A. Residue Chemistry

	1. Plant metabolism. The uptake and metabolism of spiromesifen in
primary crops is adequately understood. Radiolabeled studies have been
conducted in various plants all showing similar results. The residues of
concern are spiromesifen and its enol metabolite.

	2. Analytical method. Adequate analytical methodology using LC/MS/MS
detection is available for enforcement purposes.

	3. Magnitude of residues. Magnitude of the residue data were conducted
on pop corn with OPPTS Guideline 860.1500. The data supports
establishing the requested tolerances.

B. Toxicological Profile

	1. Acute toxicity.  Oral and dermal LD50 values were >2000 mg/kg bw. 
Inhalation LC50 values were >4873 mg/m3 air.  Spiromesifen was not
irritating to rabbit skin or eyes but did cause skin sensitization in
the Magnusson/Kligman maximization test in guinea pigs.  Acute toxicity
studies for spiromesifen support an overall toxicity Category III

	2. Genotoxicty. Several genotoxicity tests were conducted to test for
point-mutagenic activity, chromosome aberration in vitro and in vivo,
and for DNA repair.  All tests conducted were negative, indicating no
evidence of mutagenic or genotoxic potential.

	3. Reproductive and developmental toxicity. An oral developmental
toxicity study in rat did not reveal any evidence of teratogenic
potential.  The maternal and developmental NOAELs were 10 mg/kg bw/day. 
An oral developmental toxicity study in rabbits demonstrated a maternal
NOAEL of 5 mg/kg bw/day, a developmental NOAEL of 35 mg/kg bw/day and
did not reveal any teratogenic potential.  A two-generation study in
rats, with a parental systemic toxicity NOAEL of 3.3 mg/kg bw/day for
males and 4.6 mg/kg bw/day for females (based on the F1 generation), did
not reveal evidence of a primary reproductive toxicity potential.  The
reproductive NOAEL was 36.6 mg/kg bw/day for males and 14.2 mg/kg bw/day
in females.

	4. Subchronic toxicity. A subchronic toxicity feeding study with rats
over 90 days demonstrated a NOAEL of 6.3 and 7.7 mg/kg bw/day for males
and females, respectively, based on reduced body weights, effects on the
lipid metabolism (decrease of triglycerides and cholesterol) and thyroid
effects (colloidal alteration, hypertrophy) at the higher dose levels. 
A subchronic feeding study in mice over 14 weeks demonstrated a NOAEL of
3.2 and 5.1 mg/kg bw/day based on effects on lipid metabolism (decrease
of cholesterol) and adrenal effects (cytoplasmic eosinophilia).  A
14-week feeding study in dogs demonstrated a NOAEL of 9.2 and 9.3 mg/kg
bw/day based on liver effects (enzyme induction, increased liver weights
and cytoplasmic change) and thyroid effects (decreased T4).

	5. Chronic toxicity. A 12-month chronic feeding study in rats
demonstrated a NOAEL of 6.5 and 19.3 mg/kg bw/day for males and females,
respectively.  A 24-month oncogenicity study in rats demonstrated a
NOAEL of 6.1 and 19.5 mg/kg bw/day for males and females, respectively.
An oncogenicity study in the mouse revealed a NOAEL of 3.3 and 3.8 mg/kg
bw/day for males and females, respectively based on macroscopic and
microscopic adrenal effects.  There was no indication in the rat or
mouse for an oncogenic effect of spiromesifen.  A one-year feeding study
with dogs demonstrated a NOAEL of 11.5 and 10.8 mg/kg bw day for males
and females, respectively based on decreased body weights, liver effects
(increased liver weight, hepatocellular cytoplasmic change, vacuoles)
and adrenal effects (increased incidence of small cell types).

	6. Animal metabolism. Metabolism and pharmacokinetic studies in the rat
demonstrate that spiromesifen residues are rapidly absorbed, metabolized
and eliminated.  There was no evidence of accumulation of residues in
any tissues or organs.  The primary metabolites are the enol, which is
formed by cleavage of the alkyl ester group, and the 4-hydroxymethyl
metabolite.  Several other metabolites are also formed.

	7. Metabolite toxicology. In addition to parent, the metabolites of
concern are those containing the enol and 4-hydroxymethyl moieties. 
Since both moieties are primary metabolites in mammalian systems
following the oral administration of spiromesifen to rats, the
toxicology data for spiromesifen adequately covers the metabolites.

	8. Endocrine disruption. There is no evidence to suggest that
spiromesifen has any primary endocrine disruptive potential. 
Reproductive and developmental findings provided no evidence of an
enhanced sensitivity of the young.  All prospective endocrine and
endocrine-related changes which were noted were considered a function of
the chemical's biological mode of action, the degree of exposure, a
response secondary to other changes (e.g. enhanced liver metabolism), an
aging or strain-specific phenomenon, or some combination of these
factors.

C. Aggregate Exposure

	1. Dietary exposure. Acute dietary exposure limits for all populations,
including infants and children, are 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. For
the chronic dietary analysis, the chronic reference dose (cRfD), of
0.033 mg/kg/day was derived from a parental systemic NOAEL of 3.3
mg/kg/day (based on the F1 generation) in a 2-generation reproduction
toxicity study in rats and the application of an UF of 100. As the
toxicology database is adequate for Food Quality Protection Act (FQPA)
purposes and there are no concerns or residual uncertainties for
pre-/post-natal toxicity, an FQPA safety factor of 1 was applied to the
chronic toxicology values, resulting in a chronic population adjusted
dose (cPAD) of 0.033 mg/kg/day.  As a conservative measure, the cPAD
values were used for all population sub-groups when conducting the
assessments.

	i. Food. Assessments were conducted to evaluate the potential risks due
to chronic dietary exposure of the entire U.S. population and selected
population subgroups to residues of spiromesifen and its enol
metabolite.  These assessments cover the established and proposed uses
of spiromesifen on legume vegetables, brassica (head and stem, broccoli
and cabbage; leafy, mustard greens), corn (field), corn (pop), corn
(sweet), cotton, cucurbits (cantaloupe, cucumbers, and summer squash),
fruiting vegetables (peppers and tomatoes), leafy greens (head and leaf
lettuce and spinach), potatoes, strawberries (low growing berries: Crop
Subgroup 13-07-G)  and succulent shelled, edible-podded and dry shelled
beans.  Potential exposure from the rotational crops of alfalfa,
sugarbeets, barley, wheat, and oats are included. These assessments also
include secondary residues in animal tissues resulting from registered
and proposed uses.  Chronic exposure, calculated using DEEM-FCID Version
2.16, for the most exposed subpopulation, Children 1-2 years, equated to
3.3% of the cPAD.  The exposure to the U.S. population equated to 0.9%
of the cPAD. These Tier 3 chronic dietary exposure estimates,
incorporating Bayer CropScience estimates of  percent crop treated, are
well below EPA’s level of concern for the overall U.S. population as
well as the various population subgroups.

	ii. Drinking Water. The tolerances requested in pop corn will not alter
potential risks from exposure to residues of spiromesifen or degradates
through drinking water. A Tier II drinking water assessment for
spiromesifen and its enol metabolite was conducted using PRZM/EXAMS
(Pesticide Root Zone Model/Exposure Analysis Modeling System) to
calculate surface water estimated drinking water concentrations (EDWCs).
 The Screening Concentration in Ground Water (SCI-GROW) model was used
to calculate ground water EDWCs. The highest value for a chronic
assessment resulted from the Florida strawberry, surface water scenario.
The EDWC for combined residues of spiromesifen and its enol metabolite,
expressed as parent equivalents, was 5.4 ppb. The chronic EDWC
represents the upper 1-in-10 year mean annual concentration. All EDWCs
values are much lower than the drinking water level of comparison
(DWLOC) value of 326 µg/L (children 1-2 years old) determined for the
chronic scenario. Therefore, the EDWCs do not exceed the Agency’s
level of concern. For the most highly exposed population subgroup,
children 1-2, chronic aggregate dietary exposure (food and water)
calculated using DEEM-FCID Version 2.16 was 3.8% of the cPAD. For the
overall U.S. population, chronic aggregate dietary exposure was 1.2% of
the cPAD. Aggregate exposures are based on an estimated drinking water
concentration of 5.4 µg/L.

  

	2. Non-dietary exposure. There are no indoor or outdoor residential
uses associated with this product.

D. Cumulative Effects

	Spiromesifen represents a new class of chemistry, ketoenoles.  There
are no data available to indicate that toxic effects produced by
spiromesifen are a result of a common mechanism and should be cumulated
with those of any other compound. 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 produced by
other substances. Bayer will submit information, if necessary, for EPA
to consider concerning any potential cumulative effects of spiromesifen
consistent with the schedule established by EPA at 62 Federal Register
42020 (Aug. 4, 1997) and other EPA publications pursuant to the Food
Quality Protection Act.

E. Safety Determination

	1. U.S. population. Based on the exposure assessments described above
and on the completeness and reliability of the toxicity data, it can be
concluded that total aggregate exposure to spiromesifen from all label
uses will utilize less than 2 percent of the RfD for chronic dietary
exposures to the U.S. population and all population subgroups. EPA
generally has no concerns for exposures below 100 percent of the RfD,
because the RfD represents the level at or below which daily aggregate
exposure over a lifetime will not pose appreciable risks to human
health.  Thus, it can be concluded that there is a reasonable certainty
that no harm will result to the U.S. population from aggregate exposure
to spiromesifen residues.

	2. Infants and children. The Agency has previously concluded that the
toxicology database is adequate for Food Quality Protection Act (FQPA)
purposes and that there are no concerns or residual uncertainties for
pre-/post-natal toxicity. Therefore, a FQPA factor of 1X was selected.
Available studies include developmental toxicity studies in rats and
rabbits, a two-generation reproductive toxicity study in rats, and acute
and subchronic neurotoxicity studies in rats. 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 maternal toxicity.
There are no neurotoxicity concerns based on acute and subchronic
neurotoxicity studies. The most highly exposed population subgroup was
children 1-2 with a total aggregate exposure to spiromesifen from all
label uses utilizing less than 5 percent of the RfD for chronic dietary
exposures. EPA generally has no concerns for exposures below 100 percent
of the RfD, because the RfD represents the level at or below which daily
aggregate exposure over a lifetime will not pose appreciable risks to
human health.  Thus, it can be concluded that there is a reasonable
certainty that no harm will result to infants and children from
aggregate exposure to spiromesifen residues.

F. International Tolerances

	Codex maximum residue levels (MRLs) are not yet established  for
spiromesifen.

