Document ID: EPA-HQ-OPP-2013-0258-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-06-05T04:00Z

COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE  (7/1/2006)

EPA Registration Division contact: [Julie Chao, (703) 308-8735]

[BASF Corporation]

[3E8146]

	EPA has received a pesticide petition (3E8146) from [BASF Corporation],
[P.O. Box 13528, Research Triangle Park, NC 27709] 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.

	1. by establishing a tolerance for residues of

	[metaflumizone] in or on the raw agricultural commodity [tomato] at
[0.6] parts per million (ppm); [bell pepper] at [0.6] ppm and [eggplant]
at [0.6] ppm.  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. [In three plant metabolism studies (cabbage,
tomato and cotton), the major component of the residue was
metaflumizone.  The major degradate was the ketone, M320I04 and an
oxidized and cyclized metabolite, M320I23, was present in lesser
amounts.  These four compounds were defined as the residues of concern
and were incorporated into an analytical method.  In the confined
rotational crop studies plant uptake was very limited and the residues
were a mixture of minor and polar components.]

	2. Analytical method. [BASF Analytical Method No. 531/0 was developed
to determine residues of metaflumizone and its metabolites M320I04 and
M320I23 in crop matrices.  In this method, residues of metaflumizone are
extracted from plant matrices with methanol/water (70:30; v/v) and then
partitioned into dichloromethane.  For oily matrices, the residues are
extracted with a mixture of isohexane/acetonitrile (1:1; v/v).  The
final determination of metaflumizone and its metabolites is performed by
LC/MS/MS.]

	3. Magnitude of residues. [Crop field trials were conducted in Europe
to determine the magnitude of residues of Metaflumizone in/on raw
agricultural commodities of tomato and Pepper.  Ten field trials and ten
glasshouse trials were conducted in north and south Europe for tomato. 
Fifteen glasshouse trials were conducted in north and south Europe for
bell pepper.  Metaflumizone (formulated as a representative 240 g/L SC
Formulation with BASF formulation code BAS 320 00 I, tradename of
ALVERDE®) was applied at the proposed maximum label use rate and at
various pre-harvest intervals (PHI).  In addition, a processing study
was conducted on tomato to determine the concentration factors during
normal processing of the raw agricultural commodity.]

B. Toxicological Profile

	1. Acute toxicity.  [Based on the available acute toxicity data,
metaflumizone and its formulated product do not pose acute toxicity
risks.  For metaflumizone:

Oral LD50                 Rat	      LD50 > 5000 mg/kg b.w.       
category IV  TC \l5 " 

Oral LD50                 Mouse	      LD50 > 5000 mg/kg b.w.       
category IV

Dermal LD50            Rat	      LD50 > 5000 mg/kg b.w.        category
IV

Inhalation LC50       Rat	      > 5.2 mg/L                              
category IV

Eye Irritation           Rabbit	      Not irritating                    
     category IV

Skin Irritation          Rabbit	      Not irritating                    
     category IV

Skin Sensitization    Guinea pig   Not sensitizing (Maximization Test)]

	2. Genotoxicty. [In a battery of three in vitro and two in vivo
mutagenicity assays consisting of all required end-points (point
mutation, chromosomal damage, and DNA damage and repair), the
weight-of-the-evidence for metaflumizone indicates a lack of potential
genotoxicity.  

Specifically, for the battery of three in vitro mutagenicity assays with
metaflumizone, no positive responses were observed for increased
revertant frequencies with and without metabolic activation [bacterial
reverse mutation assay] or for increased mutant frequencies with and
without metabolic activation [HGPRT locus assay].  Although there was a
positive result for a statistically increased number of structurally
aberrant metaphases in the chromosomes, which indicates clastogenic
potential under in vitro conditions, this result was only observed
without metabolic activation [cytogenicity study with V79 cells.  

Importantly, the potential biological significance of this apparent
chromosome damage observed in vitro only without metabolic activation,
was evaluated in vivo using the mouse micronucleus assay.  Testing in
the in vivo micronucleus study with NMRI mice was conducted at a high
dose level (2000 mg/kg b.w.) that demonstrated clinical symptoms of
toxicity, including piloerection and poor general state, in 5 of 5
animals.  No significant or dose-related increases in chromosomal damage
were observed in this in vivo test, indicating that metaflumizone does
not cause chromosomal aberrations in intact animals.     

Moreover, it has also been recognized by U.S. EPA that more weight
should be placed on in vivo systems than in vitro systems as expressed
in the Agency’s weight-of-evidence for genotoxic evaluation of a
chemical included in the "Guidelines for Mutagenicity Risk Assessment"
(Federal Register, September 24, 1986, Vol. 51: 34006-34012).  Thus, the
negative in vivo results (non-clastogenicity for chromosomal
aberrations) observed in the mouse micronucleus assay and the rat
hepatocytes assay, should override the positive results obtained in the
in vitro assay only without metabolic activation.  Furthermore, it has
been noted that in vitro systems may simulate abnormal physiological
conditions from prolonged exposure to a chemical in the absence of S-9
metabolic activation [Brusick, D.J. (editor) 1987. Genotoxicity Produced
in Cultured Mammalian Cell Assay by Treatment Conditions. Mutation
Research, Vol. 189, No.1: 1-69] and [Sofuni, T. 1993. Japanese
Guidelines for Mutagenicity Testing. Environmental and Molecular
Mutagenesis, Vol. 21, No.1: 2-7].  Consequently, based on the
weight-of-the-evidence presented above, metaflumizone does not pose a
genotoxic concern.]

	3. Reproductive and developmental toxicity. [Potential reproductive
toxicity of metaflumizone was investigated in a two-generation
reproduction toxicity study in Wistar rats by oral gavage
administration.  Originally, the highest dose tested by oral gavage was
75 mg/kg b.w../day, which induced both excessive maternal toxicity (very
high incidences of poor general health in females during premating,
gestation, and lactation; and statistically decreased food consumption,
body weights, and body weight gain) as well as excessive developmental
toxicity (statistically impaired pup body weights and body weight gain),
which altogether resulted in high pup mortality.  Consequently, a
meaningful assessment of the potential reproductive toxicity of the test
compound at this excessively toxic dose level was not possible. 
Thereafter, for the next two successive parental generations of rats,
which were originally derived from the parents treated at 75 mg/kg
b.w./day, the highest dose tested was 50 mg/kg b.w./day. 

Subsequently, the NOAEL for parental toxicity was 20 mg/kg b.w./day,
based on the following effects for females at 50 mg/kg b.w./day (highest
dose tested for two consecutive generations) -- increased incidences of
poor general health in females during premating, gestation, and
lactation; 3 of 25 dams with complete litter losses; and statistically
significantly reduced body weights during premating, gestation, and
lactation.  

The NOAEL for offspring/pup toxicity was 20 mg/kg b.w./day, based on a
slight increased incidence of pup mortality at 50 mg/kg b.w./day. 
Whereas the NOAEL for fertility in this study was 50 mg/kg b.w./day
(highest dose tested for two generations), the NOAEL for reproductive
performance was considered to be 20 mg/kg b.w./day, based on 3 of 25
dams with complete litter losses, of which 2 of these 3 dams had
indications of poor nursing for their first generation of pups.  It is
noteworthy that because most of the pup mortality was due to poor
nursing in only 2 of 25 dams, this finding may be considered to be
incidental.  Importantly, no comparable impairment of reproductive
performance occurred for the succeeding parental generation treated by
oral gavage administration at 50 mg/kg b.w./day.      

In a developmental (teratology) toxicity study in the Wistar rat, the
results indicated that the NOAEL for maternal toxicity was 40 mg/kg
b.w./day, based on statistically decreased food consumption and body
weight gains at 120 mg/kg b.w./day (highest dose tested).  The NOAEL for
fetal (prenatal)/developmental toxicity was 120 mg/kg b.w./day (highest
dose tested).  In addition, there were no indications of any teratogenic
effects in the rat fetuses at 120 mg/kg b.w./day (highest dose tested). 
Therefore, metaflumizone is considered to be neither a developmental
toxicant nor a teratogenic agent in the rat.  

In a developmental (teratology) toxicity study in the Himalayan rabbit,
the results indicated that the NOAEL for maternal toxicity was 100 mg/kg
b.w./day, based on several clinical symptoms of toxicity (including
ataxia and poor general state) occurring in 4 of 25 does at 300 mg/kg
b.w./day, for which 2 of these 4 does had abortions prior to being
sacrificed early, with a third doe at 300 mg/kg b.w./day being
sacrificed moribund.  Similarly, the NOAEL for fetal (prenatal) /
developmental toxicity was 100 mg/kg b.w./day, based on slightly
decreased mean fetal body weights as well as an increased rate for a
certain skeletal variation, namely incomplete ossification of
sternabrae.  Because developmental toxicity was only observed at dose
levels that were maternally toxic, metaflumizone is not selectively
toxic to the fetal rabbit.    

Lastly, in this rabbit developmental toxicity study, there were no
indications of any teratogenic effects in the rabbit fetuses at 300
mg/kg b.w./day (highest dose tested).  Therefore, metaflumizone is not
teratogenic in the rabbit.

An acute dietary endpoint was not established for the general
population, including infants and children, since an endpoint of concern
(effect) attributable to a single dose was not identified in the
database.  Studies considered for this endpoint included the acute
neurotoxicity study for which a LOAEL was not observed. 

An acute dietary endpoint was established for females 13-49 years old
based on a developmental effect observed in the rabbit developmental
toxicity study that can be potentially due to a single dose of
metaflumizone.  The effects consisted of an absent subclavian artery in
the offspring at the LOAEL of 300 mg/kg b.w./day metaflumizone (NOAEL =
100 mg/kg b.w./day).  A combined uncertainty factor (UF) of 300 was
applied to account for interspecies and intraspecies extrapolation (100)
and a 3X FQPA safety factor was retained because the rabbit
developmental toxicity study was performed via oral gavage dosing,
resulting in an ARfD of 0.33 mg/kg b.w./day.]

	4. Subchronic toxicity. [In the Sprague-Dawley rat, treatment by oral
gavage with metaflumizone for a subchronic duration (90-day timepoint in
the chronic toxicity/carcinogenicity study) resulted in reduced food
consumption and/or decreased mean body weight and/or body weight gains
in males and females at 300 mg/kg b.w./day and in increased incidences
of hepatocellular centrilobular hypertrophy in the livers of males at
300 mg/kg b.w./day.  Under the conditions of the study, the NOAEL for
oral administration of metaflumizone for 90 days was 60 mg/kg b.w./day.

In the beagle dog, treatment by oral gavage with metaflumizone for a
subchronic duration (90-day timepoint in the chronic toxicity study)
resulted in reduced body weight gain and/or decreased food consumption
in several dogs at 30 mg/kg b.w./day and slightly decreased mean MCHC at
30 mg/kg b.w./day.  Under the conditions of the study, the NOAEL for
oral administration of metaflumizone for 90 days was 12 mg/kg b.w./day.

For a subchronic (90-day) dermal toxicity study conducted with
metaflumizone in Wistar rats, the results support a NOAEL of 100 mg/kg
b.w./day, based on decreased food consumption (females) and decreased
body weight gain in males and females at 300 mg/kg b.w./day, the next
highest dose tested.  Several microscopic changes were observed in
female animals at 300 mg/kg b.w./day and above, but these morphologic
changes were regarded to be indirect effects of the impaired body weight
gain.    

For a subacute (28-day) inhalation toxicity study conducted with
metaflumizone in Wistar rats, the results support a NOAEL of 0.03 mg/L,
based on decreased food consumption (females) and decreased body weight
/ body weight gain (females) and several microscopic changes in the
respiratory tract at 0.10 mg/L, the next highest dose tested.  Several
microscopic changes in non-respiratory tract tissues were observed in
animals at these two dose levels, but these morphologic changes were
regarded to be indirect effects of the impaired body weight / body
weight gain.   

Testing for metaflumizone’s potential immunotoxicity, two studies were
conducted, namely “28-Day Oral Immunotoxicity Study [by
Thymic-Dependent Antibody Response (TDAR) Assay] in the Female Wistar
Rat”  and  “28-Day Oral Immunotoxicity Study [by Natural Killer (NK)
Cell Assay] in the Female Wistar Rat.”   Results from both studies
indicate a lack of immunotoxic potential for metaflumizone (BAS 320 I)
up to the highest dose tested (HTD).  Both Study Reports have been
submitted to U.S. EPA (in 2011).  

  

 

	5. Chronic toxicity. [In the Sprague-Dawley rat, treatment by oral
gavage with metaflumizone for a 2-year chronic duration resulted in
dose-related increased incidences of hepatocellular centrilobular
hypertrophy in the livers of males and females at 60 mg/kg b.w./day and
at 300/200 mg/kg b.w./day and hepatocellular basophilic alteration in
males at 60 and 300 mg/kg b.w./day.  [NOTE:  Beginning the first day of
Week 3, the dose level of the high-dose females was lowered from 300 to
200 mg/kg b.w./day, due to an adverse effect of -71% decreased body
weight gain as compared to controls.]  

Therefore, the no-observable-adverse-effect-level (NOAEL) for systemic
toxicity following oral administration of metaflumizone for 24 months to
Sprague-Dawley rats was 30 mg/kg b.w./day for males and females. 
Importantly, treatment with metaflumizone to rats for 2 years resulted
in no test substance-related neoplastic findings, and therefore, the
NOAEL for oncogenicity was 300/200 mg/kg b.w./day (highest dose tested).
   

In the CD-1 mouse, treatment by oral gavage with metaflumizone for an
18-month chronic duration resulted in a treatment-related increased
incidence of increased brown pigment in the spleens of male and female
animals administered 1000 mg/kg b.w./day (highest dose tested), as
compared to controls.  Under the conditions of the study, the NOAEL for
systemic toxicity following oral administration of metaflumizone for 18
months to CD-1 mice was 250 mg/kg b.w./day (the next highest dose
tested) for males and females.  Importantly, treatment with
metaflumizone to mice for 18 months resulted in no test
substance-related neoplastic findings, and therefore, the NOAEL for
oncogenicity was 1000 mg/kg b.w./day (highest dose tested).

In the beagle dog, treatment via gelatin capsules with metaflumizone for
a 12-month chronic duration resulted in reduced body weight gain and/or
decreased food consumption in several dogs at 30 mg/kg b.w./day and
slightly decreased mean MCHC at 30 mg/kg b.w./day.  Under the conditions
of the study, the NOAEL for oral administration of metaflumizone for 12
months was 12 mg/kg b.w./day. 

Threshold Effect.  For estimated chronic exposure, the calculation of
the chronic reference dose (chronic RfD) is based on the results of the
chronic toxicity studies in the rat, mouse, and dog, and the
two-generation reproduction study in the rat.  For metaflumizone, the
lowest NOAEL for chronic toxic effects is 12 mg/kg b.w./day from the
12-month dog study.  A safety factor of 100 and an additional FQPA
safety factor of 3 was applied to the NOAEL to account for the higher
absorption observed with dietary exposures, resulting in a chronic RfD
of 0.04 mg/kg b.w./day.

Non-Threshold Effect.  Since there were no test substance-related
neoplastic findings following long-term treatment with metalfumizone to
mice for 18 months or to rats for 24 months, the NOAEL for oncogenicity
in both studies was established at the respective highest doses tested. 
Therefore, metaflumizone should be classified as "not likely to be a
human carcinogen."]

	6. Animal metabolism. [In the rat, goat and hen metabolism studies, the
majority of the dose was rapidly excreted in the feces.  The low levels
that were absorbed were distributed throughout various tissues. 
Metaflumizone was the major component of the extractable residues in all
tissues, milk, eggs and is the only residue of concern.  Metabolism of
metaflumizone occurs by hydroxylation and conjugation on either of the
phenyl rings or at the ethylene bridge and are the major routes of
detoxification.  Cleavage of the semicarbazide bond to yield M320I04
also occurs, usually with accompanying conjugation.  The only residue of
concern is metaflumizone.]

	7. Metabolite toxicology. [Toxicity of the metabolites of metaflumizone
with potential exposure to humans was concurrently evaluated during
toxicity testing of the parent except for the metabolite M320I23 that
was not observed in the rat metabolism study.  The Z-isomer (M320I02) of
metaflumizone was evaluated in additional toxicity tests to confirm no
differences between the minor Z-isomer component and metaflumizone with
a 9 to 1 E-isomer to Z-isomer ratio, respectively.  The results show no
toxicological concerns:

Toxicity Studies with the metabolite M320I23 of metaflumizone

(a)  Acute Toxicity Study with Metabolite M 320I023

The metabolite M 320I023 of metaflumizone demonstrates low acute
toxicity via the oral route of exposure in the rat.

Oral LD50  > 2000 mg/kg b.w. (category III).

(b)  Subchronic Toxicity Study with Metabolite M 320I023

In the Sprague-Dawley rat, treatment by oral gavage with metabolite M
320I023 of metaflumizone for a subchronic (90-day) duration resulted in
systemic toxicity effects of increased relative liver weights (females)
and increased incidences of liver hepatocellular centrilobular
hypertrophy in males and females at 1000 mg/kg b.w./day (highest dose
tested), as compared to controls.  Under the conditions of the study,
the NOAEL for oral administration of the metabolite M 320I023 of
metaflumizone for 90 days was 200 mg/kg b.w./day (next highest dose
tested) in males and females.  

(c)  Mutagenicity/Genotoxicity Studies with Metabolite M 320I023 

In a battery of three in vitro and one in vivo mutagenicity assays
consisting of all required end-points (point mutation, chromosomal
damage, and DNA damage and repair), the weight-of-the-evidence for the
metabolite M 320I023 (parent ketone) of metaflumizone insecticide
indicates a lack of potential genotoxicity. 

Specifically, for the battery of three in vitro mutagenicity assays with
metabolite M 320I023 of metaflumizone, no positive responses were
observed for increased revertant frequencies with and without metabolic
activation [bacterial reverse mutation assay] or for increased mutant
frequencies with and without metabolic activation [HGPRT locus assay]. 
Although there was a positive result for a statistically increased
number of structurally aberrant metaphases in the chromosomes, which
indicates clastogenic potential under in vitro conditions, this result
was only observed with metabolic activation [cytogenicity study with V79
cells].  

Importantly, the potential biological significance of this apparent
chromosome damage observed in vitro only with metabolic activation, was
evaluated in vivo using the mouse micronucleus assay.  Testing in this
in vivo micronucleus study with NMRI mice was conducted at a high dose
level (2000 mg/kg b.w.), that demonstrated no clinical symptoms of
toxicity but which represents the limit dose for this assay.  No
significant or dose-related increases in in vivo chromosomal damage were
observed, indicating that the metabolite M 320I023 of metaflumizone does
not cause chromosomal aberrations in intact animals.     

Moreover, it has also been recognized by U.S. EPA that more weight
should be placed on in vivo systems than in vitro systems as expressed
in the Agency’s weight-of-evidence for genotoxic evaluation of a
chemical included in the "Guidelines for Mutagenicity Risk Assessment"
(Federal Register, September 24, 1986, Vol. 51: 34006-34012).  Thus, the
negative in vivo results (non-clastogenicity for chromosomal
aberrations) observed in the mouse micronucleus assay should override
the positive results obtained in the in vitro assay only with metabolic
activation.  Furthermore, it has been noted that in vitro systems may
simulate abnormal physiological conditions [Brusick, D.J. (editor) 1987.
Genotoxicity Produced in Cultured Mammalian Cell Assay by Treatment
Conditions. Mutation Research, Vol. 189, No.1: 1-69].  Additionally, it
has been reported in the literature that S-9 metabolic activation does
not often have adequate cofactors for activating detoxifying mechanisms
found in the whole animal system [Ashby, J. 1983. The unique role of
rodents in the detection of possible human carcinogens and mutagens.
Mutation Research, Vol. 115: 117-213] [Galloway, S.M. 1994. Chromosome
Aberrations Induced In Vitro:  Mechanisms. Delayed Expression, and
Intriguing Questions.  Environmental and Molecular Mutagenesis, Vol. 23,
Supplement 24: 44-53].  Consequently, based on the
weight-of-the-evidence presented above, the metabolite M 320I023 of
metaflumizone does not pose a genotoxic concern.  

Therefore, as indicated from the results of the mammalian toxicity
studies as well as the mutagenicity assays, metabolite M 320I023 of
metaflumizone does not demonstrate more adverse toxicity when compared
to metaflumizone.  

 

Toxicity Studies with the Z-Isomer of metaflumizone

(a)  Acute Toxicity Study with Z-Isomer

The Z-isomer of metaflumizone demonstrates low acute toxicity via the
oral route of exposure in the rat. 

Oral LD50 > 5000 mg/kg b.w. (category IV).

(b)  Subchronic Toxicity Study with Z-Isomer

In the Sprague-Dawley rat, treatment by oral gavage with the Z-isomer of
metaflumizone for a subchronic (90-day) duration resulted in impaired
body weight gain only in females at the mid-dose (300 mg/kg b.w./day)
and the high-dose (1000 mg/kg b.w./day), as compared to controls. 
Several microscopic changes were observed in female animals at these two
dose levels, but all morphologic changes were regarded to be indirect
effects of the impaired body weight gain.  Under the conditions of the
study, the NOAEL for oral administration of the Z-isomer of
metaflumizone for 90 days was 1000 mg/kg b.w./day (highest dose tested)
in males and 100 mg/kg b.w./day (lowest dose tested) in females.  

(c)  Mutagenicity/Genotoxicity Study with Z-Isomer

In an in vitro mutagenicity assay with the Z-isomer of metaflumizone,
there were no positive responses observed for increased revertant
frequencies with and without metabolic activation [bacterial reverse
mutation assay].

Therefore, as indicated from the results of the mammalian toxicity
studies as well as the mutagenicity assay, the minor isomer of
metaflumizone, namely the Z isomer, does not demonstrate more adverse
toxicity when compared to metaflumizone.]

	8. Endocrine disruption. [Data from the reproduction / developmental
toxicity and short-and long-term repeated dose toxicity studies with
metaflumizone in the rat, rabbit, mouse, or dog, do not suggest any
endocrine disruption activity.  This information is based on the absence
of any treatment-related effects from the histopathological examination
of reproductive organs as well as a low level of concern for possible
effects on fertility, reproductive performance, or any other aspect of
reproductive function, or on growth and development of the offspring.]

C. Aggregate Exposure

	1. Dietary exposure. 

Food. [

A dietary exposure analysis was conducted for all registered uses of
Metaflumizone at the tolerance values of 0.04 ppm and tomato, pepper and
eggplant at the proposed tolerance of 0.6 ppm. 

Acute Dietary Food Exposure:  The Health Effects Division (HED) of EPA
has determined that there are no toxic effects attributable to a single
dose of metaflumizone for the general populations including infants and
children.  Therefore, a quantitative acute dietary exposure and risk
assessment for these sub-populations is not required.  

   

Acute dietary assessments were conducted to evaluate the potential risk
due to acute dietary exposure to females 13 – 49 years old.  The ARfD
for metaflumizone is 1.0 mg/kg bw/day.  The FQPA safety factor for
metaflumizone has been set to 3.  Therefore, the aPAD is 0.33 mg/kg
bw/day.  The tier 1 acute dietary exposure estimates were based on
established and proposed tolerance values, 100 percent crop treated
values, concentration/processing factors and the USDA NHANES 2-day food
consumption data for 2003-2008 and the EPA Food Commodity Ingredient
Database (FCID) as of February 2012 using the Dietary Exposure
Evaluation Module (DEEM-FCID) software, version 3.14.  Drinking water
exposure was included in the dietary exposure analysis.  Tolerances for
meat, milk, egg, and poultry are not required.  

Exposure estimates for the metaflumizone acute dietary assessments were
well below U.S. EPA’s level of concern (See tables below).  The
estimated acute dietary exposure for females 13 – 49 years old was
0.57 %.  Additional refinements such as the use of anticipated residues
and predicted percent crop treated would further reduce the estimated
acute dietary exposure.

Table 1. Summary of Acute Dietary Exposure and Risk for Metaflumizone
Considering Tomatoes, Bell Peppers, Eggplant, Grape, Crop Group 10 –
Citrus Fruits Group, Crop Group 14 – Tree Nuts Group and Drinking
Water.  

Population	Exposure Estimate	%aPAD

Subgroups	(mg/kg b.w./day)	 

Females (13-49 years old)	0.00190	0.57

aPAD = acute population adjusted dose (aPAD = 0.33 mg/kg bw/day)

Chronic Dietary Food Exposure: 

A tier 1 dietary exposure assessment was conducted for all
sub-populations including infants and children.  The ADI for
metaflumizone is 0.12 mg/kg bw/day.  The FQPA safety factor for
metaflumizone has been set to 3.  Therefore, the cPAD is 0.04 mg/kg
bw/day.  The tier 1 chronic dietary exposure estimates were based on the
established and proposed tolerance values, 100 percent crop treated
values, concentration/processing factors and the USDA NHANES 2-day food
consumption data for 2003-2008 and the EPA Food Commodity Ingredient
Database (FCID) as of February 2012 using the Dietary Exposure
Evaluation Module (DEEM-FCID) software, version 3.14. Drinking water
exposure was included in the dietary exposure analysis.  Tolerances for
meat, milk, egg, and poultry are not required.  

Exposure estimates for the metaflumizone chronic dietary assessments
were well below U.S. EPA’s level of concern (See tables below.  The
most highly exposed sub-group was children 1-2 years old and the
exposure accounted for 3.2% of the cPAD.  Additional refinements such as
the use of anticipated residues and predicted percent crop treated would
further reduce the estimated chronic dietary exposure.

Table 2.  Summary of Chronic Dietary Exposure and Risk for Metaflumizone
Considering Tomato, Bell Pepper, Eggplant, Grape, Crop Group 10 –
Citrus Fruits Group, Crop Group 14 – Tree Nuts Group,  and Drinking
Water.

Population	Exposure Estimate	%cPAD

Subgroups	(mg/kg b.w./day)	 

U.S. Population	0.00060	1.5

All Infants (< 1 year old)	0.00034	0.8

Children (1-2 years old)	0.00126	3.2

Children (3-5 years old)	0.00124	3.1

Children (6-12 years old)	0.00076	1.9

Youth (13-19 years old)	0.00051	1.3

Females (13-49 years old)	0.00054	1.4

Adults (20-49 years old)	0.00051	1.3

Adults (50+ years old)	0.00051	1.3

cPAD = chronic  population adjusted dose (cPAD = 0.04 mg/kg bw/day)]

	ii. Drinking Water. [The estimated drinking water concentrations
(EDWCs) used in this assessment were from the HED human health
assessment of metaflumizone, December 21, 2011.  PRZM-EXAMS modeling
resulted in the highest surface water values.  The model was run using
the fly bait application scenario to turf to represent application to
use sites such as recreational facilities and outdoor recreational areas
including parks, picnic grounds, and camp grounds.  The acute and
chronic surface water EDWCs were 1.14 and 0.597 ppb, respectively.  The
acute and chronic ground water EDWC was 2.1 x 10-3 ppb.  The drinking
water exposure was included in the dietary assessment.   ]

	2. Non-dietary exposure. [

Metaflumizone is registered in the U.S. for use as a fire ant bait and a
fly bait.  These uses can result in residential exposure.  The exposure
and MOE values for these uses were estimated using EPA’s 2012
Residential SOPs. The MOE values were calculated using a short-term
dermal NOAEL of 100 mg ai/kg bw/day and short-term incidental oral NOAEL
of 20 mg ai/kg bw/day.  The calculated MOEs for all adult and infant
exposures are greater than 100 and therefore do not exceed EPA’s level
of concern.  

Table 3.  Summary of Residential and Recreational Post-Application
Exposure and Risks from use of Fire Ant Bait.  

Fire Ant Bait

Population and activity	Route of Exposure	Dose (mg/kg bw/day)	MOE

Adult -- Residential Handler	Dermal	0.000048	2,100,000

	Inhalation	0.00000015	52,000,000

	Combined	--	ARI = 15,000

Adult – Residential Post-application	Dermal	0.000334	300,000

Adult – Golfer Post-application	Dermal	2.36E-05	4,200,000

Adolescent – Golfer Post-application	Dermal	0.000028	3,600,000

Children (1 to <2 year olds) –

Post-application	Dermal	0.000655	150,000

	Incidental oral hand-to-mouth	6.04E-06	3,300,000

	Incidental oral object-to-mouth	3.70E-07	54,000,000

	Combined oral h-t-m and dermal	--	ARI = 1,513

Table 4.  Summary of Recreational Post-Application Exposure and Risks
from use of Metaflumizone Fly Bait.  

Fly Bait

Population and activity	Route of Exposure	Dose (mg/kg bw/day)	MOE

Adult – Post-application	Dermal	0.00117	86,000

Children (1 to <2 years old) – Post-application	Dermal	0.00229	44,000

	Incidental oral hand-to-mouth	0.0000211	950,000

	Incidental oral object-to-mouth	0.0000013	15,000,000

	Combined oral hand-to-mouth and dermal	--	ARI = 432

  

	3. Aggregate exposure. 

[Acute Aggregate Risk:  

No acute residential/recreational exposures are expected.  The acute
aggregate risk includes only exposure to females 13-49 years old from
food and water.  The food and drinking water exposure accounts for less
than 1 % aPAD which is below HED’s level of concern.  

Short-/Intermediate Term Aggregate Risk:

There is the potential for short-term, non-dietary exposure of children
and adults to metaflumizone from the use as a fire ant bait and a fly
bait.   Therefore, the short-term aggregate exposure includes
residential/recreational exposure, food and water exposure.   Because
the level of concern (LOC) for oral exposure is different than the LOC
for dermal exposure, an Aggregate Risk Index (ARI) is used.  An ARI >1
indicates an acceptable exposure. In the tables below, the incidental
oral exposure for the hand-to-mouth exposure was aggregated with the
dietary and post-application dermal exposure for both the fire ant and
fly bait uses.

Table 5.  Summary of Short-/Intermediate Term Aggregate Risk from Fire
Ant Bait Use.

	Food + water	Non-dietary oral	Dermal	Aggregate

Population Sub-Group	MOE	MOE	MOE	ARI

US population	33,501	NA	299,895	108

Children 1-2	15,873	3,300,000	152,724	51

Table 6.  Summary of Short-/Intermediate Term Aggregate Risk from Fly
Bait Use.

	Food + water	Non-dietary oral	Dermal	Aggregate

Population Sub-Group	MOE	MOE	MOE	ARI

US population	33,501	NA	85,684	99

Children 1-2	15,873	945,846	43,636	46

The ARI values are all greater than 1 which indicates  acceptable
exposures.  

Chronic Aggregate Risk:

No chronic residential/recreational exposure is expected.  The chronic
aggregate risk includes only exposure from food and water.  The chronic
food and drinking water exposure for all sub-populations are below
HED’s level of concern.  ]

D. Cumulative Effects>  [Section 408(b)(2)(D)(v) requires that, when
considering whether to establish, modify, or revoke a tolerance, the
Agency consider ``available information'' concerning the cumulative
effects of a particular pesticide's residues and ``other substances that
have a common mechanism of toxicity.

 

The EPA is currently developing methodology to perform cumulative risk
assessments.  At this time, there is no available data to determine
whether metaflumizone has a common mechanism of toxicity with other
substances or how to include this pesticide in a cumulative risk
assessment.]

E. Safety Determination

	1. U.S. population. [Using the conservative exposure assumptions
described above and based on the completeness and the reliability of the
toxicity data, BASF has estimated the aggregate exposure to
metaflumizone is well below the EPA’s level of concern.  ]

	2. Infants and children. [All subpopulations based on age were
considered. Infants and children aggregate risk is well below EPA’s
level of concern.  BASF, considering a worst-case situation, concludes
with reasonable certainty that no harm will result to infants or
children from aggregate exposure to metaflumizone residues.]

F. International Tolerances

	[Maximum residue levels (MRLs) have been established for metaflumizone
by the Codex Alimentarius Commision (CODEX) in potato, tomato, pepper,
eggplant, Brussels sprout, Chinese cabbage, lettuce, and animal
products.  Harmonized EU MRLs have been established for metaflumizone in
potato, tomato, pepper, eggplant, leafy brassica, Brussels sprout,
lettuce and similar and animal products. 

Codex (based on parent only)

Potato	0.02

Tomato	0.6

Pepper, inc chili pepper	0.6

Peppers chili, dried	6

Eggplant	0.6

Brussels sprout	0.8

Chinese cabbage	6

Lettuce	7

Swine (all)	0.02

Bovine (meat, kidney, liver, fat, offal)	0.02

Sheep, goat (meat, kidney, liver, fat, offal)	0.02

Milk	0.01

Cream	0.02

EU harmonized (based on parent + M320I04)

Potato	0.05

Tomato	0.6

Pepper, inc chili pepper	1

Eggplant	0.6

Brussels sprout	1

Head cabbage	1

Leafy brassica	10

Lettuce and similar except scarole	10

Swine (all)	0.02

Bovine (meat, kidney, liver, fat, offal)	0.02

Sheep, goat (meat, kidney, liver, fat, offal)	0.02

Poultry (meat, liver, kidney, offal)	0.02

Poultry fat	0.1

Milk and cream	0.02

Eggs	0.02

]