Document ID: EPA-HQ-OPP-2008-0168-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-04-16T04:00Z

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

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

	

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[BASF Corporation]

[7F7260]

	EPA has received a pesticide petition ([7F7260]) 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 [grape] at
[0.01] parts per million (ppm), [crop group 10: citrus fruits group] at
[0.01] ppm, and [crop group 14: tree nuts group] at [0.01] 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, the residues of concern in plants, and 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. [Field trials were carried out in order to
determine the magnitude of residue in grapes, citrus, and tree nuts. 
Field trials were conducted in the required regions.  Field trials were
carried out using the maximum label rate, the maximum number of
applications and the minimum preharvest interval.  In addition,
processing studies were conducted on grapes and citrus to determine the
concentration factor during normal processing of the raw agricultural
commodities.]

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.]

	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.

Lastly, in 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 change in males and females at 300 mg/kg b.w./day, the next
highest dose tested.]

	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 is applied to the NOAEL of
12 mg/kg b.w./day, which results in a chronic RfD of 0.12 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. [

Metaflumizone and its metabolites (M320I04, M320I23) are expressed as
the parent compound (metaflumizone).  A dietary exposure analysis was
conducted for grape, crop group 10 – citrus fruits group, crop group
14 – tree nuts group and all pending uses.  The pending uses includes
cotton, cottonseed oil, potential secondary residues in meat, fat,
byproducts, milk, and eggs, potatoes, sweet potatoes, yams, leafy greens
subgroup, leaf petioles subgroup, head & stem brassica subgroup, leafy
brassica greens subgroup, fruiting vegetables except cucurbits, cotton.

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.  HED has set an
aPAD for females 13 – 49 years old.  

   

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 1.  Therefore, the aPAD is 1.0 mg/kg
bw/day.  The tier 1 acute dietary exposure estimates were based on the
proposed tolerance values, 100 percent crop treated values,
concentration/processing factors and consumption data from the USDA
Continuing Survey of Food Intake by Individuals (CSFII 1994 - 1996,
1998) and the EPA Food Commodity Ingredient Database (FCID) using
Exponent's Dietary Exposure Evaluation Module (DEEM-FCID) software. 
Result exposure estimates were compared against the metaflumizone acute
Population Adjusted Dose (cPAD) of 1.0 mg/kg b.w./day.   

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 ?
%.  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 Grape, Crop Group 10 – Citrus Fruits Group, Crop Group 14
– Tree Nuts Group,  all pending,  and Secondary Residues in Meat, Fat,
Milk and Eggs

Population	Exposure Estimate	%aPAD

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

Females (13-49 years old)	0.070633	7.06

aPAD = acute population adjusted dose (aPAD = 1.0 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 cRfd for
metaflumizone is 0.12 mg/kg bw/day.  The FQPA safety factor for
metaflumizone has been set to 1.  Therefore, the cPAD is 0.12 mg/kg
bw/day.  The tier 1 chronic dietary exposure estimates were based on the
proposed tolerance values, 100 percent crop treated values,
concentration/processing factors and consumption data from the USDA
Continuing Survey of Food Intake by Individuals (CSFII 1994 - 1996,
1998) and the EPA Food Commodity Ingredient Database (FCID) using
Exponent's Dietary Exposure Evaluation Module (DEEM-FCID) software. 
Result exposure estimates were compared against the metaflumizone
chronic Population Adjusted Dose (cPAD) of 0.12 mg/kg b.w./day.    

Exposure estimates for the metaflumizone chronic dietary assessments
were well below U.S. EPA’s level of concern (See tables below.  The
most highly exposure sub-group was children 3 – 5 years old and the
exposure accounted for ?% 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 Grape, Crop Group 10 – Citrus Fruits Group, Crop Group 14
– Tree Nuts Group,  all pending and Secondary Residues in Meat, Fat,
Milk and Eggs

Population	Exposure Estimate	%cPAD

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

U.S. Population	0.015792	13.2

All Infants (< 1 year old)	0.008408	7.0

Children (1-2 years old)	0.019314	16.1

Children (3-5 years old)	0.019165	16.0

Children (6-12 years old)	0.01567	13.1

Youth (13-19 years old)	0.013229	11.0

Females (13-49 years old)	0.016063	13.4

Adults (20-49 years old)	0.015845	13.2

Adults (50+ years old)	0.016113	13.4

cPAD = chronic  population adjusted dose (cPAD = 0.12 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, January 24, 2006.  The EDWCs used in this
assessment included the total residue for metaflumizone and metabolite
M320I23.  The acute and chronic surface water EDWCs were 6.02 and 5.80
ppb, respectively.  The acute and chronic ground water EDWC was 0.00717
ppb.  The estimated drinking water exposure is shown in the table below.
  The acute drinking water exposure for females 13-49 years old accounts
for less than 1% aPAD.  The chronic drinking water exposure for all
sub-populations including infants and children was less than 1% cPAD.   

Table 3.  Estimated Acute Drinking Water Exposure for Females Ages 13-49
Years Old for Metaflumizone. 

Population sub-group	Acute Exposure (95th percentile)	% aPAD

US Population	NA	NA

All infants (< 1 year)	NA	NA

Children 1-2	NA	NA

Children 3-5	NA	NA

Children 6-12	NA	NA

Youth 13-19	NA	NA

Adults 20-49	NA	NA

Adults 50+ yrs	NA	NA

Females 13 - 49 yrs	0.000836	0.08

aPAD = acute population adjusted dose (aPAD = 1.0 mg/kg bw/day)

Table 4.  Estimated Chronic Drinking Water Exposure for all
Sub-populations including Infants and Children.  

Population sub-group	Chronic  Exposure 	% cPAD

US Population	0.000122	0.1

All infants (< 1 year)	0.000401	0.3

Children 1-2	0.000182	0.2

Children 3-5	0.00017	0.1

Children 6-12	0.000117	0.1

Youth 13-19	0.000088	0.1

Adults 20-49	0.000114	0.1

Adults 50+ yrs	0.00012	0.1

Females 13 - 49 yrs	0.000114	0.1

cPAD = chronic  population adjusted dose (cPAD = 0.12 mg/kg bw/day) ]

	2. Non-dietary exposure. [

Metaflumizone is registered for fire ant bait and spot-on treatment for
pets.  These two uses can result in residential exposure.  The EPA HED
has evaluated these uses and determined the exposure.  The exposure and
MOE values in the below tables are from the HED document January 24,
2006.   The MOE values were calculated using the a short-term dermal
NOAEL = 100 mg ai/kg bw/day and short-term incidential oral NOAEL = 20
mg ai/kg bw/day.  The calculated MOEs for all homeowner and toddler
exposures are greater than 100 and therefore do not exceed EPA’s level
of concern.  

Table 5.  Summary of Residential and Recreational Post-Application
Exposure and Risks from use of Fire Ant Bait.  

Fire Ant Bait	mg/kg bw/day	MOE

Toddler oral hand to mouth (turf grass)	0.000015	1333333

Toddler oral ingestion of granules	0.013	1538

Toddler oral object to mouth (turf)	0.00000093	21505376

Adult dermal pos-app (Res. Turf)	0.000232	431034

Toddler dermal post-app (Res. Turf)	0.00039	256410

Adult golfer dermal post-app (turf)	0.000016	6250000

Child golfer dermal post-app (turf)	0.0000272	3676471

Toddler oral (hand to mouth + object to mouth)	0.000016	1250000

Table 6. Summary of Post Application Exposure and Risk from Pet Spot-on
Treatments. 

Pet spot treatments	mg/kg bw/day)	MOE

Adult, dermal	0.29	345

Toddler, incidential oral ingestion 	0.035	571

Toddler, dermal	0.16	625

  

	3. Aggregate exposure. 

[Acute Aggregate Risk:  

No acute residential/recreational exposure are expected.  The acute
aggregate risk includes only exposure from food and water.  The food and
drinking water exposure accounts for 7.15% aPAD which is below HED’s
level of concern.  

Short-Term Aggregate Risk:

There is the potential for short-term, non-dietary exposure of children
and adults to metaflumizone from the use as fire ant bait and/or pet
spot-on treatment of dogs and cats.  Therefore, the short-term aggregate
exposure includes residential/recreational, food and water exposure.  
The target MOE for metaflumizone aggregate risk is 100.  

Table 7.  Summary of Shor-Term Aggregate Risk from Fire Ant Bait Use.

	Food + water	Non-dietary oral	Dermal	Aggregate

Population Sub-Group	MOE	MOE	MOE	MOE

US population	1257	NA	431034	1253

All infants (< 1 yr old)	2270	1333333	256410	2247

Children 1-2	1026	1333333	256410	1021

children 3-5	1034	1333333	256410	1029

Children 6-12	1267	NA	3676471	1266

Youth 13-19	1502	NA	3676471	1501

Adults 20-49	1253	NA	431034	1250

Adults 50 + years	1232	NA	431034	1229

The aggregate MOE values are all greater than the HED level of concern
which indicates that the aggregate use is below HED’s level of
concern.  

Table 8.  Summary of Shor-Term Aggregate Risk from Pet Spot-On Treatment
use.

	Food + water	Non-dietary oral	Dermal	Aggregate

Population Sub-Group	MOE	MOE	MOE	MOE

US population	1257	NA	345	271

All infants (< 1 yr old)	2270	571	625	264

Children 1-2	1026	571	625	231

children 3-5	1034	571	625	232

Children 6-12	1267	NA	NA	1267

Youth 13-19	1502	NA	NA	1502

Adults 20-49	1253	NA	345	270

Adults 50 + years	1232	NA	345	269

The aggregate MOE values are all greater than the HED level of concern
which indicates that the aggregate use is below HED’s level of
concern.  

Chronic Aggregate Risk:

No chronic residential/recreational exposure are 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 are 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 remained
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

	[No Maximum residue levels (MRLs) have been established for
metaflumizone by the Codex Alimentarius Commision (CODEX) or in Canada
and Mexico.]