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

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 weightof-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 weightof-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.

i. 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 subpopulations 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 subgroup 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 10-3ppb. 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 Postapplication Dermal 0.000334 300,000

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

Adolescent – Golfer Postapplication Dermal 0.000028 3,600,000

Children (1 to <2 year olds) –

Post-application

Dermal 0.000655 150,000

Incidental oral hand-tomouth 6.04E-06 3,300,000

Incidental oral object-tomouth 3.70E-07 54,000,000

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

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-tomouth 0.0000211 950,000

Incidental oral object-tomouth 0.0000013 15,000,000

Combined oral hand-tomouth 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

]