Document ID: EPA-HQ-OPP-2010-0261-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-05-05T04:00Z

MacroButton macIb01 i  

<EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  >

<EPA Registration Division contact: [Shaunta Hill, 703/347-8961]>

<INSTRUCTIONS:  Please utilize this outline in preparing the pesticide
petition.  In cases where the outline element does not apply, please
insert “NA-Remove” and maintain the outline. Please do not change
the margins, font, or format in your pesticide petition. Simply replace
the instructions that appear in green, i.e., “[insert company
name],” with the information specific to your action.>

<TEMPLATE:>

<[BASF Corporation]>

<[0F7695]>

<	EPA has received a pesticide petition ([0F7695]) 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 by
establishing a tolerance for residues of [ametoctradin,
5-ethyl-6-octyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine] in or on the raw
agricultural commodities [brassica, head and stem, subgroup, at 12 parts
per million (ppm); brassica, leafy greens, subgroup, at 50 ppm; grape at
5 ppm; hop, dried cones, at 9 ppm; onion, bulb, subgroup, at 1.2 ppm;
onion, green, subgroup, at 16 ppm; raisin at 8 ppm; vegetable, fruiting,
group, at 2 ppm; vegetable, leafy, except brassica, group, at 70 ppm;
vegetable, cucurbit, group, at 4.5 ppm; vegetable, tuberous and corm,
subgroup, at 0.05 ppm ] and by establishing an exemption from the
requirement of a tolerance [for the metabolites M650F03,
(7-amino-5-ethyl[1,2,4]triazolo[1,5-a]pyrimidine-6-y-l)acetic acid, and
M650F04, 7-amino-5-ethyl[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic
acid in all food crops.]  EPA has determined that the petition contains
data or information regarding the elements set forth in section 408
(d)(2) of  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>

>

<	2. Analytical method. [The proposed enforcement method for
ametoctradin was fully validated.  Ametoctradin is extracted with a
mixture of methanol/water. An aliquot of the extract is centrifuged and
partitioned against dichloromethane. The final determination of
ametoctradin is performed by HPLC-MS/MS.  This method has a limit of
quantitation of 0.01 mg/kg and is suitable for enforcement purposes. ]>

<	3. Magnitude of residues. [Supervised field trials were carried out to
determine the magnitude of the residue in/on brassica, head and stem,
subgroup; brassica, leafy greens, subgroup; grape; hop; dried cones;
onion, bulb, subgroup; onion, green, subgroup; raisin; vegetable,
fruiting, group; vegetable, leafy, except brassica; vegetable, cucurbit,
group; and vegetable, tuberous and corm, subgroup.  The number and
locations of field trials are in accordance with OPPTS Guideline
860.1500. Field trials were carried out using the maximum label rates,
the maximum number of applications, and the minimum pre-harvest interval
(PHI) for all the crops. Detected residues of BAS 650 F in all crops
support the proposed tolerances.]

<B. Toxicological Profile>

<	1. Acute toxicity.  

[BAS 650 F and its formulated products have a favorable acute toxicity
profile.   The acute toxicity studies place technical BAS 650 F in the
toxicity category III for the acute oral and the acute dermal category
and category IV for the acute inhalation.  BAS 650 F is category IV for
both eye and skin irritation and is not a dermal sensitizer. ]

>

<	2. Genotoxicty. [BAS 650 F was tested for its genotoxic potential in a
battery of six in vitro or in vivo studies covering the required
endpoints of point mutations, chromosomal damage and DNA damage and
repair.  BAS 650 F did not demonstrate any genotoxic effects.>  BAS 650
F was negative for inducing mutations in both an in vitro Ames test and
an in vitro forward mutation assay in mammalian cells (HPRT test with
and without metabolic activation).  Both an in vitro and an in vivo
chromosome aberration assay (with and without metabolic activation)
showed no evidence of a clastogenic effect.  An in vivo micronucleus
test and an in vivo unscheduled DNA synthesis (UDS) test were also
negative. These studies demonstrate that BAS 650 F is not genotoxic.]

<	3. Reproductive and developmental toxicity. [The reproductive and
developmental toxicity of ametoctradin was investigated in a
2-generation rat reproduction study as well as in rat and rabbit
developmental toxicity studies. In the reproduction study, there were no
effects on fertility. There were no parental toxicity or pup effects at
any of the tested doses (up to and including the limit dose).  The
resulting parental systemic and developmental toxicity NOAEL’s are
1000 mg/kg bw.>

In the rat developmental toxicity study, the administration of
ametoctradin elicited no signs of maternal toxicity, had no influence on
gestational parameters and induced no signs of developmental toxicity at
the dose levels tested (up to and including the limit dose). Based on
these results, the no observed adverse effect level (NOAEL) in rat for
maternal and prenatal developmental toxicity is the limit dose level of
1000 mg/kg bw/d.

The administration of ametoctradin to rabbits elicited no signs of
maternal toxicity, had no influence on gestational parameters and
induced no signs of developmental toxicity at the dose levels tested (up
to and including the limit dose). Based on these results, the no
observed adverse effect level (NOAEL) in rabbit for maternal and
prenatal developmental toxicity is the limit dose level of 1000 mg/kg
bw/d.]

<	4. Subchronic toxicity. [The subchronic toxicity of ametoctradin was
investigated in 90-day feeding studies with rats, mice and dogs as well
as a dermal 28-day repeat dose study with rats.  Dosing at limit doses
(about 1000 mg/kg bw) in these studies caused no substance-related
adverse findings. Due to the lack of adverse findings, target organs
were not identified.  The lowest NOAEL in subchronic oral toxicity
studies was 912 mg/kg bw/day in the dog 90-day study.

The neurotoxic potential of ametoctradin was studied following both
acute and subchronic oral administration in the rat.  In the acute
neurotoxicity study there were no test-item related findings in the
clinical examinations, functional observational battery or the
measurement of motor activity at doses up to and including the limit
dose (2000 mg/kg bw).  Nor did neuropathology reveal any indications for
neurotoxicity at the limit dose. Therefore, ametoctradin did not cause
neurotoxicity up to the limit dose of 2000 mg/kg body weight in animals
of both sexes.

Ametoctradin was also tested in rats in a subchronic neurotoxicity study
at doses up to 15000 ppm in the diet (921.2 mg/kg bw, male and 1077.2
mg/kg bw, female) over a period of three months.  There were no
test-item related findings in the clinical examinations, functional
observational battery or the measurement of motor activity. The
neuropathological treatment-related findings (included brain weight
determination, necropsy and neuropathological examinations by light
microscopy) also showed no treatment-related findings. In summary,
ametoctradin did not show any neurotoxic potential up to the limit dose
of 15000 ppm (921.2 mg/kg bw, male and 1077.2 mg/kg bw, female).]

>

<	5. Chronic toxicity. [The results of long-term oral exposure studies
indicate that ametoctradin is not carcinogenic in mice or rats.  The
chronic toxicity/oncogenicity studies with ametoctradin included a
12-month feeding study with Beagle dogs, an 18-month C57BL/6 J Rj mouse
feeding study and a 24-month Wistar rat chronic/oncogenicity study.

At the limit dose in Beagle dogs, Wistar rats and C57BL/6 J Rj mice
there was no test substance-related adverse findings or evidence of
carcinogenicity.  The resulting NOAEL’s in the mouse oncogenicity
study were 6000 ppm for both sexes (1099 mg/kg bw for the male and 1543
mg/kg bw for the female).  In the rat chronic/oncogenicity study the
NOAEL’s were 15000 ppm for both sexes (870.7 mg/kg bw for the male and
979.3 mg/kg bw for the female).  In the chronic dog study, the NOAEL’s
were 30000 ppm for both sexes (848 mg/kg bw for the male and 936 mg/kg
bw for the female).]

>

<	6. Animal metabolism. [Rat, goat and hen metabolism studies were
conducted to determine the nature of ametoctradin residues in animals.
All studies were conducted with radio labeled ametoctradin.  In
ruminants and poultry ametoctradin is rapidly absorbed and excreted.
Ametoctradin is metabolized in goats and hens by oxidation of the
aliphatic side chain to the respective terminal carboxylic acid and
subsequent stepwise oxidative cleavage of the side chain (loss of
C2-units) analogous to the (-oxidation of fatty acids. The metabolic
pathways in rats, goats and hens were qualitatively similar.]>

	7. Metabolite toxicology. [No metabolites of toxicological concern were
identified.  M650F03 and M650F04, soil metabolites of BAS 650 F, were
evaluated for toxicological relevance.  These metabolites are
structurally similar to each other and to the parent ametoctradin.  To
further investigate the metabolites’ properties, genotoxicity studies
and sub-chronic dietary studies in the rat were conducted.  M650F03 was
not genotoxic in an Ames test (with and without S-9 activation) or in an
HPRT test in CHO cells (with and without S-9 activation). No sign of
chromosomal aberrations was present in vitro (V79 cells, with and
without S-9 activation) or in vivo (NMRI mice, micronucleus test). The
90-day dietary study demonstrated that as with the parent,
administration of M650F03 at dose levels up to and including the limit
dose resulted in no adverse substance-related findings.  M650F04 was not
genotoxic in an Ames test (with and without S-9 activation) or in an
HPRT test in CHO cells (with and without S-9 activation). M650F04 caused
no clastogenic effects in vitro (V79 cells, with and without S-9
activation). The 90-day dietary study demonstrated that as with the
parent, administration of M650F04 at dose levels up to and including the
limit dose resulted in no adverse substance-related findings. Studies
with the M650F03 and M650F04 metabolites confirmed that they are not
toxicologically relevant.]  

	8. Endocrine disruption. [No specific tests have been conducted with
ametoctradin to determine whether the chemical may have an effect in
humans that is similar to an effect produced by a naturally occurring
estrogen or other endocrine effects.  However, there were no significant
findings in other relevant toxicity studies (e.g., sub-chronic and
chronic toxicity, developmental toxicity and multi-generation
reproductive studies) which would suggest that ametoctradin produces any
endocrine disruption.]

>

<

C. Aggregate Exposure>

<	1. Dietary exposure. [The dietary exposure assessment for ametoctradin
was conducted using tolerance level residues, 100% crop treated factors,
and default processing factors.  The crops and residue values used in
the assessment were: brassica, head and stem, subgroup, = 12 parts per
million (ppm); brassica, leafy greens, subgroup = 50 ppm; grape = 5 ppm;
hop, dried cones = 9 ppm; onion, bulb, subgroup = 1.2 ppm; onion, green,
subgroup = 16 ppm; raisin = 8 ppm; vegetable, fruiting, group = 2 ppm;
vegetable, leafy, except brassica, group = 70 ppm; vegetable, cucurbit,
group = 4.5 ppm; vegetable, tuberous and corm, subgroup = 0.05 ppm.  An
acute dietary endpoint was not determined because there was no
toxicological effect from a single exposure to ametoctradin.  The
chronic dietary endpoint is based on a NOAEL of 871 mg/kg bw – day
with a safety factor of 100 which resulted in a cPAD = 8.71 mg/kg bw
–day.  ]>

<Food. [

Acute Dietary Exposure Assessment

An acute assessment was not needed since there were no toxic effects
attributable to a single dose.  Therefore, a quantitative acute dietary
exposure and risk assessment were not required.  

Acute Dietary Exposure Assessment 

The chronic dietary exposure is shown in the table below.  The exposure
includes all food commodities and drinking water.  The dietary (food +
drinking water) utilized less than 1% of the cPAD for all populations.  

Table 1.  Summary of Chronic Dietary Exposure Assessment 

Considering All Proposed Tolerances for ametoctradin.  The assessment
includes food + drinking water.

Population

Subgroups	Exposure Estimate

(mg/kg b.w./day)	%cPAD

U.S. Population	0.037532	0.4

All Infants	0.022184	0.3

Children 1-2 years	0.054469	0.6

Children 3-5 years	0.050184	0.6

Children 6-12 years	0.037335	0.4

Youth 13-19 years	0.030329	0.3

Adults 20-49 years	0.036924	0.4

Adults 50+ years	0.037945	0.4

Females 13 - 49	0.037273	0.4

%cPAD = percent of chronic population adjusted dose 

Exposure estimates based on tolerance values, default processing  
factors, and 100% CT for all crops/commodities

 The results indicate that the exposure for ametoctradin is well below
the EPA level of concern.

The risk assessment was repeated with contribution from the metabolite
residues in rotational crops.  The highest total residue value of 0.8
ppm was observed in the field rotational crop study, derived from the
sum of the M650F03 and M650F04 residues in parent equivalents from a
118-day wheat straw sample.  For this assessment, this value of 0.8 ppm
was applied to all crops in the DEEM database that could possibly be
considered for crop rotation.  315 commodities were included.  In
addition, this value was also applied to potato commodities, since it is
higher than the proposed tolerance in potatoes.  The result of this
assessment is shown in Table 2.

Table 2.    Chronic Dietary Risk Assessment considering parent residue
on target crops and 0.8 ppm metabolite residue in rotational crops

	(315 commodities included)

Consumer Group	%ADI

US Population (total)	0.4

All infants (<1 yr)	0.4

Children 1-2 yrs	0.8

Children 3-5 yrs	0.7

Children 6-12 yrs	0.5

Youth 13-19 yrs	0.4

Adults 20-49 yrs	0.5

Adults 50+	0.5

Females 13-49 yrs	0.5

This assessment is overly conservative, especially considering the fact
that metabolite residues in rotational crops were relatively low in
consumer food items, compared to feed items.  When the results from the
two risk assessments are compared, it can be seen that there is no
significant difference in the consumer risk assessment when the two soil
metabolites are included.  All consumer groups are below 1% of the ADI
for both assessments.] 

>

<ii. Drinking water. 

[The drinking water exposure was modeled for all proposed uses using the
proposed label directions and the appropriate environmental fate data
for ametoctradin.  The highest drinking water values were obtained from
the PA tomato scenario.  Based on the PRZM/EXAMS model, the peak EDWCs
for chronic exposure are estimated to be 0.206 ug/L in surface water.

Acute Aggregate Exposure and Risk (Food and water)

Toxicology studies have shown that ametoctradin poses no acute dietary
risk.  Therefore an acute aggregate exposure assessment was not
required.

Short- and Intermediate Term Aggregate Exposure and Risk (food, water,
and residential)

Residential uses for ametoctradin are not being pursued, therefore a
short and intermediate term aggregate exposure and risk assessment was
not required.

 Chronic Aggregate Exposure and Risk (food and water)

The aggregate chronic risk includes residues of ametoctradin from food
and water (Table 1). The results demonstrate there are no safety
concerns for any subpopulation based on the proposed new uses, and that
the results clearly meet the FQPA standard of reasonable certainty of no
harm.] 

>

<	2. Non-dietary exposure. [Residential uses for ametoctradin are not
being pursued, therefore, a non-dietary exposure and risk assessment was
not required. ]>

<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." Unlike other pesticides for which EPA has
followed a cumulative risk approach based on a common mechanism of
toxicity, EPA has not made a common mechanism of toxicity finding as to
ametoctradin. In addition, ametoctradin does not produce a toxic
metabolite produced by other substances. Therefore, for the purposes of
this tolerance action, BASF assumes that ametoctradin does not have a
common mechanism of toxicity with other substances.]

>

<E. Safety Determination>

<	1. U.S. population. [Based on this risk assessment, BASF concludes
that there is a reasonable certainty that no harm will result to the
general population from the aggregate exposure to ametoctradin.]>

<	2. Infants and children. [Based on this risk assessment, BASF
concludes that there is a reasonable certainty that no harm will result
to infants or children from the aggregate exposure to ametoctradin.]>

<F. International Tolerances>

<	[A maximum residue level (MRL) has not been established for
ametoctradin in any crop by the Codex Alimentarius Commission.]>

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