Document ID: EPA-HQ-OPP-2008-0886-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-04-13T04:00Z

Notice of Filing of Pesticide Petition 8E7476 by Interregional Research
Program #4 

<EPA Registration Division contact: Susan Stanton (703) 305-5218>

<Interregional Research Program #4 (IR-4)>

<PP#8E7476>

<	EPA has received a pesticide petition (PP#8E7476) from Interregional
Research Program #4, 500 College Road East, Suite 201W, Princeton, NJ  
08540  proposing, pursuant to section 408(d) of the Federal Food, Drug,
and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by
establishing a tolerance for residues of formetanate hydrochloride
(N,N-dimethyl-N′-[3-[[(methylamino)carbonyl]oxy]phenyl]methanimidamide
) in or on the raw agricultural commodity Onion, bulb, subgroup 3-07A at
0.06 parts per million (ppm).  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>

<	1. Plant metabolism. Plant metabolism studies in three crops indicate
that the metabolic pathway in plants is similar with resulting
metabolites containing the formamidine moiety.  In most cases, parent
formetanate was the only or the predominant  terminal residue identified
in the extractable radioactivity in plants.  Formetanate residues are
found mainly on the surface (peel) of fruit.  The Agency has previously
determined that only parent formetanate HCl is the residue of concern to
be included in the tolerance expression and the dietary risk
assessment.>

<	2. Analytical method. A validated residue analytical method exists for
quantitation of formetanate residues in onion.  Samples are extracted
with buffered organic solvent and the formetanate in the resulting
extract is purified through a C-18 cartridge.  Residues were identified
and quantified by HPLC-MS/MS.  The method has a Limit of Quantitation of
0.002 ppm and a Limit of Determination of 0.0007 ppm.  The method was
validated by fortifying onions from a control site fortified to 0.002,
0.05 and 1.0 ppm.  The average recovery was 89 ± 13%.>

<	3. Magnitude of residues. Dry bulb onions are the sole representative
commodity for Crop Subgroup 3-07A.  Nine residue trials with dry bulb
onions were conducted in 2006.  Application in all cases was in
conformity to the use pattern on the proposed label.  Residue samples
were collected in duplicate 30 and 14 days following the second and
final application.  As onions are not consumed “as is” but peeled
and washed, two duplicate samples were collected from each plot with one
duplicate being further peeled and washed.  Residues from unpeeled
onions were used to propose the tolerance level but residues from
peeled, washed onions were used to assess the dietary risk of this
proposed new use.  Residues of formetanate hydrochloride were below 0.03
ppm in raw onions in all scenarios tested.

An earlier, exploratory study conducted in Idaho in 2004 determined the
terminal residues in dry bulb onions following nine treatment regimens. 
One of the use patterns tested was sufficiently similar to the proposed
use pattern that the resulting residues may be considered for
tolerance-setting purposes.  Specifically, onions treated once with
Carzol SP at 1.25 lb product per acre (1.15 lb ai/A) 15 days before
harvest had whole-onion residues of 0.048 and 0.056 ppm.  Residues in
peeled, washed onions from that plot were undetectable.  The LOQ for the
analytical method used was 0.002 ppm and the LOD was 0.0007 ppm.

In summation, the highest observed residue in the RAC (onion bulbs) in
ten applicable MOR trials was 0.056 ppm, leading to the proposed
tolerance of 0.06 ppm in raw onions.  For dietary assessment purposes,
fourteen peeled, washed onion samples (two from the 2004 study and
twelve from the 2006 study) had undetectable residues. Four washed,
peeled onion samples had finite residues between varying from 0.0023 to
0.0263 ppm. >

<B. Toxicological Profile>

<	1. Acute toxicity.  Formetanate HCl has high acute toxicity via the
oral route, moderate acute toxicity via the inhalation route and has low
acute toxicity via the dermal route. It is not an eye irritant but is a
dermal sensitizer. Exposure to formetanate hydrochloride resulted in
decreased plasma, whole blood and/or brain cholinesterase. 
Cholinesterase inhibition (ChEI) appears to be the only manifestation of
exposure.  An aPAD of 0.00065 mg/kg bw has been set for formetanate
hydrochloride based on a comparative ChE inhibition study in rats.>   

]

<	2. Genotoxicty. There is no evidence of genotoxicity from formetanate
hydrochloride.>

<	3. Reproductive and developmental toxicity. Formetanate HCl did not
result in developmental toxicity in either rats or rabbits or in
reproductive effects in the multi-generation reproduction study.  There
was no indication of increased  offspring susceptibility in these
studies.>

<	4. Subchronic toxicity. Cholinesterase inhibition is the only
manifestation of exposure observed in the subchronic toxicity studies
supporting formetanate HCl.>

<	5. Chronic toxicity. Cholinesterase inhibition is the only
manifestation of exposure observed in the chronic toxicity studies
supporting formetanate HCl.  These studies indicate that the magnitude
of cholinesterase inhibition does not increase with continued exposure
because of the rapid reversibility of inhibition.  Therefore, chronic
exposure to formetanate HCl may be considered as a series of acute
exposures, indicating that a chronic dietary risk assessment is not
necessary.

Formetanate hydrochloride is classified as a group “E” carcinogen,
and therefore a cancer exposure assessment is not required.>

<	6. Animal metabolism. In the rat metabolism study, greater than 90% of
the dose was recovered in the urine within 24 hours and less than 10%
was recovered in the feces.  Intravenous dosing, repeated oral dosing or
a high dose had no significant effects on the disposition of
formetanate.  Terminal disposition of radioactivity demonstrated the
highest levels in liver, gastrointestinal tract, adrenals, fat, residual
carcass and eyes.  In most cases these organs had levels near the lower
limit of detection.>

<	7. Metabolite toxicology. The Agency has previously determined that
the only residue of toxicological concern is parent formetanate HCl.>

<	8. Endocrine disruption. There was no evidence of endocrine disruptor
effects in the toxicological studies supporting formetanate HCl.>

<C. Aggregate Exposure>

<	1. Dietary exposure. Tolerances have been established in 40 CFR
180.276 for the residues of formetanate HCl in or on a variety of raw
agricultural commodities.  Risk assessments were performed to assess
dietary exposures from formetanate HCl in food as follows:>

<	i. Food. A dietary risk analysis was performed with DEEM-FCID v2.14 on
the current label plus Crop Subgroup 3-07A commodities treated with
formetanate at the proposed use pattern using  the dry bulb onion data
described above.  Infants, the subpopulation with the lowest Margin of
Exposure (MOE) had a total exposure (99.9th Percentile) of 0.000269
mg/kg bw/day (MOE = 241).  This exposure was statistically
indistinguishable from an assessment performed without the addition of
Crop Subgroup 3-07A commodities which resulted in an exposure of 0.00267
mg/kg bw/day (MOE = 243).  The exposure of the US Population as a whole
was 0.000114 mg/kg bw/day (MOE = 568).>

<	ii. Drinking water. Formetanate HCl is not expected to reach
groundwater in appreciable quantities.  Surface water data do not exist
for formetanate.  A Tier I screening assessment performed using very
conservative PRIZM/EXAMS assumptions, predicted that worst-case
theoretical residues of formetanate in drinking water accounts for 61%
of the aPAD.  The Agency has previously determined that “…use of the
99.9th percentile to estimate exposure significantly overstates exposure
and thus the estimated slight exceedance of the aPAD (117%) for infants
does not show a risk of concern.  This is confirmed by the fact the
estimated exposure for this population group declines below the aPAD at
the 99.86th percentile level.” (73 FR 9230, February 20, 2008)>

<	2. Non-dietary exposure. Only agricultural uses are registered for
formetanate HCl. There are no uses that would result in residential or
recreational exposures.>

<D. Cumulative Effects>

<	Formetanate HCl belongs to the N-methyl carbamate class of chemicals
for which a revised cumulative assessment has been completed.  (72 FR
54686, September 26, 2007)  This “Revised N-Methyl Carbamate
Cumulative Risk Assessment” concludes that the cumulative risks from
food, water and residential exposure to N-methyl carbamates do not
exceed the Agency’s level of concern.>

<E. Safety Determination>

<	1. U.S. population. A Tier 3 probabilistic dietary risk analysis was
performed using DEEM-FCID v. 2.16 for both the current label and the
label plus dry bulb onions assuming 100% onion acreage treated.  The
incremental dietary risk to the average consumer rose slightly from
17.38% aPAD to 17.58% aPAD.  The Margin of Exposure thereby decreased
slightly from 575 to 568.>

<	2. Infants and children. The incremental dietary risk from onions to
infants and children younger than 12 years was negligible.  Infants have
the lowest MOE as a group with the highest %aPAD risk (41%aPAD both
before and after addition of onions).  The subpopulation with the
highest increase in acute dietary risk was youths 13-19 years with 7.63%
aPAD (MOE = 1311) before onion addition and 8.49% aPAD (MOE = 1177)
after onion addition.>

<F. International Tolerances>

<	The Codex Alimentarius has not set an Maximum Residue Levels (MRL) for
formetanate hydrochloride.>

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