Document ID: EPA-HQ-OPP-2010-0346-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-10-27T04:00Z

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

<EPA Registration Division contact: Mr. Tony Kish, PM-22, 703-308-9443>

<State of Florida, Department of Citrus>

<Petition Number: (To be Assigned by EPA)>

<	EPA has received a pesticide petition (to be inserted by EPA)) from
State of Florida, Department of Citrus, 605 East Main Street, P.O. Box
9010, Bartow, FL 33831-9010 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 temporary tolerances for residues
of 5-chloro-3-methyl-4-nitro-1H-pyrazole (CMNP) and its metabolite
(5-chloro-4-nitro-1H-pyrazol-3-yl)-methanol (CHNP)   in or on the raw
agricultural commodities:

oranges at 0.80 parts per million (ppm)

and its processed commodities:

orange juice at 0.025 parts per million (ppm)

orange oil at 0.070 parts per million (ppm)

orange dried pulp (also referred to as dried pomace) at 1.80 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.

<The orange metabolism of CMNP is adequately understood for the purposes
of establishing the proposed tolerances.  CMNP metabolites include
(5-chloro-4-nitro-1H-pyrazol-3-yl)-methanol (CHNP) and its glucoside. 
Based on results of the CMNP orange metabolism study, the residue of
concern was defined as CMNP parent compound and its metabolite comprised
of CHNP/CHNP-glucoside. 

2. Analytical method.

In all plant matrices, the residue of concern, parent CMNP and CHNP/CHNP
glucoside, can be determined using HPLC/MS-MS following sample
extraction, hydrolysis (to convert CHNP-glucoside to its aglycone, CHNP)
and solid-phase clean up.  The limits of quantitation (LOQ) for the
analytes for the various commodities are as follows:

Oranges – 			0.025 ppm for both CMNP and CHNP/CHNP glucoside

Orange juice - 			0.025 ppm for both CMNP and CHNP/CHNP glucoside

Orange oil – 			0.025 ppm for both CMNP and CHNP/CHNP glucoside

Orange dried pulp (pomace) – 	0.025 ppm for both CMNP and CHNP/CHNP
glucoside

>

<	3. Magnitude of residues.

Field magnitude of residue trials with CMNP were conducted in Florida
between 2006 and 2008 at 10 sites in Hamlin, Pineapple, and Valencia
oranges.  Oranges were harvested at three days post application and
samples analyzed for CMNP and its metabolite CHNP (including the
glucoside conjugate).  Combined residues of CMNP and CHNP in the raw
agricultural commodity averaged 0.194 ppm (ranging from 0.095 to 0.446
ppm).

Two decline trials were conducted in the spring and fall of 2008 where
oranges were harvested at 0, 3, 5 and 7 days after application.  
Combined CMNP and CHNP residues immediately post application averaged
0.419 ppm (ranging from 0.337 to 0.501 ppm) and declined to an average
of 0.170 ppm (ranging from 0.164 to 0.176 ppm) at seven days post
application.

A total of three processing trials, in which oranges harvested three
days post-application were sent to a processing center (University of
Idaho Food Technology Center), were conducted.  A subsample of the bulk
unwashed oranges was placed into frozen storage and the remaining
oranges were processed into orange juice, orange oil and orange dried
pulp (also known as dried pomace).  All four matrices were then sent
frozen for analysis and all commodities were analyzed for residues of
CMNP and its primary metabolite, CHNP.  Combined CMNP and CHNP residues
in the raw agricultural commodity averaged 0.123 ppm (ranging from 0.057
to 0.178 ppm) in these studies.  There was no detectable residue in any
sample of orange juice.  There was a single orange oil sample with CMNP
residue exceeding the method LOQ .  No orange oil sample had detectable
residue of CHNP.  CMNP and CHNP residues in dried orange pulp ( dried
pomace) averaged 0.867 ppm (ranging from 0.467 ppm to 1.374 ppm).

>

<B. Toxicological Profile>

	1. Acute toxicity.

Acute toxicity endpoints for CMNP technical are as follows:

Acute oral (up/down) - LD50			197.1 milligrams/kilogram

Acute dermal-rats - LD50			>5000 milligrams/kilogram

Acute inhalation – rats – LC50			>2.03 milligrams/Liter

Eye irritation – rabbits				Ocular irritation persisted for 21 days

Skin irritation – rabbits				Slight irritation cleared by 7 days

Dermal sensitization (Buehler) - Guinea Pig	Not a contact sensitizer

A 28 day dermal toxicity study in the rat in which CMNP was administered
to at least 10% of the skin surface at doses of 0, 30, 75, 150, and 250
mg/kg bw/day resulted in a NOAEL of 250 mg/kg bw/day for both sexes.

<	

2. Genotoxicity.

A battery of mutagenicity studies with CMNP yielded negative results in
reverse mutation assay (Salmonella typhimurium), mammalian cell
cytogenetics assay (chromosome aberration), and rat bone micronucleus
assay.  

>

<	

3. Reproductive and developmental toxicity.

A developmental toxicity study was conducted with CMNP using rats
gavaged with doses of 0, 5, 50, or 100 mg/kg bw/day from days 6 through
19 of gestation.  The maternal toxicity LOAEL was 50 mg/kg bw/day based
on liver effects.  The maternal NOAEL was 5 mg/kg bw/day.  The
developmental LOAEL was 100 mg/kg bw/day based on fetal variations.  The
developmental NOAEL was 50 mg/kg bw/day.

A developmental toxicity study was conducted with CMNP using rabbits
gavaged with doses of 0, 5, 25, 75, or 125 mg/kg bw/day.  The maternal
toxicity NOAEL was 75 mg/kg bw/day and LOAEL was 125 mg/kg bw/day based
upon reduced body weight gain, reduced feed consumption, and clinical
signs.  The developmental toxicity NOAEL was 75 mg/kg bw/day and LOAEL
was 125 mg/kg bw/day based upon reduced fetal body weight.

A two-generation reproduction study was conducted in rats in which CMNP
was administered at dietary doses of 0, 6.7, 50, or 100 mg/kg bw/day. 
The LOAEL for male and female adults was 50 mg/kg bw/day based upon
findings in livers and kidneys.  The NOAEL for male and female adults
was 6.7 mg/kg bw/day.  For developmental toxicity, the LOAEL was 100
mg/kg bw/day based upon offspring systemic toxicity (in the presence of
parental systemic toxicity).  The developmental NOAEL was 50 mg/kg
bw/day.>

<	4. Subchronic toxicity

Ninety day feeding studies have been conducted with CMNP in rats, mice,
and dogs.  In the rat study, CMNP was administered in the diet at doses
of 0, 5, 15, or 75 mg/kg bw/day.  The NOAEL was 15 mg/kg bw/day and the
LOAEL was 75 mg/kg bw/day based upon liver and kidney findings.  In the
mouse study, CMNP was administered in the diet at doses of 0, 5, 150, or
300 mg/kg bw/day.  The NOAEL was 5 mg/kg bw/day and the LOAEL was 150
mg/kg bw/day based upon liver effects.  In the dog study, CMNP was
administered via capsule at 0, 5, 15, or 75/60 mg/kg bw/day.  The dose
of Group 4 was lowered from 75 to 60 mg/kg bw/day at study day 14 based
on reduced food consumption.   The LOAEL was 75/60 mg/kg bw/day based
upon reduced body weight gain.  The NOAEL was 15 mg/kg bw/day.>

<	5. Chronic toxicity.

A 52-week chronic toxicity study was conducted in dogs in which CMNP was
administered in gelatin capsules at doses of 0, 5, 15, or 60 mg/kg
bw/day. There were no deaths during this study.  There were no
definitive effects related to CMNP on clinical observations, hematologic
parameters, urinalysis parameters, ophthalmology, organs weights or
gross or microscopic pathology. The LOAEL was 60 mg/kg bw/day based upon
reduced body weight gains in both sexes.  The NOAEL was 15 mg/kg bw/day.
>

<	6. Animal metabolism.

In a rat metabolism study, 14C-CMNP was administered in a single oral
gavage dose of 10 mg/kg body weight in an aqueous methylcellulose
solution.  Urine, cage rinse, feces, and expired air were collected for
up to 168 hours post dosing.  Over 85% of dosed radioactivity was
recovered in the urine and feces.  The bulk of the dosed radioactivity
was recovered during the first 24 hours.  The total radioactivity
recovered was >95% for both sexes.  CMNP was extensively metabolized in
the rat with the major metabolite being identified as CMNP sulfonic
acid.    Minor routes of metabolism included formation of glucuronic
acid conjugates, oxidation to form CHNP followed by conjugation with
glucuronic acid and sulfonic acid, dechlorination and gluthathione
conjugation followed by further metabolism to form a mercapturic acid
conjugate.  N-acetyl-amino-CMNP
(5-chloro-3-methyl-1H-pyrazole-4-acetamide) was also detected as a minor
metabolite in urine.  >

<	7. Metabolite toxicology.

Pathways of metabolism of CMNP can be characterized by Phase I oxidation
and Phase II conjugation reactions involving glutathione conjugation and
glucuronidation as well as nitroreduction/acetylation.  The conjugated
metabolites are all much more highly polar entities than parent compound
and can be considered metabolically detoxified and excretable.  The
toxicities of CHNP and N-acetyl-amino-CMNP were assessed during the
conduct of CMNP-required mammalian toxicity studies.  >

<	8. Endocrine disruption.

No consistent treatment effects were observed on the endocrine system in
CMNP toxicology studies.   >

<C. Aggregate Exposure>

<	1. Dietary exposure.

Calculated maximum residue levels (MRLs) in oranges and orange products,
potential residues in meat and milk products, potential maximum residues
in surface and ground waters, and dietary exposures and risks were
assessed with the Dietary Exposure Evaluation Model  (DEEM – FCID,
Version 2.16), based on the CSFII Food Consumption 1994 – 1996 and
1998.  The assessment was a conservative Tier I screening level
assessment:  100% of all orange products were assumed to contain the
MRL(including oranges produced in states where CMNP registration is not
being pursued); 100% of meat and milk commodities were assumed to be
derived from livestock fed dried pulp (also known as dried pomace) at
the MRL; 100% of surface and ground water was assumed to contain the
maximum residue modeled and summed from GENEEC2 and SCI-GROW; and, the
lowest observed NOAEL was used for both the acute and chronic assessment
(5 mg/kg BW/day).>

<	i. Food.

The lowest toxicology no observed adverse effect level (NOAEL) of 5
mg/kg bw/day was conservatively used for both acute and chronic
assessments.  The reference dose (RfD) was assumed to be based on
typical 10X  intraspecies and 10X interspecies uncertainty factors.  >

<	ii. Drinking water.

Potential CMNP residues in surface and ground water were conservatively
calculated using GENEEC2 for surface water and SCI-GROW for ground
water.  Residues were assumed to occur in all water consumed from all
surface and ground water sources at the highest concentration sum of the
GENEEC2 and SCI-GROW models. >

<	

2. Non-dietary exposure.

CMNP will be used only on commercially grown oranges in Florida.  CMNP
has no non-food or residential uses that could result in non-dietary
exposure requiring aggregation.

Bystander exposure was not considered a concern.  Potential exposure to
drift during application was considered negligible when compared with
the open-cab airblast operator.  Exposure to drifted residues would be
negligible when compared with the exposure of hand-harvesters.  Due to
the low volatility of CMNP, exposure to volatilized vapors is considered
unlikely.  Therefore, these routes of exposure were not quantified.

The exposure of mixer/loaders handling the liquid product (open-pour)
was assessed with the EPA Guide to the Pesticide Handlers Exposure
Database.  When wearing a baseline clothing ensemble of shoes, socks,
long pants, long-sleeved shirt and chemical resistant gloves, margins of
exposure (MOE) based on the 28-day rat dermal NOAEL of 250 mg/kg BW/day
exceeded 25,000 and inhalation MOEs based on the 28-day rat dietary
NOAEL of 15 mg/kg BW/day exceeded 29,000.  Margins of exposure for the
open-cab airblast operator in the same clothing ensemble exceeded 2,400
and 7,700 by the dermal and inhalation routes.   Hand-harvesting was
conservatively modeled with the EPA convention of a transfer coefficient
of 3,000 cm2/ hr for hand-thinning tree fruits, a task EPA considers to
have greater exposure potential than hand-harvesting.  At the baseline
clothing ensemble (with bare hands), dermal MOEs ranged from >430 at day
2 postapplication to ~870 at day 7, the most likely span of days of
reentry.  Inhalation exposure for low volatility products is typically
not assessed. 

>

<D. Cumulative Effects

CMNP is not known to have a common mechanism of toxicity with other
products.  A cumulative assessment was not necessary.

<<E. Safety Determination>>>

<	1. U.S. population.

In the acute DEEM assessment of dietary plus drinking water exposure,
the MOE for the US population was ~1,950 at the 95th percentile of
exposure.  The MOE for females 13 – 49 years old was ~2,200.  In the
chronic assessment, the MOE for the US population was ~5,300.

>

<	2. Infants and children.

In the acute assessment, the most highly exposed subpopulation at the
95th percentile was non-nursing infants <1 year old, with a MOE of ~600.
 In the chronic assessment, the most highly exposed subpopulation was
children 3 – 5 years old, with a MOE of ~1,470.  Based on the
toxicology studies, fetuses and juvenile animals do not appear to be
more sensitive than adult animals.>

<F. International Tolerances>

<Maxium residue levels (MRL) in oranges or processed fractions have not
been established for CMNP in any country.>

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