Document ID: EPA-HQ-OPP-2012-0815-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-12-19T05:00Z

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: (1F7826)

	EPA has received a pesticide petition 1F7826 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 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.

An acute neurotoxicity study conducted in rats with oral doses of CMNP  up to 125 mg/kg showed no evidence of neurotoxicity.
	
      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.

A 90-day neurotoxicity study was conducted using male and female rats with CMNP administered in the diet.  There were no CMNP-related findings during daily observations, weekly detailed physical examinations, functional observational batteries, motor activity assessments, or measurements of grip strength and hindlimb foot splay.  There were no histologic changes in the central or peripheral nervous system tissues related to CMNP.  In this study, the no-observable-effect level (NOEL) for CMNP administered via the diet for 90 days was considered to be 75 mg/kg/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. 

An 18-month in-feed carcinogenicity study in CD-1 mice was conducted at dietary concentrations equivalent to 0, 5, 100 and 200 mg/kg/day.  Treatment effects included
higher liver and kidney weights among mid and high dose males and females.  Histopathological examinations included an increased incidence of atypical renal tubule hyperplasia and a statistically significant increased incidence of renal tubule tumors (adenomas and/or carcinomas) in mid and high dose males and in high dose females as compared with controls.   Histopathological examinations of lung tissues resulted in an increased incidence of bronchiole/alveolar hyperplasia in high dose females as compared with controls.  In these lung tissues there was also a statistically significant increased incidence of bronchiolo/alveolar adenomas and carcinomas in high dose females as compared with controls.  

 A 104-week chronic toxicity/oncogenicity study was conducted in Sprague-Dawley rats.  Treatment effects included higher liver weights in high dose groups of both sexes.  The only microscopic observation was increased incidence of hyperplasia of the pancreatic islets in mid and high dose males and high dose females.  Based on the effects observed,in the pancreas, the NOEL for chronic tox in the rats receiving CMNP in the diet was 5 mg/kg/day.  Carcinogenic evaluations were an increased incidence of preneoplastic changes consisting of minimal to mild pancreatic islet cell hyperplasia in high dose groups of both sexes.  The increased incidence of islet cell adenomas in the high dose males and females was not statistically or biologically different when compared to the two control groups.  All other tumors observed in the test substance treated groups were also similar to one or both control groups and/or occurred sporadically without relationship to dose.  The types of tumors observed were common neoplasms in this age and strain of rat.

      6. Immunotoxicity

Male and female rats were administered CMNP orally via gavage at doses up to 100 mg/kg/day for 28 days.  Animals were examined for viability, clinical observations, body weights and feed 
consumption values at periodic intervals.  At terminal sacrifice a gross necropsy was performed and each rat's liver, thymus and spleen were weighed.  Based on the weight of evidence, exposure to CMNP Technical did not adversely affect the humoral immune response.  The NOAEL of CMNP Technical is 5 mg/kg/day.  The immunotoxicity NOAEL is greater than 100 mg/kg/day (the highest dose tested).

      7. Animal metabolism.

In a rat metabolism study, [14]C-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.  

      8. 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.  

      9. 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 assessments were conservative Tier I screening level assessments:  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; and 100% of surface and ground water was assumed to contain the 30-year average residue concentration from PRZM/EXAMS.  This was a Tier 1 assessment with one refinement.  CMNP is not intended to be used on fresh oranges, only mechanically harvested processing oranges.  The contribution of fresh oranges to the diet was reduced to one percent crop treated (DEEM Adj. Factor #2). 

Risk assessments were based on the lowest observed NOAELs of 5 mg/kg BW for maternotoxicity in a rat developmental toxicity study (acute assessment) and 6.2 mg/kg BW for female mice in an 18-month carcinogenicity study (chronic assessment).  Based on the toxicology studies, fetuses and juvenile animals do not appear to be more sensitive than adult animals.  The acceptable margins of exposure and reference dose (RfD) were assumed to be based on typical 10X intraspecies and 10X interspecies uncertainty factors.

	i. Food.

As noted above, this was a conservative Tier 1 assessment of all commodities that might bear residues. 

	ii. Drinking water.

Both the acute and chronic assessments used PRZM/EXAMS index reservoir modeling and the 30-year average concentration.  This exceeded the calculated ground water concentration and is therefore more conservative.

      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 cm[2]/ 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 ~24,900 at the 95[th] percentile of exposure.  The MOE for females 13  -  49 years old was ~29,300.  In the chronic assessment, the MOE for the US population was ~ 75,000.

	2. Infants and children.

In the acute assessment, the most highly exposed subpopulation at the 95[th] percentile was non-nursing infants <1 year old, with a MOE of ~7,300.  In the chronic assessment, the MOE was ~21,000 for the most highly exposed subpopulation, non-nursing infants.   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.