


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

EPA Registration Division contact: Richard Gebken, (703) 305-6701


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:

Bayer CropScience

[Insert petition number]

EPA has received a pesticide petition ([insert petition number]) from Bayer CropScience, 2 T. W. Alexander Drive, 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. 

(Options (pick one)

 By establishing a tolerance for residues of  

The insecticide chemical ethiprole, 1 H-pyrazole-3-carbonitrile, 5-amino-1-[2,6-dichloro-4-(trifluromethyl)phenyl]-4-(ethylsulfinyl),and its sulfone metabolite (RPA 097973) 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-ethylsulfonylpyrazole-3-carbonitrile, expressed as parent equivalent,  in or on the raw agricultural commodity  of coffee (green beans), together with the processed commodities of roasted coffee and instant coffee, at 0.1 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. [The metabolism of ethiprole in crop plants has been determined in cotton, rice and sweet pepper and fully described in reports submitted previously.  Although the majority of the extractable residue in virtually all the plant parts of rice was parent ethiprole, one metabolite, the ethiprole sulfone RPA097973,  accounted for more than 10% of total radioactive residue in the rice metabolism study.  In the other crops, ethiprole accounted for the majority of the total radioactive residue and extensive metabolism did not occur.  However in pepper fruits fruits, metabolism was more extensive with 16.4% of sulfone RPA097973 present in red (mature) fruits at harvest.  In green (immature) fruits, the ethiprole amide RPA112916 as well as sulfone are present at >10% levels. EPA has previously determined that the residue definition for risk assessment is parent ethiprole plus the sulfone metabolite.  At the same time EPA recommended that the amide metabolite be included analysis in any fruit crops.  Therefore Parent ethiprole, ethiprole sulfone and ethiprole amide were included in the analytical methods for coffee analysis.]  

      2. Analytical method. [Practical enforcement analytical methods for detecting and measuring levels of ethiprole parent, ethiprole sulfone and ethiprole amide have been developed and validated in/on all appropriate plant and animal matrices.  The limit of quantification (LOQ) for all three compounds, expressed as parent equivalents, was established at 0.002 ppm in coffee (green beans) and at 0.005 ppm in the processed commodities of roasted beans and instant coffee.  The method LOQ in all animal commodities is 0.01 ppm.  However there are no animal feed items involved in this submission.  Therefore, these analytical methods are adequate to allow monitoring for residues at the levels proposed for the tolerances.]

      3. Magnitude of residues. [Ten rice crop field trials were conducted in Brazil (5), Colombia (2), Costa Rica (2) and Mexico (1) where Curbix SC 200 was applied according to the use pattern in Brazil, which represents the critical GAP.  Total ethiprole residue (parent, sulfone and amide), expressed as parent equivalents, in coffee (green bean) collected 58-60 days after the last application were 0.01 to 0.060 ppm.  Using the OECD MRL calculator and total ethiprole residues, the calculated tolerance for coffee (green beans) would be 0.09 ppm.  However Bayer is proposing a tolerance of 0.1 ppm in order to harmonize with a major exporter.

	Two processing studies, conducted in Colombia and Mexico, gave total ethiprole processing factors of: 1.2 and 1.1 respectively for roasted coffee and instant coffee.  The RAC tolerance of 0.1 ppm is therefore proposed for the processed commodities of roasted beans and instant coffee.]
 
B. Toxicological Profile

	1. Acute toxicity.  [Technical ethiprole (RPA 107382) shows a low order of acute toxicity with a rat oral LD50 greater than 5000 mg/kg, (Category IV), a rat dermal LD50 greater than 2000 mg/kg (Category III), and a rat inhalation LD50 greater than 5.2 mg/L (Category IV).  Technical ethiprole is a non-irritant in the eye and skin irritation studies in the rabbit, and is not a skin sensitizer.]

	2. Genotoxicty. [Ethiprole has been evaluated for genotoxicity in a battery of tests, including bacterial and mammalian cell gene mutation assays, in vivo and in vitro tests for clastogenicity, and an in vivo unscheduled DNA synthesis test.  All of these tests were negative and thus, ethiprole is not genotoxic.]

	3. Reproductive and developmental toxicity. [In a developmental toxicity study in rats, maternal and fetal NOAELs were 3 and 10 mg/kg/day, respectively.  The maternal LOAEL of 10 mg/kg/day was based on a transient decrease in body weight and increased liver weight, while the fetal LOAEL of 30 mg/kg/day was based on enlarged thymus and ossification delays in a few bones.  

In a developmental toxicity study with rabbits, the maternal and fetal NOAEL was 0.5 mg/kg/day.  The LOAEL of 2.0 mg/kg/day was based on reductions in maternal body weight gains and food consumption and ossification delays in a few bones in fetuses. 

In a 2-generation reproductive toxicity study, the reproductive NOAEL was the highest dose tested of 500 ppm.  For general systemic toxicity, effects in offspring and parents were observed at 500 ppm.  Parental toxicity consisted of lower body weights and increased liver and thyroid weights with associated microscopic changes.  Toxicity in offspring included lower body weights and delays in preputial separation and vaginal patency.  The NOAEL was 75 ppm for offspring and for parental/systemic toxicity.]

	4. Subchronic toxicity. [Ninety-day feeding studies were conducted in rats and dogs.  In dogs, body weight gain was severely affected at 200 ppm in males with only a slight effect on food consumption.  Body weight gains were also lower in males at 90 ppm and in females at 200 ppm.  One female at 200 ppm was sacrificed moribund on Day 24.  In rats, liver (hepatocellular hypertrophy) and thyroid (follicular epithelial hypertrophy/hyperplasia) were identified as target organs.  Histopathological changes in the thyroid were attributable to changes in thyroid hormones secondary to induction of liver enzymes.  Overall, the rat was the most sensitive species with a NOAEL of 20 ppm (1.2 and 1.5 mg/kg/day, males and females, respectively).]

      5. Neurotoxicity.  [Acute and subchronic neurotoxicity studies were conducted in rats.  The NOAEL of 25 mg/kg in the acute neurotoxicity study was based on minimal and transient changes in females (lower level of arousal and closed eyes) at 35 mg/kg.   In addition, at higher dose levels findings included chewing, decreases in landing foot splay, reduced activity and rearing counts, alterations in grip strength and reduced motor activity.  All findings attributable to treatment were observed 4 hours after dosing.  Animals were considered comparable to control at subsequent evaluations, and microscopic evaluation of selected nerve tissues revealed no changes.  In the subchronic study, no evidence of neurotoxicity was observed at 400 ppm, 28.7 mg/kg and 33.0 mg/kg, in males and females, respectively, the highest level tested.]

	6. Chronic toxicity. [In the combined chronic/carcinogenicity study in rats, microscopic changes were observed in the liver, thyroid, kidneys, and lungs.  These changes were observed mainly at 250 ppm and included: colloid mineralization, follicular cell hypertrophy/hyperplasia and adenomas in the thyroid; eosinophilic and basophilic tigroid foci of cellular alteration, bile duct hyperplasia and sclerosis and focal sinusoidal dilatation in the liver; foci of alveolar macrophages in the lungs; and an increase in severity of chronic nephropathy in the kidneys.  At 75 ppm, colloid mineralization and follicular cell hypertrophy were also observed in the thyroid.  Changes in the thyroid were attributable to an imbalance in thyroid hormones secondary to induction of liver enzymes.  The NOAEL was 20 ppm equivalent to 0.85 and 1.17 mg/kg/day in males and females, respectively.  In the mouse carcinogenicity study, the liver was the only target organ.  An increased incidence of hepatocellular adenomas was observed in high dose females only.  The NOAEL was 300 ppm in males (50.8 mg/kg/day) and 150 ppm in females (36.3 mg/kg/day).]

	7. Animal metabolism. [Livestock metabolism studies were conducted with phenyl ring labelled 14C-ethiprole in lactating goats and laying hens.  Complete reports of these studies were submitted with this petition.  In the hen, the majority of the administered dose was eliminated in the excreta, accounting for 87.79% and 90.89% in the low and high dose hen groups respectively. Ethiprole is initially metabolized in the laying hen via oxidation, reduction, and hydrolysis followed by additional metabolism pathways such as conjugation, oxidative de-alkylation, alkyl hydroxylation, etc. The main residue in all tissues, organs and egg yolks is the ethiprole sulfone RPA097973. In egg whites, dihydroxy-RPA097973 is the main component followed by RPA097973.

In the corresponding 14C-ethiprole study with lactating goats, the majority of the administered dose was eliminated in the urine and feces, accounting for 77.3% and 77.05% in the low and high dose groups respectively.  Parent ethiprole and the sulfide RPA107566 were the major components in both 72 and 168 hour high dose feces at 32 to 37% and 57 to 58% TRR, respectively; sulfone RPA097973 was also identified at <5% TRR in each sample.  Ethiprole was found to initially metabolize in the lactating goat via oxidation, reduction, and hydrolysis followed by additional metabolism pathways such as conjugation.  The main residue in all tissues and milk was ethiprole sulfone RPA097973.  Parent ethiprole can also transfer to milk and other tissues when administered at sufficiently high doses.

Based on the nature of the residue studies in goat and hen, the main residue in all tissues, egg and milk is determined to be parent ethiprole and its sulfone metabolite RPA097973, thus, these compounds were included in the analytical methods for analysis of animal matrices and in the tolerance expression.  Based upon the results of the cattle and hen feeding studies submitted with this petition, reasonable dietary burden calculations have been made and appropriate tolerances proposed for meat, milk poultry and egg commodities.

In the rat, ethiprole was initially metabolized via oxidation, reduction, and hydrolysis followed by additional metabolism pathways such as conjugation. In the rat, ethiprole was quickly absorbed and excreted with the bulk of the dose excreted by 48 h post dose. The major route of excretion was feces.  Tissue distribution of radioactivity was widespread with the highest levels found in kidney, lung, thyroid, liver, skin and fur, and adrenal gland.   The metabolite profiles in male and female animals were qualitatively similar following both single (low and high doses) and repeated dosing.  These results indicated that the metabolic pathway was unchanged following single or repeat administration of ethiprole.  Metabolism of ethiprole was extensive and occurred primarily via oxidation of the nitrile group, reduction of the sulfoxide group, or oxidation of the sulfoxide group which was then further metabolized and conjugated.]

	8. Metabolite toxicology. [In plant and livestock metabolism studies, the sulfone (RPA 097973) was the major metabolite.  In the pepper metabolism study, the amide (RPA 112916) appeared as a major metabolite in the edible portions.  Both of these metabolites were seen in the rat metabolism study and are considered to be similar in toxicity relative to the parent ethiprole.]

	9. Endocrine disruption. [The toxicology database for ethiprole is current and complete.  Studies in this database include evaluation of the potential effects on reproduction and development, and an evaluation of the pathology of the endocrine organs following short- or long-term exposure. These studies revealed no primary endocrine effects.]

C. Aggregate Exposure

	1. Dietary exposure. [An aggregate assessment of human exposure to ethiprole is not necessary because the only potential source for ethiprole exposure is food.  There are no residential use products, and residues are not anticipated in drinking water because applications are not made to crops in the U.S.]

	i. Food. [See the Safety determination section of this Public Summary below for an assessment of the acute and chronic risks due to ethiprole.]

	ii. Drinking water. [No assessment of human exposure to ethiprole through drinking water was necessary since ethiprole will not be applied in the United States.]

	2. Non-dietary exposure. [No assessment of non-dietary exposures is necessary for this petition since ethiprole will not be registered or applied in the United States.]

D. Cumulative Effects 

      [Section 408(b)(2)(D)(v) requires that the Agency must consider "available information" concerning the cumulative effects of a particular pesticide's residues and "other substances that have a common mechanism of toxicity." Available information in this context include not only toxicity, chemistry, and exposure data, but also scientific policies and methodologies for understanding common mechanisms of toxicity and conducting cumulative risk assessments. Although the Agency has some information in its files that may turn out to be helpful in eventually determining whether a pesticide shares a common mechanism of toxicity with any other substances, EPA does not at this time have the methodologies to resolve the complex scientific issues concerning common mechanism of toxicity in a meaningful way for most registered pesticides.]





E. Safety Determination

      1. U.S. population.  [i. Acute Risk.  Conservative Tier 1 acute dietary assessments were conducted with DEEM-FCID v4.02 assuming tolerance-level residues on all foods and 100% crop treated.  Estimated acute dietary exposures for the general U.S. population and select subpopulations have been calculated with DEEM-FCID assuming tolerance-level residues on all foods and 100% crop treated. The 95th percentile acute dietary exposure for the general U.S. population is 0.0059 mg/kg/d (4% aRfD).  Exposures less than the 100% aRfD indicate reasonable certainty of no harm from the consumption of food with tolerance-level residues of ethiprole.  ii. Chronic Risk.  Conservative Tier 1 chronic dietary assessments were conducted with DEEM-FCID assuming tolerance-level residues on all foods and 100% crop treated.  The chronic dietary exposure for the general U.S. population for ethiprole exposures through imported tea and rice is 0.0003 mg/kg/d (10% cRfD).  Exposures less than 100% cRfD indicate a reasonable certainty of no harm from the consumption of food with tolerance-level residues of ethiprole.]
         
      2. Infants and children. [i. Safety Factor for Infants and Children. It is the position of Bayer CropScience that the FQPA safety factor is not necessary because developmental toxicity and offspring toxicity NOAELs/LOAELs are well characterized; and the endpoints of concern used for overall risk assessments are appropriate for the route of exposure and population subgroups.  

ii.  Acute Risk. The acute dietary exposure for infants (<1 yr. old) (the most highly exposed subpopulation) is 0.0013 mg/kg/d (17% aRfD). Exposures less than the aRfD indicate a reasonable certainty of no harm from the consumption of food with tolerance-level residues of ethiprole.  

iii.  Chronic Risk.  The chronic dietary exposure for infants < 1 yr. old (the most highly exposed subpopulation) is 0.0012 mg/kg/d (41% cRfD).  Exposures less than the cRfD indicate a reasonable certainty of no harm from the consumption of food with tolerance-level residues of ethiprole.  Therefore, it can be concluded that there is a reasonable certainty that no harm will result to infants and children from aggregate, chronic exposure to ethiprole residues.]

F. International Tolerances 
      
      [Brazil has recently established an MRL of 0.1 ppm for coffee (green beans).  Canada currently maintains a default MRL of 0.1 ppm for ethiprole in coffee (green beans).  Several countries, including the EU member states, maintain a default MRL of 0.01 ppm for ethiprole in coffee (green beans).  There is currently no CODEX MRL for ethiprole in coffee.]
     

