Document ID: EPA-HQ-OPP-2012-0796-0003
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: Tony Kish, 703-308-9443

Chemtura Corporation

[Insert petition number]

	EPA has received a pesticide petition ([insert petition number]) from Chemtura Corporation, 199 Benson Rd, Middlebury, CT 06749 requesting, 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

   
   	1. by establishing a tolerance for residues of

	Ipconazole (2-[(4-chlorophenyl)methyl]-5-(1-methylethyl)-1-(1H-1,2,4-triazole-1-ylmethyl)cyclopentanol) from the treatment of seed prior to planting in or on the raw agricultural commodity Legume Vegetables (succulent or dried), Crop Group 6 at 0.01 parts per million (ppm) and the deletion of the tolerance for "Pea and bean, dried shelled, except soybean, subgroup 6C".  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 nature of the residues of ipconazole in wheat grown from seeds treated with ipconazole is adequately understood.  The major residues found are triazolylalanine, triazolylpyruvate and triazolylacetic acid.  Minor metabolites include tert-hydroxy-isopropyl-ipconazole and hydroxy-ipconazole-glycoside.  A soybean metabolism study conducted recently also shows the presence of these metabolites at low levels. The metabolism of ipconazole in plants is therefore adequately understood. The residue of concern for tolerance purposes is ipconazole only.

	2. Analytical method.  Analytical methods have been developed, validated (including radiovalidation), and independently validated for the determination of ipconazole, triazolylalanine, triazolylacetic acid and triazolylpyruvate in wheat forage, hay, straw, and grain and in corn forage, cobs and straw using liquid chromatography-tandem mass spectrometry (LC-MS/MS).  The limit of quantitation of 0.01 ppm for each analyte in each matrix was determined as the lowest level validated. It has further been validated in soybean RACs (succulent seed with pod, succulent seed without pod, and soybean seed) on ipconazole, with a limit of quantitation of 0.01 ppm.

	3. Magnitude of residues. Crop residue trials were conducted on soybeans at five locations in 2007 and 2008 in the USA at an exaggerated rate of 5X. RACs of succulent 

seed with pod, succulent seed without pod, and soybean seed were analyzed for ipconazole. No quantifiable residues of ipconazole were found in any of the RACs, at a limit of quantitation of 0.01 ppm. Chemtura is therefore proposing a tolerance of 0.01 ppm, based on field trials on soybeans at the exaggerated rate of 5X. 

B. Toxicological Profile   

	1. Acute toxicity.  Ipconazole Technical and Ipconazole end-use product Rancona(R) 3.8 FS have low acute oral, dermal, and inhalation toxicity in laboratory animals.  The oral LD50 in rats for Rancona 3.8 FS is 5.3 g/kg for males and 3.7 g/kg for females. The oral LD50 is 1.3 g/kg for male rats and 0.89 g/kg in female rats for the Ipconazole Technical.  The oral LD50 for Ipconazole Technical in male mice is 0.53 g/kg and 0.47 g/kg for female mice. The dermal LD50 for Ipconazole Technical in rats is greater than 2 g/kg and the dermal LD50 for Rancona 3.8 FS in rats is greater than 5 g/kg. The 4 hour inhalation LC50 in rat for Ipconazole Technical and Rancona 3.8 FS are greater than 1.88 and 2.59 mg/l, respectively.  In the eye irritation studies, Rancona 3.8 FS and Ipconazole Technical were all mildly irritating to rabbit eyes.  Rancona 3.8 FS was found to be slightly irritating to the skin of rabbits. Ipconazole Technical was found to be non-irritating to the skin of rabbits. Ipconazole Technical and Rancona 3.8 FS were non-sensitizing on the skin of guinea pigs.

	2. Genotoxicty.  Ipconazole Technical was evaluated and found to be negative in the Ames Reverse Mutation, CHO HGPRT Mammalian mutation, Bacillus subtilis DNA Repair, Chinese Hamster Lung Chromosome Aberration and Mouse Micronucleus assays.

	3. Reproductive and developmental toxicity. Rabbit Teratology Study: Ipconazole was evaluated in a rabbit teratology study at dose levels of 0, 2, 10 and 50 mg/kg/day. At the 50 mg/kg/day, there was a tendency for reduction of maternal body weight gain and food consumption during dosing. A tendency for reduction of fetal body weights and placental weights were seen at the high dose (50 mg/kg/day) when compared to the concurrent controls. There was no increase in fetal variations or malformations at any dosage level. The NOEL for maternal and developmental toxicity was 10 mg/kg/day
Rat Teratology Study: Ipconazole was evaluated in a teratology study with the Sprague Dawley rat at dose levels of 0, 3, 10 and 30 mg/kg/day. At the 30 mg/kg/day dose level, there was a statistically significant reduction in maternal body weight gain and food consumption during dosing. There was a statistically significant reduction in fetal body weights at the high dose level (30/mg/kg/day) with an increase in the incidence of visceral and/or skeletal variations. There was no increase in fetal malformations at any dose level. The NOEL for maternal and developmental toxicity was 10 mg/kg/day.
Rat Reproduction Study: Ipconazole was evaluated through dietary administration to two successive generations of Han Wistar rats at 0, 30, 100 or 300 ppm. The no-observed adverse- effect-level (NOAEL) for the reproductive performance of the FO and F1 adults 

was 300 ppm. The NOAEL for the general toxicity of the FO and Fl females was 100 ppm, in view of minor but statistically significant reductions in bodyweight gain during gestation and food consumption during gestation and lactation. The NOAEL for the growth of the offspring was 100 ppm, in view of reduced weight gain seen among F1males at 300 ppm, but was 300 ppm for the survival and general condition of the Fl and F2 offspring.

	4. Subchronic toxicity. Thirteen Week Rat Feeding Study: Ipconazole was fed to male and female Fischer-344 rats for thirteen weeks at dietary concentrations of 30, 120, 500 and 2000 ppm. At the 500 and 2000 ppm dosage levels, there was a reduction in body weight gain and food consumption. Effects were seen on numerous clinical chemistry parameters at 500 and 2000 ppm. Histopathological effects observed at 500 and 2000 ppm include erosion, hyperplasia, and hyperkeratosis of the stomach, hyperkeratosis of the esophagus and hepatocellular swelling. The 500 ppm dose group had an increase in liver and salivary gland weight. Effects at 2000 ppm included a decrease in red blood cell concentration and hepatocellular hyperplasia. No treatment related effects were seen on neurobehavior in a standard Functional Observation Battery conducted at weeks 8 and 13. No effects were seen on neuropathology. The NOAEL for subchronic toxicity in rats was 120 ppm (7.22 mg/kg/day). 

Thirteen Week Rat Feeding Study: Ipconazole was administered for 90 days to Han Wistar rats at dietary concentrations of 0, 30, 70, 150, and 300 ppm in females or 600 ppm in males.  At the highest dietary concentration there was evidence of non-specific toxicity.  The principal target organ was the stomach, where there were changes in response to an irritant property of the test material at 150 ppm or more. In addition to the standard parameters evaluated in the guideline subchronic oral study, neurobehavioral testing was performed on 10 animals/sex/dose at weeks 2, 4, 8, and 13. Changes in the kidney and uterus were considered secondary to the non-specific toxic effects.  This study provided no evidence that Ipconazole was neurotoxic.  In considering dietary concentrations for the combined toxicity and carcinogenicity study in Han Wistar rats, the findings in the stomach preclude the use of levels of 300 ppm or more and indicate that the highest concentration in the combined toxicity and carcinogenicity study should be in the region of 200 ppm.  No toxicologically significant findings were evident at 30 or 70 ppm and, as a result, the no-observed-adverse-effect level (NOAEL) in this study was considered to be 70 ppm, equivalent to 5.8 mg/kg/day in males and 7.0 mg/kg/day in females.

Subchronic Oral Toxicity Study:  Three groups of nine male and nine female mice (CD-1 mice) received Ipconazole orally, via the diet, at concentrations of 30, 150 or 500 ppm. A similarly constituted control group received untreated diet throughout the treatment period. There were no signs related to treatment. Biochemical investigation of the plasma after 13 weeks of treatment revealed slightly high aspartate amino-transferase activities in females receiving 500 ppm, low plasma cholesterol concentrations in animals receiving 150 or 500 ppm and low total protein and albumin concentration in females receiving 500 ppm. Liver weights were high in males and females given 500 ppm. Macroscopic examination after 13 weeks of treatment revealed pale livers for one male and one female given 500 ppm. Histopathological findings related to treatment comprised hepatocyte vacuolation in the livers of males given 150 ppm and males and females given 500 ppm. It is concluded that dietary administration of Ipconazole, a fungicide, to CD-1 mice for 13 weeks at concentrations up to 500 ppm was well tolerated, though there was non-specific toxicity at 500 ppm. Changes in the liver were either adaptive (hypertrophy) or toxic (fatty vacuolation) and in males given 500 ppm there were changes in the stomach in response to irritation. The no-observed-adverse-effect-level (NOAEL) in this study is considered to be 30 ppm (equivalent to 4.4 mg/kg/day in males and 5.1 mg/kg/day in females).

Thirteen Week Dog Feeding Study: Ipconazole was fed to male and female Beagle dogs for thirteen weeks at dietary concentrations of2, 10 and 40 mg/kg/day. The target organs were identified as the liver and eyes (lens). At dosage levels of 10 and 40 mg/kg/day there was a lens fiber anomaly in males as well as clinical signs that were attributable to the irritant potential of ipconazole presented by reddening of gums, ears, muzzle, eyes and neck. Liver weights were increased at 40 mg/kg/day and centrilobular hepatocellular hypertrophy and bile duct proliferation were seen. The NOAEL for subchronic toxicity in dogs was 2 mg/kg/day).

28 Day Rat Inhalation: Sprague-Dawley rats were exposed for 6 hours/day to 0, 100, 300 or 1000 mg/m3 of Ipconazole for 5 days/week for 4 consecutive weeks.  Animals could not tolerate the 1000 mg/m3 and this exposure level was terminated after the 12th exposure; animals were subject to a 2 week recovery period.  Treatment related effects included decreased body weight gain in male at the 100-1000 mg/m3 and in females at 1000 mg/m3.  Histopathologic changes included hyperplasia, hyperkeratosis, and/or metaplasia of epithelium of the esophagus, stomach, hard palate at 100-1000 mg/m3; larynx at 30-1000 mg/m3; and skin at 300-1000 mg/m3.  Hepatocellular hypertrophy in the 100-1000 mg/m3 females and 1000 mg/m3 males was associated with liver weight increase.  Liver changes also resolved following the recovery period in the 1000 mg/m3 animals.  The NOAEL for systemic toxicity was 30 mg/m3 while the NOAEL for upper respiratory tract and upper digestive tract (portal of entry) was < 30 mg/m3.

28 Day Rat Dermal: Male and female CD[(R)] [Crl:CD[(R)](SD)] rats were observed for subchronic toxicity following 4 weeks of 5 days/week dermal dosing for 6 hours each day at dose levels of 0, 10, 150, and 1000 mg/kg/day.  Erythema was observed at 1000 mg/kg/day in males and females during the last 2 weeks of the study.  Microscopically, test article-related lesions were observed in the treated skin in some treated animals at all dose levels and consisted of minimal to mild epidermal hyperplasia and hyperkeratosis.  Minimal to moderate esophageal, pharyngeal, and laryngeal hyperkeratosis and minimal to mild hyperkeratosis was observed within the non-glandular portions of the stomach at all dose levels; interpreted to be irritation due to inadvertent oral ingestion of the test article.  On the basis of the results of this study, the no-observed-adverse-effect-level (NOAEL) is considered to be 150 mg/kg/day.  

	5. Chronic toxicity. Dog Chronic Feeding Study: lpconazole was administered in capsules to male and female Beagle dogs for one year at concentrations of 1.5, 5 and 20 mg/kg/day. At 5 or 20 mg/kg/day there was reddening of the skin and at 20 mg/kg/day there was some non-specific toxicity in two females and the target organs were identified as the liver, eyes (lens) and adrenal. lpconazole exerts its antifungal action by the inhibition of sterol synthesis. The NOAEL for chronic toxicity in dogs 1.5 mg/kg/day.
Rat Chronic Feeding/Oncogenicity Study: The chronic toxic and carcinogenic potential of ipconazole, when administered to male and female HsdBrl Han: Wist (Han Wistar) rats, via the diet, was assessed over a period of 52 and 104 weeks. The initial dietary concentrations given to these groups were 0, 30, 80, 200 or 300 ppm.  However, the dietary concentrations given to females in the 200 and 300 ppm groups were reduced from Week 2 to 120 and 200 ppm, respectively, following advice from the US EPA. Treatment caused only an initial non-specific toxic response at 300 ppm. The histopathological examination did not reveal any neoplastic or non-neoplastic change. The no-observed-adverse-effect level (NOAEL) was concluded to be 300 ppm in the males (equivalent to an overall mean achieved dosage of 13.3 mg/kg/day) and 200 ppm in the females (equivalent to an overall mean achieved dosage of 12.6 mg/kg/day). 
Mouse Oncogenicity Study: Ipconazole was not oncogenic when administered in the diet to CD-I mice for eighteen months at concentrations of 15, 175 or 350 ppm. Treatment related effects included reduced body weight gain in females at 350 ppm. There were treatment-related non-neoplastic findings in the liver of animals given 175 or 350 ppm and in the stomach of females given these dietary concentrations, though there was no evidence of treatment-related neoplastic change. Consequently, the no-observed-adverse-effect level (NOAEL) in this study was concluded to be 15 ppm (equivalent to an overall mean achieved dosage of 1.9 mg/kg/day in males and 2.3 mg/kg/day in females).

	6. Animal metabolism. Pharmacokinetic parameters in the rat: Following single oral doses of [14C-benzyl methylene]ipconazole or [14C-triazole]ipconazole at levels of 2 and 100 mg/kg, greater than 90% of the radioactivity was eliminated in urine and feces within 72 hours. Excretion was mainly via the feces and was higher in male rats than in females. Urinary excretion was higher in females than in males. Excretion and retention of radioactivity during 0- 120 hours after the final dose following administration of 14 consecutive daily oral doses of 14C-[benzyl methylene]ipconazole was also investigated and excretion was rapid with greater than 90% of the dose excreted within 48 hours after the final dose. There were no substantial differences in excretion patterns between single and repeat low level oral doses. In bile duct-cannulated rats, absorption was higher at the low dose compared to the high dose and higher in male rats than in females. Bile was an important route of excretion. After administration of [14C-benzyl methylene]ipconazole at 2 mg/kg, no major differences in pharmacokinetic parameters were observed between the sexes apart from Tmaz, which occurred later in male rats. After administration of [14Ctriazole] ipconazole, lower Cmax and AUC parameters were observed for females relative to males. There were no sex differences in the time taken to reach Cmax or the terminal half life. Following the administration of single oral doses of 100 mg/kg [14C-benzyl]ipconazole, both Cmax, and AUC increased in comparison to the 2 mg/kg dose. After 14 consecutive daily doses of [14C-benzyl methylene]ipconazole at 2 mg/kg, exposure was higher in males than in females. Tmax occurred at 1 hour for both sexes which was earlier in males than after a single dose. The terminal half life of radioactivity was longer after repeated oral doses indicating that changes in clearance and/or volume of distribution of radioactivity occurred during repeated dosing. In all cases, T 112 was shorter for plasma than whole blood, indicating a transfer of radioactivity into red blood cells. After repeated oral daily dosing, the whole blood to plasma ratio was increased by approximately two fold thus indicating an increased distribution of radioactivity into the red blood cells.

	7. Metabolite toxicology.  Metabolites from the goat metabolism study essentially matched those produced in the rat. In addition to triazole, intact ipconazole metabolites were characterized as further oxidized and conjugated. In addition, cyclization occurred to produce both hemiacetals and lactones. In plants, intact ipconazole metabolites were also found in the rat. In addition to intact metabolites, wheat and soybean produced triazole conjugates - triazolylalanine, triazolylpyruvic acid and triazolylacetic acid. Although not produced in the rat, triazolylalanine, triazolylacetic acid, and by inference, triazolylpyruvic acid, have been evaluated in a recent human health risk assessment for triazole-derived fungicides (EPA, Memorandum entitled, " I ,2,4-Triazole, Triazole Alanine, Triazole Acetic Acid: Human Health Aggregate Risk Assessment in Support of Reregistration and Registration Actions for Triazole-derviative Fungicide Compounds", dated February 7, 2006. In this risk assessment, it was assumed that triazole conjugates were all toxicologically equivalent to triazolylalanine. It was concluded that the risk from these metabolites was below HED's level of concern.

	8. Endocrine disruption.  There are no known reported adverse reproductive or developmental effects in domestic animals or wildlife as a result of exposure to this chemical. A standard battery of required toxicity tests have been conducted on ipconazole. No effects were seen in the reproduction or teratology studies to indicate that ipconazole has an effect on the endocrine system.

C. Aggregate Exposure  

	1. Dietary exposure.  Based on dietary, drinking water, and non-occupational exposure assessments, there is reasonable certainty of no harm to the US population, any population subgroup, or infants and children from chronic exposure to ipconazole.

	i. Food.  Chronic dietary exposures were estimated utilizing the Dietary Exposure
Evaluation Model software with Food Commodity Intake Database (DEEM-FCID) version 3.15.  All crops were assumed to be 100% treated. For the general US population, the estimated chronic dietary exposure is 0.3% of the cPAD. The most highly exposed subpopulation, children 1-2 years, has an estimated total ipconazole exposure equal to 0.7% of the cPAD. The total chronic dietary exposure associated with proposed uses of ipconazole on legume vegetables (crop group 6) has been demonstrated to be less than the cPAD, and are therefore not of concern. It is considered that this assessment is highly conservative because it includes tolerance level residues and 100% crop treated in the proposed crops.

	ii. Drinking water.  Exposure to ipconazole and potential residues in drinking water is expected to be negligible. The maximum application rate for ipconazole on an area basis is that for wheat at 0.00223 lb ai/A. This value is derived from an application rate on seed of 2.5 g ai/100 kg seed and a planting rate of 100 kg seed per hectare. Surface and ground water impacts from such a low rate seed treatment use are expected to be negligible. Screening level water modeling using SCI-GROW for ground water and FIRST for surface water demonstrate that the annual concentration in ground water is 0.05 ppb in ground water and 1.8 ppb in surface water. At these very low concentrations, exposures from drinking water will be negligible for all subpopulations. Therefore, it is not necessary to include potential residues in drinking water for this assessment. This is consistent with EPA practice, which generally does not include estimates of residues in drinking water for seed treatment uses.

	2. Non-dietary exposure. Food uses described in this petition are strictly agricultural, and will not add to any residential non-dietary exposure that may exist.

D. Cumulative Effects

	Ipconazole is a member of the triazole-containing class of pesticides. Although
conazoles act similarly in plants (fungi) by inhibiting ergosterol biosynthesis, there is no
relationship in their mechanism of toxicity in mammals. There is no evidence to indicate that conazoles share a common mechanism of toxicity and the EPA is still investigating on the feasibility of a cumulative risk approach based on a common mechanism of toxicity.

E. Safety Determination

	1. U.S. population.  Chronic Risk. The chronic Population Adjusted Dose (cPAD) of 0.015 mg/kg bw/day was based on the NOAEL of 1.5 mg/kg/day from the 1 year dog study and a 100x uncertainty factor and a 1x FQPA safety factor. The chronic dietary exposure to the U.S. population (total) was 0.000043 mg/kg/day or 0.3% of the cPAD.

	2. Infants and children.  Chronic Risk. The chronic dietary exposure to infants was 0.000068 mg/kg bw/day, or 0.5% of the cPAD.  The chronic dietary exposure to children 1 -  2 years old, the most sensitive group, was 0.000108 mg/kg bw/day, or 0.7% of the cPAD. Therefore, chronic aggregate exposure from ipconazole is not expected to exceed the cPAD.

F. International Tolerances

            No Codex MRLs have been established for the requested uses. Canada has established an MRL of 0.01 ppm for dried shelled pea and bean, except soybean (Crop Subgroup 6C); cereal grains (Crop Group 15, except rice); dry soybeans and peanuts. Ipconazole is currently registered in Argentina, Australia, Belarus, Bolivia, Bulgaria, Canada, China, Czech Republic, France, Hungary, Italy, Japan, Kazakhstan, Mexico, Moldova, Poland, Romania, Russian Federation, Ukraine, United Kingdom, Uruguay
 and the United States.