Document ID: EPA-HQ-OPP-2015-0263-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-05-20T04:00Z

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

Interregional Research Project Number 4 (IR-4)

Petition Number, PP# 5E8350

	EPA has received a pesticide petition, PP# 5E8350, from Interregional Research Project Number 4 (IR-4), 500 College Road East, Suite 201W, Princeton, New Jersey, 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 the fungicide cyazofamid, 4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfonamide and its metabolite 4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile (CA), calculated as the stoichiometric equivalent of cyazofamid in or on the following raw agricultural commodity: Herb subgroup 19A at 90 parts per million (ppm);  Upon approval of the aforementioned tolerance, IR-4 requests to remove from 40 CFR 180.601, the established tolerance for residues of cyazofamid in or on basil, dried leaves at 90 ppm and basil, fresh leaves at 30 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

Plant metabolism. The plant metabolism of cyazofamid is understood for the purposes of this petition.  The proposed metabolic pathways in plants (tomato, potato and grape) are identical.  Nature of the residue studies showed that other than parent cyazofamid, no single identifiable residue represents more than about 7% of the total radioactive residue.  The nature of the residue studies showed that cyazofamid was the major identifiable residue with low levels of CCIM.  The tolerance expression for the proposed crops, will include parent, cyazofamid, and the metabolite CCIM. 

	2. Analytical method. Residues of cyazofamid and CCIM were extracted from samples (2.5 g for fresh chives; and 1 g for dried chives) with acetonitrile.  The combined extracts were partitioned with hexane and then reduced to near dryness.  The residues were dissolved in 20% acetonitrile/water and passed through a solid phase extraction column (SPE).  The residues were eluted with 60/40 acetonitrile/water and then diluted in 50/50 acetonitrile/water.  The samples were quantitated by LC/MS/MS.

	3. Magnitude of residues. Chives: A total of six (6) field trials and three (3) greenhouse trials were conducted on chives during the 2010 growing season.  Nine (9) foliar applications were applied at 7 (+1) day intervals at the target rate of 0.078 lb. a.i./A for a total of approximately 0.702 lb. a.i./A/season.  Chives were harvested at 0 day PHI.  One decline trial was included with sampling at 0, 3, 7, 10 and 14 days after the last application.  The results show that the maximum total residue (cyazofamid + CCIM) after nine applications of cyazofamid with a 0 day PHI in fresh chives was 3.6 ppm and in dried chives was 14.8 ppm.  (Basil is currently approved at the tolerances of 30 ppm for fresh and 90 ppm for dried basil.)

B. Toxicological Profile

	1. Acute toxicity.  Results from a battery of acute toxicity studies place technical cyazofamid in Toxicity Category IV for oral LD50, inhalation LC50 and eye irritation, and Category III for dermal irritation and dermal LD50.  Technical cyazofamid was determined to be a weak dermal sensitizer. In an acute neurotoxicity study, no treatment related effects were observed at any dose.  The NOEL was 2,000 mg/kg bw.

	2. Genotoxicty. A battery of five tests has been conducted to assess the genotoxic potential of technical cyazofamid.  Assays conducted included in vitro reverse gene mutation tests in bacteria and in vitro forward gene mutation test in a mammalian cell system, a chromosomal damage test in mammalian cells, a DNA repair test in bacteria, and an in vivo micronucleus test in mice. Cyazofamid did not elicit a genotoxic response in any of the studies conducted. 

	3. Reproductive and developmental toxicity. In a two-generation reproductive toxicity study, the only effects observed were body weight effects which were observed at 20,000 ppm in dams during gestation and lactation and in weanling pups.  No reproductive effects were observed.  The NOEL for reproductive effects was 20,000 ppm (1,338 mg/kg bw/day).  The NOEL for parental toxicity was 2,000 ppm (134 mg/kg bw/day).
In a rat developmental study, pregnant rats were dosed by gavage with cyazofamid from Days 0 to 19 of gestation.  There were no treatment-related effects observed in the study.  The NOEL for maternal effects was 1,000 mg/kg bw/day.  Due to the increased incidence of bent ribs, a reversible developmental anomaly, in fetuses treated at the highest dose, the developmental NOEL was set conservatively at 100 mg/kg bw/day. 
In a rabbit developmental study, pregnant rabbits were dosed by gavage with cyazofamid on Days 4 to 28 of gestation.  There were no treatment-related effects observed in the study.  The NOEL for maternal and developmental effects was 1000 mg/kg bw/day.
The developmental studies (prenatal developmental studies in rat and rabbit and the two generation reproduction study in rat) provided no indication of increased sensitivity of rats or rabbits from in utero or post-natal exposure to cyazofamid.  Cyazofamid is not a developmental or reproductive toxicant.

	4. Subchronic toxicity. The oral toxicity of cyazofamid was investigated in rats and dogs in 13-week studies.  The exposure was by dietary administration for the rats and by capsule for the dogs.  There were no treatment-related effects observed in dogs up to 1,000 mg/kg bw/day which was the highest dose tested.  In rats, treated at 5,000 ppm there was a treatment related increase in kidney and liver weights and increased observation of basophilic tubules.  The latter was observed only in males.   The NOEL was 500 ppm which was equivalent to a dosage of 29.9 mg/kg bw/day to males and 33.3 mg/kg bw/day to females.

	5. Chronic toxicity. A combined chronic and oncogenicity study was conducted in rats.  Cyazofamid was administered continuously for a period of 104 weeks to male and female Fischer rats.  Cyazofamid was not carcinogenic in this study.  The NOEL for chronic effects was 5000 ppm (171 mg/kg bw/day).
In a long-term feeding study, mice were dosed with cyazofamid in the diet for 78 weeks.  There was no evidence of carcinogenicity.  The NOEL was 700 ppm (94.8 mg/kg bw/day for males) based on increased incidence of skin lesions in the high dose animals.
In a chronic dog study, four groups of six dogs/sex/group received cyazofamid via capsule for 52 weeks. The NOEL was determined as 200 mg/kg bw/day based on increased cysts in parathyroids in both sexes and increased pituitary cysts in females at the LOAEL of 1,000 mg/kg bw/day.

	6. Animal metabolism. Studies on the metabolism of cyazofamid in animals using radioactive test material have been conducted with cyazofamid, labeled with [14]C in two positions, the benzene [[14]C-Bz]- or imidazole [[14]C-Im] position.  Absorption is rapid, but the percentage of Cyazofamid absorbed after an oral dosage decreases as the dosage is increased. All absorbed radiocarbon is rapidly eliminated with urinary and biliary elimination of radiocarbon nearly complete within 24 hours. The metabolic pathway of cyazofamid includes the rapid hydrolysis of the dimethylsulfonamide group and the oxidation of the benzyl methyl group.

	7. Metabolite toxicology. Comparison of the metabolism of cyazofamid by plants and in animals indicates that a number of the identified metabolites are common to both plants and animals but metabolism in plants is more extensive than in animals.  The data indicate that the final products of the metabolism of cyazofamid in animals and plants represent differences in the extent of metabolism.  Several of the metabolites resulting from cyazofamid are similar in plants and animals and, therefore, have already been evaluated toxicologically.

	8. Endocrine disruption. An evaluation of the potential effects on the endocrine systems of mammals has not been determined; however, no evidence of such effects was reported in subchronic, chronic or reproductive toxicology. There was no observed pathological finding of the endocrine organs in these studies, and there were no reproductive effects at the maximum dose tested of 20,000 ppm.  There is no evidence at this time that cyazofamid causes endocrine effects.

C. Aggregate Exposure

	1. Dietary exposure.  Potential dietary exposures from food were estimated for all proposed and established tolerances for the crops listed below, using the Dietary Exposure Evaluation Model-Food Consumption Intake Database (DEEM-FCID[TM]) version 2.16, and percent crop treated of 100%.  The following raw agricultural commodities were included: beans, snap and lima; leafy greens (subgroup 4A); brassica (cole) leafy vegetables (crop group 5) including turnip greens; carrots; cucurbits (crop group 9); fruiting vegetables (crop groups 8-10); tuberous and corm vegetables (subgroup 1C); grapes; basil; chives; and hops.  
For chronic dietary exposure, the chronic reference dose (RfD) of 0.95 mg/kg bw/day was proposed by EPA for humans, based on the NOAEL from the mouse carcinogenicity study (94.5 mg/kg bw/day) and dividing by an uncertainty factor of 100.  The chronic population adjusted dose (cPAD) is also 0.95 mg/kg bw/day since the FQPA safety factor is 1 for cyazofamid.
For acute dietary exposure, the acute RfD of 1.0 mg/kg bw/day was based on the NOAEL of 100 mg/kg bw/day from the rat developmental toxicity study adjusted by the uncertainty factor of 100.  The acute population adjusted dose (aPAD) is also 1 mg/kg bw/day since the cyazofamid FQPA safety factor is 1.

	i. Food. Tier 1 chronic and acute dietary exposure analyses were conducted for cyazofamid in/on the crops noted above to determine the exposure contribution of these commodities to the diet and to ascertain the chronic and acute risk potential.  The estimates were based on current and proposed tolerance level residues for all crops, potato and tomato processing studies, conservative market share assumptions of 100% crop treated, and consumption data from the USDA's CSFII (1994 through 1996 and 1998) continuing survey of food intake.  Since specific processing studies demonstrated that residues were unlikely to concentrate in processed commodities, no adjustment for processing factors was necessary.
Even using all of the worst case exposure scenarios listed above, the Tier 1 chronic dietary (food + drinking water) exposure estimates resulted in an estimated exposure for the general U.S. population of 0.007364 mg/kg bw/day.  This exposure corresponds to 0.8% of the cPAD of 0.95 mg/kg bw/day.  The highest exposure estimate calculated was for the subgroup, children 1-2 years old.  This exposure was determined to be 0.012948 mg/kg bw/day (1.4% of the cPAD). 
A Tier 1 acute dietary exposure assessment was performed for the subpopulation of females aged 13-49 years old only, since the only endpoint of concern was from the rat prenatal developmental study.  The acute dietary exposure estimate for females aged 13-49 is 0.022706 mg/kg bw/day, well below HED's level of concern at the 95th percentile.   This is equivalent to 2.27% of the aPAD.

It can be concluded that acute or long-term dietary exposure to cyazofamid through residues on treated beans, snap and lima, leafy greens (subgroup 4A), brassica (cole) leafy vegetables (Crop Group 5), including turnip greens, carrots, cucurbit vegetables (Crop Group 9), fruiting vegetables (Crop Group 8-10), tuberous and corm vegetables (subgroup 1C), grapes, herbs (Crop Subgroup 19A), and hops, should not be of cause for concern.

	ii. Drinking water. Since cyazofamid is intended for application outdoors to turf, ornamentals, and field grown crops, the potential exists for parent and or metabolites to reach ground or surface water that may be used for drinking water.  EPA assumed drinking water concentrations of 133 ppb and 136 ppb for the chronic and acute assessments, respectively, based on modeling of potential surface water residues of CTCA (the terminal degradate of cyazofamid) for the turf/ornamental use.  Because the application rates for the proposed uses are lower than the rate for turf/ornamentals, the turf use represents the worst-case for potential drinking water residues.  Therefore, these estimates of drinking water were directly entered into the dietary exposure model.

	2. Non-dietary exposure. 

Cyazofamid can be applied to commercially treated residential turf and ornamentals only.  Therefore, non-occupational exposure of cyazofamid to the general population is not expected, however, postapplication exposure is possible.  For Dermal Short-Term exposure, no toxicity was found at 1000 mg/kg in a 28-day dermal toxicity study, therefore, in the absence of any hazard identified for children, a risk assessment was not necessary.  The residential dermal MOE for adults of 1,100, based on 2 hours of extensive contact with the turf, was used to calculate the adult short-term aggregate risk assessment in the EPA assessment. EPA calculated non-occupational/residential MOEs for the day of application.  
The post application children's MOE (including incidental oral exposures) from residential lawns is 1,600.  All MOEs, including children's aggregate, are greater than 100, and therefore, are not of concern.  

D. Cumulative Effects

Cyazofamid is a cyanoimidazole fungicide.  Since there are no other members of this class of fungicides, it is considered unlikely that cyazofamid would have a common mechanism of toxicity with any other pesticide in use at this time.

E. Safety Determination

	1. U.S. population. Dietary and occupational exposure will be the major routes of exposure to the U.S. population. Ample margins of safety have been demonstrated for both situations. For the general U.S. population, the chronic dietary exposure to cyazofamid is 0.007364 mg/kg bw/day, which utilizes less than 1% of the RfD for the overall U.S. population, assuming 100% of the crops are treated. A cancer dietary assessment was not conducted because this product has been classified as "not likely to be carcinogenic to humans."
An acute aggregate risk assessment was conducted for the population subgroup of concern, females 13-49 years old.  Since an appropriate endpoint for the general population was not identified, a corresponding assessment is not required for any other population subgroup.  For this subgroup, the acute dietary (food and drinking water) risk assessment reported above as 0.022706 mg/kg bw/day (95th percentile), 2.27% of the aPAD, represents the acute aggregate risk since the dietary route alone is relevant for acute exposure and risk assessment.
The short-term aggregate risk is made up of average dietary exposures from food and drinking water sources as well as from dermal and oral residential exposure.   Potential inhalation exposure was not considered since it is negligible when assessing re-entry risks.  The aggregate short-term MOE for the US general population is 1018.

Using only pesticide handlers exposure data base (PHED) data levels A and B (those with a high level of confidence), the margins of exposure (MOE) for occupational exposure are 341 to 98,000 for use on turf and ornamentals and of 23,000 to 220,000 for use on crops.  Based on the completeness and reliability of the toxicity data and the conservative exposure assessments, there is a reasonable certainty that no harm will result from the aggregate exposure of residues of cyazofamid including all anticipated dietary exposure and all other non-occupational exposures.

	2. Infants and children. As noted above, chronic dietary exposure of the most highly exposed subgroup in the population, children, 1-2 years old, is 0.022706 mg/kg bw/day or 2.27% of the RfD.  The short-term aggregate risk MOE for children (food and residential) is 1325. Thus, it can be concluded that there is reasonable certainty that no harm will result to infants and children from acute or chronic exposure to Cyazofamid.

Based on the completeness and reliability of the toxicity data, the lack of toxicological endpoints of special concern, the lack of any indication of greater sensitivity of children, and the conservative exposure assessment, there is a reasonable certainty that no harm will result to infants and children from the aggregate exposure to residues of cyazofamid from all anticipated sources of dietary and non-occupational exposure. 

F. International Tolerances

Presently, there is no Codex maximum residue levels (MRLs) established for residues of cyazofamid on any crop.  The following Canadian tolerances have been established: Carrots, 0.09 ppm; Potatoes, 0.02 ppm; and Tomatoes (Import), 0.2 ppm; Cucurbits, 0.1 ppm; Grape (Import), 1.2 ppm; and Spinach, 9.0 ppm.