**EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR**

**PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA**  **Registration Division contact:**  **Laura Nollen , (703) 30**  **5 -**  **7390 Interregional Resea**  **rch Project Number 4 (IR -**  **4) Petition # 1E7929**  EPA has received a pesticide petition , PP# 1E7929, from 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 c yazofamid, 4
- chloro
- 2
- cyano -N,N
- dimethyl
- 5
- (4
- methylphenyl )
- 1 H
imidazo le
- 1
- sulfonamide (CA) and its metabolite CCIM, 4
- chloro
- 5
- (4
- methylphenyl )
- 1 H
- imidazole
- 2
- carbonitrile (CA) , expressed as cyazofamid in or on the following raw agricultural commodities : b ean, succulent, at 0. 4 parts per million (ppm) ; b ean, succulent, s hel led at 0.0 7 ppm; l eafy greens subgroup 4A at 9 .0 ppm; b asil, f resh leaves at 3 0 .0 ppm; b asil, dried leaves at 80.0 ppm; v egetable, tuberous and c orm , subgroup 1C at 0.02 ppm; and v egetable, f

ruiting, group 8
- 10 at 0
. 4 0 ppm. Upon approval of the aforementi oned tolerances, this petition additionally proposes to amend 40 CFR part 180.601 by removing the established tolerance s for resides of cyazofamid in or on the following commodities : spinach at 9.0 ppm; potato at 0.02 ppm; vegetable, fruiting, group 8 at 0 .40 ppm; and okra at 0.40 ppm. These tolerances are being proposed to be removed, as they will be superseded by inclusion in crop group or subgroup tolerances. EPA has determined that the petition contains data or information regarding the elements set for th 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 sh owed 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. Th e 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 (5 g for l eaf lettuc e, head lettuce , snap beans & lima beans ; 2.5 g for fresh basil ;2

and 1 g for dried basil ) with acetonitrile. The combined extracts were partitioned with hexane and then reduced to near dry ness . The residues were dissolved in 20% acetonitrile/water and pa ssed through a solid phase extraction column (SPE). The residues we re eluted with 60/40 acetonitrile/water and then diluted in 50/50 acetonitrile/water. The samples were quantitated by L C/MS/MS. 3. Magnitude of residues. The results from 21 field tri als (10 on head lettuc e and 11 on leaf lettuce) conducted during the 200 8
- 2009 growing season show that the maximum total residue (cyazofamid + CCIM) after one directed application to the seed or transplant at the time of planting and an additional five to seven applications of cyazofamid at approximately 7 d ay intervals with a 0 day

P HI was 2.0 ppm in head lettuce and 4.5 ppm in leaf lettuce
. The results from 8 field trials conducted on lima beans in 2009 show that the maximum total residue (cyazofamid + CCIM) after six or seven applications of cyazofamid at approximately 7 day intervals with a 0 day

P HI was 0. 057 ppm. The results from 8 field trials conducted on snap beans in 2007 show that the maximum total residue (cyazofamid + CCIM) after six or seven applications of cyazofamid at 6
- 9 day intervals with a 0 day P HI was 0.23 ppm. The results from 4 field trials and 2 greenhouse trials conducted on basil during the 2009
- 2010 growing season show that the maximum total residue (cyazofamid + CCIM) after nine applications of cyazofamid at 7 (±1) day intervals with a 0 day

P HI in fresh basil was 15.1 ppm and in dried basis was 45 ppm . B. Toxicological Profile 1. Acute toxicity. Results from a battery o f acute toxicity

s tudies place technical cyazofamid in Toxicity

C ategory IV for oral LD 50 , inhalation L C 50 and eye irritation, and Category I II for dermal irritation and dermal LD 50 . T echnical cyazofamid was determined to be a weak dermal sensitizer. Inan acute neurotoxicity s tu dy , no treatment related effects were observed at any dose. The NOELwas 2,000 mg/kg bw. 2. Genotoxicty. A battery of five tests has been conducted to assess the genotoxic potential of technical cyazofamid. Assay s conducted included in vitro reverse gene mutation tests in bacteria and in vitro forward gene mutation test in a mammalian cell sy stem, 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. Ina two - generation reproductive toxicity s tudy , the only

e ffects observed were body w eight effects which were observed at 20,000 ppm in dams during gestation and lactation and in weanling pups. N o reproductive effects were observed. The NOEL for reproductive effects was 20,000 ppm (1,338 mg/kg bw/day). The NOEL for parental toxicity w as 2,000 ppm (134 mg/kg bw/day). In a rat developmental study , pregnant rats were dosed by g avage with cyazofamid from Day s 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 incid ence of bent ribs, a rev ersible developmental anomal y, in fetuses treated at the highest dose,3

the developmental NOEL was set conservativel y at 100 mg/kg bw/day
. In a rabbit developmental study, pregnant rabbits were dosed by g avage with cyazofamid on Day s 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 generati on reproduction study i n rat) provided no indication of increased sensitivity o f rats or rabbits from in utero or post - natal exposure to cyazofamid. C yazofamid is not a developmental or reproductive toxicant. 4. Subchronic toxicity. The oral toxicity o f cyazofamid was investigated in rats and dogs in 13
- week studies. The exposure was by dietary administration for the rats and by c apsule for the dogs. There were no treatment - related effects observed in dogs up to 1,000 mg/kg bw/d ay

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 onl y in males. The NOE L was 500 ppm which wa s equivalent to a dosage of 29.9 mg/kg bw/day t o males and 33.3 mg/kg bw/day

to females. 5. Chronic toxicity. A combined chronic and oncogenicity study w as conducted in rats. C yazofamid was administered continuously for a period of 104 weeks to male and female Fischer rats. C yazofamid 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/da y for males) based on increased incidence of skin lesions in the high dose animals. Ina c hronic dog study , four groups of six dogs/sex/group received cyazofamid via capsule for 52 week s. The NOELw as determined as 200 mg/kg bw/day b ased on increased cy sts in parathyroids in both sexes and increased pituitary c ys ts in females at the L OAEL 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 rapidl y eliminated with urinary and biliary elimination of radiocarbon nearl y complete within 24 hours. The metabolic pathway o f cyazofamid includes the rapid hydrol ys is 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 meta bolites 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. S everal of the metabolites resulting from cyazofamid are similar in plants and animals and, therefore, have already been evaluated toxicologicall y.4 8. Endocrine disruption
. An evaluation of the potential effects on the endocrine sy stems 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 reproducti ve 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 w ere included: bean s , snap and lima; leafy greens (subgroup 4A); brassica (cole) leafy

vegetables (crop group 5) including turnip greens; carrot s ; cucurbits (crop group 9); fruiting vegetables (crop groups 8
- 10 ); tuberous and corm vegetables (subgroup 1C) ; grapes ; and hops. For chronic dietary

e xposure, the chronic reference dose (RfD) of 0.95 mg/kg bw/day was proposed by

E PA 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 o f 100 mg/kg bw/day from the rat developmental t oxicity s tudy a djusted 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 e xposure anal ys es w ere 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 residu es 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 demonstrate d that residues were unlikely t o 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 0.00 7364 mg/kg bw/day
. This e xposure 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 ye ars old
. This exposure was determined to be 0.01 2 948 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 con cern was from the rat prenatal developmental study
. The acute dietary e xposure estimate for females aged 13
- 49 is 0.0 22706 mg/kg bw/day , well below HED’s level of concern at the 95th percentile. This is equivalent to 2.27 % of the aPAD.5

It can be conclu ded that acute or long
- term dietary e xposure to cyazofamid through residues on treated beans, snap and lima, leafy greens (subgroup 4A), brassica (cole) leafy v egetables (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, and hops , should not be of cause for concern. ii. Drinking water
. Since cyazofamid is intended for application outdoors to turf, ornamental s, 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, resp ectively , 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 commerciall y treated residential turf and ornamentals only
. Therefore, n on - 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 applicatio n 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. S ince there are no other members of this class of fun gi cides, 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 th e 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 0.00 7364 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 to6

be carcinogenic to humans.” An acute aggregate risk assessment was conduct ed 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 di etary (food and drinking water) risk assessment reported above as 0.0 22706 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 s hort
- 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 onl y pesticide handlers exposure data base (PHED) data levels A and B (those with a high level of confidence), the margin s of exposure (MOE) for occupational exposure are 341 to 98,0 00 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 aggre gate exposure of residues of cyazofamid including all anticipated dietary exposure and all other non
- occupational exposures. 2. Infants and children
. As noted above, c hronic dietary exposure of the most highl y exposed subgroup in the population, children, 1
- 2 years old , is 0.0 22706 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 o f the toxicity

d ata, the lack of toxicological endpoints of special concern, the lack of any indication of greater sensitivity o f children, and the c onservative 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 (MRL s) established for residues of cyazofamid on any

crop. The following Canadian tolerances have been establishe d: 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
.