EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS

PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: Tony Kish, (703) 308

- 94 43

ISK Biosciences Corporation

P etition 5F8352

EPA has received a pesticide petit ion 5F8352 from ISK Biosciences Corporation, 7470 Auburn Road, Suite A, Concord, Ohio 44077, 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

e stablishing a tolerance for residues of the fungicide Cyazofamid, 4

- chloro

- 2

- cyano

- N,N

- dimethyl

5

- (4

- methylphen yl)

- 1 H

- imidazole

- 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 commodit ies : Bulb Vegetable crop group 3

- 07

, at 2.0 parts per million (ppm) ; EPA has determined that the petition contains data or information regarding the elements se t 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. Resi due Chemistry

1. 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 studi es 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 5 g samples
of onions wit h acetonitrile. After shaking and centrifugation, the extracts were diluted 4 fold with a
50 % acetonitrile/water and filtered through a PTFE filter . The filtrate w as diluted 5 fold with 50/50 acetonitrile/water. The samples were quantitated by LC/MS/MS.

3. Magnitude of residues. Dry Bulb and Green O nions : A total of 15 field trials were
conducted on dry bulb (10) and green (5) onions during the 201 4 growing season. Six (6 ) foliar applications were applied at 7 ( + 1) day inter vals at the target rate of 0.071 lb. a.i./A for a total of approximately 0. 42 lb. a.i./A/season. Onions were harvested at 0 day PHI. One decline trial was included with sampling at 0, 1, 3 and 7 days after the last application. T he results show that the maximum total residue (cya zofamid + CCIM) after six application s of cyazofamid with a 0 day PHI

in green onion s was 1.16 ppm and in dry bulb onions was 0.89 ppm

.

B. Toxicological Profile

1. Acute toxicity. Results from a battery of acute toxicity studies place technical2

cyazofamid in Toxicity Category IV for oral LD 50 , inhalation LC 50 and eye irritation, and Category III
for dermal irritation and dermal LD 50 . Technical cyazofamid was determined to be a weak dermal sensitizer. In an acute neurotoxicity st udy, 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 inclu ded 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 n ot 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 r at 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 incidenc e of bent ribs, a

rev ersible 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. T he 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 wh ich 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 equ ivalent 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 evid ence 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.3

6. Animal metabolism. Studies on the metabolism of cyazofami d 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 hydrolysi s 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 t he 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

mamm als 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: bea n s , snap and lima; dry bulb and green onions (bulb vegetable crop group 3

- 07); leafy greens (subgroup 4A); brassica (cole) leafy vegetables (crop g roup 5) including turnip greens; carrot s ; cucurbits (crop group 9); fruiting vegetables (crop groups 8

- 10 ); t uberous 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, t he 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 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 w ere 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 s urvey of food intake. Since specific4

processing studies demonstrate d 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 0.00 8632 mg/kg bw/day. This e xposure corresponds to 0. 9 % of the cPAD of 0.95 mg/kg bw/day. T he highest exposure estimate calculated was for the subgroup

, non

- nursing
Infants . This exposure was determined to be 0.01 7515 mg/kg bw/day (1. 8 % 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 0.0 45281 mg/kg bw/day

, well below HED’s level of concern at the 95th percentile. This is equivalent to 2.60 % of the aPAD.

It can be concluded that acute or long

- term dietary exposure to cyazofamid through residues on

treated beans, snap and lima, dry bulb and green onions (bulb vegetable crop group 3

- 07), leafy greens (subgroup 4A), brassi ca (cole) leafy vegetables (Crop Group 5), including turnip greens, carrots, cucurbit vegetables (Crop Group 9) , fruit ing vegetables (Crop Group 8

- 10 )

, tuberous and corm vegetables (subgroup 1C), grapes, herbs (Crop Subgroup 19A)

, and hops , should not be o f
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 direct ly entered into the dietary exposure model.

2. Non

- dietary exposure

. Cyazofamid can be applied to commercially treated residential
turf and ornamentals only . Therefore, n on

- occupational exposure of cyazofamid to the general populat ion 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 w as 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 ther efore, are not of

concern

.

D. Cumulati ve 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 a t this time.5

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 gen eral U.S. population, the chronic dietary exposure to cyazofamid is 0.00 8632 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 0.0 45281 mg/kg bw/day (95th percentile), 2.60 % of the aPAD , repr esents 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 res idential 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 l evels A and B (those with a high level of confidence), the margin s 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 to xicity 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, c hronic dietary exposure of the most highly exposed subgroup in the population, non

- nursing infants , is 0.0 17515 mg/kg bw/day or 1.8 % of the
RfD. The short

- term aggregate risk MOE for children (f ood 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 l ack of toxicological endpoints of special concern, the lack of any indication of greater sensitivity of 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 exposur e.

F. International Tolerances

Presently, t here is no Codex maximum residue levels (MRLs) 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

.