EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: Laura Nollen, (703) 305-7390

Interregional Research Project Number 4 (IR-4)

Petition Number 9E7615

EPA has received a pesticide petition (PP 9E7615) from IR-4, 

500 College Road East, Suite 201 W., 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)-1Himidazole-1-sulfonamide and its metabolite CCIM, 4-chloro-5-(4-methylphenyl)-1Himidazole-2-carbonitrile, expressed as cyazofamid, in or on the following raw 

agricultural commodities: brassica, head and stem, subgroup 5A at 1.2 parts per 

million (ppm); brassica, leafy greens, subgroup 5B at 12.0 ppm; turnip, greens at

12.0 ppm; spinach at 9.0 ppm; and hops at 10.0 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 Brassica (cole) crops, turnip greens, spinach, and hops, will 

include parent, cyazofamid, and the metabolite CCIM. 

2. Analytical method. Residues of cyazofamid and CCIM were extracted from 

samples (5 g for broccoli, cabbage, mustard greens & spinach; 1 g for hops) with 

acetonitrile. The combined extracts were partitioned with hexane and then reduced 

to 1-2 mL. The residues were dissolved in 20% acetonitrile/water and passed 

through a Nexus or Strat-X Polymeric solid phase extraction column (SPE). The 
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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. The results from 6 field trials conducted in 2006 

show that the maximum total residue (cyazofamid + CCIM) in broccoli flower heads 

was 0.915 ppm after one application applied as a drench to the base of the plants at 

the time of transplanting and five applications of cyazofamid at 7 (±1) day intervals 

with a 0 day PHI. The results from 9 field trials show that the maximum total 

residue (cyazofamid + CCIM) in cabbage (head) was 0.895 ppm after one 

application applied as a drench to the base of the plants at the time of transplanting

and five applications of cyazofamid at 7 (±1) day intervals with a 0 day PHI. The 

results from 9 field trials show that the maximum total residue (cyazofamid + 

CCIM) in mustard greens was 6.856 ppm after one application applied as a drench 

to the base of the plants at the time of transplanting and five applications of 

cyazofamid at 7 (±1) day intervals with a 0 day PHI. The results from 10 field trials 

show that the maximum total residue (cyazofamid + CCIM) in spinach (leaves) was 

6.620 ppm after five applications of cyazofamid at 7 (±1) day intervals with a 0 day 

PHI. The results from 3 field trials show that the maximum total residue 

(cyazofamid + CCIM) in hops was 7.03 ppm after six applications of cyazofamid at 7 

(±1) day intervals with a 3 day PHI.

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 
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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 

14C in two positions, the benzene [14C-Bz]- or imidazole [14C-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. 
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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-FCIDTM) 

version 2.16, and percent crop treated of 100%. The following raw agricultural 

commodities were included: brassica (cole) leafy vegetables (crop group 5) including 

turnip greens; carrot; cucurbits (crop group 9); fruiting vegetables (crop groups 8);

okra; potatoes; grapes (east of the Rocky Mountains); spinach; 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 0.004969 mg/kg bw/day. This exposure 

corresponds to less than 1% of the cPAD of 0.95 mg/kg bw/day. The highest 

exposure estimate calculated was for the subgroup all infants (< 1 year). This 

exposure was determined to be 0.012254 mg/kg bw/day (1.3% 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 
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aged 13-49 is 0.012142 mg/kg bw/day, well below HED’s level of concern at the 95th

percentile. This is equivalent to 1.21% of the aPAD.

It can be concluded that acute or long-term dietary exposure to cyazofamid through 

residues on treated brassica (cole) leafy vegetables (Crop Group 5), including turnip 

greens, carrots, cucurbit vegetables (Crop Group 9), fruiting vegetables (Crop 

Group 8), grapes, hops, okra, potatoes, and spinach, 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 
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dietary exposure to cyazofamid is 0.0004339 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 0.009951 mg/kg bw/day (95th percentile), 

1.21% 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 

1040.

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, all infants (< 1 yr old), is 0.010897 mg/kg 

bw/day or 1.1% of the RfD. The short-term aggregate risk MOE for children (food 

and residential) is 1400. 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 are 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 
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ppm.