Document ID: EPA-HQ-OPP-2011-0906-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-12-08T05:00Z

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

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

<  SEQ CHAPTER \h \r 1 Interregional Research Project Number 4 (IR-4)>

<Petition # 1E7929>

<	EPA has received a pesticide petition, PP# 1E7929, from   SEQ CHAPTER
\h \r 1 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   SEQ CHAPTER \h
\r 1 cyazofamid,   SEQ CHAPTER \h \r 1
4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfonam
ide (CA) and its metabolite CCIM,
4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile (CA), expressed
as cyazofamid in or on the following raw agricultural commodities: bean,
succulent, at 0.4 parts per million (ppm); bean, succulent, shelled at
0.07 ppm; leafy greens subgroup 4A at 9.0 ppm; basil, fresh leaves at
30.0 ppm; basil, dried leaves at 80.0 ppm; vegetable, tuberous and corm,
subgroup 1C at 0.02 ppm; and vegetable, fruiting, group 8-10 at 0.40
ppm. 

Upon approval of the aforementioned tolerances, this petition
additionally proposes to amend 40 CFR part 180.601 by removing the
established tolerances 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are being proposed to be removed, as they will be superseded by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
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.   SEQ CHAPTER \h \r 1 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.   SEQ CHAPTER \h \r
1 >

<	2. Analytical method.   SEQ CHAPTER \h \r 1 Residues of cyazofamid and
CCIM were extracted from samples (5 g for leaf lettuce, head lettuce,
snap beans & lima beans; 2.5 g for fresh basil; and 1 g for dried basil)
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. The results from 21 field trials (10 on head
lettuce and 11 on leaf lettuce) conducted during the 2008-2009 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 day intervals with a 0 day PHI 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 PHI 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 PHI 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 PHI in fresh basil was
15.1 ppm and in dried basis was 45 ppm.  >

<B. Toxicological Profile>

<	1. Acute toxicity.   SEQ CHAPTER \h \r 1 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.   SEQ CHAPTER \h \r 1 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.   SEQ CHAPTER \h \r 1 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.   SEQ CHAPTER \h \r 1 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.   SEQ CHAPTER \h \r 1 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.   SEQ CHAPTER \h \r 1 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   SEQ CHAPTER \h \r 1 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.   SEQ CHAPTER \h \r 1 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.   SEQ CHAPTER \h \r 1 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.   SEQ CHAPTER \h \r 1  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: 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; 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.   SEQ CHAPTER \h \r 1 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 +   SEQ CHAPTER \h \r 1 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, and hops, should not be of cause for concern.>

<	ii. Drinking water.   SEQ CHAPTER \h \r 1 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. 

  SEQ CHAPTER \h \r 1 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>

<  SEQ CHAPTER \h \r 1 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.   SEQ CHAPTER \h \r 1 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.   SEQ CHAPTER \h \r 1 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.    SEQ CHAPTER \h \r 1 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.

 >

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