Document ID: EPA-HQ-OPP-2007-0872-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-09-28T04:00Z

Notice of Filing: PP#7E7244

Interregional Research Project Number 4 (IR-4)

 EPA Registration Division contact: Susan Stanton (703) 305-5218

	EPA has received a pesticide petition (PP#7E7244) 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 cyazofamid,
4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfonam
ide  (CA) in or on the raw agricultural commodity carrot, roots at 0.06
parts per million (ppm). EPA has determined that the petition contains
data or information regarding the elements set forth in section
408(d)(2) of the FFDCA; 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                                      

	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
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 residue in wine made from cyazofamid treated grapes is CCIM.    The
tolerance expression for carrot, roots, will include parent, cyazofamid,
and the metabolite CCIM.

	2. Analytical method. Residues of cyazofamid and CCIM were extracted
from 20 grams of carrot with acetonitrile.  After filtration, the
extract was transferred to a separatory funnel, washed with hexane,
cleaned up on a Nexus SPE column, and the eluate was concentrated by
using a TurboVap LV workstation.  After reconstitution in 50:50
acetonitrile:water, quantitation was achieved by LC/MS/MS.

	3. Magnitude of residues. Residue data from 14 field trials (13 to 16
day PHI) on carrots conducted in 2004 showed that mean cyazofamid
residues were 0.015 ppm for treatments in which sprinkler irrigation was
permitted within six hours of application and 0.018 ppm for treatments
in which sprinkler irrigation was delayed for 24 hours following
application to determine the effects of irrigation timing.  The maximum
total residue (cyazofamid plus CCIM) was 0.050 ppm following five
applications of cyazofamid and a PHI of 14 days.  CCIM residues were
<0.01 ppm at all sites.  The study had a target of one pre-emergent
broadcast application followed by four directed foliar applications, all
at 0.156 lb a.i./A (0.78 lb a.i/A total) of Ranman 400SC formulation at
approximately 14 day intervals.

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, cyazofamid was dosed by gavage  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 with cyazofamid by gavage 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 the
test material 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.  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. A chronic reference dose (RfD) of 0.95 mg/kg
bw/day is proposed 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 1
mg/kg bw/day because the FQPA safety factor is 1 for cyazofamid.  The
acute RfD of 1.0 mg/kg bw is based on the NOAEL of 100 mg/kg bw/day from
the rate developmental toxicity study adjusted by the uncertainty factor
of 100.  The acute population adjusted dose (aPAD) is also 1 mg/kg
bw/day because the cyazofamid FQPA safety factor is 1.

	i. Food.  Tier 1 chronic and acute dietary exposure analyses were
conducted for  cyazofamid  in/on cucurbits, potatoes, tomatoes, wine
grapes and carrots 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 tolerance level residues
for potatoes, tomatoes and wine grapes and proposed tolerance for
carrot, as well as potato and tomato processing studies, 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. 
Although carrot culls are an animal feed item, it was assumed that no
secondary tolerances in meat or milk would be necessary due to the low
residues in carrots and the lack of significant bioaccumulation in
mammals.  Even using all of the worst case exposure scenarios listed
above, the Tier 1 chronic dietary exposure estimates resulted in an
estimated exposure for the U.S. population of 0.000417 mg/kg bw/day. 
This exposure corresponds to much less than 1% of the RfD of 0.95 mg/kg
bw/day.  The highest exposure estimate was calculated for the western
region population subgroup.  This exposure was determined to be 0.000548
mg/kg bw/day (0.1% of the RfD).

The Tier 1 acute dietary assessment is based on an endpoint from a
prenatal developmental study.  As such, the only subpopulation of
interest for acute dietary exposure in females aged 13-49 uears old. 
Acute dietary exposures for the above listed crops were calculated using
DEEM-FCID.  The per capita acute dietary exposure estimate for females
aged 13-49 is 0.001049 mg/kg bw/day at the 95th percentile, which
accounts for less than 1% of the aPAD.  It can be concluded that acute
or long-term dietary exposure to cyazofamid through residues on treated
cucurbits, potatoes, tomatoes, carrots and imported wine grapes should
not be of cause for concern.

	ii. Drinking water. Since cyazofamid is intended for application
outdoors to field grown potato, tomato, cucurbits and carrot crops, the
potential exists for parent and or metabolites to reach ground or
surface water that may be used for drinking water.  The calculated
Drinking Water Levels of Comparison (DWLOCs) for chronic exposure for
the general population,  females 13-49 years old  and all infants and
children were estimated to be 33,000 ppb, 28,000 ppb, and 9,500 ppb,
respectively.  The calculated (DWLOCs) for acute exposure for  females
13-49 years old was estimated to be 30,000 ppb.  The chronic and acute
DWLOC values are well above the modeled chronic Drinking Water Estimated
Concentrations (DWECs) of 8.890 ppb (surface water) and 0.544 ppb
(ground water) and acute DWECs of 9.277 ppb (surface water) and 0.544
ppb (ground water).  Therefore, there is comfortable certainty that no
harm will result from combined dietary food and water exposure due to
the use of cyazofamid on cucurbits,  potatoes, tomatoes and carrots.

	2. Non-dietary exposure. No petition for registration of cyazofamid is
being made for either indoor or outdoor residential use. 
Non-occupational exposure of cyazofamid to the general population is
therefore not expected and is not considered in aggregate exposure
estimates.

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 U.S. population, the
chronic dietary exposure to cyazofamid is 0.000417 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. The acute dietary exposure to
females aged 13-49 years, the subpopulation of interest, is 0.001049
mg/kg bw/day (95th percentile).  Using only pesticide handlers exposure
data base (PHED) data levels A and B (those with a high level of
confidence), the margin of exposure (MOE) for occupational exposure is
5,195 for mixer/loaders, and 5,884 for aerial applicators. 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. Chronic dietary exposure of the most highly
exposed subgroup in the population, children 1-6, is 0.000435 mg/kg
bw/day or <0.1% of the RfD.  The per capita acute dietary exposure
estimate for females aged 13-49 years is 0.001049 mg/kg bw/day at the
95th percentile, which accounts for less than 1% of the aPAD.  There are
no residential uses of 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. 
Accordingly, there is no need to apply an additional safety factor for
infants and children.

F. International Tolerances

	There are presently no Codex maximum residue limits established for
residues of cyazofamid on any crop.

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