COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE

(1/1/2006)

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

Interregional Research Project Number 4 (IR-4) 

PP# 8E7427

by establishing a tolerances for combined residues of the fungicide
cyazofamid, 

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) in or on
the raw agricultural commodities: Fruiting Vegetables Group 8 and Okra
at 0.8 parts per million (ppm); Grapes - East of the Rocky Mountains at
1.5 ppm.  It is also proposed to delete the existing tolerance of 0.2
ppm for tomato since the proposed fruiting vegetables crop group
tolerance will replace the current tomato tolerance of 0.2 ppm.  The
grape tolerance will change from the current import tolerance to a
regional tolerance.   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.

                                      

. Residues of cyazofamid and CCIM were extracted from 20 grams of pepper
with acetonitrile.  After filtration, the extract was evaporated to near
dryness and reconstituted with 2% sodium sulfate.  The analytes were
removed by partitioning with methylene chloride.   After reconstitution
in 50:50 acetonitrile:water, quantitation was achieved by LC/MS/MS.

The method for grapes and tomatoes was discussed in a previous Federal
Register notice on May 7, 2003. 

The grape and tomato residue data were discussed in a previous Federal
Register notice on May 7, 2003. 

Residue data from greenhouse transplant trials on tomatoes were
conducted at four sites.  The plants were transplanted at approximately
1, 7, 14, 21, and 28 days after treatment of approximately 0.78 lb
ai/100 gal.  The application rate was 10X the  proposed rate of 0.078
ai/100 gal.  No quantifiable residues of cyazofamid or CCIM were
observed in tomato samples.

.  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.

. 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.

. 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 0.95 mg/kg bw/day because the
FQPA safety factor is 1 for cyazofamid.

.  Tier 1 chronic and acute dietary exposure analyses were conducted for
 cyazofamid  in/on carrots, cucurbit vegetables (Crop group 9), fruiting
vegetables (Crop group 8), grapes, okra, and potatoes 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 carrot, cucurbit vegetables,
potatoes, and proposed tolerances for fruiting vegetables, okra and
grapes, as well as grape, 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 (food + drinking water) exposure estimates
resulted in an estimated exposure for the general U.S. population of
0.0004339 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 was
calculated for the all infants (< 1 year) subgroup.  This exposure was
determined to be 0.010897 mg/kg bw/day (1.1% of the cPAD).

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 0.009951 mg/kg bw/day at the 95th percentile, which
accounts for 1% of the aPAD.

. Since cyazofamid is intended for application outdoors to turf,
ornamentals, field grown carrots, cucurbit vegetables, fruiting
vegetables, grapes, okra and potatoes 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.

. 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 0.0004339 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. The acute dietary exposure to females aged
13-49 years, the subpopulation of interest, is 0.009951 mg/kg bw/day
(95th percentile). 

. 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 per capita acute dietary exposure estimate for females
aged 13-49 years is 0.009951 mg/kg bw/day at the 95th percentile, which
accounts for 1% of the aPAD.

  The following Canadian tolerances have been established: Carrots, 0.09
ppm; Potatoes,  0.02 ppm; Tomatoes (Import), 0.2 ppm; and Wine grapes
(Import), 1.2 ppm.

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