UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

	OFFICE OF CHEMICAL SAFETY

	AND POLLUTION PREVENTION

  SEQ CHAPTER \h \r 1 MEMORANDUM

Date:  		11/24/2010

SUBJECT:	Fluazinam.  Addendum to Previous Human Health Risk Assessment
for Petitions for the Establishment of Tolerances and Registration of
New Uses on Apples and Carrots.

PC Code:  129098	DP Barcodes:  D381528

Decision Nos.:  437290	Registration No.: 71512-1

Petitions:  9E7570  Carrots

                  9F7571  Apples	Regulatory Action:  Section 3
Registration

Risk Assessment Type:  Single Chemical

                                         Aggregate	Case No.:  NA

TXR No.:  NA	CAS No.:    SEQ CHAPTER \h \r 1 79622-59-6

MRID Nos.:  47949001, 48103501,

                       48103502, 48154701	40 CFR:  §180.574



		              									

FROM:  	Douglas Dotson, Ph.D., Chemist

		Risk Assessment Branch II

		Health Effects Division (7509P)	  SEQ CHAPTER \h \r 1 

		

THROUGH:	Dennis McNeilly, Chemist

		Richard Loranger, Ph.D., Senior Scientist

		Risk Assessment Branch II

		Health Effects Division (7509P)

TO:		Laura Nollen/Barbara Madden, RM Team 5, RIMUERB

		John Bazuin/Tony Kish, PM Team 22, Fungicide Branch

		Registration Division (7505P)		  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h
\r 1 

		

Executive Summary

In early 2010, HED completed a human health risk assessment for proposed
uses of the fungicide fluazinam,
3-chloro-N-[3-chloro-2,6-dinitro-4-(trifluoromethyl)phenyl]-5-(trifluoro
methyl)-2-pyridinamine, on apples, carrots, head lettuce, leaf lettuce,
and the Bulb onion subgroup (13-07B) (Memo, D365940, D. Dotson, et al.,
3/31/2010).  HED recommended in favor of tolerances for head lettuce,
leaf lettuce, and the Bulb onion subgroup; however, because of major
data deficiencies, HED was not able to recommend in favor of tolerances
on apple and carrot commodities.  These data deficiencies are discussed
in detail in the residue chemistry summary document (Memo, D360840, D.
Dotson, 3/31/2010) that was written in support of the risk assessment. 
In addition, the deficiencies are discussed in a 75-day letter that the
Agency provided to the registrant, ISK Biosciences.  The deficiencies
related to an apple processing study, a cattle feeding study, and the
analytical method for the metabolites AMPA and DAPA in fat, liver, and
kidney.  The previous residue chemistry summary document addressed all
residue chemistry aspects associated with the tolerance petitions.  HED
also prepared a response to the data deficiencies that can be referred
to for more details concerning the deficiencies (Memo, D381302, D.
Dotson, 11/24/2010).  This current risk assessment addresses ISK’s
responses to the cited data deficiencies and HED’s conclusions to
those responses.

This risk assessment for the proposed uses on apples and carrots is
being performed as a joint review with Canada’s Pest Management
Regulatory Agency (PMRA).

Summary of Data Deficiencies Associated with PP#s 9E7570 and 9F7571
Cited in Previous Risk Assessment 

In the previous risk assessment, HED concluded that an analytical method
was not available for enforcement of fluazinam tolerances in animal
commodities.  HED recommended that the registrant submit an adequate
enforcement method and an independent laboratory validation (ILV) for
the method.  The method needed to be adequate for analysis of parent
fluazinam as well as the metabolites AMPA and DAPA in animal commodities
for which tolerances would be established.  HED also recommended that
the registrant submit the results of an acceptable dairy cattle feeding
study.  Residues of the metabolites AMPA and DAPA in animal commodities
needed to be successfully quantified if they were present at levels
above the limit of quantitation.  HED recommended that the registrant
submit the results of an acceptable apple processing study.  The study
needed to be performed at a sufficiently high rate that residues of both
fluazinam and AMGT were quantifiable in the raw agricultural commodity
(RAC).  Finally, HED recommended that ISK submit multiresidue method
testing data for the regulated animal metabolites, AMPA and DAPA.

In response to these data deficiencies, ISK Biosciences submitted an
analytical method and ILV for the analysis of fluazinam, AMPA, and DAPA
in fat, liver, and kidney.  In addition, ISK submitted additional data
for the AMGT metabolite in apples in order that the apple processing
study could be upgraded to acceptable.  Finally, ISK submitted a
rebuttal to the data deficiencies cited in the cattle feeding study. 
The multiresidue data for AMPA and DAPA remain outstanding.

Summary of Hazard and Risk Characterizations

When HED prepared the previous human health risk assessment for
fluazinam, it did so on the assumption that ISK Biosciences might
resolve the data deficiencies in the near future.  As a result, all of
the hazard and risk characterizations associated with the use of
fluazinam on apple and carrot commodities as well as the potential risk
resulting from exposure through consumption of animal commodities were
discussed and accounted for in the previous human health risk assessment
prepared for the proposed uses (Memo, D365940, D. Dotson, et al.,
3/31/2010).  For all exposure scenarios, risk estimates were not of
concern to HED for the current and proposed uses of fluazinam.

Ingredient Profile

The ingredient profile for the proposed uses was discussed in the
previous human health risk assessment prepared for the proposed uses.

Hazard Characterization/Assessment, FQPA Considerations 

There have been no changes to the hazard characterization, endpoint
selection, or FQPA assessment.

Dietary Exposure/Risk Characterization

Apple, carrot, and livestock commodities were included in the dietary
exposure assessment performed in support of the previous risk
assessment.  There are no changes in the inputs to the dietary exposure
assessments (i.e., the estimated drinking water concentrations, percent
crop treated estimates, etc.) or in the acute or chronic dietary risk
estimates.  The cRfD is protective of cancer effects.  The dietary risk
estimates for the current and proposed uses of fluazinam are not of
concern to HED.

Residential Exposure/Risk Characterization

There are no residential/non-occupational uses for fluazinam; therefore,
risk assessments for these types of uses are not needed.

Aggregate Risk Assessments,

As there are no changes to the dietary exposure estimates and there are
no residential uses, there are no changes in the aggregate exposure and
risk estimates.  The cRfD is protective of cancer effects.  The
aggregate risk estimates for the current and proposed uses of fluazinam
are not of concern to HED.

Occupational Exposure/Risk Pathway

Occupational exposures resulting from uses on apples and carrots were
assessed in the previous risk assessment.  The occupational risk
estimates for the current and proposed uses of fluazinam are not of
concern to HED.

Data Needs and Label Recommendations

With the exception of the multiresidue method testing data for the
regulated animal metabolites, AMPA and DAPA, ISK Biosciences has
resolved the data deficiencies associated with the apple and carrot
tolerance petitions.  There are no outstanding data deficiencies that
would preclude establishment of tolerances and conditional registration
for apple, carrot, and livestock commodities.  Although analyte-specific
methods are available for AMPA and DAPA in animal commodities,
multiresidue method testing data continue to be required for these
regulated animal metabolites.

For any future uses that involve major feed items and significantly
higher dietary burdens, more vigorous extraction steps might be required
in the method for kidney and liver along with radiovalidation data to
demonstrate improved extractability.  

HED recommends that the tolerances specified in Table 1 be established,
and that the multiresidue methods testing data for AMPA and DAPA be made
a condition of registration.

The registrant needs to submit a revised Section F in which the
recommended tolerances and correct commodity definitions listed in Table
1 are proposed.

α,α,α-trifluoro-2-nitro-p-toluidino)-3-chloro-5-(trifluoromethyl)
pyridine), DAPA
(3-chloro-2-(2,6-diamino-3-chloro-α,α,α.-trifluoro-p-toluidino)-5-(tr
ifluoromethyl)-pyridine), and their sulfamate conjugates.”  

Analytical Methodology

Tolerance Enforcement Method for Animal Commodities

In response to the deficiency cited in the analytical method for AMPA
and DAPA in liver and kidney, ISK submitted an analytical method
entitled “Enforcement Method for the Analysis of Fluazinam and its
Metabolites AMPA and DAPA in Milk and Meat (Document Number
IB-2009-JLW-005-01).”  ISK also submitted an ILV for this method.  The
method is written for LC/MS/MS analysis of fluazinam, AMPA, and DAPA and
their sulfamate conjugates in bovine liver, fat, and milk.  The reported
method LOQ was 0.01 ppm for each analyte in liver, fat, and milk.

HED concludes that ISK’s analytical method entitled “Enforcement
Method for the Analysis of Fluazinam and its Metabolites AMPA and DAPA
in Milk and Meat” is adequate as an enforcement method for residues of
fluazinam, AMPA, and DAPA and their sulfamate conjugates in kidney,
liver, and fat.  The method was successfully validated based on the
Series 860.1340 Residue Chemistry Guidelines in one attempt for
fluazinam, AMPA, and DAPA in beef kidney and beef liver.  The beef fat
method was validated after two attempts with minor modification of the
method after the first method trial.

Food Residue Profile

Residues in Meat, Milk, Poultry, and Eggs

Because of the potential for residues to be present in animal
commodities, ISK submitted a dairy cattle feeding study with the
original submission.  Based on the poor recoveries of metabolites AMPA
and DAPA from liver and kidney and the mixed storage stability results,
the residue data from the cattle feeding study were not adequate to
satisfy data requirements.  HED determined that, in order to support
tolerances for apples and carrots, the registrant needed to submit a new
cattle feeding study in which a method with better recoveries of AMPA
and DAPA from liver and kidney was used.

In lieu of submitting a new cattle feeding study, ISK Biosciences
submitted a rebuttal to the data deficiency (MRID 47746605).  The
rebuttal is entitled “Rebuttal Response to Upgrade Magnitude of
Fluazinam Residues in Bovine Tissues and Milk from a 28-Day Feeding
Study.”  ISK explained that liver and kidney are metabolic matrices,
and as a result, residues are unstable during storage, and recoveries
are low when samples are analyzed.

The poor storage stability of AMPA and DAPA in liver and kidney, the
poor recovery from these matrices when the feeding study was performed,
and the results of the depuration study all support ISK’s assertion
that liver and kidney are metabolic matrices that cause the rapid
decline of AMPA and DAPA residues.  HED agrees with ISK Biosciences that
another animal feeding study does not need to be performed.

HED previously determined that a tolerance of 0.05 ppm would be adequate
to cover residues in the fat and meat byproducts of cattle, goat, horse,
and sheep (Memo, D360840, D. Dotson, 3/31/2010).  As a result, HED
recommends in favor of the establishment of tolerances of 0.05 ppm for
the fat and meat byproducts of cattle, goat, horse, and sheep.

Processing Studies

HED originally concluded that the apple processing study was not
adequate to satisfy data requirements.  In apples, the metabolite AMGT
is a residue of concern for risk assessment.  AMGT is not a residue of
concern for tolerance expression, however.  In the processing study
there were no quantifiable residues of AMGT in raw apples.  In several
of the field trials that were performed, however, raw apples contained
AMGT residues at, or above, the limit of quantitation.  Of the 42 field
trial values, 32 were below the LOQ of 0.01 ppm, 6 were 0.01 ppm, 3 were
0.02 ppm, and 1 was 0.03 ppm.  Canadian and U.S. residue chemistry
guidelines state that in the processing study, if residues in the RAC
are below the LOQ, but quantifiable residues occurred in the RAC in
field trials performed at the maximum requested label rate, that the
processing study should be conducted at exaggerated rates in order to
ensure that quantifiable residues will be present in the RAC. 
Quantifiable residues are needed in the RAC in order to determine a
reliable concentration factor.

HED requested that the processing study be repeated at a sufficiently
high rate that residues of both parent and AMGT would be quantifiable in
the RAC.  Instead of performing a new processing study, however, the
registrant submitted additional data from the initial study.  When the
laboratory personnel originally analyzed the samples, they did not
quantitate samples in which the AMGT residue levels were below the LOQ. 
As a result, it was not possible to determine processing factors.  ISK
Biosciences submitted an amended report in which the residue levels that
were between the LOD and LOQ were measured.  As stated above, the LOQ
was 0.01 ppm.  The original electronic data were not saved by the
performing laboratory.  As a result, residues were quantitated by
manually measuring peak heights.

AMGT is not a residue of concern for tolerance expression.  As a result,
the results of the processing study are not relevant to tolerance
enforcement.  AMGT is a residue of concern for risk assessment, however.
 As a result, the results of the processing study have the potential to
affect the dietary risk estimates.

Although the peak heights for AMGT in raw apples and the processed
commodities were small, HED believes that they are large enough compared
to the noise level in the chromatograms that they can be quantitated to
2-significant figure accuracy by manually measuring peak heights. 
Because of the small peak heights and the fact that the AMGT residue
levels are below the LOQ, there is a higher degree of uncertainty in the
processing factors for AMGT than there is for the parent.  Regardless,
the results for AMGT in apple pomace are comparable to those of the
parent.  That is, in juice and cider, both compounds were reduced,
whereas in wet pomace and dry pomace, residues concentrated slightly. 
The processing factors that were determined are consistent with what
would be expected based on separation of apples into components.  In the
Dietary Exposure Evaluation Model (DEEM, Version 7.81), the maximum
theoretical concentration factor for apple juice is only 1.3x.  This
default factor is based on the assumption that when the juice is
expressed from raw apples, all of the pesticide partitions into the
juice.  This is why it’s considered to be a maximum concentration
factor.  The 860 Residue Chemistry Guidelines provide factors of 1.2,
1.4, and 2 for the juices of grapes, tomatoes, and citrus, respectively.
 The Guidelines also provide a value of >14x as the maximum theoretical
concentration factor for apples, based on observed values for apple
pomace.  Although there is a higher degree of uncertainty in the AMGT
processing factors than in the fluazinam processing factors, HED
believes that the AMGT processing factors are sufficiently precise for
risk assessment purposes.  The factors were determined to 2-significant
figure accuracy, and they are consistent with what would be expected
based on separation of apples into components.

The processed apple commodities that impact the dietary risk estimates
are wet apple pomace and apple juice.  Wet apple pomace is an animal
feed item.  A conservative tolerance level of 5.0 ppm was used to
calculate the maximum expected dietary burden.  AMGT is not a residue of
concern in animal commodities, though.  The only way it would affect the
dietary burden is if it gets metabolized to AMPA and DAPA.  However,
AMGT residues in field trials were so low that any AMPA or DAPA that
would form would be negligible.  As for apple juice, HED believes that
the processing factor was determined precisely enough that AMGT residues
could be completely accounted for in this commodity.  In the acute
dietary exposure analysis, the recommended tolerance of 2.0 ppm was used
for apple juice along with the DEEM default processing factor of 1.3x. 
In the chronic dietary exposure analysis, the average combined
(fluazinam + AMGT) residue value of 0.215 ppm was used for apple juice
along with the DEEM default processing factor of 1.3x.  The default
value of 1.3x is a conservative estimate of residue concentration, as
discussed above.

For the reasons discussed above, HED concludes that the residue data for
fluazinam and AMGT in the submitted apple processing study are
acceptable.  Residues of fluazinam concentrated in wet pomace
(processing factor of 2.8x) and dry pomace (processing factor of 3.6x),
but did not concentrate in juice and cider (processing factor of <0.4x
each).  Residues of AMGT concentrated in wet pomace (processing factor
of 1.3x) and dry pomace (processing factor of <2.8x), but did not
concentrate in juice and cider (processing factors of 0.5x and 0.7x,
respectively).  The submitted data satisfy the deficiency cited in the
previous residue chemistry summary document and risk assessment.

The highest average field trial value for fluazinam was 1.54 ppm. 
Multiplying this value by the wet pomace processing factor of 2.8x
yields a residue value of 4.3 ppm.  Based on this value, a tolerance of
5.0 ppm needs to be established for apple, wet pomace.  AMGT is not
included in the tolerance expression for apples.  As a result, AMGT
residues do not need to be accounted for in the tolerance.  A separate
tolerance is not needed for juice based on the fact that fluazinam
residues are lower in juice than they are in the RAC.  Although ISK
Biosciences submitted processing data for dry pomace and cider, the
Agency does not establish tolerances for these commodities.

    

Tolerance Harmonization

There are currently no established Codex, Canadian, or Mexican maximum
residue limits (MRLs) for fluazinam on apples or carrots.  These
tolerance petitions are being evaluated as a joint review with
Canada’s PMRA.  The USEPA and PMRA will be harmonizing the tolerances
for the apple and carrot commodities.  The recommended tolerance for
carrot, roots is 0.70 ppm.  The NAFTA-harmonized tolerance generator
directs that the tolerance for apple should be 1.5 ppm.  The USEPA and
PMRA have agreed to establish the tolerance at 2.0 ppm.  Canada does not
establish tolerances for livestock feed items.  As a result, only the
U.S. will be establishing a tolerance for apple, wet pomace.  The U.S.
is establishing tolerances of 0.05 ppm for the fat and meat byproducts
of cattle, goats, horses, and sheep.  Canada is not establishing
tolerances for livestock commodities.

Data Needs 

With the exception of the multiresidue method testing data for the
regulated animal metabolites, AMPA and DAPA, ISK Biosciences has
resolved the data deficiencies associated with the apple and carrot
tolerance petitions.  There are no outstanding data deficiencies that
would preclude establishment of tolerances and conditional registration
for apple, carrot, and livestock commodities.  Although analyte-specific
methods are available for AMPA and DAPA in animal commodities,
multiresidue method testing data continue to be required for these
regulated animal metabolites.

  

The registrant needs to submit a revised Section F in which the
recommended tolerances and correct commodity definitions listed in Table
1 are proposed.

For any future uses that involve major feed items and significantly
higher dietary burdens, more vigorous extraction steps may be required
in the method for kidney and liver along with radiovalidation data to
demonstrate improved extractability.  

Recommended Tolerances

Although the NAFTA-harmonized tolerance generator recommends a tolerance
of 1.5 ppm for apples, the USEPA and PMRA have agreed to establish the
tolerance at 2.0 ppm.  This increase is being made because in one of the
field trials, residue values were 1.31 and 1.49 ppm and in another field
trial, residues were 1.39 and 1.67 ppm.  These field trials were
performed in arid regions (Toppenish, Washington and Eckert, Colorado,
respectively).  The next highest field trial value after these four was
0.17 ppm.  The U.S. and Canada agreed that a tolerance of 2.0 ppm might
be needed to protect farmers who grow apples in arid regions.  Although
the NAFTA-harmonized tolerance generator recommends a tolerance of 1.5
ppm, the OECD tolerance generator recommends a tolerance of 2.0 ppm for
this same data set.  The recommended tolerance for apple, wet pomace is
5.0 ppm.  The recommended tolerance for carrot, roots is 0.70 ppm.

HED recommends in favor of the establishment of tolerances of 0.05 ppm
for the fat and meat byproducts of cattle, goats, horses, and sheep. 
Although ISK Biosciences proposed tolerances of 0.03 ppm for the meat of
cattle, goat, horse, and sheep, these tolerances are not needed based on
the results of the cattle feeding study and the calculated dietary
burden for dairy cattle.  Although ISK Biosciences proposed tolerances
of 0.03 ppm for the liver and kidney of cattle, goat, horse, and sheep,
these tolerances are not needed either, because tolerances are being
established for the meat byproducts of cattle, goat, horse, and sheep. 
HED’s Chemistry Science Advisory Council (ChemSAC) determined that
individual tolerances are not needed for liver and kidney when a
tolerance is being established for meat byproducts (ChemSAC Minutes,
7/18/2007).

The recommended tolerances and correct commodity definitions are listed
in Table 1.

HED recommends that 40CFR §180.574(a) be amended by adding the
following for the livestock commodity tolerances:  “Tolerances are
established for residues of fluazinam
(3-chloro-N-[3-chloro-2,6-dinitro-4-(trifluoromethyl)phenyl]-5-(trifluor
omethyl)-2-pyridinamine), including its metabolites and degradates, in
or on the commodities in the table below.  Compliance with the tolerance
levels specified below is to be determined by measuring only fluazinam,
AMPA
(2-(6-amino-3-chloro-α,α,α-trifluoro-2-nitro-p-toluidino)-3-chloro-5-
(trifluoromethyl) pyridine), DAPA
(3-chloro-2-(2,6-diamino-3-chloro-α,α,α.-trifluoro-p-toluidino)-5-(tr
ifluoromethyl)pyridine), and their sulfamate conjugates.”

Table 1.  Tolerance Summary for Fluazinam.

Commodity	Proposed  Tolerance (ppm)	Recommended Tolerance (ppm)
Comments; Correct Commodity Definition

PP#9E7570

Carrot, roots	0.8	0.70	Adequate carrot residue data are available.  The
NAFTA-harmonized tolerance generator directs that the tolerance for this
data set should be 0.70 ppm.  

PP#9F7571

Apples	1.7	2.0	Adequate apple residue data are available.  The
NAFTA-harmonized tolerance generator directs that the tolerance for this
data set should be 1.5 ppm.  The USEPA and PMRA agreed to establish the
tolerance at 2.0 ppm at such time as the data deficiencies were
resolved.

Apple

Apple, pomace, wet	5.0	5.0	Adequate apple processing data are available
for both fluazinam and AMGT.

Apple, wet pomace

Cattle, fat	0.03	0.05	An adequate cattle feeding study is available. 
Based on the results of the study, the maximum expected residue in meat
byproducts and fat is 0.045 ppm.

Based on the results of the feeding study, tolerances are not needed for
milk and meat of cattle, goat, horse, and sheep.

Cattle, kidney	0.03	Not required

	Cattle, liver	0.03	Not required

	Cattle, meat	0.03	Not required

	Cattle, meat byproducts	0.03	0.05

	Goat, fat	0.03	0.05

	Goat, kidney	0.03	Not required

	Goat, liver	0.03	Not required

	Goat, meat	0.03	Not required

	Goat, meat byproducts	0.03	0.05

	Horse, fat	0.03	0.05

	Horse, kidney	0.03	Not required

	Horse, liver	0.03	Not required

	Horse, meat	0.03	Not required

	Horse, meat byproducts	0.03	0.05

	Milk	0.03	Not required

	Sheep, fat	0.03	0.05

	Sheep, kidney	0.03	Not required

	Sheep, liver	0.03	Not required

	Sheep, meat	0.03	Not required

	Sheep, meat byproducts	0.03	0.05

	

References

Fluazinam.  Human Health Risk Assessment for the Proposed Uses on
Apples, Carrots, Lettuce, and the Bulb Onion Subgroup (3-07A), and a
Request for a Reduced Tolerance on the Bushberry Subgroup (13-07B),
D365940, D. Dotson, et al., 3/31/2010

Fluazinam.  Petitions for the Establishment of Tolerances and
Registration of New Uses on Apples and Carrots.  HED’s Conclusions
Regarding Registrant’s Response to Data Deficiencies, D381302, D.
Dotson, 11/24/2010

Fluazinam.  Petitions for the Establishment of Tolerances and
Registration of New Uses on Apples, Carrots, Lettuce, and Bulb Onion
Subgroup (3-07A), and a Request for a Reduced Tolerance on Bushberry
Subgroup (13-07B).  Summary of Analytical Chemistry and Residue Data,
D360840, D. Dotson, 3/31/2010

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␆ഁ׆Ā֠ༀꂄᄅ悄ㇺĤ葞֠葠褐摧籊+ᜀe and Chronic
Aggregate Dietary (Food and Drinking Water) Exposure and Risk
Assessments for the Section 3 Registration Action on Apples, Carrots,
Head Lettuce, Leaf Lettuce, and the Bulb Onion Subgroup (3-07A),
D374522, 3/31/2010

Fluazinam: Occupational and Residential Risk Assessment for Proposed Use
of Fluazinam on Apples, Carrots, Lettuce (Head and Leaf), and Onions
(Bulb), D371446, Z. Figueroa, 2/19/2010. 

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