Document ID: EPA-HQ-OPP-2005-0265-0034
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-04-14T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES AND

TOXIC SUBSTANCES

MEMORANDUM

Date:	February 4, 2009 

SUBJECT:	Dicloran (DCNA).   Response to Waiver Request on Residue Data
Requirements.

PC Code:  031301	DP Barcode:  D358087

Decision No.:  334070	Registration No.:  Not Applicable

Petition No.: Not Applicable	Regulatory Action: Response to DCI Comments

Risk Assessment Type: Not Applicable	Case No.: 0113

TXR No.: Not Applicable	CAS No.: 99-30-9

MRID No.: 47573501	40 CFR: 180.200

FROM:	Christine L. Olinger, Chemist

		Risk Assessment Branch 7

		Health Effects Division (7509P)

		Office of Pesticide Programs

THRU:	Donna S. Davis, Chemist

		Michael S. Metzger, Chief,

		Risk Assessment Branch 7

		Health Effects Division (7509P)

		Office of Pesticide Programs

TO:	James Parker, CRM

		Reregistration Branch 1

		Special Review and Reregistration Division (7508P)

		Office of Pesticide Programs

I.  ACTION REQUESTED

Gowan Company has submitted a request for waiving several residue
studies required in the residue chemistry chapter of the Reregistration
Eligibility Decision (RED) for the fungicide dicloran (aka DCNA,
2,6-dichloro-4-nitrobenzenamine).   These studies were levied in a
Generic Data Call-In (DCI) dated July 29, 2008 and identified as
GDCI-031301-27262.  

II. CONCLUSIONS

HED agrees that the storage stability information requested under
guideline number 860.1300 can be waived.  The confirmatory method
requested under 860.1340 can also be waived, but the remaining requests
under 860.1340 are still needed.  All of the other residue chemistry
studies requested in the DCI are needed to support the registration and
tolerances for dicloran (DCNA).

III. DETAILED CONSIDERATIONS

A brief description of the rationale for the waiver request for each
guideline is provided below, followed by the HED response.

  

860.1300 Nature of the Residue in Livestock 

Additional storage stability data demonstrating stability for 24 months
were requested to support the poultry and ruminant nature of the residue
studies.  

Registrant Position

Gowan responded that sufficient data are available to support these
studies, specifically that residues of dicloran per se has been shown to
be stable in poultry commodities.  In addition, the registrant stated a
study amendment was submitted to the Agency describing analyses of that
the tissues from the metabolism study after 12 months of storage and
they are concerned about the stability of the residues.

Agency Response

The need for additional storage stability information was originally
identified when the studies were initially reviewed (DP Barcodes D270711
and D270712; 5/22/01; T. Bloem), and also required in the Residue
Chemistry Chapter to the Reregistration Eligibility Decision (RED) (C.
Olinger, 8/9/05, DP Barcode D318895).  Although these studies did not
include the storage stability data typically submitted to support nature
of the residue studies, there is enough information from the DCNA
database to waive this study.  Nature of the residue studies are
primarily used to determine the residues of concern for tolerance and
risk assessment.  The additional storage stability information requested
is not likely to affect the HED decision on the residues of concern in
livestock.  HED agrees that this study can be waived and no further
nature of the residue studies in livestock are required.

860.1340 Residue Analytical Method - Plants

A confirmatory method enforcing plant tolerances was required in the RED
(C. Olinger, 8/9/05, DP Barcode D318895).  

Registrant Position

The registrant believes that sufficient methodology is available to
confirm DCNA residues by enforcement agencies, as DCNA is recovered by
one of the FDA multiresidue methods, according to the FDA PESTDATA
listing.

Agency Response

HED agrees that a confirmatory method for residues in plant is no longer
required.  HED has confirmed that PESTDATA does report very good
recoveries for DCNA.  Therefore, no additional methods are required for
plant commodities; however, the requirement for residue analytical
methods in livestock cannot be waived, as described below. 

860.1340 Residue Analytical Method – Livestock Commodities

860.1360 Multi-Residue Method Testing – Livestock Commodities

860.1380 Storage Stability Data – Livestock Commodities

860.1480 Magnitude of the Residue – Meat, Milk, Poultry, and Eggs

A livestock feeding study in ruminants was required in the DCI.  If the
results of this study indicates the need for livestock tolerances, then
additional supporting studies are needed, including a tolerance
enforcement method for livestock commodities (if the plant method is not
applicable),  multi-residue method testing for one of the livestock
metabolites, and storage stability data if the samples from the feeding
study are stored greater than 30 days.

Registrant Position

Gowan is concerned that a method for determining the livestock
metabolites is not feasible, based on studies conducted in soil.  They
also believe sufficient mammalian feeding studies are available,
including studies in cows, pigs, rats, goats, and humans, and no further
studies should be required.

Agency Response

HED based the need for a livestock feeding study on a goat metabolism
study reviewed in 2001 (DP Barcodes D270711 and D270712; 5/22/01; T.
Bloem); results are summarized in Table 1.  Goats were dosed at a
feeding level of approximately 360 ppm for five days, and quantifiable
residues were found in all matrices tested.  The highest residues in
milk were found in the final samples collected, which may indicate that
the residues may not have reached a plateau.  The Metabolism Assessment
Review Committee (T. Bloem, DP Barcode D274726, 5/8/01) determined that
the parent dicloran and the metabolite DCAP, a major milk metabolite,
should be included in the tolerance expression, and that dicloran, DCAA,
DCHA, DCAP, DCNP, and A-1, should be included in the dietary risk
assessment for livestock commodities.

Table 1.  Summary of Goat Metabolism Study Conducted at a Dosing Level
of 360 ppm for Five Days 1

	ppm Dicloran Equivalents (% TRR)

	Liver	Kidney	Fat	Muscle	Milk

Total Radioactive Residues, ppm	17.70	1.39	1.24	0.11	3.57

	dicloran	--	--	1.00 (80.7%)	0.02 (15.7%)	0.70 (19.6%)

	DCAA	0.12 (0.7%)	--	0.03 (2.3%)	0.02 (14.7%)	--

	DCHA	0.18 (1.0%)	--	0.05 (4.3%)	0.01 (12.8%)	0.04 (1.1%)

	DCPD	0.04 (0.2%)	0.07 (4.9%)	--	<0.01 (3.0%)	0.06 (1.7%)

	DCNP	0.28 (1.6%)	0.05 (3.4%)	--	<0.01 (1.1%)	0.04 (1.0%)

	DCAP	1.32 (7.5%)	0.05 (3.4%)	--	--	0.92 (25.7%)

	3,5-DCHA	--	--	--	<0.01 (2.8%)	--

	A-1	6.80 (38.5%)	 0.49 (35.3%)	0.01 (1.0%)	<0.01 (3.0%)	1.12 (31.5%)

	A-2	1.56 (8.8%)	0.13 (9.4%)	--	0.01 (6.9%)	0.13 (3.6%)

	A-3	2.11 (11.9%)	0.26 (18.6%)	--	--	--

total 

identified	1.91

(10.8%)	0.17

(11.7%)	1.08

(87.3%)	0.06

(50.1%)	1.76

(49.1%)

total identified/characterized	12.38

(70.0%)	1.05 

(75.0%)	1.09 

(88.3%)	0.07

(60.0%)	3.01

(84.2%)

1Table excerpted from DP Barcodes D270711 and D270712; 5/22/01; T.
Bloem. Dicloran = 2,6-dichloro-4-nitroaniline; DCPD =
4-amino-2,6-dichloroaniline; DCHA = 2,6-dichloro-4-hydroxyaniline; DCAA
= 4-amino-3,5-dichloroacetanilide; DCAP = 4-amino-2,6-dichlorophenol;
DCNP = 2,6-dichloro-4-nitrophenol; the petitioner proposed that A-1 was
partially comprised of 2,6-dichloro-3-glutathione-4-nitroaniline and
4-amino-3-chloro-5-glutathioneacetanilide.

The Residue Chemistry Chapter to the RED (C. Olinger, 8/9/05, DP Barcode
D318895) provided an estimate of the maximum theoretical dietary burden.
 Recently HED has updated the approach to estimating livestock dietary
burdens, so a revised dietary burden is provided in Table 2.  The
estimated dietary burdens have decreased from 55 ppm to 20 ppm for dairy
cattle and from 59 ppm to 6.1 ppm for beef cattle.  Despite these
reductions, there is still potential for quantifiable residues in
livestock commodities.  For example, in the livestock metabolism study
(at a dosing level of 360 ppm), the total identified residues of risk
assessment concern in milk were 1.63 ppm.  If the residues are
extrapolated to the maximum reasonable dietary burden, and assuming
residues are linear, the total residues would be 0.09 ppm.  Since these
residues cannot be considered negligible residues, and residues in milk
may not have reached a plateau, a livestock feeding study reflecting 28
days of dosing is needed to determine if quantifiable residues would be
expected at the maximum reasonable dietary burden.

Table 2. Maximum Reasonable Livestock Dietary Burdens for DCNA.

	%  Diet	Dietary Contributions (ppm)

Feedstuff	Type	Tolerance (ppm)	% Dry Matter	Beef	Dairy	Poul-try	Swine
Beef	Dairy	Poul-try	Swine

Roughage

Untreated	R	0	--	15	45	NU	NU	0	0	0	0

Carbohydrate Concentrate

Carrot Culls	CC	24	12	NU	10	NU	NU	0	20	0	0

Potato culls	CC	1.75	20	30	0	NU	NU	2.6	0	0	0

Potato processed waste	CC	1.75	15	30	0	NU	NU	3.5	0	0	0

Untreated	CC	0	--	20	35	75	85	0	0	0	0

Protein Concentrate

Untreated	PC	0	--	5	10	25	15	0	0	0	0

Totals	--	--	--	100	100	100	100	6.1	20	0	0

The registrant has stated that many mammalian feeding studies are
available.  However, the Residue Chemistry Data Requirements (860
series) clearly state that a 28-day feeding study is required when the
metabolism studies indicate the potential for quantifiable residues in
livestock commodities used for human food.  According to the
registrant’s chart of available mammalian feeding studies (p. 22 of
MRID 47573501) only one dairy cattle 28-day study is available, which
was conducted in 1968 (MRID No. 00095935).  Livestock commodities were
analyzed only for the parent dicloran.  The parent was the predominant
residue in only one commodity in the metabolism study, fat.  One of the
residues, DCAP, was found in greater amounts than the parent compound in
milk.  Therefore, HED needs a 28-day day feeding study to accurately
quantify exposure to dicloran and its metabolites in livestock
commodities.

If the feeding study demonstrates the need for livestock tolerances then
reliable enforcement methods for the determination of dicloran and DCAP
residues will be needed.  Multi-residue method testing will be required
for DCAP as well.  If the samples from the livestock feeding study are
stored for more than 30 days, a storage stability study will be needed
to support the feeding study as well.  The registrant has argued that
they have tried to develop methods for these compounds in soil and found
that they were unstable.  However, the characteristics of soil are very
different than livestock commodities.  The registrant was successful in
analyzing for these compounds in the livestock metabolism studies.  In
milk, residues were extracted with methanol and the extract was analyzed
directly.

In conclusion, HED recommends against waiving the livestock feeding
study, the residue analytical method for livestock, the multiresidue
method testing for the livestock metabolite DCAP, and the storage
stability testing for livestock commodities. 

860.1380 Storage Stability Data – Plant Commodities

860.1500 Crop Field Trials

860.1520 Processing Studies

860.1900 Field Accumulation in Rotational Crops

In association with some proposed new uses of DCNA, HED reviewed new
plant metabolism studies (DP Barcodes D270711 and D270712; 5/22/01; T.
Bloem) and identified new residues of concern, DCHA and A-1.  The RED
chapter required additional crop field trial and processing studies (for
the pre-harvest uses of DCNA) including the analysis for the metabolites
of concern, not just the parent.  In the interim, HED used metabolite
ratios from the plant metabolism studies to obtain a rough estimate of
exposure to the metabolite in order to conduct a dietary risk assessment
for the RED.

Registrant’s Position

The registrant believes that they will be unable to develop analytical
methods for these metabolites, based on difficulties obtained when
analyzing for these compounds in soil.  In addition, since no dietary
risks of concern were identified when using the rough metabolite ratios,
the registrant believes that the studies will not affect any regulatory
decision.

Agency Response

The registrant has not provided documentation of any attempts to develop
residue methods in plant commodities, only soil.  The characteristics of
soil and plant commodities are very different.   The registrant was able
to identify and quantify these compounds in plant metabolism and
confined rotational crop studies.   HED would need extensive
documentation of attempts to develop methods in plant commodities before
we would consider waiving these studies based on the inability to
develop data collection methods for the metabolites.

The registrant has also argued that the use of ratios from the plant
metabolism studies is sufficient for risk assessment purposes.  In the
absence of crop field trial, rotational crop, and processing studies for
metabolites, HED uses ratios from metabolism studies to obtain a
reasonable rough estimate of exposure to metabolite residues.  However,
HED recognizes that there can be considerable uncertainty in applying
these ratios from controlled studies from a few crops to many different
commodities and different use conditions.  Therefore, HED requires
residue data for all residues of significant risk assessment concern
unless the registrant demonstrates that methods cannot be developed.  

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