Document ID: EPA-HQ-OPP-2005-0308-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2005-12-12T05:00Z

SEQ CHAPTER \h \r 1 FILE NAME:   company.wpt   (7/1/2005) (xml)

Template Number P25

Metiram import crop October 2005 (wine and banana) 	

ATTENTION: 

	All commodity terms must comply with the Food and Feed Commodity
Vocabulary database (http://www.epa.gov/pesticides/foodfeed/).

	All text in blue font (instructions for preparing the document), should
be removed prior to sending the document to the Federal Register Staff. 
Instructional text and prompts in green font should also be removed.

	

COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE

(7/1/2005)

EPA Registration Division contact: [Mary Waller, Product Manager (PM)
21, Telephone Number: (703) 308-9354]	

		

TEMPLATE:

by establishing tolerances for residues of [metiram: a mixture of 5.2
parts by weight of ammoniates of [ethylenebis(dithiocarbamato)) zinc
with 1part by weight ethylenebis (dithiocarbamic acid) bimolecular and
trimolecular cyclic anhydrosulfides and disulfides, calculated as zinc
ethylenebisdithiocarbamate] in or on the raw agricultural commodity
[grapes] at [7.0] parts per million (ppm) and in or on the raw
agricultural commodity [bananas (whole fruit)] at [5.0] 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.

                                      

. [Residue and processing studies on grapes were conducted in Germany,
France, Spain and Italy, in support of a metiram tolerance on grapes for
the purpose of importing wine into the United States.  Thirty-five (35)
field residue trials in Germany were conducted on grapes treated with
Polyram 80 DF fungicide.  Fifteen (15) residue trials in Germany, France
and Spain were conducted with a solo formulation of metiram (5 trials),
a formulation of metiram and pyraclostrobin (5 trials), or a solo
formulation of pyraclostrobin (5 trials).  An additional seven (7)
residue trials were conducted with a formulation of metiram and
pyraclostrobin.  Four (4) residue studies in Italy were conducted with a
formulation of metiram and cymoxanil.  Three grape processing studies,
consisting of a total of 10 trials, were preformed in Germany (4
trials), France (4 trials) and Spain (2 trials).  These studies are
considered suitable for deriving processing factors.  

.  [A developmental toxicity study in rats tested metiram via oral
gavage at doses of 0, 40, 80 and 160 mg/kg/day.  At 160 mg/kg/day, a
slightly decreased body weight gain was observed in the dams.  Also at
160 mg/kg/day, increased pre- and post-implantation losses, decreased
litter size, and decreased litter weight was observed.  Metiram was not
teratogenic.  The NOAEL for both maternal and developmental toxicity was
80 mg/kg/day.  A developmental toxicity study in rabbits tested metiram
at doses of 0, 10, 40 and 120 mg/kg/day. The NOAEL for maternal toxicity
was 10 mg/kg/day based on abortions at 40 and 120 mg/kg/day.  The NOAEL
for developmental toxicity was 40 mg/kg/day based on slightly reduced
fetal weights at 120 mg/kg/day.  

. [Ethylenethiourea (ETU) is a metabolite of Metiram.  

		i. Acute toxicity of ETU.  Based on available acute toxicity data, ETU
does not pose an acute risk.  The acute toxicity studies place ETU in
acute toxicity category III for acute dermal; and in category IV for
acute inhalation, eye irritation and skin sensitization.  An acute oral
toxicity study has not been performed.

		ii. Genotoxicity of ETU.  ETU was tested in a series of in vitro and
in vivo genotoxicity assays.  ETU induced a variety of genotoxic
endpoints, including gene mutation assays (Ames and mouse lymphoma
assays), structural chromosomal assays (aberrations in cultured
mammalian cells, dominant lethal assay), and other genotoxic effects
(bacterial recombination assay, yeast conversion assay).  Although ETU
induced a variety of genotoxic endpoints, it does not appear to be a
potent genotoxic agent.

		iii.  Reproductive and developmental toxicity of ETU.  Developmental
defects in ETU rat studies included hydrocephalus and related CNS
lesions, skeletal malformations and various soft tissue malformations. 
Of the three rat studies conducted, the lowest NOAEL was 5 mg/kg/day
based on developmental defects of the brain (exencephaly, dilated
ventricles and hypoplastic cerebellum) at 10 mg/kg/day.

	iv.  Subchronic toxicity of ETU.  The short-term toxicity of ETU was
investigated in 13-week studies in rat, mouse and dog.  The signs of
toxicity observed were overall similar with the thyroid as the target
organ.  The effects observed typically included changes in thyroid
hormone and TSH levels as well as increased thyroid weights.  

	v.  Chronic toxicity of ETU.  The chronic toxicity of ETU was
investigated in rat, mouse and dog studies.  The signs of toxicity
observed were thyroid hyperplasia, increased thyroid weight and changes
in thyroid hormone and TSH levels.  The lowest NOAEL for chronic effects
was determined to be 2 mg/kg/day observed in the chronic dog study.

. [Metiram: The Environmental Protection agency has evaluated the
dietary exposure from metiram for apples, potatoes, and imported wine
(Metiram Acute, Chronic, and Cancer Dietary Exposure Assessments for the
Reregistration Eligibility Decision. United States Environmental
Protection Agency, PC Code:  014601, DP Barcode D290039,  October 21,
2003).  EPA has determined that for acute dietary exposure to metiram,
females ages 13-49 are the only population of concern.  EPA determined
that acute dietary exposure and risk assessment for all the general
population and all other sub-populations is not required based on
results from toxicological studies.  BASF utilized the exposure
assessments for metiram determined by the EPA and included the
additional dietary exposure for metiram from imported bananas.  The
acute dietary exposure and %aPAD utilized are shown in the table below.

Results for Metiram Acute Dietary Assessment Using the 99.9th Percentile
Exposure Value:

Population Subgroup	aPAD

(mg/kg bw/day)	99.9th Percentile

Exposure

(mg/kg bw/day)	% aPAD

Females

13-49 yrs old	0.01	0.001264	12.64

The acute dietary exposure assessment demonstrates that there is no
safety concern from the acute exposure to metiram.

The chronic dietary metiram exposure and %cPAD utilized are shown in the
table below.  

Results for Metiram Chronic Dietary Assessment:

Population Subgroup	cPAD

(mg/kg bw/day)	Exposure

(mg/kg bw/day)	% cPAD

US Population	0.0004	0.00001677	4.19

Infants < 1 yr	0.0004	0.00005402	13.51

Children 1-2 years old	0.0004	0.00007882	19.71

Children 3-5 years old	0.0004	0.00004771	11.93

Children 6–12 years old	0.0004	0.00001942	4.86

Youth 13-19 years old	0.0004	0.000006	1.50

Adults 20-49 years old	0.0004	0.00000974	2.44

Females 13-49 years old	0.0004	0.00001567	3.92

Adults 50+ years old	0.0004	0.00000852	2.13

The chronic dietary exposure assessment demonstrates that there is no
safety concern from the chronic exposure to metiram.

	ETU: Ethylenethiourea (ETU) is a metabolite of metiram and other EBDC
fungicides.  The U.S. EPA conducted an acute, chronic, and cancer
dietary exposure assessment for ETU to determine the exposure and risk
estimates that may result from the use of metiram on crops included in
the reregistration eligibility decision (RED) (Metiram Acute, Chronic,
and Cancer Dietary Exposure Assessments for the Reregistration
Eligibility Decision. United States Environmental Protection Agency, PC
Code:  014601, DP Barcode D305909,  October 13, 2004).

The EPA has determined that for acute dietary exposure to ETU, females
ages 13-50 are the only population of concern.  The EPA determined that
acute dietary exposure and risk assessment for all the general
population and all other sub-populations is not required based on
results from toxicological studies.  The results presented in this risk
assessment include EPA and higher tiered assessments conducted by BASF
(Metiram-Based Total ETU in Imported Wine: Dietary Exposure and Risk
Analysis. BASF Registration Document Number 2005/7001320, May 25, 2005).
The acute dietary exposure and %aPAD utilized are shown in the table
below.

Results for ETU Acute Dietary Assessment Using the 99.9th Percentile
Exposure Value:

Population Subgroup	aPAD

(mg/kg bw/day)	99.9th Percentile

Exposure

(mg/kg bw/day)	% aPAD

Females

13-49 yrs old	0.005	0.0015016	30.03

The acute dietary exposure assessment demonstrates that there is no
safety concern from the acute exposure to ETU.

The chronic dietary ETU exposure and %cPAD utilized are shown in the
table below.  

Results for ETU Chronic Dietary Assessment :

Population Subgroup	cPAD

(mg/kg bw/day)	Exposure

(mg/kg bw/day)	% cPAD

US Population	0.0002	0.00001157	6.43

Infants < 1 yr	0.0002	0.00001035	5.75

Children 1-2 years old	0.0002	0.00001808	10.04

Children 3-5 years old	0.0002	0.00001094	6.08

Children 6–12 years old	0.0002	0.00000378	2.10

Youth 13-19 years old	0.0002	0.00000187	1.04

Adults 20-49 years old	0.0002	0.00001052	5.84

Females 13-49 years old	0.0002	0.00001001	5.56

Adults 50+ years old	0.0002	0.00001164	6.47

The chronic dietary exposure assessment demonstrates that there is no
safety concern from the chronic exposure to ETU.

The cancer dietary ETU exposure and risk are shown in the table below. 
The Q1* value used in for the cancer risk assessment was 0.0601 (mg/kg
bw/day)-1.  

Results for ETU Cancer Dietary Assessment :

Population Subgroup	Exposure

(mg/kg bw/day)	Estimated Cancer Risk

US Population	0.00001157	6.95 x 10-7

. [The Environmental Protection Agency (EPA) has evaluated the human
exposure of metiram from drinking water and concluded that metiram will
not be present in surface or ground water because metiram is rapidly
degraded in soil and water (Metiram: Health Effects Division (HED) Human
Health Risk Assessments to support Reregistration. United States
Environmental Protection Agency, DP Barcode No. D305906, October 14,
2004).  Therefore, human exposure of metiram in drinking water is not
included in this risk assessment.  Ethylenethiourea (ETU) is a degradate
of metiram and the other Ethylenebisdithio carbamate (EBDC) fungicides
(maneb, mancozeb).  ETU may reach surface and ground water under certain
conditions.  The EPA has determined the Estimated Drinking Water
Concentrations (EDWCs) for ETU (Revised Estimated Drinking Water
Concentrations of Ethylenebisdithio carbamate(EBDC) Degradate
Ethylenethiourea (ETU) for Use in Human Health Risk Assessments. United
States Environmental Protection Agency, DP Barcode D290057, February 5,
2004).  The surface water concentrations for ETU are 1.33 ppb (ug/L) for
acute (peak) exposure, 0.1 ppb for chronic/non-cancer, and 0.08 for
chronic cancer.  The ground water concentration for ETU is 0.21 ppb. 

Aggregate exposure includes exposure from food, drinking water, and
residential uses.  The exposure from residential uses is included in the
short and intermediate-term aggregate exposure assessments.  Metiram is
not registered for any residential use and therefore, a short-term or
intermediate-term aggregate risk was not conducted.  The acute and
chronic aggregate exposure assessment includes exposure from food and
water.  Metiram residues will not be present in drinking water and
therefore, the acute and chronic aggregate assessments include only food
exposure.  The metiram food exposure assessment conducted shows that the
aggregate exposure from apples, potatoes, and wine is not of concern.  

Drinking water exposure for ETU was calculated using DEEM-FCID
commodities “Water, direct, all sources” and “water, indirect, all
sources”.  The chronic and cancer exposure was calculated using a
Estimated Drinking Water Concentration (EDWC) of 0.21 ppb.  The acute
water exposure was calculated using a EDWC value of 1.33 ppb.  

The acute aggregate exposure for ETU including food exposure shown above
with the additional exposure from drinking water is shown below.    

Population Subgroup	aPAD (mg/kg/day)	Food Exp (mg/kg/day)	Water Exp
(mg/kg/day)	Aggregate Total Exposure (food + water)	% aPAD

Females 13-49 years	0.005	0.0015016	0.000065	0.0015666	31.332

The results demonstrate that there are no acute exposure safety concerns
for females 13-49 based on established and new uses, and that the
results clearly meet the FQPA standard of reasonable certainty of no
harm.   

The chronic aggregate exposures for ETU including food exposure shown
above with the additional exposure from drinking water are shown in the
table below.

Population Subgroup	cPAD (mg/kg/day)	Food Exp (mg/kg/day)	Water Exp
(mg/kg/day)	Aggregate Exposure (food + water) 	% cPAD

US Population	0.0002	0.00001157	0.000004	0.00001557	8.65

Infants < 1 yr	0.0002	0.00001035	0.000015	0.00002535	14.08

Children 1-2 years old	0.0002	0.00001808	0.000006	0.00002408	13.38

Children 3-5 years old	0.0002	0.00001094	0.000006	0.00001694	9.41

Children 6–12 years old	0.0002	0.00000378	0.000004	0.00000778	4.32

Youth 13-19 years old	0.0002	0.00000187	0.000003	0.00000487	2.71

Adults 20-49 years old	0.0002	0.00001052	0.000004	0.00001452	8.07

Females 13-49 years old	0.0002	0.00001001	0.000004	0.00001401	7.78

Adults 50+ years old	0.0002	0.00001164	0.000004	0.00001564	8.69

The results demonstrate that there are no chronic exposure safety
concerns for any subpopulation based on established and new uses, and
that the results clearly meet the FQPA standard of reasonable certainty
of no harm.   

The cancer dietary exposure and calculated Drinking Water Levels of
Comparison for ETU are shown in the table below.

Population Subgroup	Q1* (mg/kg/day)	Food Exp (mg/kg/day)	Water Exp
(mg/kg/day)	Aggregate Exposure (food + water) 	Cancer Risk 

US Population	0.0601	0.00001157	0.000004	0.00001557	9.36 x 10-7

	[Section 408(b)(2)(D)(v) of the FFDCA requires that, when considering
whether to establish, modify, or revoke a tolerance, the EPA must
consider available information concerning the cumulative effects of a
particular pesticide’s residues and other substances that have a
common mechanism of toxicity.  

The EPA has concluded that the N-methyl carbamates subgroup should be
designated as a common mechanism group based on their shared ability to
inhibit acetylcholinesterase.  Dithiocarbamates, which includes the EBDC
fungicides, are not included in the cumulative assessment because they
do not share cholinesterase inhibition as a common principal mechanism
of toxicity.  

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