Study Title

Publicly Releasable Summary of the Petition 

for Establishment of a Tolerance for Dodine

in or on the Raw Agricultural Commodity: 

Stone Fruits (Group 12) and Tree Nuts (Group 14)

EPA Registration Action References

Petition for Establishment of Tolerances 

Dodine in or on Stone Fruits and Tree Nuts

(PP# to be assigned)

Author

Bert Volger, Ph.D.

Document Date

May 9, 2011

Prepared by

CERES International LLC

1087 Heartsease Drive

West Chester, PA 19382

Submitted by

Agriphar S.A.

Rue de Renory 26

B-4102 Ougree

Belgium



EPA Registration Division contact: Mary Waller, Registration Division
(7505P), Office of Pesticide Programs, Environmental Protection Agency,
1200 Pennsylvania Ave., NW., Washington, DC 20460–0001; telephone
number:

(703) 305–1825; e-mail address: waller.mary@epa.gov.

AGRIPHAR S.A.

	

PP (to be assigned)>

EPA has received a pesticide petition (PP # to be assigned) from
AGRIPHAR S.A., c/o CERES International LLC, 1087 Heartsease Drive, West
Chester, PA 19382, proposing pursuant to section 408(d) of the Federal
Food, Drug, and Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR part
180 by establishing a tolerance for residues of dodine (dodecylguanidine
acetate) in or on the raw agricultural commodity, stone fruits (Group
12) at 5 parts per million (ppm), tree nuts (Group 14, except almond
hulls) at 0.3 ppm, and almond hulls at 12 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 qualitative nature of the residue of dodine in plants is adequately
understood based on acceptable apple, pecan and strawberry metabolism
studies. These plant metabolism studies have demonstrated that dodine
does not metabolize and is non-systemic (does not translocate within the
plant). The results observed in the plant and livestock metabolism
studies show similar metabolic pathways. The residue of concern, which
should be regulated, is the parent compound, dodine, per se.			

	

2.	Analytical Method

	

An adequate enforcement method using gas chromatography with mass
selective detection (GC/MSD, Method 45137) is available for determining
dodine residues in or on plant commodities. Concerning tree crops, a
method using liquid chromatography with tandem mass spectrometric
detection (LC/MS/MS; METH1595.02) after the samples were extracted with
methanol, was submitted. The limit of quantitation (LOQ = 0.01 ppm) was
taken as the lowest level validated by this method, and the limit of
detection (LOD) was 0.003 ppm.

Adequate data collection method validation, independent laboratory
validation (ILV), and radio-validation data for the method has been
submitted. Since there is no reasonable expectation of finding residues
of dodine in livestock or poultry, no analytical method for animal
tissues is required. 

	

	3. 	Magnitude of Residues

	

For stone fruits (Group 12) and tree nuts (Group 14), complete sets of
residue data have been submitted in support of the petitioned
tolerances.

3.1.    	Stone Fruits

There is an adequate residue data base in support of a crop group
tolerance for stone fruits (Group 12 - representative commodities:
cherries, peaches, plums).

Regarding cherries, a total of nine sweet cherry trials were conducted
in 1997 covering EPA Regions 5, 10, and 11. Six sequential applications
were made on a 6 to 14-day schedule at the target rate of 1.3 lbs
a.i./acre, and a seasonal rate of 7.8 lbs a.i./acre. The measured dodine
residues were in the range of 0.34 to 2.2 ppm, below the established
tolerance for cherries of 3 ppm. In a more recent study (2008, 2009),
four sweet cherry trials were conducted in Michigan (EPA Region V), New
York (EPA Region I) and Washington (EPA Region XI) comparing the
magnitude of dodine residues in or on cherries following six sequential
applications of Syllit FL and Syllit 65W (side by side) at a total
seasonal application rate of 5.2 lbs a.i./acre and a pre-harvest
interval (PHI) of 7 days. The detected average dodine residues were in
the range of 1.5 to 2.9 ppm. 

Regarding peaches, a total of twelve trials were conducted in 1997
covering EPA Regions 1, 2, 5, 6, and 10. Five sequential applications
were made at 1.3 to 2.6 lbs a.i./acre, a total seasonal application rate
of 6.5 to 9.1 lbs a.i./acre, and a PHI of 14 to 15 days. The measured
dodine residues were in the range of 0.43 to 4.04 ppm, below the
established tolerance for peaches of 5 ppm. In the recently submitted
2008 field residue study, three trials were conducted in locations
representative of the major peach production areas in the United States:
New York (EPA Region I), Georgia (EPA Region II) and Michigan (EPA
Region V) comparing the magnitude of dodine residues in or on peaches
following five in season applications of Syllit FL and Syllit 65W at a
total seasonal application rate of 7.8 lbs a.i./acre and a PHI of 15
days. The detected average dodine residues were in the range of 0.75 to
1.1 ppm. 

Regarding plums, a total of six plum trials were conducted in 1995
covering EPA Regions 5, 10, and 12. Six sequential applications were
made at 1.3 lbs a.i./acre, a total seasonal application rate of 7.8 lbs
a.i./acre, and a PHI of 7 days. The measured dodine residues were in the
range of 0.36 to 1.84 ppm. However, the submitted residue data base is
complete and adequate in support of the Stone Fruits Group tolerance. 

3.2.    	Tree Nuts

There is an adequate residue data base in support of a crop group
tolerance for tree nuts (Group 14 - representative commodities: almonds,
pecans).

Regarding almonds, in 2010 a total of five field trials were conducted
in Region 10 representing most of the US almond production.  In each
trial, four applications were made to the almonds at a rate of 1.88 lbs
a.i./acre, resulting in a total seasonal application rate of
7.52 lbs a.i./acre.  Applications were made at full bloom, petal fall,
2 weeks after petal fall and 5 weeks after petal fall.  Samples were
collected at normal harvest, with the exception of the decline trial, in
which samples were also collected 10 days before normal harvest, 5 days
before normal harvest, 5 days after normal harvest and 10 days after
normal harvest.  Dodine was detected at low levels in almond nutmeat
(range <0.01 ppm to 0.106 ppm) and at higher levels in almond hulls
(range 1.2 ppm to 12.2 ppm, average 4.8 ppm).

Regarding pecans, there are field trials from 12 different locations
covering the major US pecan growing areas (EPA Region 4, and 6),
depicting dodine residues in or on pecan nutmeat and shells. These
studies were conducted in 1967 following one to eight air blast
applications at 0.5 to 4.0 lbs a.i./acre before shuck split. The
measured residues at various post-treatment intervals did not exceed 0.8
ppm for nutmeat and shells combined. In a pecan metabolism study, pecans
were treated 3 times prior to shuck split at a nominal rate of 1.7 lbs
a.i./acre yielding a dodine residue level of 0.04 ppm in the nutmeat.
Therefore, the tolerance for dodine residues in nutmeat was established
at 0.3 ppm. 

It can be concluded, when almond residue data are combined with
previously submitted pecan data, the proposed tolerance of 0.3 ppm on
tree nuts (Group 14) is adequately supported.  The data also support the
proposed tolerance of 12 ppm for almond hulls.  

B.	Toxicological Profile

	1.	Acute Toxicity

Dodine has moderate acute toxicity (Category III) in oral (LD50 = 1,456
mg/kg), dermal (LD50 > 2,000 mg/kg), and inhalation studies (LC50 = 1.05
mg/kg). No significant differences exist between females and males. The
only potential systemic toxicity observed in the acute dermal toxicity
study was a slight decrease in body weight at the limit dose. Dodine is
a severe eye irritant in rabbits and a severe dermal irritant or
sensitizer (both Category I).

	

	2.	Genotoxicity

	

The mutagenic potential of dodine was investigated in several in vivo
and in vitro studies.  Results for gene mutation from in vitro mammalian
gene mutation tests as well as from a structural chromosomal aberration
assay with and without metabolic activation were negative. Negative
results also occurred in a mouse bone marrow chromosomal aberration
test. Based on all of these assays, dodine is considered to have no
potential to induce mutagenicity.

	

	

3.	Reproductive and Developmental Toxicity

	

	i.   A two generation rat reproduction study was conducted with dose
levels of 0, 200, 400, and 800 ppm (0, 13, 26, and 53 mg/kg/day for
males and females, respectively).  There were no effects on fertility or
pregnancy at any dose level in rats over two generations.  There was a
decrease in parental body weight, body weight gain or food consumption
in both generations of rats. The offspring of both generations
demonstrated decreased body weight in the high dose group. The no
observed adverse effect level (NOAEL) was determined to be 400 ppm for
systemic effects (26 mg/kg/day for parents and offspring), and (800 ppm
for reproductive parameters ((53 mg/kg/day, LOAEL can not be
determined).

	

	ii.  Teratology studies were conducted in the rat and rabbit.  No
treatment-related mortalities were observed in either study.  No effect
on survival, development or growth of fetuses was noted in either
species in either study.  The maternal and fetal NOAEL was determined to
be (80 mg/kg/day (highest dose tested, LOAEL can not be determined) in
the rabbit study.  In the rat study, the maternal and fetal NOAEL was 10
mg/kg/day based on decreased body weight, body weight gain, and food
consumption (parents) and decreased body weight (pups).  These two
studies demonstrate that dodine was not teratogenic in either rats or
rabbits.

	

	4.	Subchronic Toxicity

	

Rats, mice and dogs all show the same toxicologic response.  The most
common effects for intermediate- or long-term oral toxicity studies were
a decrease in food consumption, body weight and /or body weight gain.
There were some clinical signs observed including excessive salvation
(dog and mice) and hunched posture/hypoactivity (rats), but only the dog
showed treatment-related dose response.

In a 28-day dermal study in rats treated with dodine, no clinical signs
were observed in males or females. Body weight, body weight gain, food
consumption, hematology and clinical chemistries showed no significant
changes. Histopathological adnormalities were limited to the dermal
lesions. The incidence and severity of dermal irritation increased with
the dose. The established systemic NOAEL was ≥200 mg/kg/day (highest
dose tested, LOAEL could not be determined). Based on severe dermal
irritation the dermal LOAEL was 50 mg/kg/day (lowest dose tested, NOAEL
could not be identified). 

	

	5.	Chronic Toxicity

	

i.   Chronic toxicity and oncogenicity was evaluated in the rat, mouse
and dog.  The rat chronic toxicity and oncogenicity was conducted with
dose levels of 0, 200, 400, and 800 ppm (Male: 0, 10, 20, and 42
mg/kg/day; Female: 0, 13, 27, and 54 mg/kg/day).  The NOAEL was 20
mg/kg/day based on decreased body weight gain (LOAEL = 42 mg/kg/day for
males and 54 mg/kg/day for females).  There was no evidence of
carcinogenicity in this study. 

ii.  A mouse chronic toxicity study was conducted with dose levels of 0,
200, 750, and 1500 ppm (Males: 0, 29, 110, and 225 mg/kg/day; Female: 0,
38, 136, and 277 mg/kg/day).  The NOAEL was 110 or 38 mg/kg/day for
males or females, respectively, based on decreased body weight, body
weight gain, and food consumption.  There was also no evidence of
carcinogenicity in this study. 

		

iii.  Chronic toxicity was investigated in dogs using dose levels of 0,
2, 10, and 20 mg/kg/day.  The NOAEL of 10 or 2 mg/kg/day for males or
females was based on decreased food consumption, and decreased weight
gain. There were no treatment-related effects in hematology, clinical
chemistry, urine analysis, ophthalmoscopic examinations, organ weights,
gross - or histopathology in either sex.

	6.	Animal Metabolism

	

 -recovery after 5 days ranged from 94 to 102% of the administered dose.
Only a small amount (≤3.4%) of the administered dose was found in
tissues, mainly in the gastrointestinal tract (0.16 to 1.1%), muscle
(0.02 to 0.61%), and skin (0.06 to 0.21%).

	

7.	Metabolite Toxicology

   

There are no metabolites of toxicological concern, and therefore no
metabolites need to be included in the tolerance expression and require
regulation. 

	

8. 	Endocrine Disruption

Special studies investigating potential estrogenic or other endocrine
effects of dodine have not been conducted.  However, in-life data from
the available toxicology studies for dodine do not indicate that dodine
is an endocrine disruptor.  Specifically, endocrine organ weights (e.g.,
thyroid, testes, ovaries, pituitary from the two-generation study) were
not adversely affected by dodine.  Milestones of sexual development were
not affected by dodine, and reproduction was not adversely affected.
Based on these observations, there is no evidence to suggest that dodine
has an adverse effect on the endocrine system. 

C.	Aggregate Exposure

	

	1.	Dietary Exposure 

	

A tolerance is proposed for residues of dodine in or on stone fruits
(Group 12), tree nuts (Group 14 - except almond hulls), and almond
hulls. For the purpose of assessing the potential dietary exposure (food
+ water) for these proposed tolerances, an exposure assessment was
conducted using Exponent’s Dietary Exposure Evaluation Model (DEEM –
FCID version 2.16), consumption data derived from the 1994 -1998 USDA
Continuing Surveys of Food Intake by Individuals (CSFII), dodine
residues at proposed tolerance levels, DEEM default processing factors,
percent crop treated values for registered uses (100% for proposed
crops), and an Estimated Drinking Water Concentration (EDWC) point
estimate for drinking water contribution. 

	

Food

a.  Acute Dietary Exposure.  No acute dietary assessments were conducted
since no toxicological endpoint attributable to a single exposure was
identified in the available toxicology studies, including the rat and
rabbit developmental studies. 

b.  Chronic Dietary Exposure.  The chronic dietary endpoint is based
upon the NOAEL of 2 mg/kg/day from the one-year dog study, and an
uncertainty factor of 100 (10X for inter-species extrapolation and 10X
for intra-species variation and 1X FQPA Safety Factor). Therefore, the
chronic Population Adjusted Dose (cPAD) was calculated as 0.02
mg/kg/day.  The chronic dietary exposure estimate for the overall US
population is 3.4% of the cPAD of 0.02 mg/kg/day.  Children 1-2 years
old, the most exposed population subgroup, utilize 20.4% of the cPAD. 
The chronic exposure estimates for the overall US population and 32
population subgroups, including infants and children, were less than 21%
of the cPAD.  Based on these exposure estimates, AGRIPHAR concludes that
there is reasonable certainty of no harm for the use of dodine on stone
fruits and tree nuts.

		

ii.        Drinking Water

	

Because of its high soil adsorption, and given the application pattern
of dodine (applied to full crop canopy), its potential to reach surface
and/or ground water is very limited. Therefore exposure via drinking
water is negligible. There are no monitoring data for dodine, so
Estimated Drinking Water Concentrations (EDWC) were calculated using
FIFRA Index Reservoir Screening Tools (FIRST) to estimate dodine
concentrations in surface water, and also using the Screening
Concentration In Ground Water (SCI-GROW) model for estimates in ground
water.  EPA calculated a chronic EDWC value of 4 ppb and 0.08 ppb for
surface and ground water, respectively, assuming the maximum use rate of
13 lbs a.i/acre/year based on the application rate for peaches, pecans,
and walnuts. This annual application rate is twice the rate of the
presently used or proposed for stone fruits and tree nuts (label range
from 3.9 to 7.8 lbs a.i./acre/year).  However, worst-case estimated
dodine residues of 4 µg/L in drinking water were included in the
chronic dietary exposure assessment.  

Non-Dietary Exposure

Not applicable. There are no current non-food uses for dodine registered
under FIFRA, as amended, and no non-food uses are proposed for dodine.

	

D.	Cumulative Effects

To our knowledge there are currently no available data or other reliable
information indicating that any toxic effects produced by dodine would
be cumulative with those of other pesticides; thus only the potential
risks of dodine have been considered in this assessment of its aggregate
exposure.

		

E.	Safety Determination

	1.	US Population

	

No acute dietary assessment was conducted because there is no
toxicological endpoint attributable to a single exposure.  A
conservative chronic exposure analysis was conducted, using tolerance
level residues, with percent crop treated information for the registered
crops obtained by EPA-BEAD (apricots = 1%, apples = 5%, bananas = 100%,
cherries = 5%, nectarines = 1%, peaches =1 %, peanuts = 100%, pears =
10%, pecans = 5%, plums = 1%,  walnuts = 5%), and no adjustment for tree
nuts other than walnuts and pecans (100% treated).  The overall chronic
dietary exposure (food + water) to dodine is low, accounting for 1.7% to
20.4% of the cPAD, depending on the population subgroup. The chronic
exposure for the general US population is 0.000685 mg/kg/day, which uses
3.4% of the cPAD (0.02 mg/kg/day).  The most sensitive population
subgroup, children 1 to 2 years of age, have a chronic exposure (food +
water) of 0.004081 mg/kg/day, which utilizes only 20.4% of the cPAD. 

 Based on the lack of acute toxicity and the chronic exposure analyses,
AGRIPHAR concludes that there is reasonable certainty that no harm will
result from acute and chronic exposure to dodine.

		

	2.	Infants and Children

	

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!mals were more sensitive to dodine than adult animals. The data taken
collectively clearly demonstrate that application of a Food Quality
Protection Act (FQPA) uncertainty factor for increased sensitivity of
infants and children is not necessary for dodine.>

		

F.	International Tolerances

	

At present, there are Codex maximum residue limits (MRLs) established
for dodine on cherries at 3 ppm, nectarines, peaches and pome fruits at
5 ppm. There is no Codex maximum residue limit (MRL) established for
dodine on tree nuts. Therefore, international harmonization is not an
issue at this time.

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