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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
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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 nonsystemic (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 
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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 preharvest 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).
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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.
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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 treatmentrelated 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. 
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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 treatmentrelated effects in hematology, clinical chemistry, urine analysis, ophthalmoscopic 

examinations, organ weights, gross - or histopathology in either sex.

6. Animal Metabolism

The metabolic pathway of dodine appears to be similar in animals and plants. In 

rats dodine was rapidly absorbed, distributed, metabolized and excreted at all dosing 

levels without significant gender differences. The major routes of excretion for dodine 

are through urine and feces with a total recovery of the administered dose. After 5 

days post-exposure 40 to 45% of the dose was excreted in the urine, and 48 to 60% in 

the feces. The key metabolic route involved is a β–oxidation pathway similar to 

medium- and long-chain fatty acid. Oxidation takes place by forming intermediate 

products with shorter chain lengths, apparently 2 carbon atoms at a time, until the 

terminal metabolites, guanidine or urea, are formed and then eliminated in the urine. 

Four metabolites were identified in the urine with the most common being an alcohol 

derivative of dodine. Dodine was not identified in the urine, but found in the feces. 

Total C

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-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 twogeneration 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.
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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. 

i. 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 
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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. 

2. 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

The toxicology database for dodine regarding potential prenatal and postnatal

effects in children is complete according to existing Agency data requirements and 

does not indicate any developmental or reproductive concerns. The developmental 

toxicity studies in rats and rabbits revealed no increased sensitivity of rats or rabbits to

in-utero exposure to dodine. The 2-generation reproduction study did not reveal any 

increased sensitivity of rats to in-utero or postnatal exposure to dodine. Furthermore, 

none of the other toxicology studies revealed any data demonstrating that young 
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animals 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.