**UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

> **WASHINGTON, D.C. 20460**

![](media/image1.wmf){width="0.85in" height="0.925in"}

> OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

January 24, 2008

**[MEMORANDUM]{.underline}**

SUBJECT: Dodine: Human Health Risk Assessment for Proposed Use Bananas
and Peanuts. PC Code: 044301, Petition No: 7F7185DP Barcode: D338147

Regulatory Action: Section 3 Registration Action

Risk Assessment Type: Single Chemical Aggregate

FROM: Edward Scollon, Toxicologist/Risk Assessor

Michael Doherty, Chemist

Suku Oonnithan, Biologist

Registration Action Branch 2

Health Effects Division (7509P)

THROUGH: Karlyn J. Bailey, Toxicologist

> Margarita Collantes, Biologist
>
> Richard Loranger, Branch Senior Scientist

Christina Swartz, Branch Chief

Registration Action Branch 2

> Health Effects Division (7509P)

TO: Mary Waller/Robert Westin, PM 21

Fungicide Branch

Registration Division (7505P)

**Table of Contents**

**1.0** **Executive Summary** 4

**2.0 Ingredient Profile** 10

2.1 Summary of Proposed Uses 10

2.2 Structure and Nomenclature 11

2.3 Physical and Chemical Properties 11

**3.0** **Hazard Characterization/Assessment** 12

3.1 Hazard and Dose-Response Characterization 12

3.1.1 Database Summary 12

3.1.1.1 Sufficiency of studies/data 12

3.1.1.2 Mode of action, metabolism, toxicokinetic data 12

3.1.2 Toxicological Effects 12

3.1.3 Dose-response 13

3.2 Absorption, Distribution, Metabolism, Excretion (ADME) 14

3.3 FQPA Considerations 14

3.3.1 Adequacy of the Toxicity Database 14

3.3.2 Evidence of Neurotoxicity 14

3.3.3 Developmental Toxicity Studies 15

3.3.4 Reproductive Toxicity Study 15

3.3.5 Additional Information from Literature Sources 15

3.3.6 Pre-and/or Postnatal Toxicity 15

3.3.6.1 Determination of Susceptibility 15

3.3.6.2 Degree of Concern Analysis and Residual Uncertainties 16

3.3.7 Recommendation for Developmental Toxicity Study 16

3.4 Safety Factor for Infants and Children 16

3.5 Hazard Identification and Toxicity Endpoint Selection 17

3.5.1 Acute Reference Dose (aRfD) - General Population and Females 13-49
17

3.5.2 Chronic Reference Dose (cRfD) 17

3.5.3 Incidental Oral Exposure (Short- and Intermediate-Term 17

3.5.4 Dermal Absorption 18

3.5.5 Dermal Exposure (Short-, Intermediate- and Long-Term) 18

3.5.6 Inhalation Exposure (Short-, Intermediate- and Long-Term) 19

3.5.7 Level of Concern for Margin of Exposure 19

3.5.8 Recommendation for Aggregate Exposure Risk Assessments 20

3.5.9 Classification of Carcinogenic Potential 20

3.5.10 Summary of Toxicological Doses and Endpoints for fluazinam for
Use in Human Risk Assessments 21

3.6 Endocrine disruption 23

**4.0 Public Health and Pesticide Epidemiology Data** 24

4.1 Incident Reports 24

**5.0 Dietary Exposure/Risk Characterization** 24

5.1 Pesticide Metabolism and Environmental Degradation
[24](#__RefHeading___Toc139001018)

5.1.1 Metabolism in Primary Crops [24](#__RefHeading___Toc139001019)

5.1.2 Metabolism in Rotational Crops 24

5.1.3 Metabolism in Livestock 24

5.1.4 Analytical Methodology 24

5.1.5 Environmental Degradation 26

5.1.6 Comparative Metabolic Profile 27

5.1.7 Toxicity Profile of Major Metabolites and Degradates 27

5.1.8 Pesticide Metabolites and Degradates of Concern 27

5.1.9 Drinking Water Residue Profile 27

5.1.10 Food Residue Profile 28

5.1.11 International Residue Limits 29

5.2 Dietary Exposure and Risk 29

5.2.1 Acute Dietary Exposure/Risk 29

5.2.2 Chronic Dietary Exposure/Risk 29

5.2.3 Cancer Dietary Risk 30

5.3 Anticipated Residue and Percent Crop Treated (%CT) Information 30

**6.0** **Residential (Non-Occupational) Exposure/Risk
Characterization** 30

**7.0** **Aggregate Risk Assessments and Risk Characterization** 36

7.1 Acute Aggregate Risk 36

7.2 Short- and Intermediate-Term Aggregate Risk 36

7.3 Long Term Aggregate Risk 37

7.4 Cancer Risk 38

**8.0** **Cumulative Risk Characterization/Assessment** 38

**9.0** **Occupational Exposure/Risk Pathway** 38

9.1 Short- and Intermediate-Term Handler Risk 39

9.2 Short- and Intermediate-Term Postapplication Risk 41

**10.0** **Data Needs and Label Requirements** 42

10.1 Toxicology 42

10.2 Residue Chemistry 42

10.3 Occupational and Residential Exposure 43

**References:** 43

**Appendix A: Toxicology Assessment** 44

A.1 Toxicology Data Requirements 44

A.2 Toxicity Profiles 45

A.3 Executive Summaries 48

**Appendix B: Metabolism Assessment** 61

B.1 Metabolism Guidance and Considerations 61

**Appendix C: Tolerance Reassessment Summary and Table** 61

**1.0 Executive Summary**

Dodine is a general use pesticide belonging to the guanidine fungicide
class. It is used as a foliar protectant against various diseases on
fruits and nuts, specifically for control of scab on apples and pears,
leafspot on cherries, foliar diseases of strawberries, bacterial
leafspot on peaches, and leaf blight of sycamores and black walnuts. The
mode of action is through disruption of cell membranes. Currently,
dodine is registered for use on apple, cherry, peach, pear, pecan,
strawberry, and walnut. AGRIPHAR SA, through their agent Ceres
International LLC, has submitted a petition, PP#7F7185, proposing the
establishment of tolerances for residues of dodine (dodecylguanidine
acetate) in/on bananas and peanuts. The Reregistration Eligibility
Decision (RED) for dodine was issued September 2005.

**HUMAN HEALTH RISK ASSESSMENT:**

**[Toxicology/Hazard]{.underline}**

Technical dodine has moderate toxicity via the acute oral, dermal and
inhalation routes of exposure (Category III). It is a severe eye
irritant (Category I) and causes severe dermal irritation (Category I);
it is not a skin sensitizer.

[]{.mark}

A definitive target organ has not been identified for dodine. The most
common effects observed in subchronic and chronic studies were decreases
in food consumption, body weight and/or body weight gain. Possible
neurological clinical signs (excessive salivation and hunched
posture/hypoactivity) were observed in chronic studies in rats and mice
but were not dose-related or statistically significant. Excessive
salivation in the chronic study in dogs showed a treatment- related dose
response; however, it was not consistent with a neurological adverse
effect since it was seen prior to dosing and was a persistent finding
throughout the study. Therefore, there is no evidence of neurotoxicity.
A developmental neurotoxicity (DNT) study is not warranted at this time.

[]{.mark}

In a rat 28-day dermal study, no mortality or clinical signs were
observed in males or females. No treatment-related effects were observed
on body weight, body weight gain, food consumption, hematology and
clinical chemistry. Histopathological alterations were limited to dermal
lesions. []{.mark}

[]{.mark}

Decreased maternal body weight gain and food consumption were observed
in a rat developmental toxicity study at 45 mg/kg/day. In a rabbit
developmental toxicity study, dams demonstrated decreased food
consumption at 80 mg/kg/day. No treatment-related effects were observed
in fetuses in the developmental studies in rats or rabbits.

Dodine did not adversely affect reproductive parameters in rats over two
generations. However, at the highest dose of 53 mg/kg/day, decreases in
parental body weight, body weight gain and food consumption were noted
in both generations of rats. Furthermore, the offspring of both
generations demonstrated decreased body weight after post-natal day 4
which continued through pre-mating.

[]{.mark}

There is no evidence of increased susceptibility (quantitative or
qualitative) in pups versus adults based on rat and rabbit developmental
studies and the rat multi-generation reproduction study. In rat and
rabbit prenatal developmental studies, there was no toxicity identified
in the fetuses up to the highest dose tested. In the two generation
reproduction study, decreases in body weight gain and food consumption
were seen in pups at the same dose at which maternal toxicity (decreased
body weight, body weight gain and food consumption) was observed.
Consequently, there is no concern for pre- or postnatal toxicity
resulting from exposure to dodine; therefore, from the toxicity
perspective and taking into account the exposure component of the risk
assessment, the FQPA safety factor can be reduced (1X).

A weight of evidence evaluation of the carcinogenic potential of dodine
was performed, and based on the results it was concluded that there is
no evidence of carcinogenicity after exposure to dodine (D323607, J.
Morales).

All toxicological endpoints chosen for risk assessment were based on
body weight effects plus, in the case of inhalation, reduced food
consumption.

**[Dietary Exposure (Food/Water)]{.underline}**

A chronic aggregate dietary (food and drinking water) exposure and risk
assessment was conducted using the Dietary Exposure Evaluation Model
DEEM-FCID™, Version 2.03 which uses food consumption data from the U.S.
Department of Agriculture's Continuing Surveys of Food Intakes by
Individuals (CSFII) from 1994-1996 and 1998. The analysis was performed
to evaluate requested new uses of dodine on bananas and peanuts and the
Agency has sufficient data to assess these uses.

The chronic assessment is based on tolerance-level residues and
incorporates percent crop treated information for pome fruit, stone
fruit, strawberry, pecan, and walnut, and assumes 100% crop treated for
bananas and peanuts. Default processing factors from DEEM 7.78 were used
for all processed commodities. An estimate of dodine residue in water
was incorporated directly into the analysis. Based on these input
parameters and assumptions, the chronic dietary risk estimate for the
U.S. population is 3% of the chronic population-adjusted dose (cPAD).
The highest risk estimate is for children 1-2 years of age at 20% of the
cPAD. Therefore, the risk estimates for all population subgroups are
below HED's level of concern (i.e., \< 100% of the cPAD). Given the use
of percent crop treated estimates, the dietary risk estimates should be
considered to be moderately refined.

**[Residential (Non-occupational) Exposure]{.underline}**

There are no registered residential and/or non-agricultural uses for
dodine, and no new such uses are being proposed. However, a related
chemical, dodecylguanidinium hydrochloride (DGH), is
[registered]{.underline} as an antimicrobial pesticide with potential
residential and non-occupational exposures from its incorporation in
paint and disposable diapers. Dodine and DGH have similar chemical
compositions and properties (i.e, both are salts of dodecylguanidine).
In the 1987 Registration Standard for Dodine, dodine and DGH were
reviewed as bio-equivalents. Because both dodine and DGH are expected to
be almost completely dissociated under most environmental conditions,
and certainly under physiological conditions, the two anions are
expected to have negligible effect on the dodecylguanidinium moiety, so
data for dodine can also be considered representative of DGH data, and
vice versa. This should be especially true for toxicological data
(D323607, J. Morales). The residential uses associated with DGH were
previously assessed by the Antimicrobial Division (AD). The DGH
assessment has also been incorporated into the dodine RED. Since AD did
not assess incidental ingestion of paint chips as part of their
assessment, HED has included an assessment for the scenario.

[Handlers]{.underline}

Dermal and inhalation exposures and risks to the residential handlers
(painters) were assessed by AD, using the Pesticide Handler Exposure
Database (PHED) and the Agency's standard values. Since residential
painters typically paint on an intermittent basis, only the short-term
exposure duration (1 -30 days) was necessary to assess. All inhalation,
dermal, and total MOEs of painters were greater than 100 and do not
exceed the Agency's level of concern for residential uses.

[Post-application]{.underline}

Post-application dermal contact with wet paint was not assessed because
the paint is expected to dry within a day, so any potential exposure is
expected to be negligible. DGH has a low vapor pressure (i.e.,
\<1x10^-7^ mmHg \@25°C), therefore it is not likely to generate
sufficient vapor to cause an inhalation concern to residential
populations performing post-application tasks or occupying recently
treated areas. Thus, there are no risk concerns and inhalation
post-application exposures were not quantitatively evaluated.

The incidental ingestion of paint chips from uses of DGH was assessed
using the HED's Residential Standard Operating Procedures (SOP). The
short-term oral MOE is greater than 100 and; therefore, is not of
concern.

DGH is also incorporated as a bacteriostat in the manufacturing of the
absorbent material used in disposable diapers. Residential dermal
exposures and risks to infants (\< 1 year old) who wear DGH-impregnated
diapers were estimated as part of this assessment. Since infants
typically wear diapers on a continuous basis, short-, intermediate- and
long-term exposure durations were assessed. No data on leaching or
migration data of DGH to skin of infants were provided to support this
use; therefore, all of the assumptions used for calculating the
exposures in this assessment are based on the Agency's standard values.

For estimating the exposure of infants to DGH when used in diapers, AD
used two transfer factors, 100% and 5%. A 100% transfer factor resulted
in MOEs of concern for all exposure durations (MOE = 36). However, using
a transfer factor of 5%, which is based on the default percent transfer
factor for pesticide residues migrating from carpets to skin surfaces
(Revisions to the Standard Operating Procedures (SOPs) for Residential
Exposure Assessments; Policy 12; US EPA, 2001), the MOEs for all
durations were greater than 100 and were not of concern (MOE = 714 ). In
order to refine dermal exposure resulting from use of DGH-impregnated
diapers and to fully answer the rate of migration of DGH to the skin of
infants, AD indicated the need for an impregnated diaper migration study
as confirmatory data to support the lower transfer factor assumption.

For purposes of refining the dermal exposure resulting from use of
diapers impregnated with DGH and incorporating this use into an
aggregate risk (ie., dietary + drinking water + residential exposure)
for the Dodine Human Health Risk Assessment, [HED]{.underline} performed
a back calculation to determine what transfer factor would be required
to reach an MOE of 120 (for purposes of aggregate risk since an MOE of
100 for diaper exposure alone will not be sufficient). The calculations
determined that a 30% transfer factor would be required to result in an
MOE of 120.

HED believes that a transfer factor of 100% is an overestimate of
exposure in determining the amount of DGH transferred to infants from
diapers. Although using either 30% or 5 % transfer factors result in
MOEs that are not of concern, HED has no means to confirm these
estimates of exposure. Therefore, **HED concurs with AD's request for**
**submission of an impregnated diaper migration study as confirmatory
data.**

**[Aggregate Risk]{.underline}**

In examining aggregate exposure, the HED aggregated exposures to dodine
in food + water with exposures to DGH from residential uses.
Accordingly, risk assessments for aggregate exposure (food + drinking
water + residential) were considered only for the short-term for adults
handling paints, and short-, intermediate-, and long-term for infants
wearing diapers.

The aggregate MOEs for adult subpopulations are \> 100 and therefore
represent risk estimates which are not of concern to HED. The aggregate
MOEs for infants wearing DGH-impregnated diapers range from 34 to 640
and indicate that there may be risks of concern, depending on what
assumptions are made regarding the amount of DGH that is transferred
from the diaper to the infant.

**[Occupational Exposure/Risk]{.underline}**

HED's level of concern is for MOEs equal to or less than 100. Therefore,
all MOEs greater than 100 are not of concern. Since the dermal and
inhalation endpoints are based on the same effects, the dermal and
inhalation exposures were added together to obtain a total MOE.

The petitioner has not submitted any product specific occupational
exposure data; therefore, HED default values and PHED were used to
estimate the exposures to pesticide handlers.

The exposure estimates indicate that the risks from all handler
scenarios are not of concern (MOEs ≥ 100) at baseline PPE (long-sleeve
shirt, long pants, shoes, socks, and no respirator), with two
exceptions. The mixer/loader scenarios at baseline resulted in risks of
concern (Dermal MOEs=11 and 94). However, the addition of gloves
resulted in MOEs (MOE \> 100) that are not of concern. Furthermore, the
label mandates use of chemical-resistant gloves for handlers under PPE.

Post-application exposures were estimated using default dermal transfer
coefficients from the HED\'s Exposure SAC Policy No. 3.1. It should be
noted that there was no transfer coefficient data in Policy 3.1 for
banana. Therefore, surrogate transfer coefficient values for
bunch/bundle crop groups (i.e., hops and tobacco) were used to assess
postapplication exposure and risk for bananas. All postapplication MOEs
were greater than 100 on day 0 after application, and therefore are not
of concern to HED.

[Restricted Entry Interval (REI):]{.underline}

Dodine has moderate acute toxicity by oral, dermal, and inhalation
routes (Categories III) and is not a skin sensitizer. However, it is a
severe dermal and eye irritant (Toxicity Categories I). Chemicals
classified as Toxicity Category I require a 48-hour REI in accordance
with Worker Protection Standards (WPS) in addition to double layer
clothing, chemical resistant footwear, gloves, respiratory device and
protective eyewear. HED concurs with the 48-hour REI on the proposed
product label.

**Environmental Justice Considerations**

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, \"Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations\"
<http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf>).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures.
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup's
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting. Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Survey of Food Intakes by Individuals (CSFII) and are used in pesticide
risk assessments for all registered food uses of a pesticide. These data
are analyzed and categorized by subgroups based on age, season of the
year, ethnic group, and region of the country. Whenever appropriate,
non-dietary exposures based on home use of pesticide products and
associated risks for adult applicators and for toddlers, youths, and
adults entering or playing on treated areas postapplication are
evaluated. Further considerations are currently in development as OPP
has committed resources and expertise to the development of specialized
software and models that consider exposure to bystanders and farm
workers as well as lifestyle and traditional dietary patterns among
specific subgroups.

**[Review of Human Research]{.underline}**

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical. These studies, which comprise the Pesticide Handlers Exposure
Database (PHED), have been determined to require a review of their
ethical conduct, and have received that review. The studies in PHED are
considered appropriate (ethically conducted) for use in risk
assessments.

**[Additional Data Needs/Recommendations]{.underline}**

[Occupational and Residential Exposure]{.underline}

-   HED recommends a conditional registration based on submission of an
    impregnated diaper migration study as confirmatory data.

[Regulatory Recommendations and Residue Chemistry
Deficiencies]{.underline}

**Directions for Use**

-   The proposed use on banana does not include a maximum seasonal rate.
    In addition, the crop field trial data from Hawaii do not reflect
    the proposed use pattern. The petitioner should modify the proposed
    label such that the use pattern on banana corresponds to the use
    pattern of the banana crop field trials: five applications at 0.71
    lb ai/A/application, for a maximum seasonal rate of 3.6 lb ai/A,
    with a minimum retreatment interval of 6 days and a PHI of 0 days.

```{=html}
<!-- -->
```
-   The petitioner has indicated that the proposed tolerance for bananas
    is intended to apply to domestic bananas as well as imported
    bananas, but that the use directions for foreign countries have not
    yet been finalized. To allow HED to determine that the submitted
    crop field trial data adequately reflect the use of dodine on
    bananas in countries outside the U.S., when the use directions have
    been finalized, the petitioner should submit copies of product
    labels (with English translations, if needed) with use directions on
    bananas from all countries in which dodine is to be applied to
    bananas destined for import into the U.S. If the finalized use
    directions differ significantly from the use patterns of the
    submitted crop field trial data, additional data may be required.

**Residue Analytical Methods**

-   Method METH1595.02 should be modified to remove the conversion of
    residue results to "dodine free base" (this calculation is made at
    the step in which standard solutions are prepared). Residue results
    [must]{.underline} be calculated in terms of dodine, as
    N-dodecylguanidine acetate in order to correspond to the tolerance
    expresson. In addition, the typographical error in step 9.3.7 of the
    method should be corrected \["Repeat steps 9.2.3 to 9.2.6 two more
    times" should be changed to "Repeat steps 9.3.3 to 9.3.6 two more
    times"\].

**Proposed Tolerances**

-   The proposed tolerance for peanut should be revised from 0.03 ppm to
    0.013 ppm.

**Confined Accumulation in Rotational Crops**

-   Confined rotational crop data are required to support the proposed
    use on peanuts. A confined rotational crop study was required in the
    Revised RED Chapter (DP# 320758, 9/14/05, D. Soderberg). These data
    remain outstanding. HED recommends the registration of the uses on
    peanuts be made conditional on the future submission of these data.

**Field Accumulation in Rotational Crops**

-   The need for field rotational crop studies and/or rotational crop
    restrictions/tolerances will be determined when an adequate confined
    rotational crop study has been submitted.

**Provided the above issues are addressed, HED recommends for the
establishment of the tolerances specified in Table C.1.**

**2.0 Ingredient Profile**

Dodine (n-dodecylguanidine acetate) is a non-systemic guanidine based
fungicide registered for the control of certain fungal diseases on
apples, cherries, peaches, pears, pecans, walnuts, strawberries, and
ornamental trees. It is a white crystalline solid formulated as wettable
powder and flowable concentrate. The proposed formulation is Syllit^®^
FL Fungicide (EPA Reg. No. 55260-6), which is a liquid flowable
containing 39.6% or 3.4 lb dodine/gallon as the sole active ingredient
(ai).

The petitioner is proposing the addition of two new sites, banana and
peanut to the registered uses of dodine. On banana, the recommended
application rate is 0.64-1.3 lb ai/A for the first application followed
by four applications at 0.64 lb ai/A at 7-15 day intervals. The product
is applied using aerial equipment in 9-18 pints/A water plus 5-7 pints
of mineral oil/A. The maximum seasonal rate is 3.83 lb ai/A. On peanut,
three applications of Syllit^®^ FL Fungicide are made at 0.64 lb
ai/A/application at 10-14 intervals using ground equipment. The maximum
seasonal rate is 1.91 lb ai/A. []{.mark}

1.  **Summary of Proposed Uses**

+----------+--------+------+--------+----------+-----+----------------+
| **Table  |        |      |        |          |     |                |
| 2.1.     |        |      |        |          |     |                |
| Summary  |        |      |        |          |     |                |
| of       |        |      |        |          |     |                |
| Proposed |        |      |        |          |     |                |
| Use      |        |      |        |          |     |                |
| Patterns |        |      |        |          |     |                |
| for the  |        |      |        |          |     |                |
| End-Use  |        |      |        |          |     |                |
| Di       |        |      |        |          |     |                |
| rections |        |      |        |          |     |                |
| for Use  |        |      |        |          |     |                |
| of       |        |      |        |          |     |                |
| D        |        |      |        |          |     |                |
| odine.** |        |      |        |          |     |                |
+==========+========+======+========+==========+=====+================+
| Applic.  | Formu  | App  | Max.   | Max.     | PHI | Use Directions |
| Timing,  | lation | lic. | No.    | Seasonal |     | and            |
| Type,    |        | Rate | A      | Applic.  | (da | Limitations    |
| and      | \[EPA  |      | pplic. | Rate     | ys) |                |
| Equip.   | Reg.   | (lb  | per    |          |     |                |
|          | No.\]  | a    | Season | (lb      |     |                |
|          |        | i/A) |        | ai/A)    |     |                |
+----------+--------+------+--------+----------+-----+----------------+
| Banana:  |        |      |        |          |     |                |
| Sigatoka |        |      |        |          |     |                |
+----------+--------+------+--------+----------+-----+----------------+
| Postem   | 3.4    | 0.64 | 5      | Not      | 0   | Applications   |
| ergence, | lb/gal | -1.3 |        | s        |     | may be made at |
| Foliar,  | FlC    |      |        | pecified |     | up to 1.3 lb   |
|          | \[552  |      |        | (NS)     |     | ai/A through   |
| Aerial   | 60-6\] |      |        |          |     | first cover    |
| e        |        |      |        |          |     | applications;  |
| quipment |        |      |        |          |     | subsequent     |
|          |        |      |        |          |     | applications   |
|          |        |      |        |          |     | to be made at  |
|          |        |      |        |          |     | 0.64 lb ai/A.  |
|          |        |      |        |          |     | A retreatment  |
|          |        |      |        |          |     | interval of    |
|          |        |      |        |          |     | 7-15 days is   |
|          |        |      |        |          |     | proposed.      |
|          |        |      |        |          |     | Applications   |
|          |        |      |        |          |     | are to be made |
|          |        |      |        |          |     | in a mixture   |
|          |        |      |        |          |     | of 1.1-2.3 gal |
|          |        |      |        |          |     | water/A and    |
|          |        |      |        |          |     | 0.6-0.9 gal    |
|          |        |      |        |          |     | mineral oil/A. |
+----------+--------+------+--------+----------+-----+----------------+
| Peanut   |        |      |        |          |     |                |
+----------+--------+------+--------+----------+-----+----------------+
| Poste    | 3.4    | 0.64 | 3      | 1.9      | 14  | Applications   |
| mergence | lb/gal |      |        | (        |     | are to begin   |
|          | FlC    |      |        | implied) |     | when disease   |
| Foliar   | \[552  |      |        |          |     | first appears  |
|          | 60-6\] |      |        |          |     | (\~35 days     |
| Ground   |        |      |        |          |     | after          |
| or       |        |      |        |          |     | planting) and  |
| aerial   |        |      |        |          |     | to be repeated |
| e        |        |      |        |          |     | at retreatment |
| quipment |        |      |        |          |     | intervals of   |
|          |        |      |        |          |     | 10-14 days.    |
|          |        |      |        |          |     | The feeding of |
|          |        |      |        |          |     | hay and vines  |
|          |        |      |        |          |     | to livestock   |
|          |        |      |        |          |     | is prohibited. |
+----------+--------+------+--------+----------+-----+----------------+

**2.2 Structure and Nomenclature**

  ------------------------------------------------------------------------
  **Table 2.2 Dodine  
  Structure and       
  Nomenclature**.     
  ------------------- ----------------------------------------------------
  Chemical structure  ![](media/image2.wmf){width="2.8069444444444445in"
                      height="1.1423611111111112in"}

  Common name         Dodine

  Company             N/A
  experimental name   

  IUPAC name          1-dodecylguanidinium acetate

  CAS name            dodecylguanidine monoacetate

  CAS registry number 2439-10-3

  End-use product     Syllit® FL Fungicide; EPA Reg. No. 55260-6; 3.4
  (EP)                lb/gal FlC formulation
  ------------------------------------------------------------------------

**2.3 Physical and Chemical Properties**

+------------------------+--------------------------+-----------------+
| **Table 2. 3           |                          |                 |
| Physicochemical        |                          |                 |
| Properties of          |                          |                 |
| Dodine.**              |                          |                 |
+========================+==========================+=================+
| Parameter              | Value                    | Reference       |
+------------------------+--------------------------+-----------------+
| Melting point/range    | Number range             | Product         |
|                        | CHAPTER136-137 ºC        | Chemistry       |
|                        |                          | Chapter of the  |
|                        |                          | Dodine          |
|                        |                          | Reregistration  |
|                        |                          | Standard        |
|                        |                          | (10/1/86)       |
+------------------------+--------------------------+-----------------+
| pH                     | 7.6 at 21 ºC (1% aqueous | MRID 45322705   |
|                        | suspension)              |                 |
|                        |                          |                 |
|                        | 7.0 at 25 ºC (saturated  |                 |
|                        | aqueous solution)        |                 |
+------------------------+--------------------------+-----------------+
| Density                | 0.55 kg/L unpacked;      | RD Memorandum,  |
|                        |                          | 9/13/88, A.     |
|                        | 0.64 kg/L packed         | Smith           |
+------------------------+--------------------------+-----------------+
| Water solubility       | 0.07%                    | 2001 Farm       |
|                        |                          | Chemicals       |
|                        |                          | Handbook        |
+------------------------+--------------------------+-----------------+
|                        | 0.104 g/100 mL at 21 ºC  | RD Memorandum,  |
|                        |                          | 9/13/88, A.     |
|                        |                          | Smith           |
+------------------------+--------------------------+-----------------+
| Solvent solubility     | Soluble in methanol and  | 2001 Farm       |
|                        | ethanol; practically     | Chemicals       |
|                        | insoluble in most        | Handbook        |
|                        | organic solvents         |                 |
+------------------------+--------------------------+-----------------+
|                        | [At 22 ºC]{.underline}   | RD Memorandum,  |
|                        |                          | 9/13/88, A.     |
|                        | 18.1 g/100 mL in         | Smith           |
|                        | methanol                 |                 |
|                        |                          |                 |
|                        | 7.8 g/100 mL in ethanol  |                 |
|                        |                          |                 |
|                        | 0.003 g/100 mL in        |                 |
|                        | acetone                  |                 |
|                        |                          |                 |
|                        | 0.0006 g/100 mL in       |                 |
|                        | n-hexane                 |                 |
|                        |                          |                 |
|                        | Insoluble in toluene     |                 |
+------------------------+--------------------------+-----------------+
| Vapor pressure         | 1.5 x 10^-7^ mm Hg at 25 | Section C of    |
|                        | ºC;                      | PP#7F7185       |
|                        |                          |                 |
|                        | No detectable vapor      | RD Memorandum,  |
|                        | pressure at 50 ºC        | DP# 273321,     |
|                        |                          | 6/18/01 H.      |
|                        |                          | Podall          |
+------------------------+--------------------------+-----------------+
| Dissociation constant, | Completely dissociated   | RD Memorandum,  |
| pK~a~                  |                          | 9/13/88, A.     |
|                        |                          | Smith           |
+------------------------+--------------------------+-----------------+
| Octanol/water          | P = 5.77; Log P = 0.76   | RD Memorandum,  |
| partition coefficient, | at 22 ºC                 | 9/13/88, A.     |
| Log(K~OW~)             |                          | Smith           |
+------------------------+--------------------------+-----------------+
| UV/visible absorption  | No color; No             | MRID 40975701   |
| spectrum               | chromophore; No          |                 |
|                        | absorption between 300 - |                 |
|                        | 540 nM                   |                 |
+------------------------+--------------------------+-----------------+

**3.0 Hazard Characterization/Assessment**

**3.1 Hazard and Dose-Response Characterization**

**3.1.1 Database Summary**

1.  **Sufficiency of studies/data**

The database for dodine is complete and there are no datagaps. The
available toxicity data are adequate to assess the chemical's hazard
potential. The database contains the following toxicity studies: (i) a
subchronic mouse toxicity study (ii) chronic rat, mouse, and dog
toxicity studies, (iii) 28-day dermal and dermal penetration studies
(rats), (iv) prenatal developmental studies (rats and rabbits), and (v)
a reproduction study in rats. There are also acute LD50 studies, a
metabolism study, and a complete mutagenicity battery.

[]{.mark}

2.  **Mode of action, metabolism, toxicokinetic data**

Dodine is a fungi-toxic cationic surfactant that has a non-specific mode
of action. Dodine acts by interfering with membrane structure, mainly by
altering cell permeability to allow leakage of phosphorus and amino
materials from poisoned cells.

1.  **Toxicological effects**

Technical dodine has moderate toxicity via the acute oral, dermal and
inhalation routes of exposure (Category III). It is a severe eye
irritant (Category I) and causes severe dermal irritation (Category I);
it is not a skin sensitizer.

[]{.mark}

A definitive target organ has not been identified for dodine. The most
common effects observed in subchronic and chronic studies were decreases
in food consumption, body weight and/or body weight gain. Possible
neurological clinical signs (excessive salivation and hunched
posture/hypoactivity) were observed in chronic studies in rats and mice
but were not dose-related or statistically significant. Excessive
salivation in the chronic study in dogs showed a treatment- related dose
response; however, it was not consistent with a neurological adverse
effect since it was seen prior to dosing and was a persistent finding
throughout the study. Therefore, there is no evidence of neurotoxicity.
A developmental neurotoxicity (DNT) study is not warranted at this time.

[]{.mark}

In a rat 28-day dermal study, no mortality or clinical signs were
observed in males or females. No treatment-related effects were observed
on body weight, body weight gain, food consumption, hematology and
clinical chemistry. Histopathological alterations were limited to dermal
lesions. []{.mark}

[]{.mark}

Decreased maternal body weight gain and food consumption were observed
in a rat developmental toxicity study at 45 mg/kg/day. In a rabbit
developmental toxicity study, dams demonstrated decreased food
consumption at 80 mg/kg/day. No treatment-related effects were observed
in fetuses in the developmental studies in rats or rabbits.

Dodine did not adversely affect reproductive parameters in rats over two
generations. However, at the highest dose of 53 mg/kg/day, decreases in
parental body weight, body weight gain and food consumption were noted
in both generations of rats. Furthermore, the offspring of both
generations demonstrated decreased body weight after post-natal day 4
which continued through pre-mating.

[]{.mark}

There is no evidence of increased susceptibility (quantitative or
qualitative) in pups versus adults based on rat and rabbit developmental
studies and the rat multi-generation reproduction study. In rat and
rabbit prenatal developmental studies, there was no toxicity identified
in the fetuses up to the highest dose tested. In the two generation
reproduction study, decreases in body weight gain and food consumption
were seen in pups at the same dose at which maternal toxicity (decreased
body weight, body weight gain and food consumption) was observed.
Consequently, there is no concern for pre- or postnatal toxicity
resulting from exposure to dodine; therefore, from the toxicity
perspective, the FQPA safety factor can be reduced (1X).

There was equivocal evidence of carcinogenicity in rat and mouse
carcinogenicity studies; however, a weight of evidence evaluation of the
carcinogenic potential of dodine was performed, and based on the results
it was concluded that there is no evidence of carcinogenicity after
exposure to dodine (D323607, J. Morales).

2.  **Dose Response**

For chronic dietary exposure, the chronic toxicity study in dogs was
used to calculate the chronic reference dose (cRfD) of 0.02 mg/kg/day.
The NOAEL of 2 mg/kg/day is based on changes in body weight in females
at the LOAEL of 10 mg/kg/day; no appropriate endpoint was identified for
acute dietary exposure. A 28-Day dermal toxicity study was used to
select the dose and endpoint for occupational and residential dermal
exposure (all durations). Although a LOAEL was not established in the
study, the NOAEL of 200 mg/kg/day is considered protective and
appropriate for endpoint selection (see section 3.5.6). The
developmental toxicity study in rats was used to select the dose and
endpoint for occupational and residential short-term inhalation
exposure. The NOAEL of 10 mg/kg/day is based on changes in body weight
in females at the LOAEL of 45 mg/kg/day. Additionally, the 2-generation
reproduction study was selected for incidental oral exposure. The
developmental (offspring) NOAEL of 26 mg/kg/day is based on decreased
pup weights at the LOAEL of 53 mg/kg/day.

1.  **Absorption, Distribution, Metabolism, Excretion (ADME)**

[]{.mark}

Dodine was rapidly absorbed, distributed, metabolized and excreted at
all dosing levels with no significant gender differences. Urine and
feces were found to be major routes of excretion for dodine. At 120
hours (5 days) post-exposure, 40.55 to 45.35 % of the dose was excreted
in the urine and 47.63 to 59.69 % was excreted in the feces in all dose
groups. Total recovery at 120 hours ranged from 93.61 to 102.22 % of the
administered dose. Tissues were collected and analyzed for
radioactivity. Upon analysis, ≤ 3.35% of the administered dose was
recovered in tissues. The highest amounts recovered were in the
gastrointestinal tract (0.16-1.14% of the dose), muscle (0.02-0.61% of
the dose) and skin (0.06-0.21%).

Urine and fecal samples from one animal/sex in each dose group were
analyzed for metabolites. In urine, the unmetabolized parent compound
was not identified; however, four metabolites were identified. The major
metabolite was an alcohol of dodine, hydroxydodecylguanidine, and
accounted for 10.98 to 23.52% of the administered dose. Females did have
a slight increase in this metabolite when compared to males. Urea and
two unidentified metabolites which appeared to be carboxylic acid
products arising from oxidation of the alkane side chain account for the
remaining metabolites. Parent compound was identified as the major
metabolite in fecal samples, accounting for 0.17 to 4.17% of the dose.

The proposed metabolic pathway for dodine in rats is a ß-oxidation
pathway similar to that for medium- and long-chain fatty acids.
Oxidation takes place by forming intermediate products with shorter
chain lengths which are eliminated in the urine. Urea is also formed in
the liver from action on dodine or one of its metabolites.

**3.3 FQPA Considerations**

**3.3.1 Adequacy of the Toxicity Data Base**

The toxicology database is adequate for the evaluation of risks to
infants and children. Acceptable studies include: developmental toxicity
studies in rats and rabbits and a 2-generation reproduction study in
rat.

**3.3.2 Evidence of Neurotoxicity**

Neurotoxicity studies are not available for dodine. Possible
neurological clinical signs (excessive salivation and hunched
posture/hypoactivity) were observed in chronic studies in rats and mice
but were not dose-related or statistically significant. Excessive
salivation in dogs showed a treatment related dose response; however, it
was not consistent with a neurological adverse effect since it was seen
prior to dosing and was a persistent finding throughout the study. In
addition, no evidence of neuropathology was observed in the available
studies.

**3.3.3 Developmental Toxicity Studies**

In a rat developmental toxicity study, decreases in body weight gain and
food consumption were observed at ≥ 45 mg/kg/day in maternal animals. No
treatment-related effects were observed in fetuses up to 90 mg/kg/day.

In a rabbit developmental toxicity study, dams demonstrated decreased
food consumption at 80 mg/kg/day; however, this finding was not
considered adverse. No treatment-related effects were observed in
fetuses up to 80 mg/kg/day.

In the rabbit developmental study, animals were not dosed up to the
limit dose of 1000 mg/kg/day and no treatment-related effects were
observed in the study up to the highest dose tested of 80 mg/kg/day.
However, the rat (LOAEL =45 mg/kg/day) is considered the most sensitive
species and is protective of potential developmental effects. Therefore,
the developmental toxicity rabbit study is acceptable for risk
assessment and data gathered from an additional study would not provide
additional information.

**3.3.4 Reproductive Toxicity Study**

In a two-generation reproduction toxicity study in rats, decreases in
parental body weight, body weight gain and food consumption were noted
in both generations of rats at 53 mg/kg/day. Additionally at 53
mg/kg/day, the offspring of both generations demonstrated decreased body
weight after post-natal day 4 which continued through pre-mating. No
treatment-related effects were noted on reproduction parameters.

**3.3.5 Additional Information from Literature Sources**

The toxicological database for dodine, including all subchronic and
chronic studies, was evaluated by an international peer review
committee. The conclusions from that report can be found under the
following reference:

JMPR Report. 2000. Pesticide Residues In Food 2000 : Dodine; First draft
prepared by Virginia A. Dobozy, US Environmental Protection Agency,
Washington DC, (4.10, page 79).
[[http://www.fao.org/ag/AGP/AGPP/Pesticid/Default.html]{.underline}](http://www.fao.org/ag/AGP/AGPP/Pesticid/Default.html)

**3.3.6 Pre-and/or Postnatal Toxicity**

1.  **Determination of Susceptibility**

There is no concern for increased quantitative and/or qualitative
susceptibility after *in utero* or postnatal exposure to dodine in
developmental toxicity studies in rats and rabbits, or a reproduction
study in rats.

**3.3.6.2 Degree of Concern Analysis and Residual Uncertainties for Pre
and/or Post-natal Susceptibility**

The purpose of the Degree of Concern analysis are: (1) to determine the
level of concern for the effects observed when considered in the context
of all available toxicity data; and (2) to identify any residual
uncertainties after establishing toxicity endpoints and traditional
uncertainty factors to be used in the risk assessment. If residual
uncertainties are identified, then HED determines whether these residual
uncertainties can be addressed by a FQPA safety factor and, if so, the
size of the factor needed.

There is no evidence (quantitative or qualitative) of increased
susceptibility and no residual uncertainties with regard to pre- and/or
postnatal toxicity following *in utero* exposure to rats or rabbits and
pre and/or postnatal exposures to rats. Therefore, it is recommended
that the FQPA safety factor be reduced to 1X and no additional safety
factors are needed (section 3.4).

**3.3.7 Recommendation for a Developmental Neurotoxicity Study**

Possible neurological clinical signs (excessive salivation and hunched
posture/hypoactivity) were observed in chronic studies in rats and mice
but were not dose-related or statistically significant. Excessive
salivation in the chronic study in dogs showed a treatment related dose
response; however, it was not consistent with a neurological adverse
effect since it was seen prior to dosing and was a persistent finding
throughout the study. In addition, no evidence of neuropathology was
observed in the available studies. Therefore, there is no evidence of
neurotoxicity. Based on the weight of evidence, a developmental
neurotoxicity (DNT) study is not warranted at this time.

3.  **Safety Factor for Infants and Children**

HED recommends the FQPA SF be reduced to 1X because there is no evidence
of increased susceptibility; there are no residual uncertainties with
regard to pre- and/or postnatal toxicity; and the toxicological database
for dodine is complete. After evaluating the toxicological and exposure
data, the dodine risk assessment team recommends that the FQPA SF be
reduced to 1X based on the following:

-   The toxicity data showed no increase in susceptibility in fetuses
    and pups with *in utero* and post-natal exposure

-   The dietary food exposure assessment is based on HED-recommended
    tolerance-level residues and health-protective modeling assumptions.
    Although percent crop treated estimates are used for crops with
    existing tolerances, the use of tolerance values for residue levels
    likely overestimate actual exposures.

-   The dietary drinking water assessment is based on values generated
    by model and associated modeling parameters which are designed to
    provide conservative, health protective, upper-bound estimates of
    water concentrations.

-   The residential exposure assessment utilizes reasonable high-end
    variables set out in HED's Residential Exposure SOPs. The aggregate
    assessment is based upon reasonable worst-case residential
    assumptions, and is also not likely to underestimate exposure/risk
    to any subpopulation, including those comprised of infants and
    children.

**3.5 Hazard Identification and Toxicity Endpoint Selection**

1.  **Acute Reference Dose (aRfD) - General Population and Females
    13-49**

No appropriate endpoint was identified for the general population or
females age 13-49 that could be attributed to a single dose.

**3.5.2 Chronic Reference Dose (cRfD)**

**Study Selected:** Chronic Toxicity-Dog

**MRID No:** 44246101

**Dose and Endpoint for Risk Assessment:** NOAEL = 2 mg/kg/day

**Uncertainty Factor:** 100X (10X interspecies extrapolation, 10X
intraspecies variability)

+-----------------------------------------------------------------------+
| **Chronic RfD** = [2 *mg/kg/day*]{.underline} = **0.02 mg/kg/day**    |
|                                                                       |
| 100 (*UF*)                                                            |
+-----------------------------------------------------------------------+

**[Comments about Study/Endpoint/UF:]{.underline}**

A chronic toxicity study in dogs was used to select the dose and
endpoint for establishing the cRfD of 0.02 mg/kg/day. This study is the
appropriate route and duration to establish a chronic dietary endpoint.
The NOAEL of 2 mg/kg/day is based on weight loss in females observed at
the LOAEL of 10 mg/kg/day. Uncertainty factors (100X) include: 10X
interspecies extrapolation and 10X intraspecies variability.

This study is classified as **Acceptable /Guideline** and satisfies the
requirements for a chronic toxicity study in dogs \[870.4100b (§83-1)\].

**3.5.3 Incidental Oral Exposure (Short and Intermediate Term)**

**Study Selected:** Reproduction and Fertility Effects - Rats

**MRID No:** 44246001

**Dose and Endpoint for Risk Assessment:** NOAEL = 26 mg/kg/day

**Uncertainty Factor:** 100X (10X interspecies extrapolation; 10X
intraspecies variability)

[]{.mark}

**[Comments about Study/Endpoint/UF:]{.underline}**

A 2-generation reproduction study in rats was used to select the dose
and endpoint for short and intermediate term incidental oral exposure.
Reductions in offspring body weight began as early as PND 4 indicating
that the effect began before the pups had direct contact with the food.
Therefore, since pup weight at birth was not affected and the effect was
evident within a few days (days 4-21), the duration is appropriate for
short-term oral exposure. Offspring body weight was also affected after
the pups started eating the treated food. Therefore, this study is also
applicable to intermediate term exposures because the rats continued to
exhibit less weight than the control group during the premating of the
F~1~ generation. Although the rat prenatal developmental study
demonstrated a lower NOAEL (10 mg/kg/day vs. 26 mg/kg/day in the
reproduction study), the reproduction study is more relevant to this
scenario since offspring effects were seen in the reproduction study at
53 mg/kg/day (doses tested were 0, 13, 26 and 53 mg/kg/day) indicating
that the threshold dose is between 26 and 53 mg/kg/day. Note that no
adverse effects were noted at a dose of 13 mg/kg/day in the reproduction
study. The NOAEL of 10 mg/kg/day determined in the rat developmental
study is likely a result of dose spacing. Therefore, based on the weight
of evidence, a NOAEL of 26 mg/kg/day is adequately protective for this
scenario and using the maternal NOAEL of 10 mg/kg/day from the prenatal
developmental study in rats would lead to a very conservative estimation
of risk. Uncertainty factors (100X) include: 10X interspecies
extrapolation and 10X intraspecies variability.

**3.5.4 Dermal Absorption**

A dermal absorption study (MRID 46621303) is available for dodine where
\[^14^C\]- Dodine (n-dodecyl-^14^C guanidine acetate) was administered
to three groups of four male Sprague Dawley CD rats/dose to a 12 cm^2^
dorsal area in a formulation and water dilution thereof at dose levels
of 4.0 and 0.004 mg/ cm^2^. The mean percent radioactivity remaining in
the treated skin in the treatment groups (0.004 mg/ cm^2^) were 36.6%,
49.5%, 45.2% and 40.3% at 8, 24, 48, 72 hours, respectively. Presumably,
the \[^14^C\]- Dodine remaining in the treated skin has the potential to
be absorbed by the skin over time; however, this is not demonstrated by
the study. In fact the radioactivity remaining at the application site
increases slightly over time indicating that the maximum absorption is
likely to happen after 72 hours. Therefore, approximately 1% (0.77%) of
the dose applied to male rats was demonstrated to be absorbed in skin
with the resulting radioactivity being found in the urine, feces,
cagewash, carcass and untreated skin. Although eight to ten hours is
considered most applicable to the typical worker and the doses used are
the typical worker doses, it is appropriate to utilize the 72 hour/low
dose dermal absorption value to be conservative in risk assessment.
These values are considered conservative because a portion of the active
ingredient was retained at the skin site and it is unlikely that all of
the skin residues will become systemically available.

**3.5.5. Dermal Exposure (Short-, Intermediate-, and Long-Term)**

**Study Selected:** 28-Day Dermal Toxicity-Rat

**MRID No:** 46420701

**Dose and Endpoint for Risk Assessment:** NOAEL ≥ 200 mg/kg/day

**Uncertainty Factor:** 100X (10X interspecies extrapolation, 10X
intraspecies variability)

**Comments about Study/Endpoint/UF:**

A 28 day dermal toxicity study in rats was used to select the dose and
endpoint for establishing short-, intermediate-, and long-term dermal
exposure. Although a definitive LOAEL associated with systemic toxicity
was not identified, the weight of evidence suggests that increasing the
dose (e.g. to more than 200 mg/kg/day) will ultimately result in similar
(body weight effects) findings seen across the toxicology database. In
addition, increased toxicity is not expected after extended treatment
periods as demonstrated in oral studies with dodine. Therefore, an
additional UF for extrapolating from a short- to long-term endpoint is
not warranted.

**3.5.6 Inhalation Exposure (Short-Term)**

**Study Selected:** Developmental Toxicity-Rat

**MRID No:** 41900304

**Dose and Endpoint for Risk Assessment:** NOAEL = 10 mg/kg/day

**Uncertainty Factor:** 100X (10X for interspecies extrapolation, 10X
for intraspecies extrapolation)

**[Comments about Study/Endpoint/UF:]{.underline}** No appropriate
inhalation toxicity studies are available for dodine. Two acute
inhalation studies were submitted; however NOAELs were not identified in
the studies. A developmental toxicity study in rats was used to select
the dose and endpoint for establishing short-term inhalation exposure.
The NOAEL of 10 mg/kg/day is based on weight loss observed in females at
the LOAEL of 45 mg/kg/day. Uncertainty factors (100X) include: 10X
interspecies extrapolation and 10X intraspecies variability.

**3.5.7 Level of Concern for Margin of Exposure**

+----------------+----------------+----------------+-----------------+
| **Table 3.5.7  |                |                |                 |
| Summary of     |                |                |                 |
| Levels of      |                |                |                 |
| Concern for    |                |                |                 |
| Risk           |                |                |                 |
| Assessment**   |                |                |                 |
+================+================+================+=================+
| **Ro           | **Short-Term** | **Inter        | **Long-Term**   |
| ute/Duration** |                | mediate-Term** |                 |
|                | **(1 - 30      |                | **(\> 6         |
|                | days)**        | **(1 - 6       | months)**       |
|                |                | months)**      |                 |
+----------------+----------------+----------------+-----------------+

  ----------------- ----------------- ----------------- -----------------
  **Occupational                                        
  (Worker)                                              
  Exposure**                                            

  **Dermal**        100               100               N/A

  **Inhalation**    100               100               N/A
  ----------------- ----------------- ----------------- -----------------

  -----------------------------------------------------------------------
  **Residential (Non-Dietary Exposure)**

  -----------------------------------------------------------------------

  ----------------- ----------------- ----------------- -----------------
  **Oral**          100               N/A               N/A

  **Dermal**        100               100               100

  **Inhalation**    100               N/A               N/A
  ----------------- ----------------- ----------------- -----------------

N/A = Not applicable

**3.5.8 Recommendation for Aggregate Exposure Risk Assessments**

As per 1996 FQPA, when there are potential residential exposures to the
pesticide, aggregate risk assessment must consider exposures from three
major sources: oral, dermal and inhalation exposures. All routes of
exposure for all durations of exposure can be aggregated based on the
common endpoint observed throughout the database (body weight effects).
A cancer aggregate risk assessment is not required because there is no
evidence of carcinogenicity (see cancer weight of evidence below).

**3.5.9 Classification of Carcinogenic Potential**

There was equivocal evidence of carcinogenicity. The following is a
weight of evidence evaluation of the carcinogenic potential of dodine:

The rat and mouse carcinogenicity studies demonstrated that dodine was
not associated with tumors in either sex in Sprague-Dawley rats or in
male CD-1 mice. In female CD-1 mice fed with dodine at the highest dose
tested (HDT) of 1500 ppm (see table 3.5.9 below), there was a
statistically significant increase in the incidence of hepatocellular
adenomas (0/60 vs 4/60 in HDT) and combined hepatocelluar adenomas and
carcinomas (0/60 in control vs 5/60). There was an increased trend in
adenomas, but there was no dose-related increase in the incidence of
carcinomas. A positive trend (p \< 0.05) with respect to dose rates was
also observed in the combined tumor group. It should be noted that this
positive trend was driven by the dose response in the adenomas (4/60 at
HDT) and a spontaneous carcinoma (0/60 in the controls vs. 1/60 in both
the low- and high- doses) seen in both the low- and high-dose group. The
combined tumors (0 % in control and 8.3% at the HDT) were outside of the
range for the historical control for Covance (the testing laboratory).
However, when compared to the historical controls of Charles River (CR)
(CD-1 mice supplier) the increase in incidence of combined tumors is
marginal (8.3 % in female test animals vs. the 1-8 % range in female CR
CD-1 mice). Charles River data indicate that more than one adenoma is
reported in more than ½ of their studies. The following table is a
summary of these findings:

+------------------------+--------+-------------+----------+-----------+
| **Table 3.5.9**        | **     |             |          |           |
|                        | Female |             |          |           |
|                        | CD-1   |             |          |           |
|                        | mice** |             |          |           |
+========================+========+=============+==========+===========+
| **Dosage**             | **0**  | **200**     | **750**  | **1500**  |
+------------------------+--------+-------------+----------+-----------+
| **Total examined (size | 60     | 58          | 59       | 60        |
| of test group)**       |        |             |          |           |
+------------------------+--------+-------------+----------+-----------+
| **Adenoma**            | 0      | 1 (1.7 %)   | 1 (1.7   | **4\*     |
|                        |        |             | %)       | (6.6 %)** |
+------------------------+--------+-------------+----------+-----------+
| **Carcinoma**          | 0      | 1 (1.7 %)   | 0        | 1 (1.7 %) |
+------------------------+--------+-------------+----------+-----------+
| **Combined**           | 0      | 2 (3.4 %)   | 1        | **5\*\*   |
|                        |        |             |          | (8.3%)**  |
| **(Adenoma &           |        |             |          |           |
| Carcinoma)**           |        |             |          |           |
+------------------------+--------+-------------+----------+-----------+
| **Combined**           |        | 3/395 (0.8  | 3/395    | 6/395     |
|                        |        | %)          | (0.8 %)  | (1.6 %)   |
| **Covance historical** |        |             |          |           |
+------------------------+--------+-------------+----------+-----------+
| **Combined**           |        | (1.25- 2 %) | (1.25- 2 | (1- 8 %)  |
|                        |        |             | %)       |           |
| **Charles River        |        | (\~3000     |          | (\~3000   |
| historical**           |        | animals     | (\~3000  | animals   |
|                        |        | reported)   | animals  | reported) |
|                        |        |             | r        |           |
|                        |        |             | eported) |           |
+------------------------+--------+-------------+----------+-----------+

\* Trend test significant at *p* \< 0.05 in females

\* \* Significantly different from controls at *p* \< 0.05

-   There were no pre-neoplastic lesions that can be associated with the
    tumor response, and therefore, no evidence indicating that the
    high-dose was associated with further progression to carcinoma. No
    other test material related tumors were seen in the study.

> In mice, dosing at the highest dose (1500 ppm) was considered to be
> adequate, but not excessive, for carcinogenicity assessment. This was
> based on no treatment -related effects on survival, decreases in body
> weight (by 9 and 14% in males and females, respectively), and
> decreases in food consumption (by 6 and 19% in males and females,
> respectively). None of these effects is considered as evidence that
> the dose was excessive. It should be noted that on the first day of
> week 44, mice were inadvertently fed diets that were subsequently
> found to contain a level of dodine well in excess of the targeted
> 1500-ppm concentration. Furthermore, in a 13-week range finding study
> with dodine in mice, it was determined that the maximum tolerated dose
> (MTD) was considered to be higher than 1250 ppm but lower than 2500
> ppm (pending MRID).

-   There is no evidence of genotoxicity, and thus no mutagenicity
    concern.

-   The structure activity relationship does not indicate a probable
    carcinogenic risk. Dodine belongs to the aliphatic and alicyclic
    fungicide class and consists of an alkyl carbon chain and a
    guanadine moiety. The alkyl carbon chain of dodine influences its
    toxic action. The 12-carbon homolog is the most effective.

-   Dodine is a fungi-toxic cationic surfactant that has a non specific
    mode of action. Dodine acts by interfering with membrane structure,
    mainly by altering cell permeability to allow leakage of phosphorus
    and amino materials for poisoned cells.

Based on the weight of evidence it can be concluded that there is no
evidence of carcinogenicity (D323607, J. Morales).

10. **Summary of Toxicological Doses and Endpoints for Dodine Use in
    Dietary and Non-Occupational Human Health Risk Assessments**

+----------+-------------+---------+--------------+-------------------+
| **Table  |             |         |              |                   |
| 3.5.10a  |             |         |              |                   |
| Summary  |             |         |              |                   |
| of       |             |         |              |                   |
| Toxic    |             |         |              |                   |
| ological |             |         |              |                   |
| Doses    |             |         |              |                   |
| and      |             |         |              |                   |
| E        |             |         |              |                   |
| ndpoints |             |         |              |                   |
| for      |             |         |              |                   |
| Dodine   |             |         |              |                   |
| Use in   |             |         |              |                   |
| Dietary  |             |         |              |                   |
| and      |             |         |              |                   |
| Non-Occu |             |         |              |                   |
| pational |             |         |              |                   |
| Human    |             |         |              |                   |
| Health   |             |         |              |                   |
| Risk     |             |         |              |                   |
| Asses    |             |         |              |                   |
| sments** |             |         |              |                   |
+==========+=============+=========+==============+===================+
| **Ex     | **Point of  | **Un    | **RfD, PAD,  | **Study and       |
| posure** | Departure** | certain | Level of     | Toxicological     |
|          |             | ty/FQPA | Concern for  | Effects**         |
| **Sc     |             | Safety  | Risk         |                   |
| enario** |             | Fa      | Assessment** |                   |
|          |             | ctors** |              |                   |
+----------+-------------+---------+--------------+-------------------+
| **Acute  | N/A         | N/A     | N/A          | No appropriate    |
| Dietary  |             |         |              | endpoint          |
| (General |             |         |              | identified.       |
| pop      |             |         |              |                   |
| ulation, |             |         |              |                   |
| i        |             |         |              |                   |
| ncluding |             |         |              |                   |
| Infants  |             |         |              |                   |
| and      |             |         |              |                   |
| Chi      |             |         |              |                   |
| ldren)** |             |         |              |                   |
+----------+-------------+---------+--------------+-------------------+
| **Acute  | N/A         | N/A     | N/A          | No appropriate    |
| D        |             |         |              | endpoint for      |
| ietary** |             |         |              | females age       |
|          |             |         |              | 13-49.            |
| **       |             |         |              |                   |
| (females |             |         |              |                   |
| 13-49    |             |         |              |                   |
| and      |             |         |              |                   |
| general  |             |         |              |                   |
| popul    |             |         |              |                   |
| ation)** |             |         |              |                   |
+----------+-------------+---------+--------------+-------------------+
| *        | NOAEL = 2   | UF      | Chronic RfD  | Chronic           |
| *Chronic | mg/kg/day   | ~A~=10X | = 0.02       | toxicity - dog    |
| D        |             |         | mg/kg/day    |                   |
| ietary** |             | UF      |              | LOAEL = 10        |
|          |             | ~H~=10X | cPAD = 0.02  | mg/kg/day based   |
| **(all   |             |         | mg/kg/day    | on body weight    |
| popula   |             | FQPA SF |              | loss in females.  |
| tions)** |             | = 1X    |              |                   |
+----------+-------------+---------+--------------+-------------------+
| **In     | NOAEL = 26  | UF      | Residential  | 2-Generation      |
| cidental | mg/kg/day   | ~A~=10X | MOE =100     | Reproduction-rat  |
| Oral     |             |         |              |                   |
| Shor     |             | UF      |              | Offspring LOAEL = |
| t-Term** |             | ~H~=10X |              | 53 mg/kg/day      |
|          |             |         |              | based on          |
| **(1 -   |             |         |              | decreased body    |
| 30       |             |         |              | weight.           |
| days)**  |             |         |              |                   |
|          |             |         |              |                   |
| **Int    |             |         |              |                   |
| ermediat |             |         |              |                   |
| e-Term** |             |         |              |                   |
|          |             |         |              |                   |
| **(1 - 6 |             |         |              |                   |
| m        |             |         |              |                   |
| onths)** |             |         |              |                   |
+----------+-------------+---------+--------------+-------------------+
| **       | NOAEL = 200 | UF      | Residential  | 28-Day Dermal     |
| Dermal** | mg/kg/day   | ~A~=10X | MOE =100     | Toxicity-rat      |
|          | (HDT)       |         |              |                   |
| **Shor   |             | UF      |              | LOAEL = not       |
| t-Term** |             | ~H~=10X |              | identified        |
|          |             |         |              |                   |
| **(1 -   |             |         |              |                   |
| 30       |             |         |              |                   |
| days),   |             |         |              |                   |
| I        |             |         |              |                   |
| ntermedi |             |         |              |                   |
| ate-term |             |         |              |                   |
| (1 - 6   |             |         |              |                   |
| months), |             |         |              |                   |
| and      |             |         |              |                   |
| L        |             |         |              |                   |
| ong-Term |             |         |              |                   |
| (\> 6    |             |         |              |                   |
| m        |             |         |              |                   |
| onths)** |             |         |              |                   |
+----------+-------------+---------+--------------+-------------------+
| *        | De          | UF      | Residential  | Developmental     |
| *Inhalat | velopmental | ~A~=10X | MOE =100     | toxicity study -  |
| ion^a^** | study       |         |              | rat               |
|          |             | UF      |              |                   |
| **Shor   | Maternal    | ~H~=10X |              | Maternal LOAEL =  |
| t-Term** | NOAEL = 10  |         |              | 45 mg/kg/day      |
|          | mg/kg/day   |         |              | based on          |
| **(1 -   |             |         |              | decreased body    |
| 30       | IAF= 100%   |         |              | weight gain and   |
| days)**  |             |         |              | food consumption. |
|          |             |         |              |                   |
| **Interm |             |         |              |                   |
| ediate-T |             |         |              |                   |
| erm^a^** |             |         |              |                   |
|          |             |         |              |                   |
| **(1 - 6 |             |         |              |                   |
| m        |             |         |              |                   |
| onths)** |             |         |              |                   |
+----------+-------------+---------+--------------+-------------------+
| **Cancer | No Evidence |         |              |                   |
| (oral,   | of          |         |              |                   |
| dermal,  | Carc        |         |              |                   |
| inhal    | inogenicity |         |              |                   |
| ation)** |             |         |              |                   |
+----------+-------------+---------+--------------+-------------------+

^a^IAF=inhalation absorption rate

+----------+-------------+----------+------------+-------------------+
| **Table  |             |          |            |                   |
| 3.5.10b  |             |          |            |                   |
| Summary  |             |          |            |                   |
| of       |             |          |            |                   |
| Toxic    |             |          |            |                   |
| ological |             |          |            |                   |
| Doses    |             |          |            |                   |
| and      |             |          |            |                   |
| E        |             |          |            |                   |
| ndpoints |             |          |            |                   |
| for      |             |          |            |                   |
| Dodine   |             |          |            |                   |
| Use in   |             |          |            |                   |
| Occu     |             |          |            |                   |
| pational |             |          |            |                   |
| Human    |             |          |            |                   |
| Health   |             |          |            |                   |
| Risk     |             |          |            |                   |
| Asses    |             |          |            |                   |
| sments** |             |          |            |                   |
+==========+=============+==========+============+===================+
| **Ex     | **Point of  | **       | **RfD,     | **Study and       |
| posure** | Departure** | Uncertai | PAD, Level | Toxicological     |
|          |             | nty/FQPA | of Concern | Effects**         |
| **Sc     |             | Safety   | for Risk   |                   |
| enario** |             | F        | As         |                   |
|          |             | actors** | sessment** |                   |
+----------+-------------+----------+------------+-------------------+
| **       | NOAEL = 200 | U        | Oc         | 28-Day Dermal     |
| Dermal** | mg/kg/day   | F~A~=10X | cupational | Toxicity-rat      |
|          | (HDT)       |          | MOE =100   |                   |
| **Shor   |             | U        |            | LOAEL = not       |
| t-Term** |             | F~H~=10X |            | identified        |
|          |             |          |            |                   |
| **(1 -   |             |          |            |                   |
| 30       |             |          |            |                   |
| days)**  |             |          |            |                   |
|          |             |          |            |                   |
| **Int    |             |          |            |                   |
| ermediat |             |          |            |                   |
| e-Term** |             |          |            |                   |
|          |             |          |            |                   |
| **(1 - 6 |             |          |            |                   |
| m        |             |          |            |                   |
| onths)** |             |          |            |                   |
+----------+-------------+----------+------------+-------------------+
| **Inha   | De          | U        | Oc         | Developmental     |
| lation** | velopmental | F~A~=10X | cupational | toxicity study -  |
|          | study       |          | MOE = 100  | rat               |
| *        |             | U        |            |                   |
| *Short-T | Maternal    | F~H~=10X |            | Maternal LOAEL =  |
| erm^a^** | NOAEL = 10  |          |            | 45 mg/kg/day      |
|          | mg/kg/day   |          |            | based on          |
| **(1 -   |             |          |            | decreased body    |
| 30       |             |          |            | weight gain and   |
| days)**  |             |          |            | food consumption. |
|          |             |          |            |                   |
| **Interm |             |          |            |                   |
| ediate-T |             |          |            |                   |
| erm^a^** |             |          |            |                   |
|          |             |          |            |                   |
| **(1 - 6 |             |          |            |                   |
| m        |             |          |            |                   |
| onths)** |             |          |            |                   |
+----------+-------------+----------+------------+-------------------+
| **Cancer | No Evidence |          |            |                   |
| (oral,   | of          |          |            |                   |
| dermal,  | Carc        |          |            |                   |
| inhal    | inogenicity |          |            |                   |
| ation)** |             |          |            |                   |
+----------+-------------+----------+------------+-------------------+

^a^ inhalation absorption rate = 100%, UF = uncertainty factor, FQPA SF
= FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL =
lowest observed adverse effect level, PAD = population adjusted dose (a
= acute, c = chronic) RfD = reference dose, MOE = margin of exposure,
LOC = level of concern, NA = Not Applicable.

**3.6 Endocrine disruption**

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) "may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate."
Following recommendations of its Endocrine Disruptor Screening and
Testing Advisory Committee (EDSTAC), EPA determined that there was a
scientific basis for including, as part of the program, the androgen and
thyroid hormone systems, in addition to the estrogen hormone system. EPA
also adopted EDSTAC's recommendation that the Program include
evaluations of potential effects in wildlife. For pesticide chemicals,
EPA will use FIFRA and, to the extent that effects in wildlife may help
determine whether a substance may have an effect in humans, FFDCA
authority to require the wildlife evaluations. As the science develops
and resources allow, screening of additional hormone systems may be
added to the Endocrine Disruptor Screening Program (EDSP). In the
available toxicity studies on dodine, there was no estrogen, androgen,
and/or thyroid mediated toxicity.

When additional appropriate screening and/or testing protocols being
considered under the Agency's EDSP have been developed, dodine may be
subjected to further screening and/or testing to better characterize
effects related to endocrine disruption.

**4.0 Public Health Data**

Reference: *Review of Dodine and Dodecylguanidine hydrochloride Incident
Reports*, DP Barcode D316590, Jerome Blondell, 05/10/2005

**4.1 Incident Reports**

Five databases were consulted for poisoning incident data. These
include: OPP Incident Data System (IDS), Poison Control Centers,
California Department of Pesticide Regulation, National Pesticide
Telecommunications Network (NPTN), and National Institute of
Occupational Safety and Health's Sentinel Event Notification System for
Occupational Risks (NIOSH SENSOR). Of all poisoning incident data
reported, there were almost no reports of ill effects concerning human
poisoning or other adverse effects from exposure to dodine and
dodecylguanidine hydrochloride.

**5.0 Dietary Exposure/Risk Characterization**

**5.1 Pesticide Metabolism and Environmental
Degradation**[]{#__RefHeading___Toc139001018 .anchor}

**5.1.1 Metabolism in Primary Crops**

[]{.mark}

The nature of the residue is adequately understood in fruiting and nut
crops based on acceptable plant metabolism studies in apple, pecan and
strawberry. These studies indicate that the residue of concern is dodine
*per se*. In the Revised Residue Chemistry Chapter of the RED, HED
concluded that no further plant metabolism studies are required
(D320758, D. Soderberg). An additional study may be needed if any future
uses are requested on crops such as leafy vegetables, root crops, or
cereal grains.

[]{#__RefHeading___Toc139001019 .anchor}

2.  **Metabolism in Rotational Crops**

No confined rotational crop data are available for dodine. A confined
rotational crop study was required in the Revised Residue Chemistry
Chapter of the RED; this data requirement remains outstanding. The need
for rotational crop restrictions and/or tolerances will be determined
when the confined rotational crop study has been submitted.

3.  **Metabolism in Livestock**

The nature of the residue in livestock other than poultry is adequately
understood based on a goat metabolism study. The residue of concern is
dodine *per se*.

No poultry metabolism data have been submitted for dodine. Based on the
fact that no detectable residues of dodine were observed in peanut meal
processed from peanuts treated at 3x the proposed maximum rate, HED
concludes that a poultry metabolism study will not be required to
support the proposed use on peanuts. The petitioner should note that a
poultry metabolism study may be required if any uses on crops with
poultry feedstuffs are proposed in the future (D320758, D. Soderberg).

4.  **Analytical Methodology**

Adequate enforcement methods are available for determining dodine
residues in/on plant commodities. A colormetric method with
spectrometric detection and various modifications is listed in PAM II as
Methods I, I(a), I(b), and I(d). Additionally, a GLC method was
submitted to the FDA in 1988 for inclusion in PAM II as Method II.

A GC/MSD method, Method 45137, has been proposed previously for use as
an enforcement method for the determination of residues of dodine in/on
plant commodities. HED has requested that the ACB evaluate GC/MSD Method
45137 to determine whether the method needs to be verified at ACB (DP#
323858, 1/18/06, D. Soderberg).

AGRIPHAR has proposed an LC/MS/MS method, METH1595.02, for the
enforcement of tolerances for residues of dodine in/on banana and peanut
commodities. AGRIPHAR submitted a copy of this method (as an appendix to
MRID 47064901), as well as copies of previous versions METH1595-00.00
and METH1595.00.01. The validated limit of quantitation (LOQ) is 0.01
ppm and the limit of detection (LOD) is 0.003 ppm in each matrix.
Although dodine reference standard is to be used to prepare all
calibration and fortification solutions for the method, the method as
written specifies that calibration and fortification standard
concentration are to be calculated in term of "dodine free base"
(presumed to be dodecylguanidine) instead of dodine (N‑dodecylguanidine
acetate), using a molecular weight conversion factor of 228.41/287.45.
Therefore, residue results generated using this method are reported in
terms of dodine free base.

LC/MS/MS method METH1595-00.00 was adequately validated using samples of
banana fortified with dodine at 0.01 ppm, 0.10 ppm and 10 ppm, and
samples of peanut and peanut oil fortified at 0.01 ppm, 0.10 ppm, and
1.0 ppm. Recoveries of dodine ranged 84-122% (mean ± SD = 105 ± 10%)
from whole banana, 88-106% (98 ± 5.5%) from peanut, and 90-101% from
peanut oil (100 ± 5.3%).

No validation data were included for peanut meal. However, adequate
concurrent method recovery data were included with the peanut processing
study submitted in conjunction with this petition. The concurrent method
validation data in combination with the method validation data are
sufficiently representative of the expected residue levels for the
commodities included in the petition associated with this petition.

The LC/MS/MS method uses a single ion transition to quantitate residues
of dodine in/on banana and peanut matrices (228.6→186.3 m/z), and
specifies two additional parent-daughter ion transitions (228.6→85.3 m/z
and 228.6→71.2 m/z) which may be used for analyte confirmation. No
additional confirmatory analysis procedures will be required.

No radiovalidation data were submitted for LC/MS/MS method
METH1595-00.00, METH1595-00.01, or METH1595.02. Adequate radiovalidation
data have been submitted previously for a proposed enforcement method,
GC/MS Method 45137 (DP# 320758, 9/14/05, D. Soderberg). The initial
extraction procedures of GC/MSD Method 45137 are very similar to those
of LC/MS/MS methods METH1595-00.00, METH1595-00.01, and METH1595.02.
Therefore, HED concludes that the radiovalidation data for GC/MSD Method
45137 may be translated to support LC/MS/MS methods METH1595-00.00,
METH1595-00.01, and METH1595.02.

Adequate independent laboratory validation data were submitted for the
method using samples of banana, peanut, peanut meal, and peanut oil.
Adequate recoveries were obtained for all matrices using the method as
written. (D320758, D. Soderberg; D 338572/D342401. M. Doherty).

**[Conclusions:]{.underline}** The submitted residue analytical method
data are tentatively adequate to satisfy data requirements provided the
method is revised as specified. Method METH1595.02 must be modified to
remove the conversion of residue results to "dodine free base" (this
calculation is made at the step in which standard solutions are
prepared). Residue results [must]{.underline} be calculated in terms of
dodine, as N‑dodecylguanidine acetate. In addition, the typographical
error in step 9.3.7 of the method should be corrected \["Repeat steps
9.2.3 to 9.2.6 two more times" should be changed to "Repeat steps 9.3.3
to 9.3.6 two more times"\].

LC/MS/MS method METH1595.02 does not require Agency method validation
due to its similarity to existing, validated methods for dodine.

Due to the specifications of the method, all residue results for the
crop field trial and processing studies associated with this petition
were reported by the petitioner in terms of dodine free base. The study
reviewer recalculated the residue results in terms of dodine using a
molecular weight conversion factor of 1.258 (287.45/228.41). The
recalculated LOQ was 0.013 ppm and the recalculated LOD was 0.004 ppm.

Because no tolerances are proposed or required for livestock
commodities, no enforcement method for livestock commodities is needed
at this time.

5.  **Environmental Degradation**

Dodine is a water soluble (630 mg/L) salt of a strong base, and is
completely dissociated to dodecylguanidinium ion and acetate in aqueous
solutions under normal environmental conditions. In the field, dodine
was almost exclusively confined to the 0-6 inch depth of bareground
plots; it is immobile (K~ads~ = 2202 - 18,019 L/kg); is generally not
expected to persist in aerobic soils (half-lives 17.5 - 22.3 d). The
potential for dodine to reach drinking water sources is limited. With a
low estimated vapor pressure of 1.5 x 10^-7^ torr for dodine (EPI
Suite), volatilization is an unlikely route of dissipation; however,
dodine may be transported off-site to drinking water sources as
entrained sediment or via spray drift during aerial, airblast or ground
spray applications. Once in aquatic environments, dodine is resistant to
hydrolysis (half-lives 576-1198 d) and photolysis (641-770 d). In
aerobic aquatic environments, dodine is likely to be moderately
persistent to persistent (half-lives 38.9, 59.8, 227 d). In anaerobic
aquatic environments, dodine is likely to be very persistent (half-life
2,492 d). Major degradates (excluding CO~2~) were not identified in the
available studies, but recovery of ^14^CO~2~ from dodine radiolabeled in
the guanidine moiety was approximately 90% in the aerobic soil study in
the laboratory. Minor degradates of dodine expected in the environment
are *n*-dodecylaminohydroxymethylamine, and guanidine. The former is
formed at less than 5% of the total residue only after weathering for
about a year, and is therefore not expected to be a significant part of
exposure to dodine. In addition to being a very minor degradate,
*n*-dodecylaminohydroxymethylamine was seen at significant levels in rat
urine (above), so it is expected to be part of the total toxic exposure
seen by the rats when they were dosed with dodine in the toxicology
studies.

**5.1.6 Comparative Metabolic Profile**

[]{.mark}

The proposed metabolic pathway for dodine in rats is through a
ß-oxidation pathway similar to medium- and long-chain fatty acids.
Oxidation takes place by forming intermediate products with shorter
chain lengths and these are eliminated in the urine. Urea is also formed
in the liver.

In livestock and plants the metabolism of dodine appears to follow a
similar metabolic route to that in rats. The terminal carbon on the
dodecyl chain of dodine is oxidized to a carboxyl group and then the
chain rapidly degrades, apparently 2 carbon atoms at a time, consistent
with ß -oxidation until all that remains are the terminal metabolites:
guanidine or urea. Thus, during metabolism of dodine in livestock, there
is intermediate formation of dodecyl carboxylic acid guanidine, octyl
carboxylic acid guanidine, and hexyl carboxylic acid guanidine in the
tissues.

7.  **Toxicity Profile of Major Metabolites and Degradates of Concern**

The major metabolites of dodine in foods in general are guanidine and
urea - both common natural products with virtually no expected toxicity.
In goat tissues, the n-alkyl carboxylic acid guanidine metabolites
present a significant portion of the residue. These metabolites,
however, are unlikely to share any of the biological effects of dodine
since along with a quaternary amine they also have carboxylic groups at
the distal end of the alkyl group.

8.  **Pesticide Metabolites and Degradates of Concern**

  ------------------------------------------------------------------------
  **Table 5.1.8                                        
  Summary of                                           
  Metabolites                                          
  and Degradates                                       
  to be included                                       
  in the Risk                                          
  Assessment and                                       
  Tolerance                                            
  Expression**                                         
  -------------- ------------------- ----------------- -------------------
  **Matrix**                         **Residues        **Residues included
                                     included in Risk  in Tolerance
                                     Assessment**      Expression**

  Plants         Primary Crop:       Parent dodine     Parent dodine
                 bananas                               

                 Primary Crop:       Parent dodine     Parent dodine
                 bananas                               

                 Rotational Crop\*   N/A               NA

  Livestock      Ruminant            Parent dodine     Parent dodine

                 Poultry\*           N/A               N/A

  Drinking Water                     Parent dodine     N/A
  ------------------------------------------------------------------------

\* study is not available

9.  **Drinking Water Residue Profile**

[]{.mark}

The drinking water residues used in the dietary risk assessment were
provided by the Environmental Fate and Effects Division (EFED) in the
following memorandum: *Drinking Water Assessment for the Section 3 New
Use Petitions for the Use of Dodine on Bananas and Peanuts*. (Marietta
Echeverria, D338149, 16 OCT 2007) and incorporated directly into this
dietary assessment. Water residues were incorporated in the DEEM-FCID
into the food categories "water, direct, all sources" and "water,
indirect, all sources." The provided FIRST chronic surface water
estimate of 0.004 ppm is greater than the groundwater estimate (\<
0.00008 ppm; Table 5.1.9) and was used in the dietary assessment.

[]{.mark}

+---------------------------+-----------------+----------+------------+
| **Table 5.1.9. Tier I     |                 |          |            |
| estimated drinking water  |                 |          |            |
| concentrations (EDWCs)    |                 |          |            |
| resulting from            |                 |          |            |
| applications of dodine.** |                 |          |            |
+===========================+=================+==========+============+
| **Drinking water source   | **Use**         | **Acute  | **Chronic  |
| (model)**                 |                 | (ppb)**  | (ppb)**    |
|                           | **(modeled      |          |            |
|                           | rate)**         |          |            |
+---------------------------+-----------------+----------+------------+
| Surface water (FIRST)     | Pecan, peach,   | 110      | 4.0        |
|                           | walnut          |          |            |
|                           |                 |          |            |
|                           | (13 lb/A/yr)    |          |            |
+---------------------------+-----------------+----------+------------+
| Groundwater (SCIGROW)     |                 | 0.08     | \<0.08     |
+---------------------------+-----------------+----------+------------+

10. **Food Residue Profile**

Insufficient use pattern information has been submitted to determine the
adequacy of the banana crop field trial data. The petitioner has only
submitted use pattern information for bananas grown in the U.S. The
submitted crop field trial data are not in complete agreement with the
proposed use directions (a total of 5 applications at 0.64-1.3 lb
ai/A/application, with applications at 1.3 lb/A through first cover
applications, and applications at 0.64 lb ai/A for subsequent
application); the RTI and PHI of the field trials do agree with the
proposed minimum RTI and PHI. Provided the petitioner modifies the
proposed use on bananas to conform to the use pattern of the crop field
trials, the submitted data are adequate to support use of dodine on
bananas grown in the U.S. Additional use pattern information for banana
importing countries is needed before HED may determine whether the
submitted crop field trial data are adequate to support the proposed
tolerance for bananas.

Based on the requirements identified in *NAFTA Guidance Document on Data
Requirements for Tolerances on Imported Commodities in the United States
and Canada* (December 2005), a total of 12 crop field trials are
required to support an import tolerance for banana (approximately 99.7%
of the banana consumed in the U.S. is imported, and banana accounts for
0.2-1.0% of the North American diet). Using the import values reported
above, HED would require 3 trials with banana in each of Costa Rica,
Ecuador, and Guatemala, 2 trials in Columbia, and 1 trial in Honduras.
The petitioner conducted a total of 12 trials with bananas, in Colombia
(1 trial), Costa Rica (3 trials), Ecuador (3 trials), Guatemala (1
trial), Hawaii (2 trials), Honduras (1 trial), and Martinique (1 trial).
Although the submitted field trials do not conform exactly to the
requirements, HED concludes that the number and location of banana crop
field trials are adequate.

Provided the directions for use are modified to be in accord with the
use patterns used in the field trials and the use patterns in the U.S.
are the same as those being proposed for other banana-growing countries,
the available data support the proposed tolerance (0.50 ppm) for
residues of dodine in/on banana.

The submitted peanut crop field trial data are adequate to satisfy data
requirements. The use pattern of the field trials adequately reflects
the maximum proposed use pattern for dodine on peanut. Generally, HED
requires that 9 crop field trials be conducted for peanut to support a
registration when residues are below the LOQ, in Zone 2 (5 trials), 3 (1
trial), 6 (2 trials), and 8 (1 trial). The petitioner previously
requested approval of a reduced field trial data set for peanut, based
on residues below the LOQ in/on four trials conducted in Zone 2 at 1x (3
trials) and 3x (1 trial) the proposed maximum seasonal rate. The request
was addressed by the HED Chemistry Science Advisory Council (see minutes
of 3/29/06 meeting), which concluded that a reduced field trial data set
was acceptable provided that two additional trials be conducted in Zones
6 and 8 and that residues were below the LOQ in/on samples from these
additional trials. The petitioner has conducted 6 trials for peanuts, in
Zone 2 (4 trials), 6 (1 trial), and 8 (1 trial) and residues were below
the LOQ in/on all samples. Therefore, the number and location of crop
field trials are adequate for the purposes of this petition.

Because the petitioner has proposed a feeding restriction for peanut
hay, neither residue data nor a tolerance is required for peanut hay.

The available field trial data will support a tolerance for residues of
dodine in/on peanut at the LOQ, 0.013 ppm.

HED does not require residue data for any processed commodities of
banana. Residue data are required for peanut processed commodities meal
and refined oil. The submitted processing data are adequate to satisfy
data requirements. The data indicate that residues of dodine are not
likely to concentrate above the LOQ in peanut meal or refined oil. No
tolerances for peanut processed commodities are needed.

11. **International Residue Limits**

No Codex, Canadian, or Mexican Maximum Residue Limits (MRLs) for dodine
exist on bananas and peanuts; therefore, no tolerance harmonization
issues are associated with these commodities.

1.  **Dietary Exposure and Risk**

    1.  **Acute Dietary Exposure/Risk**

No acute dietary endpoint was identified for dodine; therefore, an acute
dietary risk assessment was not conducted.

2.  **Chronic Dietary Exposure/Risk**

A chronic aggregate dietary (food and drinking water) exposure and risk
assessment was conducted using the Dietary Exposure Evaluation Model
DEEM-FCID™, Version 2.03 which use food consumption data from the U.S.
Department of Agriculture's Continuing Surveys of Food Intakes by
Individuals (CSFII) from 1994-1996 and 1998.

The chronic dietary risk estimate for the U.S. population is 3.4 % of
the chronic population-adjusted dose (cPAD). The highest risk estimate
is for children 1-2 years of age at 20% of the cPAD. Therefore, the risk
estimates for all population subgroups are below HED's level of concern
(i.e., \< 100% of the cPAD). Given the use of percent crop treated
estimates, the dietary risk estimates should be considered to be
moderately refined.

+-----------------+--------+-------+--------+-------+--------+-------+
| Table 5.2.2.    |        |       |        |       |        |       |
| Summary of      |        |       |        |       |        |       |
| Dietary (Food   |        |       |        |       |        |       |
| and Drinking    |        |       |        |       |        |       |
| Watery)         |        |       |        |       |        |       |
| Exposure and    |        |       |        |       |        |       |
| Risk for Dodine |        |       |        |       |        |       |
+=================+========+=======+========+=======+========+=======+
| Population      | Acute  |       | C      |       | Cancer |       |
| Subgroup        | D      |       | hronic |       |        |       |
|                 | ietary |       | D      |       |        |       |
|                 |        |       | ietary |       |        |       |
+-----------------+--------+-------+--------+-------+--------+-------+
|                 | D      | \%    | D      | \%    | D      | Risk  |
|                 | ietary | a     | ietary | c     | ietary |       |
|                 | Ex     | PAD\* | Ex     | PAD\* | Ex     |       |
|                 | posure |       | posure |       | posure |       |
|                 | (mg/k  |       |        |       |        |       |
|                 | g/day) |       | (mg/k  |       | (mg/k  |       |
|                 |        |       | g/day) |       | g/day) |       |
+-----------------+--------+-------+--------+-------+--------+-------+
| General U.S.    | N/A    |       | 0.     | 3     | Not    |       |
| Population      |        |       | 000674 |       | likely |       |
|                 |        |       |        |       | a      |       |
|                 |        |       |        |       | human  |       |
|                 |        |       |        |       | carc   |       |
|                 |        |       |        |       | inogen |       |
+-----------------+--------+-------+--------+-------+--------+-------+
| All Infants (\< |        |       | 0.     | 18    |        |       |
| 1 year old)     |        |       | 003504 |       |        |       |
+-----------------+--------+-------+--------+-------+--------+-------+
| **Children 1-2  |        |       | **0.00 | *     |        |       |
| years old**     |        |       | 4072** | *20** |        |       |
+-----------------+--------+-------+--------+-------+--------+-------+
| Children 3-5    |        |       | 0.     | 12    |        |       |
| years old       |        |       | 002365 |       |        |       |
+-----------------+--------+-------+--------+-------+--------+-------+
| Children 6-12   |        |       | 0.     | 4     |        |       |
| years old       |        |       | 000886 |       |        |       |
+-----------------+--------+-------+--------+-------+--------+-------+
| Youth 13-19     |        |       | 0.     | 2     |        |       |
| years old       |        |       | 000336 |       |        |       |
+-----------------+--------+-------+--------+-------+--------+-------+
| Adults 20-49    |        |       | 0.     | 2     |        |       |
| years old       |        |       | 000325 |       |        |       |
+-----------------+--------+-------+--------+-------+--------+-------+
| Adults 50+      |        |       | 0.     | 2     |        |       |
| years old       |        |       | 000441 |       |        |       |
+-----------------+--------+-------+--------+-------+--------+-------+
| Females 13-49   |        |       | 0.     | 2     |        |       |
| years old       |        |       | 000351 |       |        |       |
+-----------------+--------+-------+--------+-------+--------+-------+

\* %PADs are reported to 2 significant figures. The values for the
highest exposed population for each type of risk assessment are bolded.

**5.2.3 Cancer Dietary Risk**

There was no evidence of carcinogenicity in studies in rats and mice. As
a result, HED believes that there is no cancer risk associated with
dodine.

2.  **Anticipated Residue and Percent Crop Treated (%CT) Information**

The chronic assessment is based on tolerance-level residues and
incorporates percent crop treated information for pome fruit, stone
fruit, strawberry, pecan, and walnut, and assumes 100% crop treated for
bananas and peanuts. Default processing factors from DEEM 7.78 were used
for all processed commodities. An estimate of dodine residue in water
was incorporated directly into the analysis.

6.  **Residential (Non-Occupational) Exposure/Risk Characterization**

There are no residential and/or non-agricultural uses currently
registered for dodine, and no new proposed uses at this time. However, a
closely related chemical, dodecylguanidine hydrochloride (DGH, PC Code
044303) is used as an antimicrobial in household, industrial, and
commercial products having residential and non-occupational exposure
potential. Dodine (n-dodecylguanidine acetate; Chemical Code No. 044301;
Case No. 0161) and DGH (dodecylguanidine hydrochloride; Chemical Code
No. 044303; Case No. 0161) are in the same case number based on their
similar chemical compositions and properties. In the 1987 Registration
Standard for Dodine, dodine and DGH were reviewed as bio-equivalents.
Because both dodine and DGH are expected to be almost completely
dissociated under most environmental conditions, and certainly under
physiological conditions, the two anions are expected to have negligible
effect on the dodecylguanidinium moiety, so data for dodine can also be
considered representative of DGH data, and vice versa. This should be
especially true for toxicological data (D323607, J. Morales). The
Antimicrobials Division (AD) previously assessed the potential for
non-dietary residential exposures and risks for the antimicrobial uses
of DGH in paints and impregnated disposable diapers (DGH, Dietary and
Non-dietary Exposures and Risks from Antimicrobial Uses, C.Walls,
D313682, 5/26/2005) which was included in the dodine RED (Morales, J.
J., D323607,11/15/2005). HED has incorporated this assessment into the
residential exposure assessment.

**6.1 Handler Exposure**

**6.1.1 Paints**

AD assessed the exposures and risks to the residential painters using
the dermal and inhalation exposures from the PHED. Since residential
painters typically paint on an intermittent basis, only the short-term
exposure duration (1 -30 days) was necessary to assess.

All of the assumptions used for calculating the exposures in this
assessment are based on the Agency's standard values. The assumptions
used to calculate the MOEs are presented in Table 6.1.1.

All inhalation, dermal, and total MOEs of painters were greater than 100
and therefore represent risk estimates that do not exceed the Agency's
level of concern for residential uses.

<table>
<colgroup>
<col style="width: 14%" />
<col style="width: 7%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 11%" />
<col style="width: 11%" />
<col style="width: 9%" />
<col style="width: 10%" />
<col style="width: 9%" />
</colgroup>
<thead>
<tr class="header">
<th colspan="10"><strong>Table 6.1.1. Short-term Residential Exposures
and Risks from Handling DGH Treated Paint</strong> (From Morales, J. J.,
D323607, 11/15/2005).</th>
</tr>
<tr class="odd">
<th rowspan="2">Exposure Scenario</th>
<th colspan="2"><p>Unit Exposure</p>
<p>(mg/lb ai)<sup>a</sup></p></th>
<th rowspan="2">Amount Handled (gal/day)</th>
<th rowspan="2"><p>Application Rate</p>
<p>(lb ai/gal)<sup>b</sup></p></th>
<th colspan="2">Daily Dose (mg/kg/day)<sup>c</sup></th>
<th colspan="2">MOEs<sup>d</sup></th>
<th rowspan="2">Total MOE<sup>e</sup></th>
</tr>
<tr class="header">
<th>Dermal</th>
<th>Inhalation</th>
<th>Dermal</th>
<th>Inhalation</th>
<th>Dermal</th>
<th>Inhalation</th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td>Applying paint with a paint brush</td>
<td>180</td>
<td>0.28</td>
<td>2</td>
<td>0.0035</td>
<td>0.018</td>
<td>0.000028</td>
<td>11,000</td>
<td>360,000</td>
<td>11,000</td>
</tr>
<tr class="even">
<td>Applying paint with an airless sprayer</td>
<td>38</td>
<td>0.83</td>
<td>15</td>
<td>0.0035</td>
<td>0.029</td>
<td>0.00062</td>
<td>7,000</td>
<td>16,000</td>
<td>4,900</td>
</tr>
<tr class="odd">
<td>Applying paint with an aerosol can</td>
<td>190</td>
<td>1.3</td>
<td>0.28</td>
<td>0.0035</td>
<td>0.0027</td>
<td>0.000018</td>
<td>75,000</td>
<td>550,000</td>
<td>66,000</td>
</tr>
</tbody>
</table>

^a^ UE = unit exposures for residential painters were derived from PHED
Version 1.1, May 1997 "Best Available Grades" (PHED, 1977) wearing
single layer of clothing and no gloves, body weight = 70 kg.

^b^ Use rate was derived from maximum concentration listed on product
labels. Labels 67869-43 and 67869-30 are 35% ai and list 0.1% product
added to coating systems (paints and coatings as finished products).
0.0035 lb ai/gal = 0.1% product x 35% ai x 10 lb paint/gal (assumed
paint density).

^c^ Daily Dose (mg/kg/day) = UE (mg/lb ai) x Amt handled (gal/day) x
Application Rate (lb ai/gal)/Body weight (kg).

^d^ Short-term Dermal and Inhalation MOE = NOAEL (mg/kg/day)/Short-term
dose (mg/kg/day). Dermal NOAEL = 200 mg/kg/day; Inhalation NOAEL = 10
mg/kg/day; Target dermal and inhalation MOE = 100.

^e^ Total MOE = 1/\[(1/MOE~dermal~ + 1/MOE~inhalation~)\]

**6.2 Post-application Exposure**

**6.2.1 Dermal and Inhalation Postapplication Exposure to Paint**

Post-application dermal contact with wet paint was not assessed because
the paint is expected to dry within a day, so any potential exposure is
expected to be negligible. Furthermore, DGH has a low vapor pressure
(i.e., \<1x10^-7^ mmHg \@25°C), therefore it is not likely to generate
sufficient vapor to cause an inhalation concern to residential
populations performing post-application tasks or occupying recently
treated areas. Thus, there are no risk concerns and inhalation
post-application exposures were not quantitatively evaluated.

**6.2.2 Incidental Ingestion of Paint Chips**

The incidental ingestion of paint chips from uses of DGH was assessed
using the HED's Residential Standard Operating Procedures (SOP).
Exposure is anticipated to be short-term in duration.

The HED level of concern is equal to a MOE of 100 for all residential
uses. The short- term oral MOE is greater than 100 and therefore not of
concern. This estimate may be somewhat underestimating the exposure
since it is assumed that the percent of active ingredient in the wet
paint is unchanged when it dries. Dry paint has a higher percent of
active ingredient. Table 6.2.2 summarizes the short- term oral MOE for
ingestion of paint chips containing pesticide residues by children.

+---------------+-----+-----+-----+-------+-----+--------+---------+
| **Table       |     |     |     |       |     |        |         |
| 6.2.2:        |     |     |     |       |     |        |         |
| Po            |     |     |     |       |     |        |         |
| stapplication |     |     |     |       |     |        |         |
| Exposure and  |     |     |     |       |     |        |         |
| Risk          |     |     |     |       |     |        |         |
| Ingestion of  |     |     |     |       |     |        |         |
| Paint Chips** |     |     |     |       |     |        |         |
+---------------+-----+-----+-----+-------+-----+--------+---------+
| **Scenario**  | *   | **P | **  | **CF1 | *   | **PDR  | **MOE   |
|               | *Ig | ^a  | F** | (mg   | *BW | ^b^    | ^c^**   |
|               | R** | ^** |     | /g)** | (kg | (      |         |
|               |     |     |     |       | )** | mg/kg/ |         |
|               | **  |     |     |       |     | day)** |         |
|               | (G/ |     |     |       |     |        |         |
|               | day |     |     |       |     |        |         |
|               | )** |     |     |       |     |        |         |
+---------------+-----+-----+-----+-------+-----+--------+---------+
| Paints and    | 0   | 0.  | 0.2 | 1,000 | 10  | 0      | 93,000  |
| Coatings EPA  | .04 | 035 |     |       |     | .00028 |         |
| Reg           |     |     |     |       |     |        |         |
| No.67896-43   |     |     |     |       |     |        |         |
| and 678969-30 |     |     |     |       |     |        |         |
+---------------+-----+-----+-----+-------+-----+--------+---------+

a\. % of ai in product is 35%; however, the % of ai in paint is 0.035%
(35% x 0.1% product added to paint or coating = 0.035%)

b\. PDR = potential dose rate = IgR x (P/100) x F x CF1 ÷BW (10 kg)

c\. MOE = NOAEL (26 mg/kg/day)/PDR

**6.2.3 Impregnated Disposable Diapers**

DGH is also incorporated as a bacteriostat in the manufacturing of the
absorbent material used in disposable diapers. AD assessed the
residential dermal exposures and risks to infants (\< 1 year old) who
wear DGH-impregnated diapers. Since infants typically wear diapers on a
continuous basis, short-, intermediate- and long-term exposure durations
were assessed.

No data on leaching or migration data of DGH to skin of infants were
provided to support this use, therefore all of the assumptions used for
calculating the exposures in this assessment are based on the Agency's
standard values. The application rate of 0.007 g ai/diaper is based on
assuming that there is 10 g of absorbent fiber in each diaper which is
treated with 0.2% product containing 35% ai (0.007 g ai/diaper = 10
g/diaper x 0.2% product x 35 % ai). It was also assumed that an infant
(\< 1 year old) wears 8 diapers per day.

For estimating the exposure of infants to DGH when used in diapers, AD
used two transfer factors, 100 and 5%. A 100% transfer factor resulted
in MOEs of concern for all exposure durations (MOE = 36). However, using
a transfer factor of 5%, which is based on the default percent transfer
factor for pesticide residues migrating from carpets to skin surfaces
(Revisions to the Standard Operating Procedures (SOPs) for Residential
Exposure Assessments; Policy 12; US EPA, 2001), the MOEs for all
durations were greater than 100 and were not of concern (MOE = 714 ). In
order to refine dermal exposure resulting from use of DGH-impregnated
diapers and to fully answer the rate of migration of DGH to the skin of
infants, AD indicated the need for an impregnated diaper migration study
as confirmatory data to support the lower transfer factor assumption.

For purposes of refining the dermal exposure resulting from use of
diapers impregnated with DGH and incorporating this use into an
aggregate risk estimate (ie., dietary + drinking water + residential
exposure) for the Dodine Human Health Risk Assessment, HED back
calculated to determine what transfer factor would be required to reach
an acceptable MOE of 120 (for purposes of aggregate risk since a MOE of
100 for diaper exposure alone will not be sufficient). The calculations
determined that a 30% transfer factor would be required to result in an
MOE of 120. The assumptions, resulting exposures, and MOEs are presented
in Table 6.2.3.

HED believes that a transfer factor of 100% is an overestimate of
exposure in determining the amount of DGH transferred to infants from
diapers. Although using either 30 or 5 % transfer factors result in MOEs
that are not of concern, HED has no means to confirm these estimates of
exposure. Therefore, **HED concurs with AD's request for** **submission
of an impregnated diaper migration study as confirmatory data.**

  -------------------------- ------------ -------------- ---------------- ----------------
  **Table 6.2.3 Short-,                                                   
  Intermediate-, and                                                      
  Long-Term Residential                                                   
  Exposures and Risks from                                                
  Infants Wearing                                                         
  DGH-impregnated Diapers**                                               

  **Details**                **Acronyms   **No           **Confirmatory   **Confirmatory
                             Used**       Confirmatory   data needed**    data needed**
                                          data needed**                   

  Application Rate (g        AR           0.007          0.007            0.007
  ai/diaper) ^a^                                                          

  Exposure Frequency         EF           8              8                8
  (diapers/day)^b^                                                        

  Percent Transfer (%)^b^    TF           **100%**       **30%**          **5%**

  Conversion factor (1000    CF           1000           1000             1000
  mg/g)                                                                   

  Body Weight (kg) ^b^       BW           10             10               10

                                                                          

  Dermal Dose (ST/IT/LT )    ST/IT/LT PDD 5.6            1.68             0.28
  (mg/kg/day)^c^                                                          

                                                                          

  ST, IT and LT MOE^d^                    **36**         120              714
  -------------------------- ------------ -------------- ---------------- ----------------

^a^ The application rate of 0.007 g ai/diaper is based on assuming that
there is 10 g of absorbent fiber in each diaper which is treated with
0.2% product containing 35% ai, 0.007 g ai/diaper = 10 g/diaper x 0.2%
product x 35 % ai

^b^ AD standard exposure assumption

^c^ PDD (mg/kg/day) = AR (g ai/diaper) x EF (diapers/day) x TF (%) x CF
(1000mg/g) / BW (10kg for child \< 1 year old)

^d^ MOE = NOAEL (mg/kg/day) / PDD (mg/kg/day) where ST/IT/LT dermal
NOAEL = 200 mg/kg/day. ST/IT/LT Target MOEs = 100.

3.  **Residential Aggregate Risk**

Because of the similarity between dodine and DGH, HED has considered the
contribution of DGH residential uses to the overall aggregate assessment
for dodine.

In evaluating residential uses, HED combines risk estimates resulting
from separate exposure scenarios (i.e., oral, dermal, and inhalation)
when it is likely they can occur simultaneously based on the use pattern
and the behavior associated with exposed population. In an effort to
facilitate an aggregate risk estimate for the Human Health Risk
Assessment for dodine (dietary + drinking water + residential exposure)
the residential exposure components (exposure to DGH from application of
paint and impregnated diapers) have been identified and summarized in
the following sections.

**6.3.1 Short-term Aggregate Residential Exposure Risk**

The short-term aggregate exposure for adults consists of combining adult
dietary (food + drinking water) and both dermal and inhalation exposure
as a result of handling paint. Of the three handler paint scenarios
provided in Table 6.1.1, applying paint with an airless sprayer was the
most conservative assessment, and therefore, it is used to represent
adult residential exposure estimates for the overall human health
aggregate risk assessment. Aggregate exposure for children consists of
children's dietary (food + drinking water) and dermal exposure resulting
from use of diapers since inhalation exposure is expected to be
negligible. Although there is a potential for oral exposure to children
from incidental ingestion of paint chips, HED does not believe that this
would occur on a regular basis. Therefore, based on this professional
judgment, HED did not include oral exposure due to ingestion of paint
chips into the aggregate assessment for short-term exposure. The
short-term residential MOEs to be used for the human health aggregate
assessment are summarized in the Table 6.3.1.

  --------------------------------------------------------------------------------------------------
  **Table 6.3.1: Short-term                                                      
  Residential Aggregate Risk**                                                   
  ---------------------------------- ------------------- ----------------------- -------------------
  **Scenario**                       **MOE~Dermal\ ~**   **MOE~Inhalation\ ~**   **MOE~Total\ c~**

  Adults                                                                         

  Paint Products (Short-Term,        7,000 ~a~           16,000 ~a~              4,900
  Adults)                                                                        

  Children                                                                       

  Disposable Diapers (Short-,        714 ~b~             n/a                     714
  Intermediate-, Long-Term, Infants)                                             
  at **5%** Transfer factor                                                      

  Disposable Diapers (Short-,        120 ~b~             n/a                     120
  Intermediate-, Long-Term, Infants)                                             
  at **30%** Transfer factor                                                     

  Disposable Diapers (Short-,        36 ~b~              n/a                     **36**
  Intermediate-, Long-Term, Infants)                                             
  at **100%** Transfer factor                                                    
  --------------------------------------------------------------------------------------------------

a\. Paint dermal and Inhalation MOE are based on calculations for
applying paint with sprayer scenario shown in Table 6.1.1. This scenario
assumes worst case of all paint scenarios

b\. Diaper dermal MOEs are based on calculations from Table 6.2.3.

c\. MOE ~TOTAL~ = [1]{.underline}\_\_\_\_\_\_\_\_\_\_\_

[1]{.underline} + [1]{.underline}

MOE~DERMAL~ MOE~INHAL~

**6.3.2 Intermediate- and Long-Term Aggregate Residential Exposure
Risk**

Intermediate- and long-term residential aggregate exposures (food +
drinking water + intermediate- and long-term residential exposure)
result only from infants wearing DGH-impregnated diapers. Intermediate-
and long-term exposures to DGH in paints are not anticipated for adult
handlers. Since the intermediate- and long-term dermal exposures and
endpoints are the same as the short-term dermal values the MOEs will be
the same as those provided in Table 6.3.1. No additional calculations
are required. Risk resulting from short-term aggregate exposure to
wearing DGH-impregnated diapers is equivalent to the risk from
intermediate- and long-term aggregate exposures.

7.  **Aggregate Risk Assessments and Risk Characterization**

In accordance with the FQPA, HED must consider and aggregate (add)
pesticide exposures and risks from three major sources; food, drinking
water and residential exposure. In an aggregate assessment, exposures
from relevant sources are added together and compared to quantitative
estimates of hazard (e.g. a NOAEL or PAD), or the risks themselves can
be aggregated. When aggregating exposures and risk from various sources,
HED considers both the route and duration of exposure.

1.  **Acute Aggregate Risk**

No acute dietary endpoint was identified for dodine; therefore, an acute
aggregate risk assessment was not conducted.

[]{.mark}

2.  **Short- and Intermediate Term Aggregate Risk**

In determining short- and intermediate-term aggregate risks, HED
examined the oral (i.e. dietary) and non-oral routes (i.e., dermal and
inhalation) of exposure. Dietary (food + drinking water) exposure
estimates are found in Table 5.2.2. Incidental oral exposure (ingestion
of paint chips) was not aggregated as it is considered a non-routine
event and not likely to occur on a regular basis. Residential handler
exposure (i.e., non-oral routes of exposure) is expected to be
short-term only and consisted of combined dermal and inhalation exposure
as a result of handling paint. Short- and intermediate-term dermal
exposure to children resulted from use of diapers impregnated with DGH.
Inhalation exposure is expected to be negligible for the diaper
scenario. The margins of exposures for residential exposure to adults
and infants are provided in Table 6.3.1.

Table 7.2 provides a summary of the aggregate margins of exposure for
adult and children subpopulations to dodine. Since the endpoints for all
routes of exposure were based on the same toxicological effects, the
following method was used to estimate exposure

MOE~tot~ = [1\_\_\_\_\_\_\_\_]{.underline}

[1]{.underline} + [1]{.underline} + [1]{.underline}

MOE~ORAL~ MOE~DERMAL~ MOE~INHAL~

Where, MOE~X~ = [NOAEL~X~]{.underline}

Exposure~X~

The aggregate risk for adult subpopulations resulted in MOEs \> 100 and;
therefore, are not of concern to HED. The aggregate risk for infants
wearing impregnated diapers resulted in MOEs ranging from 34 to 300. HED
has no means to confirm these estimates of exposure for infant use of
impregnated diapers. In order to refine dermal exposure resulting from
use of DGH-impregnated diapers and to fully answer the rate of migration
of DGH to the skin of infants, **HED recommends a conditional
registration based on submission of an impregnated diaper migration
study as confirmatory data.**

[]{.mark}

+--------------+--------+-----------+-----+------+-------+----------+
| **Table 7.2. |        |           |     |      |       |          |
| Short-Term   |        |           |     |      |       |          |
| and          |        |           |     |      |       |          |
| Inter        |        |           |     |      |       |          |
| mediate-Term |        |           |     |      |       |          |
| Aggregate    |        |           |     |      |       |          |
| Risk         |        |           |     |      |       |          |
| Ca           |        |           |     |      |       |          |
| lculations** |        |           |     |      |       |          |
|              |        |           |     |      |       |          |
| ***(inter    |        |           |     |      |       |          |
| mediate-term |        |           |     |      |       |          |
| for children |        |           |     |      |       |          |
| only)***     |        |           |     |      |       |          |
+==============+========+===========+=====+======+=======+==========+
| Population   | **     |           |     |      |       |          |
|              | Short- |           |     |      |       |          |
|              | and    |           |     |      |       |          |
|              | Inter  |           |     |      |       |          |
|              | mediat |           |     |      |       |          |
|              | e-Term |           |     |      |       |          |
|              | Scena  |           |     |      |       |          |
|              | rios** |           |     |      |       |          |
+--------------+--------+-----------+-----+------+-------+----------+
|              | LOC    | MOE       | MOE | MOE  | MOE   | A        |
|              | for    |           |     |      | inh   | ggregate |
|              | Agg    | food &    | o   | d    | alati | MOE      |
|              | regate | water^2^  | ral | erma | on^5^ |          |
|              |        |           | ^3^ | l^4^ |       | (food    |
|              | R      |           |     |      |       | and      |
|              | isk^1^ |           |     |      |       | residen  |
|              |        |           |     |      |       | tial)^6^ |
+--------------+--------+-----------+-----+------+-------+----------+
| Adult Male,  | 100    | 59,000    | N/A | 7000 | 1     | 4500     |
| Handling     |        |           |     |      | 6,000 |          |
| Paint        |        |           |     |      |       |          |
+--------------+--------+-----------+-----+------+-------+----------+
| Adult        | 100    | 74,000    | N/A | 7000 | 1     | 4600     |
| Female,      |        |           |     |      | 6,000 |          |
| Handling     |        |           |     |      |       |          |
| Paint        |        |           |     |      |       |          |
+--------------+--------+-----------+-----+------+-------+----------+
| Child-DGH    | 100    | 6400      | N/A | 714  | N/A   | 640      |
| -impregnated |        |           |     |      |       |          |
| diapers      |        |           |     |      |       |          |
+--------------+--------+-----------+-----+------+-------+----------+
|              |        |           |     | 120  |       | 120      |
+--------------+--------+-----------+-----+------+-------+----------+
|              |        |           |     | 36   |       | 36       |
+--------------+--------+-----------+-----+------+-------+----------+

^1^ Level of concern for all scenarios is 100 based on standard UF=100

^2^ MOE food = \[(short- or intermediate-term oral NOAEL)/(dietary
exposure)\] NOAEL= 26 mg/kg/day;

> Adult males (50+years)= 0.000441; Adult females (13-49)=0.000351;
> Children (1-2 years)= 0.004072 (Table 5.2.2).

^3^ MOE oral =N/A=Not applicable

^4^ MOE dermal =\[(short- or intermediate-term dermal NOAEL)/(high-end
dermal residential exposure)\] Dermal

> NOAEL = 200 mg/kg/day; Dermal MOE = Adult males (50+years)/ females
> (13-49) =7000, Children; 714, 100, and 36 (Tables 6.1.1 and 6.2.3).

^5^ MOE inhalation = \[(inhalation NOAEL)/(high-end inhalation
residential exposure)\] Inhalation NOAEL (based

on oral study) = 10 mg/kg/day; Inhalation MOEs: Adult males (50+years)/
females (13-49)=16000 (Table 6.1.1).

^6^ Aggregate MOE (food and residential) = 1/\[ \[(1/MOE food) +
(1/MOE dermal) + (1/MOE

inhalation)\]

3.  **Long-Term Aggregate Risk**

Long-term residential aggregate exposure results only from infants
wearing DGH-impregnated diapers. Risk resulting from long-term aggregate
exposure is shown in Table 7.3. As with short- and intermediate-term
durations, MOE's are shown for three transfer factors used to assess
exposure from diapers.

+--------------+--------+-----------+-----+------+-------+----------+
| **Table 7.3. |        |           |     |      |       |          |
| Long-Term    |        |           |     |      |       |          |
| Aggregate    |        |           |     |      |       |          |
| Risk         |        |           |     |      |       |          |
| Ca           |        |           |     |      |       |          |
| lculations** |        |           |     |      |       |          |
+==============+========+===========+=====+======+=======+==========+
| Population   | **Lon  |           |     |      |       |          |
|              | g-Term |           |     |      |       |          |
|              | Scen   |           |     |      |       |          |
|              | ario** |           |     |      |       |          |
+--------------+--------+-----------+-----+------+-------+----------+
|              | LOC    | MOE       | MOE | MOE  | MOE   | A        |
|              | for    |           |     |      | inh   | ggregate |
|              | Agg    | food &    | o   | d    | alati | MOE      |
|              | regate | water^2^  | ral | erma | on^5^ |          |
|              |        |           | ^3^ | l^4^ |       | (food    |
|              | R      |           |     |      |       | and      |
|              | isk^1^ |           |     |      |       | residen  |
|              |        |           |     |      |       | tial)^6^ |
+--------------+--------+-----------+-----+------+-------+----------+
| Child-DGH    | 100    | 500       | N/A | 714  | N/A   | 300      |
| -impregnated |        |           |     |      |       |          |
| diapers      |        |           |     |      |       |          |
+--------------+--------+-----------+-----+------+-------+----------+
|              |        |           |     | 120  |       | 100      |
+--------------+--------+-----------+-----+------+-------+----------+
|              |        |           |     | 36   |       | 34       |
+--------------+--------+-----------+-----+------+-------+----------+

^1^ Level of concern for all scenarios is 100 based on standard UF=100

^2^ MOE food = \[chronic dietary NOAEL)/(dietary exposure)\] NOAEL= 2
mg/kg/day;

> Children (1-2 years)= 0.004072 (Table 5.2.2).

^3^ MOE oral =N/A=Not applicable

^4^ MOE dermal =\[long-term dermal NOAEL)/(high-end dermal residential
exposure)\] Dermal

> NOAEL = 200mg/kg/day; Dermal MOE = Children; 714, 100, and 36 (Table
> 6.2.3).

^5^ MOE inhalation =N/A=Not applicable

^6^ Aggregate MOE (food and residential) = 1/\[ \[(1/MOE food) +
(1/MOE dermal)\]

**7.4 Cancer Risk**

Exposure to dodine did not result in a treatment-related increase in
tumor formation in rats and mice; therefore, a cancer risk assessment
was not conducted.

**8.0 Cumulative Risk Characterization/Assessment**

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

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to dodine and any other
substances, and dodine does not appear to produce a toxic metabolite
produced by other substances. For the purposes of this tolerance action,
EPA has not assumed that dodine has a common mechanism of toxicity with
other substances. For information regarding EPA's efforts to determine
which chemicals have a common mechanism of toxicity and to evaluate the
cumulative effects of such chemicals, see the policy statements released
by EPA's Office of Pesticide Programs concerning common mechanism
determinations and procedures for cumulating effects from substances
found to have a common mechanism on EPA's website at
http://www.epa.gov/pesticides/cumulative/.

0.  **Occupational Exposure/Risk Pathway**

Dodine (n-dodecylguanidine acetate) is a fungicide registered for the
control of certain fungal diseases on apples, cherries, peaches, pears,
pecans, walnuts, strawberries, and ornamental trees. The petitioner is
proposing a Section 3 registration for the use of dodine on bananas and
peanuts. The proposed product, Syllit® FL Fungicide (EPA Reg. No.
55260-6), is formulated as a flowable concentrate ( FlC), which contains
39.6 % dodine as the sole active ingredient (ai). Based on the proposed
use pattern of Syllit® FL Fungicide on banana and peanut, handlers and
post-application exposure is expected to be short- and intermediate-term
in duration.

1.  **Short-and intermediate-Term Handler Risk**

Based on the proposed use patterns of dodine on banana and peanut, the
handlers would be subjected to short- and intermediate-term exposures.
The intermediate-term exposures may result from multiple applications of
dodine at intervals of 7-15 days on banana and at 10-14 days on peanut.

The label specifies a basic PPE for handlers (long sleeved shirt and
long pants, socks, and shoes) plus chemical-resistant gloves made of
waterproof material, protective eyewear, chemical-resistant headgear for
overhead exposure, and a chemical-resistant apron when mixing or
loading.

The petitioner has not submitted any product specific occupational
exposure data; therefore, HED default values and PHED were used to
estimate the exposures to pesticide handlers

**Short-term Non-cancer Risks**

HED's level of concern is equal to greater than a MOE of 100. Therefore,
all MOEs greater than 100 are not of concern. Since the dermal and
inhalation endpoints are based on the same effects, the dermal and
inhalation exposures were added together to result in a Total MOE.

The exposure estimates indicate that the risks from all handler
scenarios are not of concern (MOEs ≥ 100) at baseline (long-sleeve
shirt, long pants, shoes, and socks), with two exceptions. The
mixer/loader scenarios at baseline resulted in risks of concern (Dermal
MOE=11 and 94). However, the addition of gloves resulted in MOEs that
are not of concern (MOE \> 100). Furthermore, since the label mandates
use of rubber gloves for handlers under PPE; no additional mitigation
language is required. Table 9.1 summarizes the short-term dermal and
inhalation exposures and risks to handlers.

<table style="width:100%;">
<colgroup>
<col style="width: 10%" />
<col style="width: 14%" />
<col style="width: 8%" />
<col style="width: 10%" />
<col style="width: 10%" />
<col style="width: 11%" />
<col style="width: 7%" />
<col style="width: 11%" />
<col style="width: 7%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="10"><blockquote>
<p><strong>Table 9.1: Short and Intermediate-term Handler Exposure and
Risk for Dodine</strong></p>
</blockquote></td>
</tr>
<tr class="even">
<td rowspan="2"><blockquote>
<p>Crop and Max.</p>
<p>Rate/Appl.</p>
</blockquote></td>
<td rowspan="2"><blockquote>
<p>Exposure</p>
<p>Scenario</p>
</blockquote></td>
<td rowspan="2"><blockquote>
<p>PPE <sup>1</sup></p>
</blockquote></td>
<td rowspan="2"><blockquote>
<p>Dermal Unit Exp.</p>
<p>(mg/kg/day)</p>
</blockquote></td>
<td rowspan="2"><blockquote>
<p>Inhalation Unit Exp. (µg/kg/day)</p>
</blockquote></td>
<td colspan="2"><blockquote>
<p>Dermal</p>
</blockquote></td>
<td colspan="2"><blockquote>
<p>Inhalation</p>
</blockquote></td>
<td rowspan="2"><blockquote>
<p>Total</p>
<p>MOE</p>
</blockquote></td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Dose (mg/kg/day) <sup>2</sup></p>
</blockquote></td>
<td><blockquote>
<p>MOE <sup>3</sup></p>
</blockquote></td>
<td><blockquote>
<p>Dose</p>
<p>(mg/kg/day) <sup>2</sup></p>
</blockquote></td>
<td><blockquote>
<p>MOE <sup>3</sup></p>
</blockquote></td>
</tr>
<tr class="even">
<td rowspan="4"><blockquote>
<p>Banana</p>
<p>1.3 lb ai/A.</p>
<p>(350 A/day)</p>
</blockquote></td>
<td rowspan="2"><blockquote>
<p>Mixer/loader, liquid, open mixing/loading for aerial application</p>
</blockquote></td>
<td><blockquote>
<p>Baseline</p>
</blockquote></td>
<td><blockquote>
<p>2.9</p>
</blockquote></td>
<td><blockquote>
<p>1.2</p>
</blockquote></td>
<td><blockquote>
<p>18.85</p>
</blockquote></td>
<td><blockquote>
<p>11</p>
</blockquote></td>
<td><blockquote>
<p>0.008</p>
</blockquote></td>
<td><blockquote>
<p>1,300</p>
</blockquote></td>
<td><blockquote>
<p>11</p>
</blockquote></td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Baseline + gloves</p>
</blockquote></td>
<td><blockquote>
<p>0.023</p>
</blockquote></td>
<td><blockquote>
<p>1.2</p>
</blockquote></td>
<td><blockquote>
<p>0.154</p>
</blockquote></td>
<td><blockquote>
<p>1,300</p>
</blockquote></td>
<td><blockquote>
<p>0.0078</p>
</blockquote></td>
<td><blockquote>
<p>1,300</p>
</blockquote></td>
<td><blockquote>
<p>650</p>
</blockquote></td>
</tr>
<tr class="even">
<td><blockquote>
<p>Applicator, liquid, aerial, fixed wing, enclosed cockpit</p>
</blockquote></td>
<td><blockquote>
<p>Baseline</p>
</blockquote></td>
<td><blockquote>
<p>0.005</p>
</blockquote></td>
<td><blockquote>
<p>0.068</p>
</blockquote></td>
<td><blockquote>
<p>0.0325</p>
</blockquote></td>
<td><blockquote>
<p>6,200</p>
</blockquote></td>
<td><blockquote>
<p>0.000442</p>
</blockquote></td>
<td><blockquote>
<p>23,000</p>
</blockquote></td>
<td><blockquote>
<p>5,000</p>
</blockquote></td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Flagger, liquid</p>
</blockquote></td>
<td><blockquote>
<p>Baseline</p>
</blockquote></td>
<td><blockquote>
<p>0.011</p>
</blockquote></td>
<td><blockquote>
<p>0.35</p>
</blockquote></td>
<td><blockquote>
<p>0.0715</p>
</blockquote></td>
<td><blockquote>
<p>2,800</p>
</blockquote></td>
<td><blockquote>
<p>0.00228</p>
</blockquote></td>
<td><blockquote>
<p>4,400</p>
</blockquote></td>
<td><blockquote>
<p>1,700</p>
</blockquote></td>
</tr>
<tr class="even">
<td rowspan="3"><blockquote>
<p>Peanut</p>
<p>0.64 lb ai/A.</p>
<p>(80 A/day)</p>
</blockquote></td>
<td rowspan="2"><blockquote>
<p>Mixer/loader, liquid, open mixing/loading for ground boom Appl.</p>
</blockquote></td>
<td><blockquote>
<p>Baseline</p>
</blockquote></td>
<td><blockquote>
<p>2.9</p>
</blockquote></td>
<td><blockquote>
<p>1.2</p>
</blockquote></td>
<td><blockquote>
<p>2.12</p>
</blockquote></td>
<td><blockquote>
<p>94</p>
</blockquote></td>
<td><blockquote>
<p>0.000878</p>
</blockquote></td>
<td><blockquote>
<p>11,000</p>
</blockquote></td>
<td><blockquote>
<p>93</p>
</blockquote></td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Baseline</p>
<p>+ gloves</p>
</blockquote></td>
<td><blockquote>
<p>0.023</p>
</blockquote></td>
<td><blockquote>
<p>1.2</p>
</blockquote></td>
<td><blockquote>
<p>0.0168</p>
</blockquote></td>
<td><blockquote>
<p>12,000</p>
</blockquote></td>
<td><blockquote>
<p>0.00878</p>
</blockquote></td>
<td><blockquote>
<p>11,000</p>
</blockquote></td>
<td><blockquote>
<p>5,700</p>
</blockquote></td>
</tr>
<tr class="even">
<td><blockquote>
<p>Applicator, liquid, ground boom, open cab</p>
</blockquote></td>
<td><blockquote>
<p>Baseline</p>
</blockquote></td>
<td><blockquote>
<p>0.014</p>
</blockquote></td>
<td><blockquote>
<p>0.74</p>
</blockquote></td>
<td><blockquote>
<p>0.01</p>
</blockquote></td>
<td><blockquote>
<p>20,000</p>
</blockquote></td>
<td><blockquote>
<p>0.00054</p>
</blockquote></td>
<td><blockquote>
<p>19,000</p>
</blockquote></td>
<td><blockquote>
<p>10,000</p>
</blockquote></td>
</tr>
</tbody>
</table>

1\. Baseline PPE consists of long-sleeved shirt, long pants, shoes with
socks.

2\. Dermal doses (mg/kg/day): \[max. single appl. rate \* acres
treated/day \* dermal unit exp.\*\] / body weight.

Inhalation dose (mg/kg/day): \[max. single appl. rate \* acres
treated/day \* inhal. unit exp.\] / body weight.

3\. Dermal MOE (short- and intermediate-term) = Dermal NOAEL (200
mg/kg/day) / Dermal dose (mg/kg/day),

4\. Inhalation MOE (short- and intermediate-term) = Inhalation NOAEL (10
mg/kg/day) / Inhalation dose (mg/kg/day

**9.2 Short-and Intermediate-Term Postapplication Risk**

Based on the proposed use patterns of dodine on banana and peanut, the
post-application workers would be subjected to short- and
intermediate-term exposures. The intermediate-term exposures result from
multiple applications of dodine at intervals of 7-15 days on banana and
at 10-14 days on peanut.

The petitioner has not submitted a product specific post-application
exposure study for calculating the risks to workers who may enter the
treated field for weeding, scouting, harvesting, etc. Therefore,
post-application worker exposures were estimated using default dermal
transfer coefficients from the HED\'s ExpoSAC Policy No. 3.1.

It should be noted that there was no transfer coefficient data in Policy
3.1 for banana. Therefore, surrogate transfer coefficient values for
bunch/bundle crop groups (i.e., hops and tobacco) were used to assess
postapplication exposure and risk for bananas.

All postapplication MOE were greater than 100 and therefore are not of
concern to HED.

+-------+--------+-----------+---------+---------+----------+--------+
| **    |        |           |         |         |          |        |
| Table |        |           |         |         |          |        |
| 9.2:  |        |           |         |         |          |        |
| S     |        |           |         |         |          |        |
| hort- |        |           |         |         |          |        |
| and   |        |           |         |         |          |        |
| In    |        |           |         |         |          |        |
| terme |        |           |         |         |          |        |
| diate |        |           |         |         |          |        |
| -term |        |           |         |         |          |        |
| Posta |        |           |         |         |          |        |
| pplic |        |           |         |         |          |        |
| ation |        |           |         |         |          |        |
| Risks |        |           |         |         |          |        |
| to    |        |           |         |         |          |        |
| Wo    |        |           |         |         |          |        |
| rkers |        |           |         |         |          |        |
| Ent   |        |           |         |         |          |        |
| ering |        |           |         |         |          |        |
| F     |        |           |         |         |          |        |
| ields |        |           |         |         |          |        |
| Tr    |        |           |         |         |          |        |
| eated |        |           |         |         |          |        |
| With  |        |           |         |         |          |        |
| Sy    |        |           |         |         |          |        |
| llit® |        |           |         |         |          |        |
| FL    |        |           |         |         |          |        |
| Fu    |        |           |         |         |          |        |
| ngici |        |           |         |         |          |        |
| de.** |        |           |         |         |          |        |
+-------+--------+-----------+---------+---------+----------+--------+
| **Cr  | *      | **Work    | **T     | **Dislo | **Dermal | **MOE  |
| ops** | *Appl. | A         | ransfer | dgeable | Do       | ^4^**  |
|       | Rate   | ctivity** | Coeff   | foliar  | se/Day** |        |
|       | (lb    |           | icients | residue |          |        |
|       | a      |           | (       | (       | **(mg    |        |
|       | i/A)** |           | cm2/hr) | µg/cm2) | /kg/day) |        |
|       |        |           | ^1^**   | ^2^**   | ^3^**    |        |
+-------+--------+-----------+---------+---------+----------+--------+
| B     | 1.3    | hand      | 100     | 2.92    | 0.033    | 6,000  |
| anana |        | ha        |         |         |          |        |
| (B    |        | rvesting, |         |         |          |        |
| unch/ |        | weeding,  |         |         |          |        |
| Bu    |        | scouting  |         |         |          |        |
| ndle) |        |           |         |         |          |        |
+-------+--------+-----------+---------+---------+----------+--------+
|       |        | Hand      | 2000    |         | .666     | 300    |
|       |        | ha        |         |         |          |        |
|       |        | rvesting, |         |         |          |        |
|       |        | s         |         |         |          |        |
|       |        | tripping, |         |         |          |        |
|       |        | training  |         |         |          |        |
+-------+--------+-----------+---------+---------+----------+--------+
| P     | 0.64   | ir        | 100     | 1.44    | 0.016    | 12,000 |
| eanut |        | rigation, |         |         |          |        |
|       |        | scouting  |         |         |          |        |
+-------+--------+-----------+---------+---------+----------+--------+
|       |        |           | 1500    |         | 0.246    | 800    |
+-------+--------+-----------+---------+---------+----------+--------+

1\. ExpoSAC SOP No. 3.1 (2000).

2\. DFR = AR \* F \* (1-D)^t^ \* 4.54 E+8 \* 2.47E-8

3\. DD = (DFR \* 0.001 mg/µg \* TC \* ET) / BW (70 kg)

4\. Dermal MOE = Dermal NOAEL (200 mg/kg/day) / Dermal Dose.

[Restricted Entry Interval]{.underline}

Dodine has moderate acute toxicity by oral, dermal, and inhalation
routes (Categories III) and is not a skin sensitizer. However, it is a
severe dermal and eye irritant (Toxicity Categories I). Chemicals
classified as toxicity category 1 require a 48-hour REI in accordance
with Worker Protection Standards (WPS). Therefore, HED concurs with the
48-hour REI on the proposed product label.

**10.0 Data Needs and Label Requirements**

**10.1 Toxicology**

None

**10.2 Residue Chemistry**

*Directions for Use*

-   The proposed use on banana does not include a maximum seasonal rate.
    In addition, the crop field trial data from Hawaii do not reflect
    the proposed use pattern. The petitioner should modify the proposed
    label such that the use pattern on banana corresponds to the use
    pattern of the banana crop field trials: five applications at 0.71
    lb ai/A/application, for a maximum seasonal rate of 3.6 lb ai/A,
    with a minimum retreatment interval of 6 days and a PHI of 0 days.

```{=html}
<!-- -->
```
-   The petitioner has indicated that the proposed tolerance for bananas
    is intended to apply to domestic bananas as well as imported
    bananas, but that the use directions for foreign countries have not
    yet been finalized. To allow HED to determine that the submitted
    crop field trial data adequately reflect the use of dodine on
    bananas in countries outside the U.S., when the use directions have
    been finalized, the petitioner should submit copies of product
    labels (with English translations, if needed) with use directions on
    bananas from all countries in which dodine is to be applied to
    bananas destined for import into the U.S. If the finalized use
    directions differ significantly from the use patterns of the
    submitted crop field trial data, additional data may be required.

*Residue Analytical Methods*

-   Method METH1595.02 should be modified to remove the conversion of
    residue results to "dodine free base" (this calculation is made at
    the step in which standard solutions are prepared). Residue results
    [must]{.underline} be calculated in terms of dodine, as
    N-dodecylguanidine acetate. In addition, the typographical error in
    step 9.3.7 of the method should be corrected \["Repeat steps 9.2.3
    to 9.2.6 two more times" should be changed to "Repeat steps 9.3.3 to
    9.3.6 two more times"\].

*Proposed Tolerances*

-   The proposed tolerance for peanut should be revised from 0.03 ppm to
    0.013 ppm.

*Confined Accumulation in Rotational Crops*

-   Confined rotational crop data are required to support the proposed
    use on peanuts. A confined rotational crop study was required in the
    Revised RED Chapter (DP# 320758, 9/14/05, D. Soderberg). These data
    remain outstanding. HED recommends the registration of the uses on
    peanuts be made conditional on the future submission of these data.

*Field Accumulation in Rotational Crops*

-   The need for field rotational crop studies and/or rotational crop
    restrictions/tolerances will be determined when an adequate confined
    rotational crop study has been submitted.

**10.3 Occupational and Residential Exposure**

-   HED recommends a conditional registration based on submission of an
    impregnated diaper migration study as confirmatory data.

**References:**

Corrections to Phase III --Revised as per 30-day Error Only Registrant
Comments. Dodine: HED Chapter of the Reregistration Eligibility Decision
(RED). D323607. 11/15/2005. J. Morales.

Dodine and Salts. Reregistration Eligibility Decision (RED). Summary of
Analytical Chemistry and Residue Data. D314320. 9/14/05. D. Soderberg.

Dodine. Petition for Establishment of Permanent Tolerances for Residues
of Dodine in/on Bananas and Peanuts. Summary of Analytical Chemistry and
Residue Data. D338572, D342401. M. Doherty.

Dodine. Chronic Aggregate Dietary (Food and Drinking Water) Exposure and
Risk Assessment for the Section 3 Registration on Banana and Peanut.
D346911. M. Doherty.

Dodine: Occupational Exposure Assessment for the New Uses on Banana and
Peanut. D338783. S. Oonnithan

**Appendix A: Toxicology Assessment**

**A.1 Toxicology Data Requirements**

The requirements (40 CFR 158.340) for food use for dodine are below. Use
of the new guideline numbers does not imply that the new (1998)
guideline protocols were used.

+---------------------------------------+------------+----------------+
| **Test**                              | **T        |                |
|                                       | echnical** |                |
+=======================================+============+================+
|                                       | **         | **Satisfied**  |
|                                       | Required** |                |
+---------------------------------------+------------+----------------+
| 870.1100 Acute Oral Toxicity          | yes        | yes            |
|                                       |            |                |
| 870.1200 Acute Dermal Toxicity        | yes        | yes            |
|                                       |            |                |
| 870.1300 Acute Inhalation Toxicity    | yes        | yes            |
|                                       |            |                |
| 870.2400 Primary Eye Irritation       | yes        | yes            |
|                                       |            |                |
| 870.2500 Primary Dermal Irritation    | yes        | yes            |
|                                       |            |                |
| 870.2600 Dermal Sensitization         | yes        | yes            |
+---------------------------------------+------------+----------------+
| 870.3100 Oral Subchronic (rodent)     | yes        | yes\*          |
|                                       |            |                |
| 870.3150 Oral Subchronic (nonrodent)  | yes        | yes\*\*        |
|                                       |            |                |
| 870.3200 21-Day Dermal                | yes        | yes            |
|                                       |            |                |
| 870.3250 90-Day Dermal                | no         | \-             |
|                                       |            |                |
| 870.3465 90-Day Inhalation            | no         | \-             |
+---------------------------------------+------------+----------------+
| 870.3700a Developmental Toxicity      | yes        | yes            |
| (rodent)                              |            |                |
|                                       | yes        | yes            |
| 870.3700b Developmental Toxicity      |            |                |
| (nonrodent)                           | yes        | yes            |
|                                       |            |                |
| 870.3800 Reproduction                 |            |                |
+---------------------------------------+------------+----------------+
| 870.4100a Chronic Toxicity (rodent)   | yes        | yes\*\*\*      |
|                                       |            |                |
| 870.4100b Chronic Toxicity            | yes        | yes            |
| (nonrodent)                           |            |                |
|                                       | yes        | yes            |
| 870.4200a Oncogenicity (rat)          |            |                |
|                                       | yes        | yes            |
| 870.4200b Oncogenicity (mouse)        |            |                |
|                                       | yes        | yes            |
| 870.4300 Chronic/Oncogenicity         |            |                |
+---------------------------------------+------------+----------------+
| 870.5100 Mutagenicity---Gene          | yes        | yes            |
| Mutation - bacterial                  |            |                |
|                                       | yes        | yes            |
| 870.5300 Mutagenicity---Gene          |            |                |
| Mutation - mammalian                  | yes        | yes            |
|                                       |            |                |
| 870.5375 Mutagenicity---Structural    | yes        | yes            |
| Chromosomal Aberrations               |            |                |
|                                       |            |                |
| 870.5385 Mutagenicity---Other         |            |                |
| Genotoxic Effects                     |            |                |
+---------------------------------------+------------+----------------+
| 870.6100a Acute Delayed Neurotox.     | no         | \-             |
| (hen)                                 |            |                |
|                                       | no         | \-             |
| 870.6100b 90-Day Neurotoxicity (hen)  |            |                |
|                                       | no         | \-             |
| 870.6200a Acute Neurotox. Screening   |            |                |
| Battery (rat)                         | no         | \-             |
|                                       |            |                |
| 870.6200b 90 Day Neuro. Screening     | no         | \-             |
| Battery (rat)                         |            |                |
|                                       |            |                |
| 870.6300 Develop. Neuro               |            |                |
+---------------------------------------+------------+----------------+
| 870.7485 General Metabolism           | yes        | yes            |
|                                       |            |                |
| 870.7600 Dermal Penetration           | no         | \-             |
+---------------------------------------+------------+----------------+
| Special Studies for Ocular Effects    | no         | \-             |
|                                       |            |                |
| > Acute Oral (rat)                    | no         | \-             |
| >                                     |            |                |
| > Subchronic Oral (rat)               | no         | \-             |
| >                                     |            |                |
| > Six-month Oral (dog)                |            |                |
+---------------------------------------+------------+----------------+

\*Satisfied by the chronic (rodent) toxicity study-guideline 870.4100a

\*\*Satisfied by the chronic (nonrodent) toxicity study-guideline
870.4100b

\*\*\*Satisfied by the chronic/oncogenicity study-guideline 870.4300

**A.2 Toxicity Profiles**

+-------+--------------------+-------+--------------------+----------+
| **    |                    |       |                    |          |
| Table |                    |       |                    |          |
| A.2.1 |                    |       |                    |          |
| Acute |                    |       |                    |          |
| Tox   |                    |       |                    |          |
| icity |                    |       |                    |          |
| Prof  |                    |       |                    |          |
| ile - |                    |       |                    |          |
| Dod   |                    |       |                    |          |
| ine** |                    |       |                    |          |
+=======+====================+=======+====================+==========+
| *     | **Study Type**     | *     | **Results**        | **       |
| *Guid |                    | *MRID |                    | Toxicity |
| eline |                    | (s)** |                    | Ca       |
| No.** |                    |       |                    | tegory** |
+-------+--------------------+-------+--------------------+----------+
| 870   | Acute oral \[rat\] | 001   | LC~50~ males =1931 | III      |
| .1100 |                    | 24280 | mg/kg              |          |
|       |                    |       |                    |          |
|       |                    |       | LC~50~ females     |          |
|       |                    |       | =1171 mg/kg        |          |
|       |                    |       |                    |          |
|       |                    |       | LC~50~ combined    |          |
|       |                    |       | =1456 mg/kg        |          |
+-------+--------------------+-------+--------------------+----------+
| 870   | Acute dermal       | 001   | LD~50~ \>2000      | III      |
| .1200 | \[rabbit\]         | 24280 | mg/kg              |          |
+-------+--------------------+-------+--------------------+----------+
| 870   | Acute inhalation   | 001   | LC~50~ = 1.05      | III      |
| .1300 | \[rat\]            | 57300 | mg/kg              |          |
+-------+--------------------+-------+--------------------+----------+
| 870   | Acute eye          | 001   | Severe             | I        |
| .2400 | irritation         | 24280 |                    |          |
|       | \[rabbit\]         |       |                    |          |
+-------+--------------------+-------+--------------------+----------+
| 870   | Primary dermal     | 001   | Primary Dermal     | I        |
| .2500 | irritation         | 24280 | Irritation Index,  |          |
|       | \[rabbit\]         |       | PDII - 7.5         |          |
+-------+--------------------+-------+--------------------+----------+
| 870   | Skin sensitization | 001   | Negative           | Neg      |
| .2600 | \[human\]          | 57386 |                    |          |
+-------+--------------------+-------+--------------------+----------+

+------------+----------------+---------------------------------------+
| **Table    |                |                                       |
| A.2.2.     |                |                                       |
| S          |                |                                       |
| ubchronic, |                |                                       |
| Chronic    |                |                                       |
| and Other  |                |                                       |
| Toxicity   |                |                                       |
| Profile    |                |                                       |
| for        |                |                                       |
| Dodine**   |                |                                       |
+============+================+=======================================+
| *          | **MRID No.     | **Results**                           |
| *Guideline | (year)/        |                                       |
| No./ Study | Classification |                                       |
| Type**     | /Doses**       |                                       |
+------------+----------------+---------------------------------------+
| 870.3100   |                | Satisfied by chronic toxicity study   |
|            |                | in rats- MRID 44704401                |
| 90-Day     |                |                                       |
| oral       |                |                                       |
| toxicity   |                |                                       |
| (rat)      |                |                                       |
+------------+----------------+---------------------------------------+
| 870.3100   |                | NOAEL = 350/305 mg/kg/day (M/F)       |
|            |                |                                       |
| 90-Day     |                | LOAEL = 181/223 mg/kg/day (M/F)       |
| oral       |                |                                       |
| toxicity   |                | Based on increased mortality and      |
| (mouse)    |                | clinical signs of toxicity            |
|            |                | (stiffening of the tail) in females,  |
|            |                | and decreased body weights, body      |
|            |                | weight gains, and food consumption in |
|            |                | both sexes.                           |
+------------+----------------+---------------------------------------+
| 870.3200   | 46420701(1998) | **Systemic** NOAEL = ≥200 mg/kg/day   |
|            |                |                                       |
| 21/28- Day | Accept         | LOAEL = not identified\*              |
| dermal     | able/guideline |                                       |
| toxicity   |                | **Dermal** NOAEL = not identified     |
|            | M&F: 0, 50,    |                                       |
| (rat)      | 125, 200       | LOAEL = 50 mg/kg/day based on dermal  |
|            | mg/kg/day      | irritation.                           |
|            |                |                                       |
|            |                | Based on the weight of evidence, the  |
|            |                | risk assessment team anticipates that |
|            |                | increasing dermal doses above 200     |
|            |                | mg/kg/day would result in minimal     |
|            |                | systemic toxicity (i.e. body weight   |
|            |                | effects; see section 4.4.6).          |
+------------+----------------+---------------------------------------+
| 870.3700a  | 41900304       | **Maternal** NOAEL = 10 mg/kg/day     |
|            | (1989)         |                                       |
| Prenatal   |                | LOAEL = 45 mg/kg/day based on         |
| dev        | Accept         | decreased body weight gain and food   |
| elopmental | able/guideline | consumption.                          |
| (rat)      |                |                                       |
|            | F: 0, 10, 45   | **Developmental** NOAEL = ≥90         |
|            | or 90          | mg/kg/day                             |
|            | mg/kg/day (GD  |                                       |
|            | 6-16)          | LOAEL = not identified                |
+------------+----------------+---------------------------------------+
| 870.3700b  | 41900303       | **Materna**l NOAEL = 80 mg/kg/day     |
|            | (1989)         |                                       |
| Prenatal   |                | LOAEL = not identified.               |
| dev        | Acceptable     |                                       |
| elopmental | /Non-guideline | **Developmenta**l NOAEL = ≥80         |
| in         |                | mg/kg/day                             |
| (rabbit)   | 0, 10, 40 or   |                                       |
|            | 80 mg/kg/day   | LOAEL = not identified.               |
|            | (GD 6-18)      |                                       |
+------------+----------------+---------------------------------------+
| 870.3800   | 44246001(1996) | **Parental/Systemic** NOAEL = 26      |
|            |                | mg/kg/day                             |
| Re         | Accept         |                                       |
| production | able/guideline | LOAEL = 53 mg/kg/day based on         |
| and        |                | decreased body weight, body weight    |
| fertility  | 0, 200, 400 or | gain and food consumption.            |
| effects    | 800 ppm        |                                       |
|            |                | **Reproductive** NOAEL = ≥53          |
| (rat)      | 0, 13, 26 or   | mg/kg/day                             |
|            | 53 mg/kg/day   |                                       |
|            |                | LOAEL = not identified.               |
|            |                |                                       |
|            |                | **Offspring:** NOAEL = 26 mg/kg/day   |
|            |                |                                       |
|            |                | LOAEL = 53 mg/kg/day based on         |
|            |                | decreased pup body weights.           |
+------------+----------------+---------------------------------------+
| 870.4100b  | 44246101       | NOAEL = 10/2 mg/kg/day (M/F)          |
|            | (1996)         |                                       |
| Chronic    |                | LOAEL = 20/10 mg/kg/day based on      |
| toxicity   | Accept         | decreased food consumption/decreased  |
|            | able/guideline | weight gain. (M/F)                    |
| (dog)      |                |                                       |
|            | M&F: 0, 2, 10, |                                       |
|            | or 20          |                                       |
|            |                |                                       |
|            | mg/kg/day      |                                       |
+------------+----------------+---------------------------------------+
| 870.4200   | 44703201(1998) | NOAEL = 110/38 mg/kg/day (M/F)        |
|            |                |                                       |
| Carci      | Accept         | LOAEL = 225/136 mg/kg/day based on    |
| nogenicity | able/guideline | decreased body weight, body weight    |
|            |                | gain and food consumption. (M/F)      |
| (mouse)    | 0, 200, 750 or |                                       |
|            | 1500 ppm       | **No evidence of carcinogenicity.**   |
|            |                |                                       |
|            | M: 0, 29, 110, |                                       |
|            | 225 mg/kg/day  |                                       |
|            |                |                                       |
|            | F: 0, 38, 136, |                                       |
|            | 277 mg/kg/day  |                                       |
+------------+----------------+---------------------------------------+
| 870.4300   | 44704401       | NOAEL = 20 mg/kg/day                  |
|            | (1998)         |                                       |
| Chronic/   |                | LOAEL = M: 42 mg/kg/day based on      |
|            | Accept         | decreased body weight gain; F: 54     |
| Carci      | able/guideline | mg/kg/day based on decreased body     |
| nogenicity |                | weight and food consumption.          |
|            | 0, 200, 400 or |                                       |
| (rat)      | 800 ppm        | **No evidence of carcinogenicity.**   |
|            |                |                                       |
|            | M: 0, 10, 20,  |                                       |
|            | 42 mg/kg/day   |                                       |
|            |                |                                       |
|            | F: 0, 13, 27,  |                                       |
|            | 54 mg/kg/day   |                                       |
+------------+----------------+---------------------------------------+
| 870.5100   | 40315504       | No evidence of an increase in         |
|            |                | revertants in any strain, with or     |
| Bacterial  | Accept         | without activation up to a dose of 50 |
| reverse    | able/Guideline | µg/mL.                                |
| mutation   |                |                                       |
| test       |                |                                       |
+------------+----------------+---------------------------------------+
| 870.5300   | 41711002       | No biologically significant increase  |
| Gene       | (1985)         | in the number of mutant colonies over |
| Mutation   |                | background. Dosed up to 35.0 µg/mL    |
|            | Accept         | with S9-mix and 20.0 µg/mL without.   |
| (CHO)      | able/guideline |                                       |
+------------+----------------+---------------------------------------+
| 870.5375   | 41711001       | No evidence of chromosomal            |
| Cytogene   | (1985)         | aberrations induced when dosed with   |
| tics-Human |                | up to 15.0 µg/mL with and 10.0 µg/mL  |
| L          | Accept         | without metabolic activation.         |
| ymphocytes | able/guideline |                                       |
| chromosome |                |                                       |
| aberration |                |                                       |
| test       |                |                                       |
+------------+----------------+---------------------------------------+
| 870.5385   | 42311601       | Negative in genotoxic effects in male |
| Mammalian  | (1992)         | and female mice treated with a single |
| bone       |                | oral dose of up to 400 mg/kg.         |
| marrow     | Accept         |                                       |
| c          | able/guideline |                                       |
| hromosomal |                |                                       |
| aberration |                |                                       |
| test       |                |                                       |
|            |                |                                       |
| (mouse)    |                |                                       |
+------------+----------------+---------------------------------------+
| 870.6200a  | Not available  | N/A                                   |
|            |                |                                       |
| Acute      |                |                                       |
| neu        |                |                                       |
| rotoxicity |                |                                       |
| screening  |                |                                       |
| battery    |                |                                       |
+------------+----------------+---------------------------------------+
| 870.6200b  | Not available  | N/A                                   |
|            |                |                                       |
| Subchronic |                |                                       |
| neu        |                |                                       |
| rotoxicity |                |                                       |
| screening  |                |                                       |
| battery    |                |                                       |
+------------+----------------+---------------------------------------+
| 870.7485   | 42479001       | Rapid absorption, metabolism,         |
|            | (1992)         | distribution, and excretion; major    |
| Metabolism |                | excretion routes are urine and feces. |
| and        | Accept         | Major metabolite found in urine was a |
| pharma     | able/guideline | dodine alcohol,                       |
| cokinetics |                | hydroxydodecylguanidine; parent       |
|            | Single dose of | compound found in feces.              |
| (rat)      | 40 or 400      |                                       |
|            | mg/kg ^14^     | Proposed metabolic pathway was        |
|            | C-labeled      | ß-oxidation pathway.                  |
|            | dodine         |                                       |
|            |                |                                       |
|            | 40 mg/kg/day   |                                       |
|            | non-labeled    |                                       |
|            | dodine x 14    |                                       |
|            | days with      |                                       |
|            | single dose of |                                       |
|            | 40 mg/kg       |                                       |
|            |                |                                       |
|            | ^14^ C-labeled |                                       |
+------------+----------------+---------------------------------------+

**A.3a Executive Summaries**

**A.3.1 Subchronic Toxicity**

**870.3100 Subchronic Oral Toxicity Study-Mouse**

**[EXECUTIVE SUMMARY:]{.underline}** In a subchronic oral toxicity study
(MRIDs 46585001 and 46544401), dodecylguanidine acetate (Dodine; 94.07%
a.i.; Batch \# APA batch 303/90) was administered to 10 Swiss

CR1:CDR-1 (ICR)BR mice/sex/dose in the diet at dose levels of 0, 150,
300, 600, 1250 or 2500 ppm (equivalent

to 0/0, 24/31, 48/60, 94/116, 181/223, and 350/305 mg/kg/day in
males/females) for 13 weeks.

No treatment-related effects were observed on food consumption ratios,
ophthalmoscopy, hematology, clinical

chemistry, organ weights, gross pathology, or histopathology. At 2500
ppm, treatment-related deaths were observed in 4/10 of the females.
During the first two weeks of treatment, three females were sacrificed
*in extremis* on Days 7, 8, and 14 and one female was found dead on Day
6. Stiffening of the tail was noted in 4/10 females (including the 3
females that were sacrificed) beginning on day 7 of treatment and
lasting until week 3 or until death. This observation was considered to
be treatment related and was not present in the remaining groups.
Decreased (p#0.05) body weights were observed in the males (917-24%,
Weeks 1-13) and females (910-15%, Weeks 1-2 and 6-10) resulting in
decreased (p#0.01) body weight gains in both (males968% and females944%)
sexes. Decreases (not statistically significant \[NS\]) of 30% - 46% in
mean food consumption for the 13-week treatment period were also
observed in both sexes. Decreases (NS) of 11% -12% in food consumption
was the only finding observed in the 1200 ppm group.

**The LOAEL is 2500 ppm (equivalent to 350/305 mg/kg/day M/F), based on
increased mortality and clinical signs of toxicity (stiffening of the
tail) in females, and decreased body weights, body weight gains, and
food consumption in both sexes. The NOAEL is 1250 ppm (equivalent to
181/223 mg/kg/day M/F).**

This study is classified as **acceptable/guideline.** It satisfies the
guideline requirement for a subchronic oral toxicity study (OPPTS
870.3100; OECD 410) in mice.

1.  **28-Day Dermal Toxicity Study-Rat**

**[EXECUTIVE SUMMARY:]{.underline}** In a 28-day dermal toxicity study
(MRID 46420701), dodine (98%, a.i.,

Lot No. OP750142) was applied to the shaved skin of ten Crl:CD IGS
(SD)BR rats/sex/dose at concentrations of 0 (deionized water), 50, 125,
or 200 mg/kg/day, 6 hours/day, 5 days/week for 4 consecutive weeks. A
non-GLP pilot study was conducted for dose determination.

There were no treatment-related deaths or clinical signs of systemic
toxicity in the rats. No effects on body weight, food consumption,
hematology, clinical chemistry, urinalysis, ophthalmological
examination, or organ weight were observed in either treated or control
animals. Gross and histopathological lesions observed were related only
to dermal irritation.

**Based on the results of this study, the systemic LOAEL for dodine in
male and female**

**rats can not be identified, and the systemic NOAEL is 200 mg/kg/day.**

Evidence of dermal irritation was observed in all of the treated
animals, but not in controls. The females were more affected than males.
The Draize scoring criteria used for erythema and edema in the rats
ranged from none to severe for erythema and none to slight for edema.
Only one male and female had a severe erythemic lesion in the low-dose
group and a slight dose related increase in severity of lesions in mid-
and high-dose groups was observed. For the entire study, erythema in
males was observed in 0/10, 5/10, 10/10 and 9/10 males in the control,
50, 125 and 200 mg/kg/day groups, respectively; edema was observed in
0/10, 2/10, 9/10 and 8/10 males in the control, 50, 125, and 200
mg/kg/day groups, respectively. Erythema in females was observed in all
treated groups, and edema throughout the study was observed in 0/10,
3/10, 10/10, and 10/10 females in the controls, 50, 125 and 200
mg/kg/day groups, respectively.

Gross pathology and histopathology were limited to the dermal lesions.
Scabbing was the predominant gross lesion and was identified in all dose
groups. Histopathology in the mid- and high-dose groups included ulcers,
suppurative inflammation, hyperkeratosis, epidermal hyperplasia,
subacute inflammation and parakeratosis. Minimal exudate and
parakeratosis was the only histopathological lesion identified in one
low-dose female.

**Based on the results of this study, the dermal LOAEL for dodine in
male and female rats is 50 mg/kg/day, and the dermal NOAEL is not
identified.**

This 28-day dermal toxicity study in rats is **Acceptable/Guideline.**
It satisfies the guideline requirements for a 28-day dermal toxicity
study (OPPTS 870.3200; OECD 410) in rats.

**A.3.2 Prenatal Developmental Toxicity**

7600. **870.3700 Developmental Toxicity Study- Rat**

**[EXECUTIVE SUMMARY:]{.underline}** In a prenatal developmental
toxicity study (MRID 41900304), dodine (Lot No. 92/88/2) was
administered to 25 pregnant Sprague-Dawley rats per dose by oral
intubation at doses of 0, 10, 45, or 90 mg/kg/day on gestation days 6
through 16. Animals were dosed with 10 mL of suspension (dodine and
distilled water) per kg body weight. Day 0 of gestation was based on the
presence of a copulatory plug or the presence of sperm in a vaginal
lavage. On gestation day 20, cesarean sections were performed on all
pregnant rats. The uteruses were weighed, and the following reproductive
parameters examined: number of corpora lutea, implantation sites,
live/dead fetuses, early/late resorptions and fetal weights. One-half of
the fetuses were further examined for visceral and skeletal
abnormalities and the other-half examined for soft-tissue abnormalities.

No mortality occurred in any group. The clinical sign of excessive
salivation was noted in 3/25 rats in the 90 mg/kg/day group on two
treatment days. Rats in the 90 mg/kg/day group exhibited a
non-significant decrease in mean body weight gain on gestation days 6-9.
In the 45 mg/kg/day group, weight gain was 57% of the control level on
gestation days 6-9. By gestation day 9, weight gain was similar in all
groups. Food consumption decreased during gestation days 6-10 in the 90
mg/kg/day group (70 % of controls) and slightly less in the 45 mg/kg/day
group (86% of controls) but again was similar among all groups after day
10. During gestation days 6-10, the number of rats consuming less than
20 grams of food was 1/22 (4.5%) of controls, 2/21 (9.5%) low-, 9/23
(39%) mid- and 16/24 (67%) high-dose. Upon necropsy, visual examination
of the dams' abdominal and thoracic cavity showed no abnormalities. No
statistically significant abnormalities were recorded in any of the
reproductive parameters.

**The lowest-observed-adverse-effect-level (LOAEL) for maternal toxicity
for dodine in rats is 45 mg/kg/day based on decreased body weight gain
and food consumption. The no-observed-adverse-effect-level (NOAEL) for
maternal toxicity is 10 mg/kg/day.**

No treatment-related external, visceral or skeletal
malformations/variations were observed in any fetus. Fetal body weights
were similar among control and treated groups.

**The NOAEL for developmental toxicity of dodine in rat is 90 mg/kg/day
and the LOAEL can not be determined from this study.**

This study is **Acceptable/Guideline** and does satisfy the requirements
for a developmental study in rats. \[OPPTS 870.3700(§83-3A)\].

**870.3700 Developmental Toxicity Study-Rabbit**

**[EXECUTIVE SUMMARY:]{.underline}** In a prenatal developmental
toxicity study (MRID 41900303), dodine (Lot No. 92/88/2) was
administered to pregnant New Zealand White rabbits by oral intubation at
doses of 0, 10, 40, or 80 mg/kg/day on gestation days 6 through 18.
Sixteen animals were in the 0, 10 and 40 mg/kg/day groups; twenty were
in the 80 mg/kg/day group. Animals were dosed with a volume of 4 mL/kg
of suspension (dodine and distilled water). Animals arrived to the study
facility pregnant. Doses were based on a previous study (Project No.
437724) but no details were provided. On day 29 of gestation, cesarean
sections were performed on all pregnant rabbits. The uteruses were
weighed and the following reproductive parameters examined: number of
corpora lutea, implantation sites, live/dead fetuses, early/late
resorptions and fetal weights. Two-thirds of the fetuses were further
examined for visceral and skeletal abnormalities and one-third prepared
for whole-body dissection.

Some mortalities and abortions did occur. During dosing, three does died
or were sacrificed due to dosing errors. Another doe in the high-dose
group was sacrificed due to poor condition. One doe each aborted in the
control and low-dose group and two aborted in the high dose group.
Neither the deaths nor abortions can be definitively seen as
treatment-related. No definitive treatment-related body weight or body
weight gain was recorded in the does. Food consumption was decreased
during gestation days 6-18 in the 80 mg/kg group. The amount consumed
was 77% of the control level. This trend reversed post-dosing. Visual
examination of the does' abdominal and thoracic cavity showed no
abnormalities and no statistically significant abnormalities were
recorded in any of the reproductive parameters.

**The lowest-observed-adverse-effect-level (LOAEL) for maternal toxicity
in rabbits for dodine cannot be determined. A decrease in food
consumption with no effect on body weight does not make this dose level
conclusive enough to set a LOAEL. The no-observed adverse-effect-level
(NOAEL) for maternal toxicity is 80 mg/kg/day.**

No treatment-related malformations/variations were recorded in the
external, visceral or gross soft-tissue observations in any fetus. Fetal
body weights were comparable between controls and treated animals.

**The LOAEL can not be determined from this study. The NOAEL for
developmental toxicity of dodine in rabbits is 80 mg/kg/day.**

This study is **Acceptable/Non-Guideline** and does satisfy the
requirements for a developmental study in rabbits. \[OPPTS 870.3700b
(§83-3B)\]. Although a definitive LOAEL for maternal toxicity was not
established, the rat (most sensitive species) prenatal developmental
study will be protective for all effects (MRID 41900304). Data

7601. **870.3800 Multi-generation Reproduction Study - Rat**

**[EXECUTIVE SUMMARY:]{.underline}** In a two-generation reproduction
toxicity study, dodine was administered to male and female rats at
nominal dietary concentrations of 0, 200, 400 or 800 ppm. This
corresponded to 0, 13, 26 or 53 mg/kg/day. The P animals began exposures
at 7 weeks and F1 animals began exposures at post-natal day (PND) 21;
all parental animals were exposed for approximately 10 weeks prior to
mating. Reproductive performance was not affected in any generation.
Parental toxicity was exhibited by a decrease in body weight, body
weight gain or food consumption for the high-dose P and F1 males and
females. High-dose P males and females exhibited decreased body weight
gain during premating/mating that was statistically significant. Mean
body weight in P animals was lower than controls throughout the study
but was not of toxicological concern. Food consumption in high-dose P
animals, while slightly decreased at first, was similar to controls by
week 5 during pre-mating. Food consumption decreased in P females during
lactation; however, mean body weight gain was increased in P females
when compared to controls at lactation days14-21.

**The parental systemic LOAEL is 800 ppm (53 mg/kg/day) based on
decreased** **body weight, body weight gain, and food consumption. The
parental systemic NOAEL is** **400 ppm (26 mg/kg/day).**

In high-dose F1 males, decreased body weight, body weight gain and food
consumption occurred starting on week one and was consistently lower
than controls. In high-dose F1 females, body weight was consistently
lower than controls throughout the study. Body weight gain in high-dose
F1 females decreased when compared to controls during premating, mating
and gestation periods, stabilized at lactation days 0-14 and then
increased during lactation days 14-21. Food consumption was consistently
lower than controls during the study in high-dose F1 females.

**The reproductive toxicity NOAEL is** **800 ppm (53 mg/kg/day) and the
reproductive toxicity LOAEL was not identified.**

Offspring body weight was decreased at the highest dose beginning as
early as PND 4. F1 males and females in the high-dose group showed
decreased body weight (p \< 0.05 or 0.01) during PND 4-21 and were
decreased by 7-17% in males and 9-17% in females. F2 pup body weight was
also decreased (p \< 0.01) by 8-17% in high-dose males at PND 4-21 and
high-dose females by 9-18% at PND 7-21. Total body weight gain was also
decreased for all F1 and F2 pups during PND 0-21. The lower body weight,
decreased body weight gain and decreased food consumption for adults at
the beginning of premating is a continuation of the preweaning effects.

**The offspring toxicity LOAEL is 800 ppm (53 mg/kg/day) based on
decreased pup body weights. The offspring toxicity NOAEL is 400 ppm (26
mg/kg/day).**

This study is **Acceptable/Guideline** and does satisfy the requirements
for a developmental study in rats. \[OPPTS 870.3800(§83-4)\].

**A.3.4 Chronic Toxicity**

**870.4100 ChronicToxicity-Dog**

**[EXECUTIVE SUMMARY:]{.underline}** In a chronic toxicity study (MRID
44246101), Dodine (98.6% a.i., Batch No. 1174) was administered to 4
beagle dogs/sex/group in a gelatin capsule at doses of 0, 2, 10, and 20
mg/kg/day. The capsules were administered orally once a day, 7
days/week, for at least 52 weeks. All animals survived to terminal
sacrifice. There were no dose- or treatment-related differences in
hematology, clinical chemistry, urinalyses, ophthalmoscopic
examinations, organ weights, or gross- or histopathology in either sex.

Slight to severe salivation was observed in all mid- and high-dose males
and females but not in the low-dose or control animals. Salivation was
seen most often prior to dosing, was a persistent finding during the
study, and was first noted in mid-dose males during week 10, in mid-dose
females and high-dose males during week 3, and in high-dose females
during week 2. The frequency and severity were greater in females than
in males.

No statistically significant differences were observed for group mean
values in absolute body weights, overall weight changes, food
consumption, or food efficiency between the treated and control groups
of either sex. However, one mid-dose female, one high-dose female, and
one high-dose male dog exhibited marked weight losses due to reduced
food consumption during the first few weeks of the study. Supplemental
feeding of basal diet mixed with water and/or canned dog food was
initiated during weeks 2 or 3 to promote eating by these animals and to
prevent further weight loss. The mid-dose female and the high-dose male
were returned to the basal diet starting at weeks 15 and 8,
respectively. The high-dose female required supplemental feeding
throughout most of the study to prevent continued weight loss.

**Therefore, the LOAEL for female beagle dogs is 10 mg/kg/day based on
body weight loss by individual animals and the NOAEL for female beagle
dogs is 2 mg/kg/day. The LOAEL for male beagle dogs is 20 mg/kg/day
based on body weight loss by an individual animal and the NOAEL for male
beagle dogs is 10 mg/kg/day.**

This study is classified as **Acceptable /Guideline** and satisfies the
requirements for a chronic toxicity study in dogs \[870.4100b(§83-1)\].

**A.3.5 Carcinogenicity**

**870.4200a Combined Chronic/Carcinogenicity Study -- Rat**

**[EXECUTIVE SUMMARY:]{.underline}** In a combined chronic
toxicity/carcinogenicity study (MRID 44704401), dodine ( 98.6% a.i., Lot
No. 1174) was administered continuously in the diet to 60 Sprague-Dawley
rats/sex/dose at concentrations levels of 0, 200, 400 or 800 ppm for up
to 106 weeks. Concentrations were equivalent to 0, 10.17, 20.34 or 41.93
mg/kg/day in males and 0, 13.19, 26.46 or 53.50 mg/kg/day in females,
respectively. In addition, 10 animals/sex/dose were terminated at 53
weeks for interim evaluation. Doses were based on a previous toxicity
studies (28-day dietary toxicity and 28-day oral gavage toxicity study)
and consultation with the U.S. EPA.

No treatment-related differences in mortality were noted between control
and treated groups during the study. Male rats exhibited some clinical
signs in controls, low-, mid- and high-dose including: no righting
reflex in 0, 1, 2, 3 and 4, respectively; hunched posture in 1, 2, 4 and
7, respectively and absence of grasping reflex in 2, 4, 4 and 8,
respectively. No dose-related trends were seen in females.

High-dose male rats had a decrease in body weight (p ≤ 0.01) when
compared to controls during weeks 1-25 but these decreases were ≤ 8%.
High-dose males showed decreases in body weight gain in week 1 of 20%,
weeks 1-8 of 7% and weeks 8-25 of 18% compared to controls. High-dose
males gained more weight than controls during weeks 25-53 but decreased
again during the first six months of the second year (-18%). Food
consumption was decreased slightly (-3 to 7%) in high-dose males
compared to controls during the first year but was comparable during
year two. No difference in food efficiency at any dose level was
observed.

High-dose female rats consistently had lower body weight throughout the
study compared to controls. Decreases ranged from 4% at week 1 to16% by
week 101. Body weight gain in high-dose females decreased compared to
controls 25% in week 1, 13% in weeks 1-25, 15% in weeks 25-53 and 34% in
weeks 53-77. Total body weight gain in high-dose females decreased 22%
over the 101 weeks. Females in the high-dose group had decreases in food
consumption at the following time points compared to controls (p ≤ 0.05
or 0.01): 4% at week 10, 8% at week 49, 13% at week 77 and 16% at week
97. Feed efficiency for the 101 weeks in females compared to controls
decreased by 24% in the mid-dose and 18% in the high-dose group
indicating a lack of a dose-related trend.

No treatment-related differences between treated and control groups were
observed for ophthalmic or urinalysis parameters. Differences in
hematological and clinical chemistry values were noted but were not
dose-dependent, were transient or were due to high control values thus
making them not of toxicological concern.

At the interim necropsy, no differences in organ weights of
toxicological concern were in treatment groups compared to controls. At
termination, relative liver (to brain) weight was lower (-10%, p ≤ 0.05)
in high-dose males than in controls, but no corresponding
histopathological lesions were reported. An increase in absolute and
relative (to body) epididymis weights (6-12%, p ≤ 0.05 or 0.01) in mid-
and high-dose males, and an increase in relative (to body) brain weight
(12-14%) in mid- and high-dose females, were observed, but they were not
dose-dependent.

No treatment-related gross pathological abnormalities were found in
either the control or treated groups at the interim necropsy. The only
finding at the termination necropsy was a non-dose dependent increase in
the number of high-dose females with enlarged adrenal glands (13/36
high-dose vs 8/37 control) and/or white mottled (12/36 high-dose vs.
3/37 controls) adrenal glands. No corresponding histopathological
lesions were identified.

**The lowest-observed-adverse-effect-level (LOAEL) for chronic toxicity
in male and female rats for dodine is 800 ppm (41.93/53.50 mg/kg/day,
M/F) based on treatment-related decreased body weights and food
consumption in females and a decreased body weight gain in males. The
no-observed-adverse-effect-level (NOAEL) in males and females is 400 ppm
(20.34/26.46 mg/kg/day, M/F).**

Treatment-related neoplastic lesions were not observed in any dose
groups in males or female rats at the interim or final sacrifice.
Evidence of carcinogenicity is not observed in rats.

This study is **Acceptable/Guideline** and does satisfy the requirements
for a chronic toxicity/carcinogenicity study in rats \[OPPTS 870.4300
(§83.5)\].

**870.4200b Carcinogenicity (feeding) -- Mouse**

**[EXECUTIVE SUMMARY:]{.underline}** In a mouse oncogenicity study (MRID
44703201), dodine (98.6% a.i., Lot No. 1174) was administered in the
diet to 60 Crl:CD-1 (ICR) BR mice/sex/dose at concentrations of 0, 200,
750 or 1500 ppm for up to 78 weeks. Concentrations were equivalent to 0,
29, 110 or 225 mg/kg/day in male mice and 0, 38, 136 or 277 mg/kg/day in
female mice, respectively. An additional 10 animals/sex/group were
terminated at 53 weeks for interim evaluation. Doses were based on a
previous 90-Day range-finding study and U.S. EPA consultation; details
about the previous study were included in the rat chronic
toxicity/carcinogenicity study, MRID 44704401.

No increases in mortality were observed in either sex of any group,
treated or control. An increased incidence in clinical signs of body
tremors and excessive salivation were observed in both mid- and
high-dose male and female mice but the increases were not dose-related.

Body weight of high-dose males was consistently decreased (p ≤ 0.05)
compared to controls throughout the study, 3% by week 2, 8% by week 13,
10% by week 54 and 9% at week 78. Sporadic statistical decreases
observed in low-and mid-dose males were not toxicologically significant
(p ≤ 0.05). Mid- and high-dose female body weight was also decreased (p
≤ 0.05). Mid-dose weight decreased 4, 9 and 10% compared to controls at
week 13, 58 and 78, respectively. High-dose female body weight was
decreased compared to controls by 4% at week 9 and progressed up to a
14% decrease by the end of the study.

High-dose males mean weight gain decreased (p≤ 0.05) by 32 % compared to
controls in weeks 1-7, 25% in weeks 1-14 and 26% in weeks 14-54 but did
become comparable to controls during weeks 54-78. Overall, the high-dose
males had a decrease in weight gain of 26% from weeks 1-78 compared to
controls. Mid-dose females had a progressive decrease in weight gain
compared to controls. These decreases were 10% at week 14, 23% for week
14-54 and 37% for week 54-78 with total weight gain in mid-dose females
decreasing by 20% compared to controls. Weight gain in the high-dose
females was consistently lower than controls throughout the study. These
decreases were 26% from week 1-14, 36% from week 14-54, and 63% from
week 54-78. Overall high-dose females' weight gain decreased 35%
compared to controls.

Food consumption in high-dose males decreased (p ≤ 0.05) by 16%,
compared to controls, during week 1 and although was always lower than
controls improved to a decrease of 5% by week 49. Mid-dose and high-dose
females had consistent decreases of food consumption compared to
controls during the entire study. During the first two weeks, mid-dose
female food consumption decreased from 10 to 16% and high-dose was 13%.
For the rest of the first year, the decreases remained between 6-7% for
mid-dose females and 5-11% for high-dose compared to controls. During
the second year, mid-dose females' food consumption remained decreased
between 6-10%; high-dose female food consumption progressively decreased
from 11 to 19% between weeks 53 and 77. Overall food efficiencies (%
body weight gain/food consumption) were 2.00, 1.97, 1.97 and 1.58 for
controls, low-, mid- and high-dose males and 1.96, 1.89, 1.64 and 1.19
for control, low-, mid- and high-dose females. This resulted in a food
efficiency decrease of 21% in high-dose males and 39% in high-dose
females compared to controls.

In this study, ophthalmic exam, urinalysis, clinical chemistries or
differential leukocyte counts were not performed. Differential counts
were not performed based on the lack of evidence of hematopoietic
neoplasia in the histopathological exam and the other parameters were
not required under the guidelines accepted at the time the study was
conducted.

At the interim sacrifice (53 weeks), high-dose females had an
non-toxicologically significant increase (p ≤ 0.05) in relative (to body
and brain) kidney weight compared to controls, but no corresponding
histopathological lesions were identified. At the terminal necropsy,
high-dose females had an increase in right and left absolute kidney
weight. Mid- and high-dose females also had an increase in relative (to
body) kidney weight and a decrease in relative (to brain) adrenal weight
but again no corresponding histopathological lesions were identified.
Females showed a decrease in mid- and high-dose groups in absolute brain
weight, and both high-dose males and females exhibited increased (p ≤
0.05) liver/gallbladder relative (to body) weight by 12-13 % compared to
controls.

**The lowest-observed-adverse-effect-level (LOAEL) for chronic toxicity
for dodine in mice is 750 ppm (136 mg/kg/day) for females and 1500 ppm
(225 mg/kg/day) for males based on treatment-related decreased body
weight, body weight gain and food consumption. The
no-observed-adverse-effect-level (NOAEL) is 200 ppm (38 mg/kg/day) for
females and 750 ppm (110 mg/kg/day) for males.**

At the doses tested, there was no statistical increase in the incidence
of neoplastic lesions in male mice at any site. There is some evidence
of potential carcinogenicity in high-dose female mice based on the
increase incidence (p≤ 0.05) of hepatocellular adenoma and combined
hepatocellular adenoma/carcinoma. The incidence of adenomas in high dose
females were 0/60, 1/58, 1/59 and 4/60 and rates for carcinomas were
0/60, 1/58, 0/59 and 1/60 in control, low-, mid- and high-dose groups,
respectively. Incidence rates for the combined adenoma/carcinomas in
this group were 0/60 in controls, 2/58 in low-, 1/59 in mid- and 5/60
high-dose females. The incidence of combined adenoma/carcinoma for the
high-dose females is statistically significant (p ≤ 0.05) but only
marginally higher than the upper range for historical control (8.3% vs
1-8% in the historical controls for Charles River).

This study is **Acceptable/Guideline** and does satisfy the requirements
for a carcinogenicity study in mice \[OPPTS 870.4300 (§83-2(b)\]. No
evidence of carcinogenicity.

**A.3.6 Mutagenicity**

**870.5300 *In Vitro* Mammalian Cell Gene Mutation Test**

**[EXECUTIVE SUMMARY]{.underline}:** In a mammalian cell gene mutation
assay at the HGPRT locus (MRID 41711002), Chinese hamster ovary CHO-K1
cells cultured *in vitro* were exposed to Dodine (Batch No. KG 8507, 98%
a.i.) in ethanol for five hours at concentrations of 0.0, 2.5, 5.0,
10.0, 15.0 or 20.0 μg/mL in the absence of metabolic activation (S9-mix)
and at concentrations of 0.0, 5.0, 10.0, 15.0, 20.0, 25.0, 30.0 or 35.0
μg/mL in the presence of S9-mix. Cell survival was determined 22 hours
post-treatment. Following the expression period, the frequency of
6-thioguanine mutants, expressed as mutant/10^6^ clonable cells, was
determined. The S9-fraction was obtained from rat liver; however, the
strain, sex and inducer were not specified.

Dodine was tested up to cytotoxic concentrations. Cell survival was too
low to evaluate mutagenicity at the upper concentration both with and
without S9-mix. There were no statistically significant increases in the
average mutation frequency (mutants per 10^6^ surviving cells) over the
solvent control values at any test material concentration without S9-mix
in either assay. In the presence of S9-mix, a statistically significant
increase in mutant frequency was seen at 125 μg/mL in the initial assay,
but not at higher concentrations and not at any concentration in the
repeat assay. Although statistically significant, the increase in mutant
frequency was within the solvent control range and lower than the
solvent control value in the repeat assay; therefore, it was not
considered biologically significant. The solvent control and the
positive controls (Ethyl methanesulfonate without S9-mix and
dimethylnitrosamine with S9-mix) induced the appropriate responses.
There was no biologically significant increase in the number of mutant
colonies over background with or without S9-mix.

This study is classified as **Acceptable/Guideline** and does satisfy
the requirement for *in vitro* mutagenicity (mammalian forward gene
mutation) data \[OPPTS 870.5300, OECD 476\].

[COMPLIANCE]{.underline}: Signed and dated GLP and Quality Assurance
statements were provided but the DER used to prepare this executive
summary did not report the presence of a Data Confidentiality statement.

**870.5375 *In Vitro* Mammalian Chromosome Aberration Test**

**[EXECUTIVE SUMMARY]{.underline}:** In a mammalian cell cytogenetics
assay (Chromosome aberrations) (MRID 41711001), human lymphocytes in
culture were exposed to Dodine (Lot No. KG 8507, 98% a.i.) in ethanol
for 24 hours at concentrations of 0, 0.37, 1.11, 3.33 or 10.0 μg/mL
without metabolic activation (S9-mix) or for 2 hours at concentrations
of 0, 0.56, 1.67, 5.0 or 15.0 μg/mL with S9-mix. Cells were treated with
Colcemid at 0.1 μg/mL immediately following exposure without S9-mix or
after a 22-hour incubation after exposure with S9-mix. The length of the
Colcemid treatment was not provided in the DER from which this Executive
Summary was prepared. Cells were harvested following Colcemid treatment.
Lymphocytes were obtained from a healthy male non-smoker. The
S9-fraction was obtained from Aroclor 1254 induced male Wistar rat
liver.

This executive summary was prepared from the Data Evaluation Record
(DER) written in 1992 and not from the original 1985 study. Dodine was
tested up to levels reducing the mitotic index to values approaching 50%
of the solvent control values. Cells were collected and slides prepared
by conventional cytological techniques. One-hundred well-spread
metaphases (25 per slide) were scored for chromatid and chromosome
aberrations. Numerical aberrations were not reported. No statistically
significant (Fisher's exact probability test, two-sided) increases in
the number of structural aberrations per cell over the solvent control
values were seen at any test material concentration with or without
S9-mix. The solvent and positive controls (Methyl methanesulfonate
without S9-mix and Cyclophosphamide with S9-mix) induced the appropriate
responses. There was no evidence of structural chromosomal aberrations
induced over background in this study.

This study is classified as **Acceptable/Non-Guideline** and does
satisfy the requirement for *in vitro* cytogenetic mutagenicity data
\[OPPTS 870.5375; OECD 473\]. No information was provided on the pH or
osmolality of the treatment medium and no historical control data were
provided. GLP and Quality Assurance statements were said to be provided.

**Mammalian Erythrocyte Micronucleus - Mouse**

**[EXECUTIVE SUMMARY]{.underline}:** A single acute dose selection study
(MRID 41418901) was conducted prior to the main study in order to
determine appropriate doses. The main study, a mammalian erythrocyte
micronucleus assay (MRID 41418902), was designed to evaluate the
mutagenicity of CT-334-87 (DGH, 35% a.i.) on ICR mice.

In the dose selection study, a single dose of 1500 mg/kg body weight
CT-334-87 was administered to six ICR mice (3 males, 3 females) by oral
gavage. All animals appeared normal immediately post-dosing. After about
two hours, one female was found dead and all males were "languid with
squinting eyes". The remaining two females appeared normal and healthy
during the 3-day observation period. Within 26 hours of dosing, all
males developed rough haircuts. About 44.5 hours post-dosing, the males
had rough hair coats and squinted eyes with 2 showing hunched backs.
About 67.5 post-dosing, all 3 had rough hair coats and the same 2 had
hunched backs. Based on these observations, the doses selected for the
mouse bone marrow micronucleus assay are 140, 467, and 1400 mg/kg body
weight.

In the *in vivo* mouse micronucleus assay, 10 ICR (5 male, 5 female)
mice/dose/harvest time group were administered CT-334-87 via oral gavage
at concentrations of 140, 467, or 1400 mg/kg body weight. Animals
administered the test article were euthanized 24, 48, and 72 hours
post-dosing. The positive control, Cyclophosphamide (CP), was
administered at 80 mg/kg. The vehicle control, sterile deionized water,
was administered concurrently with the test article at a volume of
10mL/kg. Positive and vehicle controls were euthanized 24 hours after
the administration of the control articles.

Within 45 minutes of dosing, two animals in the 467 mg/kg dose group had
dies. All other animals were normal after dosing and appeared healthy
4.5 hours after dosing.

About 24 hours after dosing, three males in the 1400 mg/kg dose group
and one male in the 467 mg/kg dose group, were found dead. One female in
the 467 mg/kg dose group had a distended abdomen and this condition was
unchanged 48-hours post dosing (harvest time). All males in the 467 and
1400 mg/kg dose group had rough hair coats. Several high-dose males had
squinted eyes and/or were languid. One high-dose male was languid with a
distended abdomen; he expired within 30 hours of dosing.

About 46 hours post-dosing, three animals in the 1400 mg/kg dose group
(2 males, 1 female) and one male in the 467 mg/kg dose group were found
dead. The other males had rough hair coats, but this condition subsided
prior to the 72 hour harvest. All males in the 1400 mg/kg dose groups
had rough hair coats and were languid; a few high dose males had
squinted eyes. These conditions persisted until the harvest time.

The test article, CT-334-87, induced no significant increases in
micronucleated polychromatic erythrocytes over the levels observed in
the vehicle controls in either sex or at any of the harvest times. The
positive control, CP, induced significant increases in micronucleated
PCEs in both sexes.

**The test material, CT-334-87, is considered NEGATIVE in the mouse bone
marrow micronucleus test.**

This mammalian erythrocyte micronucleus assay is classified as
**Acceptable-Guideline** and satisfies the guideline requirements for a
mammalian erythrocyte micronucleus assay \[870.5395 (§84-2)\] in the
mouse.

**Mammalian Bone Marrow Chromosomal Aberration**

**[EXECUTIVE SUMMARY:]{.underline}** Acute dose range-finding and
micronucleus assay studies (MRID 42311601) were conducted on male and
female ICR mice with dodine (94%, a.i., Lot No. 303/90). Corn oil was
the vehicle utilized. In the acute dose range-finding study, three males
and three females per dose group received a single oral gavage dose of
50.0, 162.5, 275.0, 387.5 or 500 mg/kg with the volume of test substance
administered being 10 mL/kg. A prior study indicated the LD~50~ for mice
was 266 mg/kg and was used to establish these dose selections. For the
micronucleus assay study, 15 males and 15 females were used in the
treatment groups and were administered a single dose of 100, 200 or 400
mg/kg by oral gavage with bone marrow sampling at 24, 48 and 72 hours
post-dosing. A secondary group of 5 males and 5 females were dosed at
the high-dose to ensure availability of replacements in the case of
mortality in the original group. One high-dose male was used from this
secondary group. In this same study, positive and negative controls were
utilized. Five males and five females were dosed once with vehicle only
for the negative control with sampling 24 hours post-dosing. The
positive control dosed five males and five females with cyclophosphamide
(CP) dissolved in distilled water and delivered at a single dose of 80
mg/kg by oral gavage with sampling 24 hours post-dosing.

Treated animals in the range finding study were examined for clinical
signs and/or mortality immediately after dosing and for three days
post-dosing. One male each from the 387.5 and 500 mg/kg groups was found
dead at 41 hours. All other mice in these dose groups exhibited rough
haircoats at 41 hours and were languid with rough haircoat at the
study's termination. No clinical signs were observed in the animals
dosed with ≤ 275 mg/kg. Doses for the micronucleus assay were set at
100, 200 and 400 mg/kg with 400 mg/kg being 80% of the estimated maximum
tolerated dose.

In the micronucleus assay study, one high-dose male died at 6 hours and
one male in the secondary group died at 24 hours post-dosing. The only
clinical sign reported was distended abdomens in two high-dose males, 48
and 72 hours post-dosing, respectively, and in one mid-dose male at 48
hours post-dosing. Bone marrow cell ratios of polychromatic erythrocytes
(PCEs) to normochromatic erythrocytes (NCEs) for males in all treatment
groups and harvest times were as much as or higher than the vehicle
control males. Bone marrow cells from the mid- and high-dose females at
72 hours were approximately 50% lower than the controls. However, a
statistically significant increase in the number of micronuclei in
polychromatic erythrocytes (MPEs) was not reported at any dose level or
harvest time in either males or females thus making it a negative test
for genotoxic effects. The positive control did induce a significant
(p\< 0.05) increase in the frequency of MPEs in the bone marrow cells in
both males and females.

This study is **Acceptable/Guideline** and does satisfy the requirements
for a micronucleus test. \[OPPTS 870.5385 (§84-2)\].

**A.3.7 Neurotoxicity**

Not available

**A.3.8 Metabolism**

7485. **Metabolism -- Rat**

**[EXECUTIVE SUMMARY:]{.underline}** In a metabolism and pharmacokinetic
study (MRID 42479001), male and female Sprague-Dawley (Crl: CL BR) rats
were administered by gavage either a single dose of 40 or 400 mg/kg ^14^
C-labeled dodine (\> 99% a.i., Lot No. 910225) or 40 mg/kg/day of
non-labeled dodine ( 99.8% a.i., Lot No. FF1/88) for 14 days, followed
by a single dose of radio-labeled dodine (40 mg/kg) on day 15. Five
males and five females were dosed in the single low- and high-dose
radio-labeled study; five males and six females were used in the
multiple low-dose study. All studies used corn oil as a vehicle. A
preliminary test using the 40 and 400 mg/kg radio-labeled dodine was
performed to help determine the amount of ^14^ C-labeled dodine excreted
in expired air.

In the preliminary study, most radioactivity was eliminated in the urine
and feces within 72 hours post-dosing in the low-dose group but
continued past 72 hours in the high-dose group. Expired air had \<1% of
the administered dose and the amount recovered was either ^14^ CO~2~ or
radio-labeled volatiles. Based on results, sampling to 120 hours
post-dosing was initiated in the definitive study.

In the definitive study, dodine was rapidly absorbed, distributed,
metabolized and excreted at all dosing levels with no significant gender
differences. Urine and feces were found to be major routes of excretion
for the dodine. At 120 hours (5 days) post-exposure, 40.55 to 45.35 % of
the dose was excreted in the urine and 47.63 to 59.69 % was excreted in
the feces in all dose groups. Total recovery at 120 hours ranged from
93.61 to 102.22 % of the administered dose. Tissues were collected and
analyzed for radioactivity. Upon analysis, ≤ 3.35% of the administered
dose was recovered in tissues. The highest amounts recovered were in the
gastrointestinal tract (0.16-1.14% of the dose), muscle (0.02-0.61% of
the dose) and skin (0.06-0.21%). Urine and fecal samples from one
animal/sex in each dose group were utilized in metabolite analysis. In
urine, the unmetabolized parent compound was not identified; however,
four metabolites were identified. The major metabolite found was an
alcohol of dodine, hydroxydodecylguanidine, and accounted for 10.98 to
23.52% of the administered dose. Females did have a slight increase in
this metabolite when compared to males. Fecal samples identified the
parent compound as the major metabolite, 0.17 to 4.17% of the dose.

The proposed metabolic pathway for dodine in rats was a ß-oxidation
pathway similar to medium- and long-chain fatty acids. Oxidation takes
place by forming intermediate products with shorter chain lengths and
these are eliminated in the urine. Urea is also formed in the liver from
action on dodine or one of its metabolites.

Dosing of dodine appears adequate for the pharmacokinetics and
metabolism to be identified based on the presence of radioactivity in
samples taken.

This study is **Acceptable/Guideline** and does satisfy the requirements
for a metabolism and pharmacokinetic study in rats \[OPPTS 870.7485
(§85-1)\].

7602. **Dermal Penetration-Rat**

**[EXECUTIVE SUMMARY:]{.underline}** In a dermal absorption study (MRID
46621303) \[14-C\]- Dodine (n-dodecyl-14C-guanidine acetate) was
administered to three groups of four male Sprague Dawley CD rats/dose to
a 12 cm^2^ dorsal area in a formulation and water dilution thereof at
dose levels of 4.0 and 0.004 mg/ cm^2^. Exposure durations and percent
of mean radioactivity absorbed, mean radioactivity (percent of applied
dose) remaining in the treated skin and mean radioactivity (percent of
applied dose) removed by skin swab/guaze wash following a single topical
application of a formulation of \[14-C\]- Dodine are presented in the
table below. The formulation was applied for 8 hours and then the
application site washed with 1% Tween 80 in distilled water to remove
unabsorbed material.

In the rats treated with 4.0 mg/ cm^2^ \[14-C\]- Dodine, the mean total
recoveries were 98.7 ± 2.81%, 99.5 ± 1.30%, 97.5 ± 3.54% and 98.9 ±
1.44% at 8, 24, 48 and 72 hours, respectively, following application. In
the rats treated with 0.004 mg/cm2 \[14-C\]- Dodine, the mean recoveries
were 110 ± 6.55%, 106 ± 10.8%, 108 ± 15.1% and 99.6 ± 6.85% at 8, 24,
48, 72 hours, respectively following application. No radioactivity was
detected in the blood, nor in the trapping fluids for expired carbon
dioxide and volatile organic material for any group at either dose
level. The mean percent radioactivity remaining in the treated skin in
the 0.004 mg/cm2 treatment groups were 36.6%, 49.5%, 45.2% and 40.3% at
8, 24, 48, 72 hours, respectively. Presumably, the \[14-C\]- Dodine
remaining in the treated skin has the potential to be absorbed by the
skin over time; however, this is not demonstrated by the study. In fact
the radioactivity remaining at the application site increases slightly
over time indicating that the maximum absorption is likely to happen
after 72 hours. Therefore, approximately 1% (0.77%) of the dose applied
to male rats was demonstrated to be absorbed in skin with the resulting
radioactivity being found in the urine, feces, cagewash, carcass and
untreated skin. Although eight to ten hours is considered most
applicable to the typical worker and the doses used are the typical
worker doses, it is appropriate to utilize the 72 hour/low dose dermal
absorption value to be conservative in risk assessment. These values are
considered conservative because a portion of the active ingredient was
retained at the skin site and it is unlikely that all of the skin
residues will become systemically available.

The reviewers believe that the study provides useful information,
however, since the purity of the test material was not reported, only
two doses were used, information about the vehicles were not reported,
and the exposure durations were non-guideline, the study does not
satisfy the guideline requirements for a dermal penetration study in
rats (OPPTS 870.7600 \[§85-2\]). Therefore, this study in the rat is
considered **acceptable/ non-guideline**.

**Appendix B: Metabolism Assessment**

  --------------------------------------- -----------------------------------------------------
  **Table B.1. Chemical name and          
  structure of Dodine metabolites**       

  **Chemical name**                       **Chemical structure**

  Dodine-dodecylguanidine monoacetate     ![](media/image3.wmf){width="1.804861111111111in"
                                          height="0.7527777777777778in"}

  Guanidinium hydrochloride               ![](media/image4.wmf){width="2.4895833333333335in"
                                          height="0.8770833333333333in"}

  Urea                                    ![](media/image5.wmf){width="0.7291666666666666in"
                                          height="0.5416666666666666in"}

  Hexylguanidine carboxylic acid          ![](media/image6.wmf){width="1.4583333333333333in"
                                          height="0.6458333333333334in"}

  Octylguanidine carboxylic acid          ![](media/image7.wmf){width="1.4583333333333333in"
                                          height="0.6458333333333334in"}

  Dodecylguanidine carboxylic acid        ![](media/image8.wmf){width="1.5104166666666667in"
                                          height="0.6458333333333334in"}

  dodecylaminohydroxy- methylamine        ![](media/image9.png){width="1.3541666666666667in"
                                          height="0.7256944444444444in"}

  Guanidine                               ![](media/image10.wmf){width="1.3215277777777779in"
                                          height="1.0395833333333333in"}
  --------------------------------------- -----------------------------------------------------

**Appendix C. Tolerance Reassessment Summary; Codex/International
Harmonization**

  ----------------- --------------- -------------- -----------------------
  **Table C1.                                      
  Tolerance Summary                                
  for Dodine.**                                    

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

  Banana            0.5             0.50           

  Peanut            0.03            0.013          
  ----------------- --------------- -------------- -----------------------