**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

Date: April 30, 2007

**[MEMORANDUM]{.underline}**

SUBJECT: **Lactofen:** Revised Human Health Risk Assessment for Proposed
Uses on Fruiting Vegetables and Okra. PC Code: 128888, Petition No:
PP#5E6930, DP Barcode: D339011.

Risk Assessment Type: Single Chemical Aggregate

FROM: Christine L. Olinger, Chemist/Risk Assessor

Reregistration Branch 1

Health Effects Division (7509P)

AND

Whang Phang, Ph.D., Toxicologist

Timothy Dole, ORE Assessor

Reregistration Branch 1

Health Effects Division (7509P)

THROUGH: Michael S. Metzger, Chief

> Elizabeth Méndez, Ph.D., Senior Scientist
>
> Reregistration Branch 1

Health Effects Division (7509P)

> AND

Paula Deschamp, Chief

Registration Branch 3

Health Effects Division (7509P)

TO: Dan Rosenblatt, Chief

> Minor Use and Emergency Response Branch
>
> Registration Division (7505P)
>
> And
>
> Dan Kenny/Joanne Miller
>
> Herbicide Branch
>
> Registration Division (7505P)
>
> And
>
> Amaris Johnson/Susan Lewis
>
> Reregistration Branch 1
>
> Special Review and Reregistration Division (7508P)

Valent, USA, has proposed new uses of the herbicide lactofen on fruiting
vegetables and okra. The RD of OPP has requested that HED evaluate
hazard and exposure data and conduct dietary, occupational, residential,
and aggregate exposure assessments, as needed, to estimate the risk to
human health that will result from all registered and proposed uses of
the herbicide lactofen. A summary of these findings is provided in this
document. The risk assessment, residue chemistry review, and dietary
exposure assessment were provided by Christine Olinger of RRB1; support
for the hazard characterization was provided by Whang Phang of RRB1; the
occupational exposure and risk assessment was provided by Timothy Dole
of RRB1; and the drinking water assessment was provided by James Wolf of
the Environmental Fate and Effects Division (EFED). Although the
proposed new use had been previously assessed (C. Olinger, 1/8/07, DP
Barcode: D319593), this document incorporates additional information on
the cancer classification.

***Recommendation for Tolerances and Registration***

Provided revised Sections B and F are submitted, the toxicological and
residue chemistry databases, as well as the aggregate risk assessments,
support tolerances with regional registration for fruiting vegetables
and okra. The recommended revisions are listed below:

-   The label must be amended to specify that the applications may not
    include two post-transplant applications. . The label must also be
    amended to reflect either a 30-day RTI or a minimum post-transplant
    interval of 18 days for tomatoes.

-   The label should specify examples of fruiting vegetables in the use
    directions to avoid confusion.

-   The proposed tolerance for the fruiting vegetables crop group should
    be revised to reflect the recommended tolerance definition (lactofen
    *per se*), the correct commodity definition, "Vegetable, fruiting,
    group 8," and the recommended level of 0.02 ppm.

-   The proposed tolerance for okra should be revised to reflect the
    recommended tolerance definition (lactofen *per se*) and the
    recommended level of 0.02 ppm.

Should the registrant request tolerances with a national registration in
the future, then additional crop field trials would be required.

**Table of Contents**

[**1.0** **Executive Summary** 4](#__RefHeading___Toc151953691)

[**2.0** **Ingredient Profile** 6](#__RefHeading___Toc151953692)

[**2.1** **Summary of Proposed Uses** 6](#__RefHeading___Toc151953693)

[**2.2** **Structure and Nomenclature** 7](#__RefHeading___Toc151953694)

[**2.3** **Physical and Chemical Properties**
8](#__RefHeading___Toc151953695)

[**3.0** **Hazard Characterization/Assessment**
9](#__RefHeading___Toc151953696)

[**3.1** **Hazard and Dose-Response Characterization**
9](#__RefHeading___Toc151953697)

[**3.2** **FQPA Considerations** 13](#__RefHeading___Toc151953698)

[**3.3** **Dose Response Assessment and Hazard Endpoint Selection**
14](#__RefHeading___Toc151953699)

[**3.4** **Endocrine Disruption** 18](#__RefHeading___Toc151953700)

[**4.0** **Public Health and Pesticide Epidemiology Data**
18](#__RefHeading___Toc151953701)

[**5.0** **Dietary Exposure/Risk Characterization**
18](#__RefHeading___Toc151953702)

[**5.1.** **Food Residue Profile** 18](#__RefHeading___Toc151953703)

[**5.2** **Drinking Water Residue Profile**
21](#__RefHeading___Toc151953704)

[**5.3** **Dietary Exposure and Risk** 22](#__RefHeading___Toc151953705)

[**5.2.1** **Acute Dietary Exposure/Risk**
23](#__RefHeading___Toc151953706)

[**5.2.2** **Chronic Dietary Exposure/Risk**
23](#__RefHeading___Toc151953707)

[**5.2.3** **Cancer Dietary Risk** 23](#__RefHeading___Toc151953708)

[**6.0** **Residential (Non-Occupational) Exposure/Risk
Characterization** 24](#__RefHeading___Toc151953709)

[**7.0** **Aggregate Risk Assessments and Risk Characterization**
24](#__RefHeading___Toc151953710)

[**7.1** **Acute Aggregate Risk** 25](#__RefHeading___Toc151953711)

[**7.2** **Short-Term Aggregate Risk** 25](#__RefHeading___Toc151953712)

[**7.3** **Intermediate-Term Aggregate Risk**
26](#__RefHeading___Toc151953713)

[**7.4** **Long-Term Aggregate Risk** 26](#__RefHeading___Toc151953714)

[**7.5** **Cancer Risk** 26](#__RefHeading___Toc151953715)

[**8.0** **Cumulative Risk Characterization/Assessment**
28](#__RefHeading___Toc151953716)

[**9.0** **Occupational Exposure/Risk Pathway**
28](#__RefHeading___Toc151953717)

[**9.1** **Short-/Intermediate-Term Handler Risk**
28](#__RefHeading___Toc151953718)

[**9.2** **Postapplication Risk** 29](#__RefHeading___Toc151953719)

[**10.0 Environmental Justice Considerations**
31](#__RefHeading___Toc151953720)

[**11.0 Review of Human Research** 31](#__RefHeading___Toc151953721)

[**12.0 Data Needs and Label Recommendations**
31](#__RefHeading___Toc151953722)

[**12.1** **Label Recommendations** 31](#__RefHeading___Toc151953723)

[**12.2 Proposed Tolerances** 31](#__RefHeading___Toc151953724)

[**13.0** **References** 32](#__RefHeading___Toc151953725)

[]{#__RefHeading___Toc151953691 .anchor}**1.0 Executive Summary**

> This document describes the human health risk assessment conducted for
> the herbicide lactofen in association with proposed new uses on
> fruiting vegetables and okra.
>
> Lactofen is currently registered for use on snap beans, peanuts,
> soybeans, and cottonseed and tolerances are established in 40 CFR
> 180.432 for these commodities. Lactofen is typically used early in the
> growing season, before or shortly after the crop has emerged. The
> minimum interval between the last application and harvest is 45 days,
> although for some crops it can be as long as 90 days. The registrant
> is proposing new uses on fruiting vegetables and okra and restricting
> the use to AL, AR, FL, GA, MS, NC, SC, TN, and VA. The proposed use on
> fruiting vegetables and okra would include two applications, one prior
> to planting and one after planting, with a minimum pre-harvest
> interval of 30 days.
>
> The toxicity database for lactofen is relatively complete. Lactofen
> has a low acute toxicity, generally categories III and IV. The chronic
> toxicity profile for lactofen clearly indicates that the liver and
> kidneys are the target organs for this chemical. The effects seen at
> the lowest dose levels in the chronic toxicity study included changes
> in clinical chemistry associated with liver toxicity. More severe
> effects were noted at higher dose levels. The registrant has submitted
> information on the mechanism of liver toxicity that indicates that the
> mode of action is quantitatively implausible and unlikely to take
> place in humans. Lactofen has been classified as not likely to be
> carcinogenic to humans.
>
> In a rat developmental toxicity study, the dose level that causes
> adverse effects to the developing fetus also elicits signs of toxicity
> in the maternal group (e.g., excess salivation, lethargy, and
> decreased body weight gain). Effects seen in the fetus consisted of
> decreases in fetal weight as well as skeletal variations (increased
> incidence of bent ribs, bent limb bones and a reduction in the
> ossification of the vertebral arches). Two rabbit developmental
> studies have been submitted. Although conducted in similar strains of
> rabbits according to acceptable protocols, the results of the two
> studies are somewhat inconsistent. In the first study,
> post-implantation loss was observed, but not in the second study. In
> the second study animals were not dosed high enough to observe
> developmental affects in the pups; however, maternal toxicity was
> observed. When the results of the two studies are considered together,
> there is sufficient information to set a no-effect level for the
> post-implantation loss.
>
> The Health Effects Division (HED) has selected an endpoint based on
> changes in clinical chemistry that relate to liver effects for chronic
> exposure to the general population and an endpoint for females of
> child-bearing age for acute exposure based on the post-implantation
> loss. The chronic endpoint is protective of the carcinogenic effects.
> No endpoint has been identified for the general population based on a
> single exposure to lactofen. The Food Quality Protection Act (FQPA)
> requires the Agency to consider special sensitivities of the young to
> chemical exposure. The lactofen risk assessment team has reviewed the
> entire database for lactofen and determined there is no residual
> uncertainty regarding exposure to children at any developmental stage
> and recommends that the factor be reduced to 1X.

**Sodium acifluorfen is a degradate of lactofen found in water and is
also registered as a herbicide.** Sodium acifluorfen is similar to
lactofen in that the liver and kidneys are the target organs for sodium
acifluorfen as well. Sodium acifluorfen produced developmental toxicity
(decreased fetal body weight and the increase in anatomical variations)
in rats but did not affect the reproductive parameters in rats. The
carcinogenicity data showed that sodium acifluorfen produced a
statistically significant increase in the incidence of liver and stomach
tumors in mice but not in rats. The registrant has submitted information
on the mechanism of liver toxicity that indicates that the mode of
action is quantitatively implausible and unlikely to take place in
humans. Acifluorfen has been classified as not likely to be carcinogenic
to humans[.]{.mark}

The Health Effects Division (HED) has selected an endpoint for sodium
acifluorfen based on kidney lesions for chronic exposure to the general
population and an endpoint for females of child-bearing age based on
fetal effects for acute exposure. The FQPA Safety Factor committee
retained a factor of three for the chronic dietary risk assessment and
retained a factor of ten for the acute risk assessment because of the
qualitative increase in susceptibility in the developmental study with
sodium acifluorfen and the developmental neurotoxicity data gap.

Crop field trials conducted in FL for tomatoes and peppers were
submitted in support of this petition. Typically trials in additional
states would be conducted but considering the number of trials submitted
and that no residues were detected, no additional data are required in
support of this use with a regional registration. Should the registrant
seek a national registration then additional studies would be required.

A dietary risk analysis was conducted for lactofen. The analysis,
assuming all of the crops are treated and residues are tolerance level,
showed that all populations are exposed to less than 0.1% of the
population adjusted dose (PAD) for acute and chronic risk. This is below
the Agency's level of concern (i.e., when dietary exposure exceeds 100%
of the PAD. The margin of exposure (MOE) for estimated cancer risk
greatly exceeds the target MOE, so is not of concern.

HED has also considered the exposure to lactofen and its degradates in
water. Lactofen degrades very quickly in the environment, with some
studies suggesting a half-life of three days. The primary degradate is
acifluorfen, which is also a degradate of sodium acifluorfen, a
herbicide registered for use in agricultural and residential settings. A
minor degradate is des-ethyl lactofen. Environmental fate data suggest
that while lactofen is not likely to reach water resources in any
significant quantities, acifluorfen is both mobile and persistent in the
environment. Acifluorfen has been found in monitoring studies of ground
and surface water, but insufficient monitoring data are available for
quantitation of the risk from lactofen and acifluorfen in drinking
water. The Environmental Fate and Effects Division (EFED) has provided
estimated drinking water concentrations (EDWCs) of lactofen and
acifluorfen (from lactofen applications) in ground and surface water
using models.

There are no residential uses of lactofen; therefore, HED has prepared
aggregate risk assessments that include food and drinking water
estimates only. The aggregate estimates for acute and chronic exposures
are well below the level of concern.

HED also conducted aggregate risk assessments for acifluorfen including
food exposure from acifluorfen applications, residential handler
exposure from spot treatments of acifluorfen, and drinking water
exposure to acifluorfen as a result of environmental degradation of
lactofen. The aggregate assessments for all exposure durations were
below the Agency's level of concern.

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 lactofen and any other
substances. For the purposes of this tolerance action, therefore, EPA
has not assumed that lactofen has a common mechanism of toxicity with
other substances.

Two occupational scenarios were identified and assessed for the proposed
new uses of lactofen: mixing/loading liquids for groundboom application
and applying liquids using groundboom applications. Mixing/loading
liquids for groundboom application) exceeds HED's level of concern if no
personal protective equipment (PPE) is used. However, the risk of
concern can be mitigated with a single layer of dermal personal
protective equipment (PPE). The margin of exposure (MOE) for applying
liquids using groundboom equipment at the baseline level (no PPE) does
not exceed HED's level of concern.

The proposed label indicates that lactofen should be applied to row
middles in a directed, shielded spray; therefore, post application
exposures are not expected and were not assessed.

[]{#__RefHeading___Toc151953692 .anchor}**2.0 Ingredient Profile**

[]{#__RefHeading___Toc151953693 .anchor}**2.1 Summary of Proposed Uses**

Valent has included the proposed used directions under Section B of the
petition and a supplemental label for the 2 lb/gal EC formulation of
lactofen (Cobra® Herbicide; EPA Reg. No. 59639-34). Number range CHAPTER
The proposed uses are presented in Table 2.1.

HED recommends minor changes to the labels to clarify the use directions
including: 1) specify that the applications may not include two
post-transplant applications; 2) specify a retreatment interval of
30-days or a minimum post-transplant interval of 18 days for tomatoes;
and 3)

include examples of fruiting vegetables in the use directions to avoid
confusion.

+---------+---+--------+------+-------+---------+----+----------------+
| **Table |   |        |      |       |         |    |                |
| 2.1.    |   |        |      |       |         |    |                |
| Summary |   |        |      |       |         |    |                |
| of      |   |        |      |       |         |    |                |
| Dir     |   |        |      |       |         |    |                |
| ections |   |        |      |       |         |    |                |
| for Use |   |        |      |       |         |    |                |
| of      |   |        |      |       |         |    |                |
| Lact    |   |        |      |       |         |    |                |
| ofen.** |   |        |      |       |         |    |                |
+---------+---+--------+------+-------+---------+----+----------------+
| Applic. |   | Formu  | App  | Max.  | Max.    | P  | Use Directions |
| Timing; |   | lation | lic. | No.   | S       | HI | and            |
| Type;   |   |        | Rate | Ap    | easonal |    | Limitations    |
| and     |   | \[EPA  |      | plic. | Applic. | (d |                |
| Equip.  |   | Reg.   | (lb  | per   | Rate    | ay |                |
|         |   | No.\]  | a    | S     |         | s) |                |
|         |   |        | i/A) | eason | (lb     |    |                |
|         |   |        |      |       | ai/A)   |    |                |
+---------+---+--------+------+-------+---------+----+----------------+
| F       |   |        |      |       |         |    |                |
| ruiting |   |        |      |       |         |    |                |
| veg     |   |        |      |       |         |    |                |
| etables |   |        |      |       |         |    |                |
| and     |   |        |      |       |         |    |                |
| okra    |   |        |      |       |         |    |                |
+---------+---+--------+------+-------+---------+----+----------------+
| Pre-tra | 2 |        | 0.3  | 2     | 1.0     | 30 | Use is         |
| nsplant | l |        | -0.5 |       |         |    | restricted to  |
| Po      | b |        |      |       | (i      |    | AL, AR, FL,    |
| st-tran | / |        |      |       | mplied) |    | GA, MS, NC,    |
| splant; | g |        |      |       |         |    | SC, TN, and    |
|         | a |        |      |       |         |    | VA.            |
| D       | l |        |      |       |         |    | Applications   |
| irected | E |        |      |       |         |    | are to be made |
| to row  | C |        |      |       |         |    | in 20-50       |
| m       |   |        |      |       |         |    | gal/A.         |
| iddles; | \ |        |      |       |         |    | [              |
|         | [ |        |      |       |         |    | Pre-transplant |
| Ground, | 5 |        |      |       |         |    | ]{.underline}: |
| s       | 9 |        |      |       |         |    | Applications   |
| hielded | 6 |        |      |       |         |    | are to be made |
|         | 3 |        |      |       |         |    | a minimum of   |
|         | 9 |        |      |       |         |    | 10 days prior  |
|         | - |        |      |       |         |    | to             |
|         | 3 |        |      |       |         |    | transplanting. |
|         | 4 |        |      |       |         |    |                |
|         | \ |        |      |       |         |    | [P             |
|         | ] |        |      |       |         |    | ost-transplant |
|         |   |        |      |       |         |    | ]{.underline}: |
|         |   |        |      |       |         |    | Applications   |
|         |   |        |      |       |         |    | are to be made |
|         |   |        |      |       |         |    | using an       |
|         |   |        |      |       |         |    | adjuvant such  |
|         |   |        |      |       |         |    | as crop oil    |
|         |   |        |      |       |         |    | concentrate at |
|         |   |        |      |       |         |    | 1% v:v or a    |
|         |   |        |      |       |         |    | nonionic       |
|         |   |        |      |       |         |    | surfactant at  |
|         |   |        |      |       |         |    | 0.25% v:v.     |
|         |   |        |      |       |         |    | Tomato plants  |
|         |   |        |      |       |         |    | must be at     |
|         |   |        |      |       |         |    | least 16" in   |
|         |   |        |      |       |         |    | height prior   |
|         |   |        |      |       |         |    | to             |
|         |   |        |      |       |         |    | p              |
|         |   |        |      |       |         |    | ost-transplant |
|         |   |        |      |       |         |    | application.   |
|         |   |        |      |       |         |    | Peppers must   |
|         |   |        |      |       |         |    | have been      |
|         |   |        |      |       |         |    | transplanted   |
|         |   |        |      |       |         |    | at least 45    |
|         |   |        |      |       |         |    | days before    |
|         |   |        |      |       |         |    | making a       |
|         |   |        |      |       |         |    | p              |
|         |   |        |      |       |         |    | ost-transplant |
|         |   |        |      |       |         |    | application.   |
+---------+---+--------+------+-------+---------+----+----------------+

[]{#__RefHeading___Toc151953694 .anchor}**2.2 Structure and
Nomenclature**

+-------------------+--------------------------------------------------+
| **Table 2.2.      |                                                  |
| Lactofen          |                                                  |
| Nomenclature**.   |                                                  |
+===================+==================================================+
| Chemical          | ![                                               |
| structure         | ](media/image2.wmf){width="3.1798611111111112in" |
|                   | height="0.9006944444444445in"}                   |
+-------------------+--------------------------------------------------+
| Common name       | Lactofen                                         |
+-------------------+--------------------------------------------------+
| Company           | PPG-844                                          |
| experimental name |                                                  |
+-------------------+--------------------------------------------------+
| IUPAC name        | ethyl                                            |
|                   | O-\[5-(2-chloro-α,α,α-t                          |
|                   | rifluoro-p-tolyloxy)-2-nitrobenzoyl\]-DL-lactate |
+-------------------+--------------------------------------------------+
| CAS name          | 2-ethoxy-1-methyl-2-oxoethyl                     |
|                   | 5-\[2-chl                                        |
|                   | oro-4-(trifluoromethyl)phenoxy\]-2-nitrobenzoate |
+-------------------+--------------------------------------------------+
| CAS registry      | 77501-63-4                                       |
| number            |                                                  |
+-------------------+--------------------------------------------------+
| End-use product   | 2 lb/gal EC (Cobra ^®^ Herbicide; EPA Reg. No.   |
| (EP)              | 59639-34)                                        |
+-------------------+--------------------------------------------------+
| Chemical          | ![](media/image3.wmf){width="2.15in"             |
| structure of      | height="0.8986111111111111in"}                   |
| acifluorfen       |                                                  |
| (PPG-847)         | 5-\[2-ch                                         |
|                   | loro-4-(trifluoromethyl)phenoxy\]-2-nitrobenzoic |
|                   | acid                                             |
+-------------------+--------------------------------------------------+
| Chemical          | !                                                |
| structure of      | [](media/image4.wmf){width="2.740972222222222in" |
| desethyl lactofen | height="0.9006944444444445in"}                   |
| (PPG-947)         |                                                  |
|                   | 1-(carboxy)ethyl                                 |
|                   | 5-\[2-chl                                        |
|                   | oro-4-(trifluoromethyl)phenoxy\]-2-nitrobenzoate |
+-------------------+--------------------------------------------------+
| Chemical          | ![                                               |
| structure of      | ](media/image5.wmf){width="3.1798611111111112in" |
| amino lactofen    | height="0.9097222222222222in"}                   |
| (PPG-1576)        |                                                  |
|                   | 1-(carboethoxy)ethyl                             |
|                   | 5-\[2-chl                                        |
|                   | oro-4-(trifluoromethyl)phenoxy\]-2-aminobenzoate |
+-------------------+--------------------------------------------------+
| Chemical          | ![                                               |
| structure of      | ](media/image6.wmf){width="3.1798611111111112in" |
| N-formyl lactofen | height="0.9097222222222222in"}                   |
| (PPG-2597)        |                                                  |
|                   | 1-(carboethoxy)ethyl                             |
|                   | 5-\[2-chloro-                                    |
|                   | 4-(trifluoromethyl)phenoxy\]-2-formamidobenzoate |
+-------------------+--------------------------------------------------+
| Chemical          | ![                                               |
| structure of      | ](media/image7.wmf){width="3.1881944444444446in" |
| PPG-1530; Isomer  | height="0.9104166666666667in"}                   |
| A (internal       |                                                  |
| standard)         | 1-(carboethoxy)ethyl                             |
|                   | 5-\[2-chl                                        |
|                   | oro-4-(trifluoromethyl)phenoxy\]-6-nitrobenzoate |
+-------------------+--------------------------------------------------+

[]{#__RefHeading___Toc151953695 .anchor}**2.3 Physical and Chemical
Properties**

+------------------+------------------------------+-------------------+
| **Table 2.3      |                              |                   |
| Physicochemical  |                              |                   |
| Properties of    |                              |                   |
| Lactofen.**      |                              |                   |
+==================+==============================+===================+
| Parameter        | Value                        | Reference         |
+------------------+------------------------------+-------------------+
| Melting          | \>250°C                      | 44447003^1^       |
| point/range      |                              |                   |
+------------------+------------------------------+-------------------+
| pH               | 7.2 (on Pure Active          | 44447003^1^       |
|                  | Ingredient, 1% solution) at  |                   |
|                  | 25°C                         |                   |
+------------------+------------------------------+-------------------+
| Density          | 1.34 at 24°C                 | 44447003^1^       |
| (specific        |                              |                   |
| gravity)         |                              |                   |
+------------------+------------------------------+-------------------+
| Water solubility | 0.97 ppm at 25°C             | 44447003^1^       |
|                  |                              |                   |
|                  | 0.945 ± 0.131 ppm (column    | 44460902^2^       |
|                  | elution method at 20 ± 1 °C) |                   |
+------------------+------------------------------+-------------------+
| Solvent          | [g/100 g at 23               | 44447003^1^       |
| solubility       | °C]{.underline}              |                   |
|                  |                              |                   |
|                  | kerosene 15.6                |                   |
|                  |                              |                   |
|                  | 2-ethyl-1-hexanol 18.4       |                   |
|                  |                              |                   |
|                  | N-decanol 10.1               |                   |
|                  |                              |                   |
|                  | lactic acid 0.9              |                   |
|                  |                              |                   |
|                  | Lactofen is miscible at all  |                   |
|                  | proportions with the         |                   |
|                  | following solvents at -18°C  |                   |
|                  | or higher:                   |                   |
|                  |                              |                   |
|                  | DMSO, monochlorotoluene,     |                   |
|                  | dipropylene glycol           |                   |
|                  | dibenzoate, isophorone,      |                   |
|                  | cyclohexanone, mixed xylene, |                   |
|                  | ethylene dichloride,         |                   |
|                  | acetone, DMF, amyl acetate,  |                   |
|                  | methyl isobutyl ketone.      |                   |
+------------------+------------------------------+-------------------+
| Vapor pressure   | 3.69 ± 1.73 x 10^-5^ Pa (2.8 | 44460901^2^       |
|                  | x 10-7 mm Hg)                |                   |
+------------------+------------------------------+-------------------+
| Dissociation     | Not required                 | D241826, 1/16/98, |
| constant, pK~a~  |                              | H. Podall         |
+------------------+------------------------------+-------------------+
| Octanol/water    | 1 x 10^5^ at ambient         | 44460903^2^       |
| partition        | temperature, estimated value |                   |
| coefficient,     |                              |                   |
| Log(K~OW~)       |                              |                   |
+------------------+------------------------------+-------------------+
| UV/visible       | In Review ^3^                | 44447003^3^       |
| absorption       |                              |                   |
| spectrum         |                              |                   |
+------------------+------------------------------+-------------------+

^1^ RD Memorandum, D241826, 1/16/98, H. Podall.

^2^ RD Memorandum D242241, 2/5/98, S. Mathur.

^3^ D332587, C. Olinger, In Review.

[]{#__RefHeading___Toc151953696 .anchor}**3.0 Hazard
Characterization/Assessment**

[]{#__RefHeading___Toc151953697 .anchor}**3.1 Hazard and Dose-Response
Characterization**

**Lactofen**

Lactofen has a low acute toxicity profile: the acute oral LD~50~ = 5.96
g/kg b.w. (Tox Category IV), the acute dermal LD~50~ \> 2.0 g/kg b.w.
(Tox Category III) and the acute inhalation LC~50~ \> 6.3 mg/L (Tox
Category (IV). Furthermore, lactofen is not a skin sensitizer but it is
a very slight dermal irritant. The manufacturing use product (MUP),
however, is classified as a moderate eye irritant. A summary of the
hazard profile may be found in Appendix 1 of this document.

The chronic toxicity profile for lactofen clearly indicates that the
liver and kidneys are the target organs for this chemical. In a combined
chronic/oncogenicity study in rats, no effects were seen at a dose of 2
mg/kg/day. The lowest dose at which effects were reported was 19
mg/kg/day. The effects described at this dose level included: 1) an
increased incidence of mottled or diffusely dark livers and kidneys; 2)
increased aspartate aminotransferase, alanine aminotransferase, and
alkaline phosphatase; and 3) decreases in cholesterol, total protein,
globulin, and blood urea nitrogen. Many of these changes in the clinical
chemistry are indicative of liver toxicity. At higher doses in this
study, the severity of the toxicity described above was increased, and
other toxicity included dark discoloration of the testes. Similar
effects were also reported in the subchronic oral toxicity study in
rats. At the lowest dose level in a carcinogenicity study in mice,
adaptive effects such as increases in liver weight, increases in the
incidence of hepatocytomegally, and increases in sinusoidal cell
pigmentation were observed, and are considered minor. At higher dose
levels, these signs of toxicity were more severe, and neoplastic as well
as non-neoplastic lesions in the liver were also reported. In the
chronic oral toxicity study in dogs, animals treated at a dose level of
3.96 mg/kg/day had increased incidence of proteinaceous casts in the
kidneys and statistically significant decreases in the absolute weight
of thyroid and adrenal glands in males. At the highest dose tested, 19.8
mg/kg/day, test animals had slight anemia, increased absolute kidney
weights, increased relative kidney weight (kidney/body weight ratio) as
well as an increase in the incidence of proteinaceous casts in the
kidneys.

Reproductive and developmental parameters that may be affected by
exposure to lactofen were studied in a 2-generation reproduction study,
a developmental toxicity study in rats, and two developmental toxicity
studies in rabbits. In the two-generation reproduction study in rats,
decreased pup weight and decreased absolute and relative weights of the
spleen were first reported at approximately 26.2 mg/kg/day (based on
dose administered to the parental group). It is noteworthy that these
effects are seen at the same dose level that elicits mortality and
decreased male fertility in the parental groups. In the developmental
toxicity study in rats, developmental effects were observed at the 150
mg/kg/day dose level and consisted of decreases in fetal weight as well
as skeletal variations (increased incidence of bent ribs, bent limb
bones and a reduction in the ossification of the vertebral arches). Once
again, the dose level that causes adverse effects to the developing
conceptus also elicits signs of toxicity in the parental group (e.g.
excess salivation, lethargy, and decreased body weight gain). Two rabbit
developmental studies have been submitted. Although conducted in similar
strains of rabbits according to acceptable protocols, the results of the
two studies are somewhat inconsistent. In the first study
post-implantation loss was observed, but not in the second study. In the
second study animals were not dosed high enough to observe developmental
affects in the pups; however, toxicity was observed in the maternal
animals. Maternal effects were noted in the first study as well.

The mutagenicity database for lactofen suggests that this chemical has
very little mutagenic or genotoxic activity. While a positive mutagenic
response was reported in one trial of a *Salmonella
typhimurium*/mammalian microsome mutagenicity assay, this response was
[not]{.underline} reported in the second assay conducted. In addition,
lactofen did not appear to induce chromosomal aberrations, unscheduled
DNA synthesis or inhibit DNA repair.

As a member of the diphenyl ether chemical family, lactofen is
structurally related to four other chemicals that are oncogenic in
rodents namely sodium acifluorfen (a metabolite and environmental
degradate of lactofen), nitrofen, oxyfluorfen, and fomesafen. Sodium
acifluorfen produces hepatocellular adenomas and carcinomas in mice but
is negative in rats, nitrofen produces hepatocellular carcinomas in mice
and pancreatic carcinomas in rats, oxyfluorfen produces marginally
positive liver tumors in mice but is negative in rats, and fomesafen
produces hepatocellular adenomas and carcinomas in mice. The registrant
proposed a mechanism of toxicity for lactofen based on PPARα activation
(Fricke, 2002) which was accepted by the HED Mechanism of Toxicity
Assessment Review Committee (MTARC). The Cancer Assessment Review
Committee (CARC) concurred with the MTARC's conclusion and classified
lactofen as not likely to be carcinogenic to humans at doses that do not
cause biochemical and histopathological changes in the liver of rodents.

Since the 2002 CARC report, significant research information has
accumulated on the human relevance of rodent liver tumors that are
induced through the activation of the peroxisome proliferator-activated
receptor (PPARα). Although the precise mechanism for the formation of
rodent liver tumors by a PPARα agonist has not been established, it is
accepted that the key events for the mode of action leading to rodent
hepatocarcinogenesis are well established. Further, more recent
information has established that chemicals that are PPARα agonists can
induce liver rodent tumors, but the potential for PPARα agonists to
induce liver tumors in other species, including humans, appears to be
unlikely. This is because evidence shows that quantitatively these other
species are less sensitive to the effects of PPARα agonism due to
toxicodynamic differences between human and rodent nuclear PPAR receptor
(e.g., Klaunig et al, 2003; Cheung et al., 2004; Cariello et al., 2005;
Hoivik et al., 2004). Overall, the majority of the 2003 FIFRA Scientific
Advisory Panel agreed that there are relevant data indicating that
humans are less sensitive than rodents to the hepatic effects of PPAR-α
agonists (add website). To incorporate the current state of the science,
the CARC has recently revised its approach to the hazard
characterization for pesticides that are hepatic carcinogens via PPARα
agonism to reflect this quantitative species difference. Thus, the more
appropriate characterization for lactofen is: Not Likely to be
Carcinogenic to Humans" because of available data on lactofen supports
activation of the peroxisome proliferator activated receptor alpha
(PPARα) as the mode of action for induced hepatocarcinogenesis in
rodents. Additionally, the available data on lactofen do not support
mutagenesis as an alternative mode of action. While the proposed mode of
action for liver tumors in rodent is qualitatively possible in humans,
it is quantitatively implausible and unlikely to take place in humans
based on quantitative species toxicodynamic differences in PPARα
activation. The quantification of risk is not required.

Currently the lactofen database does not contain acute neurotoxicity,
subchronic neurotoxicity, developmental neurotoxicity or acute delayed
neurotoxicity studies. The absence of these studies is not considered a
data gap since according to the Code of Federal Regulations §158.340,
these tests are not required "unless test material, is an
organophosphate, or a metabolite or degradation product thereof which
causes acetylcholinesterase depression or is structurally related to a
substance that causes delayed neurotoxicity" or unless "the acute oral,
dermal, or inhalation studies showed neuropathy or neurotoxicity." It is
noted that neurotoxicity was NOT observed in any of the submitted
toxicity studies.

The rat metabolism study showed that lactofen was metabolized to
acifluorfen, and it was eliminated via both urine and feces. While
lactofen was the primary compound found in the feces, acifluorfen
accounted for \>90% of the radioactivity in the urine. Negligible
amounts of the administered radioactivity were found in any tissue with
less than 0.8% of the administered radioactivity being found in the
liver (one of the main target organs).

**Sodium Acifluorfen**

Toxicity information is included here for sodium acifluorfen, a
registered herbicide, because acifluorfen is the major lactofen
degradate found in surface and ground water. Since hazard data are
available for sodium acifluorfen, the Agency is able to do a separate
risk assessment for sodium acifluorfen. A more complete hazard
discussion is available in the sodium acifluorfen human health risk
assessment (Farwell, 5/31/2000).

The acute toxicity data indicated that sodium acifluorfen had low acute
oral, dermal and inhalation toxicity. It was not a skin sensitizer.
However, it caused severe eye and moderate skin irritation.

The subchronic feeding study in rats and mice for sodium acifluorfen
showed a decrease in body weight and signs of liver toxicity
(characterized by increased liver weight and increased incidence of
cellular hypertrophy).

The chronic feeding toxicity studies in rats, mice, and dogs
demonstrated that sodium acifluorfen induced liver toxicity (acidophilic
cells in the liver and increased liver weight) and kidney toxicity
(nephritis/pyelonephritis and increased kidney weight). An increase in
the incidence of stomach ulcers was also seen in chronic feeding study
in rats.

The registrant has also proposed a mechanism of toxicity for sodium
acifluorfen based on PPARα activation (Farwell, 2003) which was accepted
by the HED Mechanism of Toxicity Assessment Review Committee (MTARC).
The Cancer Assessment Review Committee (CARC) concurred with the MTARC's
conclusion and classified sodium acifluorfen as not likely to be
carcinogenic to humans at doses that do not cause the biochemical and
histopathological changes in the liver of rodents. Similar to lactofen,
HED has reconsidered the mechanism of toxicity and now believes the
cancer classification should be characterized as "not likely to be
carcinogenic in humans".

Sodium acifluorfen produced developmental toxicity (decreased fetal body
weight and the increase in anatomical variations) in rats but it did not
affect the reproductive parameters in rats.

The acceptable genetic toxicology studies indicate that sodium
acifluorfen was weakly mutagenic in *Salmonella typhimurium* TA100 at
high S9-activated concentrations and weakly recombinogenic in
*Saccharomyces cerevisiae* at high nonactivated concentrations but was
negative for gene mutations in Chinese hamster ovary (CHO) cells. The
test material was also negative for clastogenic effects *in vivo* and
did not induce unscheduled DNA synthesis in primary rat hepatocytes.
Although sodium acifluorfen induced Y chromosome loss and dominant
lethal mutations in *Drosophila melanogaster*, the concern for possible
heritable effects is lessened by the negative results of the rat
dominant lethal assay. The acceptable studies satisfy the pre-1991
mutagenicity guideline requirements.

In a rat metabolism study, sodium acifluorfen was rapidly absorbed
orally and eliminated mainly in the urine (46-58% of the dose) and feces
(21-41% of the dose). The major component present in urine and feces was
unchanged acifluorfen and amine metabolite, respectively. No tissue
accumulation was observed.

[]{#__RefHeading___Toc151953698 .anchor}**3.2 FQPA Considerations**

**Lactofen**

The FQPA Safety Factor Committee met on March 13, 2000 to evaluate the
hazard and exposure data for lactofen and recommended that the FQPA
Safety Factor (as required by Food Quality Protection Act of August 3,
1996) for protection of infants and children should be 3x for lactofen,
based on a datagap of a rabbit developmental study. Although two rabbit
developmental studies were submitted, the results of these studies were
inconsistent, so a new study had been required.

The registrant submitted a request to waive the rabbit developmental
study in 2005, including additional background information on the two
prior studies. HED has reviewed their request (Phang, 2006) and
concurred with their position that sufficient information has been
submitted on developmental effects in rabbits and no further studies are
needed, so a database uncertainty factor is no longer required. However,
a LOAEL to NOAEL FQPA factor is needed as there was no NOAEL identified
in the study the Agency is now using for acute dietary endpoint
selection (for females of reproductive age), a Prenatal Developmental
Toxicity Study in Rabbits (TXR No. 003724). The endpoints of concern
identified in this study are: decreased live young/litter, increased
embryonic death/litter, and increased incidence of post-implantation
loss. These effects were noted at all dose levels (5, 15, 50 mg/kg/day)
thus a NOAEL was not established. Though a second Prenatal Developmental
Toxicity Study in Rabbits (MRIDs: 00264577 and 00264847) failed to
reproduce these effects at doses comparable to those used in the first
study, the effects in the first study are still considered valid given
the fact that the two studies were conducted in different facilities
(Huntington for the first study and Wil Labs for the second study) and
the different colonies used by these facilities may account for the
different results. It should be noted that the incidence for the effects
observed in the first study at the lowest dose tested were only
marginally higher than the historical control data submitted by the
testing facility as well as the historical control data available
through the Middle Atlantic Reproduction and Teratology Association
(MARTA). Consequently, an FQPA uncertainty factor of 3X is expected to
be protective of infants and children and will be used for the LOAEL to
NOAEL extrapolation.

The following considerations were used by the Agency when selecting an
appropriate FQPA Safety Factor:

-   there are no residual uncertainties regarding the exposure of
    infants and children to lactofen;

-   there are no outstanding datagaps for developmental toxicity or
    reproductive toxicity studies;

-   developmental effects were observed in the presence of maternal
    toxicity; and

-   the acute dietary exposure endpoints are based on the developmental
    effects found in the rabbit developmental study.

Accordingly, the Agency has reduced the FQPA safety factor for 3X for
acute exposures and 1X for chronic exposures. At this time there are no
other exposure intervals that require evaluation as there are no
residential uses of lactofen*.*

**Sodium acifluorfen**

The toxicology database provides sufficient information for selecting
various toxicity endpoints and doses for assessing the risks for sodium
acifluorfen. The Health Effects Division (HED) FQPA Safety Factor
Committee (SFC) met on September 13, 1999 to evaluate the hazard and
exposure data for sodium acifluorfen and recommended retaining the
safety factor at 10X due to the data gap for the developmental
neurotoxicity study in rats. The developmental neurotoxicity study is
designed to evaluate neurotoxic effects on the mother and fetus from the
time of implantation of the fertilized egg into the wall of the uterus
through post-natal day 21. This study may provide additional information
that could be used to further characterize the effects of sodium
acifluorfen on the developing organism. In accordance with the current
policy within the Health Effects Division, the 10x factor will be
applied to all exposure durations. A more detailed discussion of the
safety factor selection may be found in the human health assessment for
acifluorfen (Farwell, 2003).

[]{#__RefHeading___Toc151953699 .anchor}**3.3 Dose Response Assessment
and Hazard Endpoint Selection**

**Lactofen**

On February 22, 2000 the Health Effects Division (HED) Hazard
Identification Assessment Review Committee (HIARC) evaluated the
toxicology database for lactofen, re-assessed the existing reference
dose, and selected the doses and toxicological endpoints for dietary and
non-dietary exposure risk assessments. Additional data and information
have been submitted since then, including mechanistic data on the
carcinogenicity of lactofen (Fricke 2002) and a request to waive the
rabbit developmental study (Phang 2006). As previously discussed in
section 3.1 the cancer classification of lactofen should be
characterized as "not likely to be carcinogenic in humans".

The selected endpoints and doses for the lactofen assessments may be
found in Tables 3.1 and 3.2.

**Sodium Acifluorfen**

On January 19 and February 11, 1999, the Hazard Identification
Assessment Review Committee (HIARC) evaluated the entire toxicological
database on sodium acifluorfen and selected the relevant toxicity
endpoints, taking into consideration the use patterns and exposure
information on this chemical. Additional data and information have been
submitted since then, including mechanistic data on the carcinogenicity
of acifluorfen (Farwell, 2003). As previously discussed in section 3.1,
the cancer classification of acifluorfen should be characterized as "not
likely to be carcinogenic in humans". The selected endpoints and doses
for the acifluorfen assessments may be found in Table 3.3.

+---------+---------+-------------+-----------+----------------------+
| **Table |         |             |           |                      |
| 3.1     |         |             |           |                      |
| Toxico  |         |             |           |                      |
| logical |         |             |           |                      |
| Doses   |         |             |           |                      |
| and     |         |             |           |                      |
| En      |         |             |           |                      |
| dpoints |         |             |           |                      |
| for     |         |             |           |                      |
| [La     |         |             |           |                      |
| ctofen] |         |             |           |                      |
| {.under |         |             |           |                      |
| line}** |         |             |           |                      |
| **for   |         |             |           |                      |
| Use in  |         |             |           |                      |
| Dietary |         |             |           |                      |
| and     |         |             |           |                      |
| No      |         |             |           |                      |
| n-Occup |         |             |           |                      |
| ational |         |             |           |                      |
| Human   |         |             |           |                      |
| Health  |         |             |           |                      |
| Risk    |         |             |           |                      |
| Asse    |         |             |           |                      |
| ssments |         |             |           |                      |
| ^1^**   |         |             |           |                      |
+=========+=========+=============+===========+======================+
| **Expo  | **Point | **Uncer     | **RfD,    | **Study and          |
| sure/** | of      | tainty/FQPA | PAD,      | Toxicological        |
|         | Depa    | Safety      | Level of  | Effects**            |
| **Sce   | rture** | Factors**   | Concern   |                      |
| nario** |         |             | for Risk  |                      |
|         |         |             | Ass       |                      |
|         |         |             | essment** |                      |
+---------+---------+-------------+-----------+----------------------+
| Acute   | No      |             |           |                      |
| Dietary | e       |             |           |                      |
| *       | ndpoint |             |           |                      |
| General | has     |             |           |                      |
| Popu    | been    |             |           |                      |
| lation* | ide     |             |           |                      |
|         | ntified |             |           |                      |
|         | for the |             |           |                      |
|         | general |             |           |                      |
|         | pop     |             |           |                      |
|         | ulation |             |           |                      |
|         | based   |             |           |                      |
|         | on a    |             |           |                      |
|         | single  |             |           |                      |
|         | e       |             |           |                      |
|         | xposure |             |           |                      |
|         | to      |             |           |                      |
|         | la      |             |           |                      |
|         | ctofen. |             |           |                      |
+---------+---------+-------------+-----------+----------------------+
| Acute   | LOAEL = | UF~A~= 10x  | Acute RfD | Developmental        |
| Dietary | 5       |             | = 0.017   | Toxicity Study --    |
|         | mg      | UF~H~=10x   | mg/kg/day | Rabbit               |
| *       | /kg/day |             |           |                      |
| Females |         | FQPA SF= 3x | aPAD =    | LOAEL was 5 mg/kg    |
| 13-49   |         |             | 0.017     | based on decrease in |
| years   |         | (UF~L~)     | mg/kg/day | live young per       |
| of age* |         |             |           | litter accompanied   |
|         |         |             |           | by increases in post |
|         |         |             |           | implantation loss    |
|         |         |             |           | and in early         |
|         |         |             |           | embryonic            |
|         |         |             |           | death/litter.        |
+---------+---------+-------------+-----------+----------------------+
| Chronic | NOAEL=  | UF~A~ = 10x | Chronic   | Chronic Oral         |
| Dietary | 0.79    |             | RfD =     | Toxicity Study - Dog |
|         | mg      | UF~H~ = 10x | 0.008     |                      |
| *All    | /kg/day |             |           | LOAEL = 3.96         |
| Popul   |         | FQPA SF= 1x | mg/kg/day | mg/kg/day based on   |
| ations* |         |             |           | increased incidence  |
|         |         |             | cPAD =    | of proteinaceous     |
|         |         |             | 0.008     | casts in the kidneys |
|         |         |             | mg/kg/day | and statistically    |
|         |         |             |           | significant          |
|         |         |             |           | decreases in the     |
|         |         |             |           | absolute weight of   |
|         |         |             |           | thyroid and adrenal  |
|         |         |             |           | glands in males.     |
+---------+---------+-------------+-----------+----------------------+
| Cancer  | C       |             |           |                      |
| (oral,  | lassifi |             |           |                      |
| dermal, | cation: |             |           |                      |
| inha    | Not     |             |           |                      |
| lation) | likely  |             |           |                      |
|         | to be   |             |           |                      |
|         | carci   |             |           |                      |
|         | nogenic |             |           |                      |
|         | to      |             |           |                      |
|         | humans. |             |           |                      |
+---------+---------+-------------+-----------+----------------------+
| Inc     | En      |             |           |                      |
| idental | dpoints |             |           |                      |
| Oral    | and     |             |           |                      |
| Sho     | doses   |             |           |                      |
| rt-Term | have    |             |           |                      |
| (1-30   | not     |             |           |                      |
| days)   | been    |             |           |                      |
|         | s       |             |           |                      |
|         | elected |             |           |                      |
|         | for     |             |           |                      |
|         | these   |             |           |                      |
|         | sc      |             |           |                      |
|         | enarios |             |           |                      |
|         | as      |             |           |                      |
|         | there   |             |           |                      |
|         | are no  |             |           |                      |
|         | resi    |             |           |                      |
|         | dential |             |           |                      |
|         | ex      |             |           |                      |
|         | posures |             |           |                      |
|         | to      |             |           |                      |
|         | la      |             |           |                      |
|         | ctofen. |             |           |                      |
+---------+---------+-------------+-----------+----------------------+
| Inc     |         |             |           |                      |
| idental |         |             |           |                      |
| Oral    |         |             |           |                      |
| Int     |         |             |           |                      |
| ermedia |         |             |           |                      |
| te-Term |         |             |           |                      |
| (1-6    |         |             |           |                      |
| months) |         |             |           |                      |
+---------+---------+-------------+-----------+----------------------+
| Dermal  |         |             |           |                      |
| Sho     |         |             |           |                      |
| rt-Term |         |             |           |                      |
| (1-30   |         |             |           |                      |
| days)   |         |             |           |                      |
+---------+---------+-------------+-----------+----------------------+
| Dermal  |         |             |           |                      |
| Int     |         |             |           |                      |
| ermedia |         |             |           |                      |
| te-Term |         |             |           |                      |
| (1-6    |         |             |           |                      |
| months) |         |             |           |                      |
+---------+---------+-------------+-----------+----------------------+

**^1^ Explanation of Abbreviations:** Point of Departure (PoD) = A data
point or an estimated point that is derived from observed dose-response
data and used to mark the beginning of extrapolation to determine risk
associated with lower environmentally relevant human exposures. NOAEL =
no observed adverse effect level. LOAEL = lowest observed adverse effect
level. UF = uncertainty factor. UF~A~ = extrapolation from animal to
human (intraspecies). UF~H~ = potential variation in sensitivity among
members of the human population (interspecies). UF~L~ = use of a LOAEL
to extrapolate a NOAEL. UF~S\ =~ use of a short-term study for long-term
risk assessment. UF~DB~ = to account for the absence of key date (i.e.,
lack of a critical study). FQPA SF = FQPA Safety Factor. PAD =
population adjusted dose (a = acute, c = chronic). RfD = reference dose.
MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

+----------+--------+---------+------------+--------------------------+
| **Table  |        |         |            |                          |
| 3.2      |        |         |            |                          |
| Summary  |        |         |            |                          |
| of       |        |         |            |                          |
| Toxic    |        |         |            |                          |
| ological |        |         |            |                          |
| Doses    |        |         |            |                          |
| and      |        |         |            |                          |
| E        |        |         |            |                          |
| ndpoints |        |         |            |                          |
| for      |        |         |            |                          |
| [Lacto   |        |         |            |                          |
| fen]{.un |        |         |            |                          |
| derline} |        |         |            |                          |
| for Use  |        |         |            |                          |
| in       |        |         |            |                          |
| Occu     |        |         |            |                          |
| pational |        |         |            |                          |
| Human    |        |         |            |                          |
| Health   |        |         |            |                          |
| Risk     |        |         |            |                          |
| Asses    |        |         |            |                          |
| sments** |        |         |            |                          |
+==========+========+=========+============+==========================+
| **Exp    | *      | **Unce  | **Level of | **Study and              |
| osure/** | *Point | rtainty | Concern    | Toxicological Effects**  |
|          | of     | Fa      | for Risk   |                          |
| **Sc     | Depar  | ctors** | As         |                          |
| enario** | ture** |         | sessment** |                          |
+----------+--------+---------+------------+--------------------------+
| Dermal   | NOAEL  | UF      | Oc         | Developmental Toxicity   |
| Sh       | = 5    | ~A~=10x | cupational | Study -- Rabbit          |
| ort-Term | mg/    |         | LOC for    |                          |
| (1-30    | kg/day | UF      | MOE = 300  | LOAEL was 5 mg/kg based  |
| days)    |        | ~H~=10x |            | on decrease in live      |
|          |        |         |            | young per litter         |
|          |        | UF~L~   |            | accompanied by increases |
|          |        | =3X     |            | in post implantation     |
|          |        |         |            | loss and in early        |
|          |        |         |            | embryonic death/litter.  |
+----------+--------+---------+------------+--------------------------+
| Dermal   |        |         |            |                          |
| I        |        |         |            |                          |
| ntermedi |        |         |            |                          |
| ate-Term |        |         |            |                          |
| (1-6     |        |         |            |                          |
| months)  |        |         |            |                          |
+----------+--------+---------+------------+--------------------------+
| In       | NOAEL  | UF      | Oc         | Developmental Toxicity   |
| halation | = 5    | ~A~=10x | cupational | Study -- Rabbit          |
| Sh       | mg/    |         | LOC for    |                          |
| ort-Term | kg/day | UF      | MOE = 300  | LOAEL was 5 mg/kg based  |
| (1-30    |        | ~H~=10x |            | on decrease in live      |
| days)    |        |         |            | young per liver          |
|          |        | UF~L~   |            | accompanied by increases |
|          |        | =3X     |            | in post implantation     |
|          |        |         |            | loss and in early        |
|          |        |         |            | embryonic death/litter.  |
+----------+--------+---------+------------+--------------------------+
| In       |        |         |            |                          |
| halation |        |         |            |                          |
| I        |        |         |            |                          |
| ntermedi |        |         |            |                          |
| ate-term |        |         |            |                          |
| (1-6     |        |         |            |                          |
| months)  |        |         |            |                          |
+----------+--------+---------+------------+--------------------------+
| Cancer   | Cla    |         |            |                          |
| (oral,   | ssific |         |            |                          |
| dermal,  | ation: |         |            |                          |
| inh      | Not    |         |            |                          |
| alation) | likely |         |            |                          |
|          | to be  |         |            |                          |
|          | carcin |         |            |                          |
|          | ogenic |         |            |                          |
|          | to     |         |            |                          |
|          | h      |         |            |                          |
|          | umans. |         |            |                          |
+----------+--------+---------+------------+--------------------------+

**^1^ Explanation of Abbreviations:** Point of Departure (PoD) = A data
point or an estimated point that is derived from observed dose-response
data and used to mark the beginning of extrapolation to determine risk
associated with lower environmentally relevant human exposures. NOAEL =
no observed adverse effect level. LOAEL = lowest observed adverse effect
level. UF = uncertainty factor. UF~A~ = extrapolation from animal to
human (intraspecies). UF~H~ = potential variation in sensitivity among
members of the human population (interspecies). UF~L~ = use of a LOAEL
to extrapolate a NOAEL. FQPA SF = FQPA Safety Factor. PAD = population
adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE =
margin of exposure. LOC = level of concern. N/A = not applicable.

+---------+---------+-------------+-----------+----------------------+
| **Table |         |             |           |                      |
| 3.3     |         |             |           |                      |
| Toxico  |         |             |           |                      |
| logical |         |             |           |                      |
| Doses   |         |             |           |                      |
| and     |         |             |           |                      |
| En      |         |             |           |                      |
| dpoints |         |             |           |                      |
| for     |         |             |           |                      |
| [Aci    |         |             |           |                      |
| fluorfe |         |             |           |                      |
| n]{.und |         |             |           |                      |
| erline} |         |             |           |                      |
| for Use |         |             |           |                      |
| in      |         |             |           |                      |
| Dietary |         |             |           |                      |
| and     |         |             |           |                      |
| No      |         |             |           |                      |
| n-Occup |         |             |           |                      |
| ational |         |             |           |                      |
| Human   |         |             |           |                      |
| Health  |         |             |           |                      |
| Risk    |         |             |           |                      |
| Assess  |         |             |           |                      |
| ments** |         |             |           |                      |
+=========+=========+=============+===========+======================+
| **Expo  | **Point | **Uncer     | **RfD,    | **Study and          |
| sure/** | of      | tainty/FQPA | PAD,      | Toxicological        |
|         | Depa    | Safety      | Level of  | Effects**            |
| **Sce   | rture** | Factors**   | Concern   |                      |
| nario** |         |             | for Risk  |                      |
|         |         |             | Ass       |                      |
|         |         |             | essment** |                      |
+---------+---------+-------------+-----------+----------------------+
| Acute   | No      |             |           |                      |
| Dietary | e       |             |           |                      |
| *       | ndpoint |             |           |                      |
| General | has     |             |           |                      |
| Popu    | been    |             |           |                      |
| lation* | ide     |             |           |                      |
|         | ntified |             |           |                      |
|         | for the |             |           |                      |
|         | general |             |           |                      |
|         | pop     |             |           |                      |
|         | ulation |             |           |                      |
|         | based   |             |           |                      |
|         | on a    |             |           |                      |
|         | single  |             |           |                      |
|         | e       |             |           |                      |
|         | xposure |             |           |                      |
|         | to      |             |           |                      |
|         | acifl   |             |           |                      |
|         | uorfen. |             |           |                      |
+---------+---------+-------------+-----------+----------------------+
| Acute   | NOAEL = | UF~A~= 10x  | Acute RfD | Developmental        |
| Dietary | 20      |             | = 0.02    | Toxicity Study --    |
|         | mg      | UF~H~ = 10x | mg/kg/day | Rat                  |
| *       | /kg/day |             |           |                      |
| Females |         | FQPA SF=    | aPAD =    | LOAEL = 90 mg/kg/day |
| 13-49   |         | 10x         | 0.02      | based on decreased   |
| years   |         |             | mg/kg/day | fetal weight and     |
| of age* |         | Database    |           | increased incidences |
|         |         | Uncertainty |           | of dilated lateral   |
|         |         | Factor due  |           | ventricles of the    |
|         |         | to the lack |           | brain                |
|         |         | of a        |           |                      |
|         |         | de          |           |                      |
|         |         | velopmental |           |                      |
|         |         | ne          |           |                      |
|         |         | urotoxicity |           |                      |
|         |         | study       |           |                      |
+---------+---------+-------------+-----------+----------------------+
| Chronic | NOAEL=  | UF~A~ = 10x | Chronic   | 2- Generation        |
| Dietary | 1.25    |             | RfD =     | Reproduction Study - |
|         | mg      | UF~H~ = 10x | 0.013     | Rat                  |
| *All    | /kg/day |             | mg/kg/day |                      |
| Popul   |         | FQPA SF=    |           | LOAEL = 25 mg/kg/day |
| ations* |         | 10x         | cPAD =    | based on kidney      |
|         |         |             | 0.0013    | lesions (dilatation  |
|         |         |             | mg/kg/day | of tubules in outer  |
|         |         |             |           | medulla)             |
+---------+---------+-------------+-----------+----------------------+
| Dermal  | NOAEL=  | UF~A~ = 10x | Re        | Developmental        |
| Sho     | 20      |             | sidential | Toxicity Study --    |
| rt-Term | mg      | UF~H~ = 10x | LOC for   | Rat                  |
| (1-30   | /kg/day |             | MOE =     |                      |
| days)   |         | FQPA SF =   | 1000      | LOAEL = 90 mg/kg/day |
|         |         | 10x         |           | based on decreased   |
|         |         |             |           | fetal weight and     |
|         |         | Database    |           | increased incidences |
|         |         | uncertainty |           | of dilated lateral   |
|         |         | factor for  |           | ventricles of the    |
|         |         | Females     |           | brain                |
|         |         | ages 13-49  |           |                      |
+---------+---------+-------------+-----------+----------------------+
| Dermal  |         |             |           |                      |
| Int     |         |             |           |                      |
| ermedia |         |             |           |                      |
| te-Term |         |             |           |                      |
| (1-6    |         |             |           |                      |
| months) |         |             |           |                      |
+---------+---------+-------------+-----------+----------------------+
| Inh     | NOAEL=  | UF~A~ = 10x | Re        | Developmental        |
| alation | 20      |             | sidential | Toxicity Study --    |
| Short-  | mg      | UF~H~ = 10x | LOC for   | Rat                  |
| Term    | /kg/day |             | MOE =     |                      |
| (1-30   |         | FQPA SF =   | 1000      | LOAEL = 90 mg/kg/day |
| days)   |         | 10x         |           | based on decreased   |
|         |         |             |           | fetal weight and     |
|         |         | Database    |           | increased incidences |
|         |         | uncertainty |           | of dilated lateral   |
|         |         | factor for  |           | ventricles of the    |
|         |         | Females     |           | brain                |
|         |         | ages 13-49  |           |                      |
+---------+---------+-------------+-----------+----------------------+
| Inh     |         |             |           |                      |
| alation |         |             |           |                      |
| Int     |         |             |           |                      |
| ermedia |         |             |           |                      |
| te-Term |         |             |           |                      |
| (1-6    |         |             |           |                      |
| months) |         |             |           |                      |
+---------+---------+-------------+-----------+----------------------+
| Cancer  | C       |             |           |                      |
| (oral,  | lassifi |             |           |                      |
| dermal, | cation: |             |           |                      |
| inha    | Not     |             |           |                      |
| lation) | likely  |             |           |                      |
|         | to be   |             |           |                      |
|         | carci   |             |           |                      |
|         | nogenic |             |           |                      |
|         | to      |             |           |                      |
|         | humans. |             |           |                      |
+---------+---------+-------------+-----------+----------------------+

**^1^ Explanation of Abbreviations:** Point of Departure (PoD) = A data
point or an estimated point that is derived from observed dose-response
data and used to mark the beginning of extrapolation to determine risk
associated with lower environmentally relevant human exposures. NOAEL =
no observed adverse effect level. LOAEL = lowest observed adverse effect
level. UF = uncertainty factor. UF~A~ = extrapolation from animal to
human (intraspecies). UF~H~ = potential variation in sensitivity among
members of the human population (interspecies). UF~L~ FQPA SF = FQPA
Safety Factor. PAD = population adjusted dose (a = acute, c = chronic).
RfD = reference dose. MOE = margin of exposure. LOC = level of concern.
N/A = not applicable.

[]{#__RefHeading___Toc151953700 .anchor}**3.4 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 the recommendations of its Endocrine Disruptor Screening and
Testing Advisory Committee (EDSTAC), EPA determined that there were
scientific bases 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 animal toxicity studies on lactofen, there was no evidence of
estrogen, androgen, and/or thyroid mediated toxicity.

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

[]{#__RefHeading___Toc151953701 .anchor}**4.0 Public Health and
Pesticide Epidemiology Data**

HED recently reviewed the poisoning incident data on lactofen in the
following databases: OPP Incident Data System (IDS), Poison Control
Centers, California Department of Pesticide Regulation, National
Pesticide Information Center (NPIC), and National Institute of
Occupational Safety and Health's Sentinel Event Notification System for
Occupational Risks (NIOSH SENSOR). There were few reports of ill effects
from exposure to lactofen in the available data bases. No
recommendations can be made based on the limited information available
for this pesticide (Hawkins and Allender, 2006).

[]{#__RefHeading___Toc151953702 .anchor}**5.0 Dietary Exposure/Risk
Characterization**

[]{#__RefHeading___Toc151953703 .anchor}**5.1 Food Residue Profile**

Adequate studies are available depicting the metabolism of
\[^14^C\]lactofen in soybeans, peanuts, and tomatoes. Although the
quantities of individual metabolites vary between crops, the data
indicate that the metabolic pathway is similar between crops. The
metabolism of lactofen initially involves reduction of the nitro group
to an amino group, with or without loss of the ethyl ester side chains
to form the preliminary diphenyl ether metabolites: amino lactofen
(PPG-1576), N-formyl lactofen (PPG-2597), desethyl lactofen (PPG-947),
acifluorfen (PPG-947), and amino acifluorfen (PPG-2053). Subsequent
conjugation of these primary metabolites through their carboxyl and
amino groups results in the formation of complex soluble and insoluble
polar components.

Adequate studies are available depicting the metabolism of
\[^14^C\]lactofen in ruminants and poultry. Lactofen was not detected in
ruminant tissues or milk; only minor amounts of lactofen were detected
in poultry tissues. Major residues found in edible ruminant and poultry
commodities include acifluorfen, desethyl lactofen, and amino desethyl
lactofen.

The Health Effects Division Metabolism Assessment Review Committee
(MARC) met on April 4, 2000 to discuss the residues of concern in food
and water. The MARC concluded that only lactofen is of concern in
plants. Newer metabolism studies indicated that metabolites containing
the diphenyl ether linkage are not likely to be present at significant
levels under the current use conditions and there is no need to include
them in the tolerance expression and risk assessment. At this time
tolerances are not required for livestock commodities, since there is no
reasonable expectation of finite residues (40 CFR 180.6 (a)(3)).
However, should additional feed commodities be registered in the future
that would necessitate consideration of livestock commodities, all
metabolites containing the diphenyl ether linkage should be included in
the tolerance expression and risk assessment for livestock commodities.
The individual metabolites to be included in the tolerance expression,
should tolerances be necessary, are acifluorfen, des-ethyl lactofen,
amino lactofen, N-formyl lactofen, amino acifluorfen, and amino
des-ethyl lactofen.

Acceptable gas chromatography with electron capture detection (GC/ECD)
methods are available in the Pesticide Analytical Manual (PAM) Vol. II
for the enforcement of tolerances of lactofen and metabolites in plant
commodities. A modified version of Method B is listed in the U.S. EPA
Index of Pesticide Analytical Methods under lactofen. Samples from the
pepper and tomato field trials were analyzed using established GC/ECD
enforcement methods or modified versions of established enforcement
methods. The validated limits of quantitation (LOQs) were 0.01 ppm for
peppers from the 1991 trial, and 0.02 ppm for samples from all other
trials. The methods are adequate for data collection based on acceptable
method validation and concurrent recovery data.

There are no livestock feedstuffs associated with the proposed uses on
fruiting vegetables and okra. Therefore, feeding studies are not
required to support this petition.

The submitted crop field trial data for pepper and tomato do not meet
the recommendations in the guidance for guideline no. 860.1500 because
of inadequate geographic representation. However, due to the very low
residues, and the available data are in a region to that similar to
those requested in this petition for a tolerance with a regional
registration, HED will not request any additional data for the proposed
use. The data indicate that residues of lactofen were below the LOQ
(\<0.01 - \<0.02 ppm) in/on samples following application of lactofen
according to the proposed use pattern.

No crop field trial data were submitted to support the proposed use on
okra. Okra will be added to the fruiting vegetable crop group (Personal
communication, B. Schneider 10/13/06), so the tomato and pepper data may
be translated to okra.

Additional data/information are required to support the available
confined rotational and limited rotational crop data; however, the
available data suggest that the nature of the residue in rotational
crops is adequately understood and that plantback intervals are not
needed for the proposed use on fruiting vegetables and okra.

There are no established or proposed Codex, Canadian, or Mexican MRLs
for residues of lactofen in any crop. Therefore, there are no
harmonization issues with respect to U.S. tolerances.

Tolerance levels were used in the acute, chronic, and cancer assessments
for lactofen and are listed in Table 5.1 below.

  -----------------------------------------------------------------------
  Table 5.1. Tolerance Levels Used 
  in Lactofen Dietary Assessment   
  -------------------------------- --------------------------------------
  Crop                             Tolerance Level, ppm

  **Existing Tolerances**          

  Beans, Snap                      0.01

  Cotton, Gin Byproducts           0.02

  Cotton, undelinted seed          0.01

  Peanut                           0.01

  Soybean, seed                    0.01

  **Proposed Tolerances**          

  Fruiting Vegetables              0.02

  Okra                             0.02
  -----------------------------------------------------------------------

> An aggregate assessment for acifluorfen was also conducted because
> acifluorfen is an environmental degradate of lactofen. Tolerance
> values for acifluorfen were used and may be found in Table 5.2.

  -------------------------------- --------------------------------------
  Table 5.2. Tolerance Levels Used 
  in Acifluorfen Dietary           
  Assessment                       

  Crop                             Tolerance Level, ppm

  Peanut                           0.1

  Rice, grain                      0.1

  Soybean                          0.1

  Strawberry                       0.05
  -------------------------------- --------------------------------------

No concentration, reduction, or processing factors were used in this
assessment, as concentration of residues was not observed in processing
studies.

[]{#__RefHeading___Toc151953704 .anchor}**5.2 Drinking Water Residue
Profile**

The drinking water residues used in the dietary risk assessment were
provided by the Environmental Fate and Effects Division (EFED) (J. Wolf,
D319594, 10/13/06) and incorporated directly into this dietary
assessment. Acifluorfen is an environmental degradate of lactofen and
another registered herbicide, sodium acifluorfen. Therefore, EFED
estimated drinking water concentrations for both lactofen and
acifluorfen from lactofen applications. Water residues were incorporated
in the DEEM-FCID into the food categories "water, direct, all sources"
and "water, indirect, all sources."

The Tier 2 surface water EDWCs (estimated drinking water concentrations)
for lactofen and acifluorfen were generated with standard Florida pepper
and Florida tomato cropping scenarios using PRZM3 and EXAMS, and may be
found in Table 5.3. PRZM simulates pesticide fate and transport as a
result of leaching, direct spray drift, runoff and erosion from an
agricultural field and EXAMS estimates environmental fate and transport
of pesticides in surface water body for a 30-year period (1961-1990).
PRZM and EXAMS were linked by the program PE4-PL (version 01). The EDWC
assessment for surface water uses single or multiple sites which
typically represent a high-end exposure scenario from pesticide use on a
particular cropped or non-cropped site. Ground-water concentrations were
estimated using the Tier 1 screening model SCI-GROW and may be found in
Table 5.4. The models and its description are available at the EPA
internet site: <http://www.epa.gov/oppefed1/models/water/>.

For comparison purposes the EDWCs of acifluorfen from sodium acifluorfen
applications are included as well. The EDWC values are higher for
lactofen derived acifluorfen as compared to sodium acifluorfen derived
acifluorfen is likely due to the following considerations: 1) slightly
higher amount of acifluorfen applied as compared to sodium acifluorfen;
2) the PCA is lower for soybeans (0.41) compared to the default value of
0.87 when there is no PCA available; and 3) different scenarios (crops)
may also have different runoff potentials.

+----------+-------------+-------------+------------+----------------+
| Table    |             |             |            |                |
| 5.3.a.   |             |             |            |                |
| E        |             |             |            |                |
| stimated |             |             |            |                |
| Drinking |             |             |            |                |
| Water    |             |             |            |                |
| Concen   |             |             |            |                |
| trations |             |             |            |                |
| (EDWC)   |             |             |            |                |
| In       |             |             |            |                |
| Surface  |             |             |            |                |
| Water    |             |             |            |                |
| Lactofen |             |             |            |                |
| And The  |             |             |            |                |
| Aci      |             |             |            |                |
| fluorfen |             |             |            |                |
| Derived  |             |             |            |                |
| From     |             |             |            |                |
| Lactofen |             |             |            |                |
| ^1^      |             |             |            |                |
+----------+-------------+-------------+------------+----------------+
| Crop     | Chemical    | 1-in-10     |            | Long term      |
|          | Species     | year        |            | average Mean   |
|          |             |             |            | (30 yrs.)      |
|          |             | M           |            | (µg/L          |
|          |             | aximum/mean |            |                |
|          |             | (μg/L)      |            |                |
+----------+-------------+-------------+------------+----------------+
|          |             | Acute       | Chronic    | Cancer         |
+----------+-------------+-------------+------------+----------------+
| Pepper   | Lactofen    | **1.48**    | 0.040      | 0.033          |
+----------+-------------+-------------+------------+----------------+
|          | Acifluorfen | **22.5**    | 3.5        | 2.0            |
+----------+-------------+-------------+------------+----------------+
| Tomato   | Lactofen    | 1.13        | **0.044**  | 0.039          |
+----------+-------------+-------------+------------+----------------+
|          | Acifluorfen | 20.9        | **3.9**    | 1.7            |
+----------+-------------+-------------+------------+----------------+
| Table    |             |             |            |                |
| 5.3.b.   |             |             |            |                |
| E        |             |             |            |                |
| stimated |             |             |            |                |
| Drinking |             |             |            |                |
| Water    |             |             |            |                |
| Concen   |             |             |            |                |
| trations |             |             |            |                |
| (EDWC)   |             |             |            |                |
| In       |             |             |            |                |
| Surface  |             |             |            |                |
| Water of |             |             |            |                |
| Aci      |             |             |            |                |
| fluorfen |             |             |            |                |
| Derived  |             |             |            |                |
| From     |             |             |            |                |
| Sodium   |             |             |            |                |
| Aciflu   |             |             |            |                |
| orfen^2^ |             |             |            |                |
+----------+-------------+-------------+------------+----------------+
| Soybeans | Acifluorfen | 14          | **3**      | 1.4            |
+----------+-------------+-------------+------------+----------------+

^1^Bolded values were used in the dietary exposure assessment.

^2^ Addendum to EFED RED Chapter for Sodium Acifluorfen and TRED for
Lactofen (DP Barcode D291747, 09-15-03).

  -----------------------------------------------------------------------
  Table 5.4.a. SCI-GROW    
  Estimates Of Lactofen    
  And Acifluorfen EDWCs In 
  Ground Water From        
  Application of Lactofen  
  ------------------------ ----------------------------------------------
  Chemical                 Acute and Chronic (µg/L)

  Lactofen                 0.006

  Acifluorfen              2.00

  Table 5.4.b. SCI-GROW    
  Estimates Acifluorfen    
  EDWCs In Ground Water    
  From Application of      
  Sodium Acifluorfen^1^    

  Acifluorfen              3.67
  -----------------------------------------------------------------------

^1^ Addendum to EFED RED Chapter for Sodium Acifluorfen and TRED for
Lactofen (DP Barcode D291747, 09-15-03).

[]{#__RefHeading___Toc151953705 .anchor}**5.3 Dietary Exposure and
Risk**

Lactofen acute, chronic, and cancer dietary exposure assessments were
conducted using the Dietary Exposure Evaluation Model software with the
Food Commodity Intake Database (DEEM-FCID™, Version 2.03), which
incorporates consumption data from USDA's Continuing Surveys of Food
Intakes by Individuals (CSFII), 1994-1996 and 1998. The 1994-96, 98 data
are based on the reported consumption of more than 20,000 individuals
over two non-consecutive survey days. Foods "as consumed" (e.g., apple
pie) are linked to EPA-defined food commodities (e.g. apples, peeled
fruit - cooked; fresh or N/S; baked; or wheat flour - cooked; fresh or
N/S, baked) using publicly available recipe translation files developed
jointly by USDA/ARS and EPA. For chronic exposure assessment,
consumption data are averaged for the entire U.S. population and within
population subgroups, but for acute exposure assessment are retained as
individual consumption events. Based on analysis of the 1994-96, 98
CSFII consumption data, which took into account dietary patterns and
survey respondents, HED concluded that it is most appropriate to report
risk for the following population subgroups: the general U.S.
population, all infants (\<1 year old), children 1-2, children 3-5,
children 6-12, youth 13-19, adults 20-49, females 13-49, and adults 50+
years old.

For chronic dietary exposure assessment, an estimate of the residue
level in each food or food-form (e.g., orange or orange juice) on the
food commodity residue list is multiplied by the average daily
consumption estimate for that food/food form to produce a residue intake
estimate. The resulting residue intake estimate for each food/food form
is summed with the residue intake estimates for all other food/food
forms on the commodity residue list to arrive at the total average
estimated exposure. Exposure is expressed in mg/kg body weight/day and
as a percent of the cPAD. This procedure is performed for each
population subgroup.

For acute exposure assessments, individual one-day food consumption data
are used on an individual-by-individual basis. The reported consumption
amounts of each food item can be multiplied by a residue point estimate
and summed to obtain a total daily pesticide exposure for a
deterministic exposure assessment, or "matched" in multiple random
pairings with residue values and then summed in a probabilistic
assessment. The resulting distribution of exposures is expressed as a
percentage of the aPAD on both a user (i.e., only those who reported
eating relevant commodities/food forms) and a per-capita (i.e., those
who reported eating the relevant commodities as well as those who did
not) basis. In accordance with HED policy, per capita exposure and risk
are reported for all tiers of analysis. However, for tiers 1 and 2, any
significant differences in user vs. per capita exposure and risk are
specifically identified and noted in the risk assessment.

[]{#__RefHeading___Toc151953706 .anchor}**5.2.1 Acute Dietary
Exposure/Risk**

No endpoints were identified for the general population so the only
assessment was conducted for Females ages 13-49. The results of the
acute dietary exposure analysis for lactofen from food alone are
reported in Table 5.5. All exposures are below the level of concern,
with the lactofen assessments at less than 1% of the aPAD.

[]{#__RefHeading___Toc151953707 .anchor}**5.2.2 Chronic Dietary
Exposure/Risk**

The results of the chronic dietary exposure analyses for lactofen are
reported in Table 5.5 for food alone. All exposures are below the level
of concern, at less than 1% of the cPAD.

[]{#__RefHeading___Toc151953708 .anchor}**5.2.3 Cancer Dietary Risk**

A cancer assessment is not required.

+--------------------+--------------+---------+--------------+-------+
| **Table 5.5.       |              |         |              |       |
| Summary of Dietary |              |         |              |       |
| Exposure and Risk  |              |         |              |       |
| for Lactofen --    |              |         |              |       |
| Food Only**        |              |         |              |       |
+====================+==============+=========+==============+=======+
| Population         | Acute        |         | Chronic      |       |
| Subgroup           | Dietary      |         | Dietary      |       |
|                    |              |         |              |       |
|                    | (95^th^      |         |              |       |
|                    | Percentile)  |         |              |       |
+--------------------+--------------+---------+--------------+-------+
|                    | Dietary      | \% aPAD | Dietary      | \%    |
|                    | Exposure     |         | Exposure     | cPAD  |
|                    | (mg/kg/day)  |         |              |       |
|                    |              |         | (mg/kg/day)  |       |
+--------------------+--------------+---------+--------------+-------+
| General U.S.       | N/A          | N/A     | 0.000024     | \<1   |
| Population         |              |         |              |       |
+--------------------+--------------+---------+--------------+-------+
| All Infants (\< 1  |              |         | 0.000024     | \<1   |
| year old)          |              |         |              |       |
+--------------------+--------------+---------+--------------+-------+
| Children 1-2 years |              |         | 0.000051     | \<1   |
| old                |              |         |              |       |
+--------------------+--------------+---------+--------------+-------+
| Children 3-5 years |              |         | 0.000047     | \<1   |
| old                |              |         |              |       |
+--------------------+--------------+---------+--------------+-------+
| Children 6-12      |              |         | 0.000032     | \<1   |
| years old          |              |         |              |       |
+--------------------+--------------+---------+--------------+-------+
| Youth 13-19 years  |              |         | 0.000022     | \<1   |
| old                |              |         |              |       |
+--------------------+--------------+---------+--------------+-------+
| Adults 20-49 years |              |         | 0.000021     | \<1   |
| old                |              |         |              |       |
+--------------------+--------------+---------+--------------+-------+
| Adults 50+ years   |              |         | 0.000019     | \<1   |
| old                |              |         |              |       |
+--------------------+--------------+---------+--------------+-------+
| Females 13-49      | **0.000066** | \<1     | 0.000020     | \<1   |
| years old          |              |         |              |       |
+--------------------+--------------+---------+--------------+-------+

[]{#__RefHeading___Toc151953709 .anchor}**6.0 Residential
(Non-Occupational) Exposure/Risk Characterization**

There are no products containing lactofen as an active ingredient that
are registered for use in a residential or other non-occupational
setting. Therefore there is no need to conduct a residential exposure
and risk assessment. Residential exposures to the environmental
degradate acifluorfen, which does have registered residential spot
treatment uses, is discussed in the HED Chapter to the Reregistration
Eligibility Decision Document (Farwell, 2002).

Spray drift is always a potential source of exposure to residents nearby
to spraying operations. This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from groundboom application methods. The Agency has been
working with the Spray Drift Task Force, EPA Regional Offices and State
Lead Agencies for pesticide regulation and other parties to develop the
best spray drift management practices. The Agency is now requiring
interim mitigation measures for aerial applications that must be placed
on product labels/labeling. The Agency has completed its evaluation of
the new data base submitted by the Spray Drift Task Force, a membership
of U.S. pesticide registrants, and is developing a policy on how to
appropriately apply the data and the AgDRIFT computer model to its risk
assessments for pesticides applied by air, orchard airblast and ground
hydraulic methods. After the policy is in place, the Agency may impose
further refinements in spray drift management practices to reduce off
target drift and risks associated with aerial as well as other
application types where appropriate.

[]{#__RefHeading___Toc151953710 .anchor}**7.0 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 exposures. 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 risks from various
sources, HED considers both the route and duration of exposure. There
are no residential uses of lactofen, so the aggregate assessments
consider exposure from food and drinking water.

Acifluorfen is an environmental degradate of two registered herbicides,
lactofen and sodium acifluorfen. Therefore, an aggregate assessment is
required for acifluorfen considering exposures from uses of both active
ingredients. Dietary exposures included in the acifluorfen aggregate
assessment included tolerance level residues of acifluorfen (from sodium
acifluorfen uses) and modeled estimates of acifluorfen in drinking water
as a result of application of lactofen. Only the estimates in drinking
water from lactofen applications were included in the aggregate
assessments because it is unlikely that both acifluorfen and lactofen
will be used in the same area such that the exposures would be additive
and that the acifluorfen drinking water exposures have already been
assessed in the acifluorfen RED (Farwell, 2002). Also, the modeled
estimates for the new uses of lactofen are higher than the estimates
from sodium acifluorfen uses. The aggregate for acifluorfen also
includes residential exposures as sodium acifluorfen may be used as a
spot treatment in residential settings.

[]{#__RefHeading___Toc151953711 .anchor}**7.1 Acute Aggregate Risk**

Acute (one day) exposures to **lactofen** may result from consuming
treated food and drinking water. No endpoints were identified for the
general population so the only assessment was conducted for Females ages
13-49. The results of the acute aggregate assessment for lactofen are
reported in Table 7.1 for food and drinking water. All exposures are
below the level of concern, with the lactofen assessments at less than
1% of the aPAD.

The acute aggregate assessment for **acifluorfen** includes food
exposure from tolerance level residues (from sodium acifluorfen
applications) and water exposures of acifluorfen as an environmental
degradate of lactofen. No acute endpoints were identified for the
general population so the only assessment was conducted for Females ages
13-49. All exposures are below the level of concern, with the
acifluorfen assessments at 6% of the aPAD.

Both the lactofen and acifluorfen assessments are likely to be
overestimates of risk because they assume all of the crops (for which
there are registered uses) consumed in the US are treated and bear
tolerance-level residues.

[]{#__RefHeading___Toc151953712 .anchor}**7.2 Short-Term Aggregate
Risk**

A short-term assessment is not required for **lactofen** as there are no
residential uses of lactofen.

Registered residential uses of sodium acifluorfen include spot
treatments only. The short term endpoint selected applies to females
ages 13-49, but is protective of all populations. The **acifluorfen**
aggregate assessment for this exposure duration includes the average
food exposure assuming tolerance level residues, average water exposure
(acifluorfen as an environmental degradate of lactofen), and residential
handler exposures (Dole, 2003). The MOE for the aggregate assessment,
found in Table 7.3, is 16000, which exceeds the target MOE of 1000.
Therefore, short term aggregate risks are not of concern.

[]{#__RefHeading___Toc151953713 .anchor}**7.3 Intermediate-Term
Aggregate Risk**

An intermediate-term assessment is not required for **lactofen** as
there are no residential uses of lactofen.

Intermediate-term exposure is not expected for **acifluorfen** because
residential uses are limited to spot treatments that do not include
broadcast application to lawns.

[]{#__RefHeading___Toc151953714 .anchor}**7.4 Long-Term Aggregate Risk**

The results of the long-term aggregate assessment for **lactofen** are
reported in Table 7.1 for food and drinking water. All exposures are
below the level of concern, with the lactofen assessments at less than
1% of the cPAD.

The results of the long-term aggregate assessment for **acifluorfen**
are reported in Table 7.2 for food and drinking water. All exposures are
below the level of concern. The most highly exposed subgroup in the
acifluorfen assessment at 37% of the cPAD was infants, less than one
year old.

[]{#__RefHeading___Toc151953715 .anchor}**7.5 Cancer Risk**

A cancer assessment is not required.

+----------------+------------+------------+------------+------------+
| **Table 7.1.   |            |            |            |            |
| Summary of     |            |            |            |            |
| Dietary        |            |            |            |            |
| Exposure and   |            |            |            |            |
| Risk for       |            |            |            |            |
| Lactofen --    |            |            |            |            |
| Food and       |            |            |            |            |
| Drinking       |            |            |            |            |
| Water**        |            |            |            |            |
+================+============+============+============+============+
| Population     | Acute      |            | Chronic    |            |
| Subgroup       | Dietary    |            | Dietary    |            |
|                |            |            |            |            |
|                | (95^th^    |            |            |            |
|                | P          |            |            |            |
|                | ercentile) |            |            |            |
+----------------+------------+------------+------------+------------+
|                | Dietary    | \% aPAD    | Dietary    | \% cPAD    |
|                | Exposure   |            | Exposure   |            |
|                | (          |            | (          |            |
|                | mg/kg/day) |            | mg/kg/day) |            |
+----------------+------------+------------+------------+------------+
| General U.S.   | N/A        | N/A        | 0.000025   | \<1        |
| Population     |            |            |            |            |
+----------------+------------+------------+------------+------------+
| All Infants    |            |            | 0.000027   | \<1        |
| (\< 1 year     |            |            |            |            |
| old)           |            |            |            |            |
+----------------+------------+------------+------------+------------+
| Children 1-2   |            |            | **         | **\<1**    |
| years old      |            |            | 0.000052** |            |
+----------------+------------+------------+------------+------------+
| Children 3-5   |            |            | 0.000048   | \<1        |
| years old      |            |            |            |            |
+----------------+------------+------------+------------+------------+
| Children 6-12  |            |            | 0.000033   | \<1        |
| years old      |            |            |            |            |
+----------------+------------+------------+------------+------------+
| Youth 13-19    |            |            | 0.000023   | \<1        |
| years old      |            |            |            |            |
+----------------+------------+------------+------------+------------+
| Adults 20-49   |            |            | 0.000022   | \<1        |
| years old      |            |            |            |            |
+----------------+------------+------------+------------+------------+
| Adults 50+     |            |            | 0.000020   | \<1        |
| years old      |            |            |            |            |
+----------------+------------+------------+------------+------------+
| Females 13-49  | **         | **\<1**    | 0.000021   | \<1        |
| years old      | 0.000066** |            |            |            |
+----------------+------------+------------+------------+------------+

+----------------+------------+------------+------------+------------+
| > **Table 7.2. |            |            |            |            |
| > Summary of   |            |            |            |            |
| > Dietary      |            |            |            |            |
| > Exposure and |            |            |            |            |
| > Risk for     |            |            |            |            |
| > Acifluorfen  |            |            |            |            |
| > -- Food and  |            |            |            |            |
| > Drinking     |            |            |            |            |
| > Water        |            |            |            |            |
| > (Acifluorfen |            |            |            |            |
| > in Drinking  |            |            |            |            |
| > Water From   |            |            |            |            |
| > Lactofen     |            |            |            |            |
| > A            |            |            |            |            |
| pplications)** |            |            |            |            |
+================+============+============+============+============+
| Population     | Acute      |            | Chronic    |            |
| Subgroup       | Dietary    |            | Dietary    |            |
|                |            |            |            |            |
|                | (95^th^    |            |            |            |
|                | P          |            |            |            |
|                | ercentile) |            |            |            |
+----------------+------------+------------+------------+------------+
|                | Dietary    | \% aPAD    | Dietary    | \% cPAD    |
|                | Exposure   |            | Exposure   |            |
|                | (          |            |            |            |
|                | mg/kg/day) |            | (          |            |
|                |            |            | mg/kg/day) |            |
+----------------+------------+------------+------------+------------+
| General U.S.   | **N/A**    | N/A        | 0.00017    | 13         |
| Population     |            |            |            |            |
+----------------+------------+------------+------------+------------+
| All Infants    |            |            | **         | **37**     |
| (\< 1 year     |            |            | 0.000478** |            |
| old)           |            |            |            |            |
+----------------+------------+------------+------------+------------+
| Children 1-2   |            |            | 0.000324   | 25         |
| years old      |            |            |            |            |
+----------------+------------+------------+------------+------------+
| Children 3-5   |            |            | 0.00031    | 24         |
| years old      |            |            |            |            |
+----------------+------------+------------+------------+------------+
| Children 6-12  |            |            | 0.00021    | 16         |
| years old      |            |            |            |            |
+----------------+------------+------------+------------+------------+
| Youth 13-19    |            |            | 0.000142   | 11         |
| years old      |            |            |            |            |
+----------------+------------+------------+------------+------------+
| Adults 20-49   |            |            | 0.000151   | 12         |
| years old      |            |            |            |            |
+----------------+------------+------------+------------+------------+
| Adults 50+     |            |            | 0.000135   | 10         |
| years old      |            |            |            |            |
+----------------+------------+------------+------------+------------+
| Females 13-49  | *          | **6.0**    | 0.000143   | 11         |
| years old      | *0.00119** |            |            |            |
+----------------+------------+------------+------------+------------+

+----------+--------+------+---------+--------+----------+------------+
| **Table  |        |      |         |        |          |            |
| 7.3.     |        |      |         |        |          |            |
| Sh       |        |      |         |        |          |            |
| ort-Term |        |      |         |        |          |            |
| A        |        |      |         |        |          |            |
| ggregate |        |      |         |        |          |            |
| Risk     |        |      |         |        |          |            |
| Calc     |        |      |         |        |          |            |
| ulations |        |      |         |        |          |            |
| for      |        |      |         |        |          |            |
| Acifl    |        |      |         |        |          |            |
| uorfen** |        |      |         |        |          |            |
+----------+--------+------+---------+--------+----------+------------+
| **Popu   | **Shor |      |         |        |          |            |
| lation** | t-Term |      |         |        |          |            |
|          | Scen   |      |         |        |          |            |
|          | ario** |      |         |        |          |            |
+----------+--------+------+---------+--------+----------+------------+
|          | **N    | **   | *       | **Ave  | **Res    | *          |
|          | OAEL** | LOC^ | *Target | rage** | idential | *Aggregate |
|          |        | 1^** | Ma      |        | Expos    | MOE**      |
|          | *      |      | ximum** | **Food | ure^3^** |            |
|          | *mg/kg |      |         | &      |          | **(food    |
|          | /day** |      | *       | W      | **mg/    | and**      |
|          |        |      | *Exposu | ater** | kg/day** |            |
|          |        |      | re^2^** |        |          | **residen  |
|          |        |      |         | **Expo |          | tial)^4^** |
|          |        |      | **mg/k  | sure** |          |            |
|          |        |      | g/day** |        |          |            |
|          |        |      |         | *      |          |            |
|          |        |      |         | *mg/kg |          |            |
|          |        |      |         | /day** |          |            |
+----------+--------+------+---------+--------+----------+------------+
| Adult    | 20     | 1000 | 0.02    | 0.     | 0.0011   | 16000      |
| Female   |        |      |         | 000143 |          |            |
+----------+--------+------+---------+--------+----------+------------+

^1^ The LOC includes the standard inter- and intra- species uncertainty
factors totaling 100.

^2^ Target Maximum Exposure (mg/kg/day) = NOAEL/LOC

^3^ Residential Exposure was obtained from the risk assessment for
acifluorfen (Farwell, 2002).

^4^ Aggregate MOE = NOAEL/(Average Food & Water Exposure + Residential
Exposure)

[]{#__RefHeading___Toc151953716 .anchor}**8.0 Cumulative Risk
Characterization/Assessment**

Lactofen is a member of the diphenyl ether chemical family. The common
toxicity that these compounds share is induction of liver effects (liver
hypertrophy, increase in liver weight, tumors). Members of this class
have been shown to induce rodent liver effects /tumors through the
activation of the peroxisome proliferator-activated receptor (PPARα). It
should be noted that liver hypertrophy and increases in liver weight are
part of the range of morphological changes that result from
chemically-mediated effects on the PPARα receptor and
hepatocarcinogenesis. Although PPARα agonists can induce liver rodent
tumors, the potential for PPARα agonists to induce liver tumors in other
species, including humans, appears to be unlikely. This is because
evidence shows that these other species are quantitatively less
sensitive to the effects of PPARα agonism due to toxicodynamic
differences between the human and rodent nuclear PPAR receptor. Thus,
while this mode of action for liver tumors in rodent is qualitatively
possible in humans, it is quantitatively implausible and unlikely to
take place in humans. **Accordingly, although members of the diphenyl
ether family as well as other classes of compounds may share a common
hepatocarcinogenic mode of action, cumulative exposure to** PPARα
agonists **is unlikely to induce liver carcinogenesis in humans.**

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.

[]{#__RefHeading___Toc151953717 .anchor}**9.0 Occupational Exposure/Risk
Pathway**

[]{#__RefHeading___Toc151953718 .anchor}**9.1 Short-/Intermediate-Term
Handler Risk**

HED has determined that occupational handlers are likely to be exposed
during lactofen use and that these uses would result in
short/intermediate term exposures. Because the lactofen products are
typically applied only one or two times per year, long-term or chronic
exposures (i.e., daily exposures which occur for a minimum of several
months) are not expected. The anticipated use patterns and current
labeling indicate that there two exposure scenarios that are associated
with this new use. These scenarios include mix/load liquids and
groundboom application.

The handler's exposure assessments were performed using unit exposure
values from the PHED Surrogate Exposure Guide (8/98) along with the
following assumptions:

\* 80 acres are treated per day based upon the ExpoSAC Policy 9
"Standard Values for Daily Acres Treated in Agriculture". This is the
value for groundboom application to typical crops.

\* The application rate is 0.5 lbs ai per acre based upon the proposed
label.

\* The handler body weight is 70 kg based upon the fact that the
endpoint is not gender specific.

A summary of the risk estimates (i.e. MOEs) is included in Table 9.1.
The MOE for the mix/load scenario is below 100 at the baseline PPE level
and exceeds the Agency level of concern. The risk can be mitigated with
the addition of chemical resistant gloves, which is currently required
on the lactofen product label. The MOE for groundboom application is
above 100 at the baseline level and does not exceed the Agency level of
concern.

The PHED unit exposure values generally range from the geometric mean to
the median of the selected data set, and therefore tend to be central
tendency values. The daily acreage value is based upon PHED application
data normalized to an 8 hour day and cultural use patterns and is
considered to be a high end estimate. Therefore, the potential risk is
characterized as mid to high end.

[]{#__RefHeading___Toc151953719 .anchor}**9.2 Postapplication Risk**

The proposed label indicates that lactofen should be applied to row
middles in a directed, shielded spray; therefore, post application
exposures are not expected.

+------------+-----+------+------+-------+-------+-----+-----+-----+
| **Table    |     |      |      |       |       |     |     |     |
| 9.1 Short- |     |      |      |       |       |     |     |     |
| and        |     |      |      |       |       |     |     |     |
| Interme    |     |      |      |       |       |     |     |     |
| diate-Term |     |      |      |       |       |     |     |     |
| Oc         |     |      |      |       |       |     |     |     |
| cupational |     |      |      |       |       |     |     |     |
| Exposure   |     |      |      |       |       |     |     |     |
| and Risk   |     |      |      |       |       |     |     |     |
| Estimates  |     |      |      |       |       |     |     |     |
| for        |     |      |      |       |       |     |     |     |
| Proposed   |     |      |      |       |       |     |     |     |
| New Uses   |     |      |      |       |       |     |     |     |
| of         |     |      |      |       |       |     |     |     |
| Lactofen** |     |      |      |       |       |     |     |     |
+============+=====+======+======+=======+=======+=====+=====+=====+
| **Exposure | *   | **A  | **Mi | **Da  | **Da  | *   | **  | *   |
| Scenario** | *Ap | cres | tiga | ily** | ily** | *De | Inh | *Co |
|            | pli | Tre  | tion |       |       | rma | ala | mbi |
|            | cat | ated | Lev  | **Der | **    | l** | tio | ned |
|            | ion | per  | el** | mal** | Inhal |     | n** | MO  |
|            | Rat | d    |      |       | ation | *   |     | E^7 |
|            | e** | ay** |      | **Dos | ^4^** | *MO | *   | ^** |
|            |     |      |      | e^3^, |       | E^5 | *MO |     |
|            | *   |      |      | m     | **    | ^** | E^6 |     |
|            | *Lb |      |      | g/kg/ | Dose, |     | ^** |     |
|            | ai/ |      |      | day** | m     |     |     |     |
|            | Acr |      |      |       | g/kg/ |     |     |     |
|            | e** |      |      |       | day** |     |     |     |
+------------+-----+------+------+-------+-------+-----+-----+-----+
| Mi         |     |      |      |       |       |     |     |     |
| xer/Loader |     |      |      |       |       |     |     |     |
| (Baseline  |     |      |      |       |       |     |     |     |
| Dermal     |     |      |      |       |       |     |     |     |
| Unit       |     |      |      |       |       |     |     |     |
| Exposure = |     |      |      |       |       |     |     |     |
| 2.9 mg/lb  |     |      |      |       |       |     |     |     |
| ai         |     |      |      |       |       |     |     |     |
| handled,   |     |      |      |       |       |     |     |     |
| Baseline   |     |      |      |       |       |     |     |     |
| Inhalation |     |      |      |       |       |     |     |     |
| Unit       |     |      |      |       |       |     |     |     |
| Exposure = |     |      |      |       |       |     |     |     |
| 0.012      |     |      |      |       |       |     |     |     |
| mg/lb ai   |     |      |      |       |       |     |     |     |
| handled)   |     |      |      |       |       |     |     |     |
|            |     |      |      |       |       |     |     |     |
| (Single    |     |      |      |       |       |     |     |     |
| Layer      |     |      |      |       |       |     |     |     |
| Dermal     |     |      |      |       |       |     |     |     |
| Unit       |     |      |      |       |       |     |     |     |
| Exposure = |     |      |      |       |       |     |     |     |
| 0.023      |     |      |      |       |       |     |     |     |
| mg/lb ai   |     |      |      |       |       |     |     |     |
| handled)   |     |      |      |       |       |     |     |     |
+------------+-----+------+------+-------+-------+-----+-----+-----+
| Mix/Load   | 0.5 | 80   | Bas  | 0.33  | 0.    | 15  | 7   | 15  |
| Liquids    |     |      | elin |       | 00069 | ^8^ | 200 | ^8^ |
| for        |     |      | e^1^ |       |       |     | ^8^ |     |
| Groundboom |     |      |      |       |       |     |     |     |
| A          |     |      |      |       |       |     |     |     |
| pplication |     |      |      |       |       |     |     |     |
| to         |     |      |      |       |       |     |     |     |
|            |     |      |      |       |       |     |     |     |
| Fruiting   |     |      |      |       |       |     |     |     |
| Vegetables |     |      |      |       |       |     |     |     |
| and Okra   |     |      |      |       |       |     |     |     |
+------------+-----+------+------+-------+-------+-----+-----+-----+
|            | 0.5 | 80   | Si   | 0     | 0.    | 1   | 7   | 1   |
|            |     |      | ngle | .0026 | 00069 | 900 | 200 | 500 |
|            |     |      | l    |       |       | ^8^ | ^8^ | ^8^ |
|            |     |      | ayer |       |       |     |     |     |
|            |     |      | De   |       |       |     |     |     |
|            |     |      | rmal |       |       |     |     |     |
|            |     |      | PP   |       |       |     |     |     |
|            |     |      | E^2^ |       |       |     |     |     |
+------------+-----+------+------+-------+-------+-----+-----+-----+
| Applicator |     |      |      |       |       |     |     |     |
| (Baseline  |     |      |      |       |       |     |     |     |
| Dermal     |     |      |      |       |       |     |     |     |
| Unit       |     |      |      |       |       |     |     |     |
| Exposure = |     |      |      |       |       |     |     |     |
| 0.014      |     |      |      |       |       |     |     |     |
| mg/lb ai   |     |      |      |       |       |     |     |     |
| handled,   |     |      |      |       |       |     |     |     |
| Baseline   |     |      |      |       |       |     |     |     |
| Inhalation |     |      |      |       |       |     |     |     |
| Unit       |     |      |      |       |       |     |     |     |
| Exposure = |     |      |      |       |       |     |     |     |
| 0.00074    |     |      |      |       |       |     |     |     |
| mg/lb ai   |     |      |      |       |       |     |     |     |
| handled)   |     |      |      |       |       |     |     |     |
+------------+-----+------+------+-------+-------+-----+-----+-----+
| Groundboom | 0.5 | 80   | Base | 0     | 0.    | 2   | 12  | 2   |
| A          |     |      | line | .0016 | 00042 | 500 | 000 | 500 |
| pplication |     |      |      |       |       | ^8^ | ^8^ | ^8^ |
| to         |     |      |      |       |       |     |     |     |
| Fruiting   |     |      |      |       |       |     |     |     |
| Vegetables |     |      |      |       |       |     |     |     |
| and Okra   |     |      |      |       |       |     |     |     |
+------------+-----+------+------+-------+-------+-----+-----+-----+

1\. Baseline dermal PPE includes long sleeved shirt, long pants, shoes
and socks. Baseline inhalation PPE includes no respiratory protection.

2\. Single Layer PPE included Baseline PPE and chemical resistant
gloves.

3\. Dermal dose = (Application rate \* Acres Treated per Day \* Unit
Exposure \* Dermal Absorption Factor of 20 Percent)/Body Weight (70 kg).

4\. Inhalation dose = (Application rate \* Acres Treated per Day \* Unit
Exposure \* Inhalation Absorption Factor of 100 Percent)/Body Weight (70
kg).

5\. Dermal MOE = NOAEL/Dermal Dose where the NOAEL is 5 mg/kg/day from a
developmental toxicity study in rabbits.

6\. Inhalation MOE = NOAEL/Inhalation Dose where the NOAEL is 5
mg/kg/day the same study as above.

7\. Combined MOE = NOAEL/(Dermal Dose + Inhalation Dose) where the NOAEL
is 5 mg/kg/day.

8\. HED is generally not concerned if the MOE exceeds 300.

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

                                                                  

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

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

                                                                  

                                                                  

                                                                  

                                                                  

                                                                  

                                                                  

                                                                  

                                                                  

                                                                  

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

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

                                                                       

                                                                       

                                                                       

                                                                       

                                                                       

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

[]{#__RefHeading___Toc151953720 .anchor}**10.0 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,
nondietary 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.

[]{#__RefHeading___Toc151953721 .anchor}**11.0 Review of Human
Research**

This risk assessment does not rely on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.

[]{#__RefHeading___Toc151953722 .anchor}**12.0 Data Needs and Label
Recommendations**

1.  []{#__RefHeading___Toc151953723 .anchor}**Label Recommendations**

-   The label must be amended to specify that the applications may not
    include two post-transplant applications. Finally, the label must be
    amended to reflect either a 30-day RTI or a minimum post-transplant
    interval of 18 days for tomatoes.

-   The label should specify examples of fruiting vegetables in the use
    directions to avoid confusion.

    []{#__RefHeading___Toc151953724 .anchor}**12.2 Proposed Tolerances**

```{=html}
<!-- -->
```
-   The proposed tolerance for the fruiting vegetables crop group should
    be revised to reflect the recommended tolerance expression and the
    correct commodity definition, "Vegetable, fruiting, group 8," and
    the recommended level of 0.02 ppm.

-   The proposed tolerance for okra should be revised to reflect the
    recommended tolerance expression and the recommended level of 0.02
    ppm.

    []{#__RefHeading___Toc151953725 .anchor}**13.0 References**

The documents listed in Table 13.1 were considered in this risk
assessment.

  -------------------------------------------------------------------------------
  Table 13.1                          
  References                          
  ------------ --------- ------------ -------------------------------------------
  Author       Barcode   Date         Title

  C. Olinger   D333149   1/2007       Lactofen Acute, Chronic, and Cancer
                                      Aggregate Dietary and Drinking Water
                                      Exposure and Risk Assessments for the
                                      Section 3 Registration Action

  C. Olinger   D333151   1/2007       Lactofen. Addition of New Uses: Fruiting
                                      Vegetables (Crop Group 8) and Okra. PRIA
                                      R17. Summary of Analytical Chemistry and
                                      Residue Data.

  M. Hawkins   D323214   11/7/2006    Review of Lactofen Incident Reports
  and H.                              
  Allender                            

  W. Phang     D320512   10/18/2006   Lactofen: Response to a waiver request for
                                      a developmental toxicity in rabbits

  S. Diwan     N/A       10/17/2006   Lactofen - Report of the Cancer Assessment
                                      Review Committee

  J. Wolf      D319594   10/13/2006   Drinking water and aquatic exposure water
                                      assessments for IR4 Tolerance petition for
                                      the new use (R17) of lactofen on the
                                      fruiting vegetable group and okra

  S. Winfield  D296972   7/22/2004    Occupational and Residential Risk
                                      Assessment for Lactofen on Cotton and
                                      Peanuts

  M. Metzger   D292794   8/12/2003    Lactofen. Revisions to HED Tolerance
                                      Reassessment Risk Assessment

  C. Olinger   D278406   1/9/2002     Tolerance Reassessment of Lactofen:
                                      Registrant Response to Preliminary Human
                                      Health Risk Assessment

  T. Dole      D279482   11/13/2001   Sodium Acifluorfen: Second Revised
                                      Occupational and Residential Exposure and
                                      Risk Assessment for the Reregistration
                                      Eligibility Decision (RED) Document

  R. Fricke    D267472   3/12/2001    LACTOFEN: Report of the Mechanism of
                                      Toxicity Assessment Review Committee

  C. Olinger   D269621   10/12/2000   Lactofen: Preliminary Human Health Risk
                                      Assessment for Tolerance Reassessment
                                      incorporating Revised Cancer Unit Risks

  C. Olinger   D265477   4/26/2000    Lactofen: Preliminary Human Health Risk
                                      Assessment for Tolerance Reassessment

  K. Farwell   D279497   1/15/2002    SODIUM ACIFLUORFEN. HED Chapter for the
                                      Reregistration Eligibility Decision
                                      Document

  K. Farwell   D291742   7/14/2003    SODIUM ACIFLUORFEN. Revision to HED Chapter
                                      for the Reregistration Eligibility Decision
                                      Document
  -------------------------------------------------------------------------------

**Appendix A: Toxicity Profile**

Table A1. Acute Toxicity of Lactofen

+--------+-------------------+----------+----------------+------------+
| Gui    | Study Type        | A        | Results        | Toxicity   |
| deline |                   | ccession |                | Category   |
|        |                   | #(S).    |                |            |
| No.    |                   |          |                |            |
+========+===================+==========+================+============+
| 81-1   | Acute Oral        | 73859    | LD~50~ \> 5.96 | IV         |
|        |                   |          | g/kg           |            |
+--------+-------------------+----------+----------------+------------+
| 81-2   | Acute Dermal      | 73859    | LD~50~ \> 2.0  | III        |
|        |                   |          | g/kg           |            |
+--------+-------------------+----------+----------------+------------+
| 81-3   | Acute Inhalation  | 73859    | LC~50~ \> 6.3  | IV         |
|        |                   |          | m/L            |            |
+--------+-------------------+----------+----------------+------------+
| 81-4   | Primary Eye       | 73859    | Moderate eye   | III        |
|        | Irritation (MUP)  |          | irritant       |            |
+--------+-------------------+----------+----------------+------------+
| 81-5   | Primary Skin      | 73859    | Very slight    | IV         |
|        | Irritation        |          | dermal         |            |
|        |                   |          | irritant       |            |
|        | (MUP)             |          |                |            |
+--------+-------------------+----------+----------------+------------+
| 81-6   | Dermal            | 73859    | Not a dermal   |            |
|        | Sensitization     |          | sensitizer     |            |
+--------+-------------------+----------+----------------+------------+

+---------------+--------+----------------+----------------------------+
| > Table A2.   |        |                |                            |
| > Toxicology  |        |                |                            |
| > Profile for |        |                |                            |
| >             |        |                |                            |
|  **Lactofen** |        |                |                            |
+===============+========+================+============================+
| Study Type    | NOAEL  | LOAEL          | Additional Relevant Data   |
|               |        |                |                            |
|               | (mg/k  | (mg/kg/day)    |                            |
|               | g/day) |                |                            |
+---------------+--------+----------------+----------------------------+
| Acute Oral    |        | LD~50~ Males = | **Symptoms seen in all     |
| Toxicity/Rat: |        | 6.7 g/kg b.w.  | dose groups**: decreased   |
| 4.0,          |        |                | activity, ataxia,          |
| 5.06,6.93,    |        | Females = 5.25 | diarrhea, excessive        |
| 9.12, 12      |        | g/kg b.w.      | lacrimation and            |
| g/kg/day a.i. |        |                | salivation, wet abdomen.   |
|               |        | Combined -     | Significant mortality: 12  |
| Accession No. |        | 5.96 g/kg b.w. | g/kg dose \[4/5(M) and all |
| 073859        |        |                | F died on or before 3^rd^  |
|               |        |                | day of study); 6.93 g/kg   |
|               |        |                | (3/5 M and 4/5 F died      |
|               |        |                | within first 3 days of     |
|               |        |                | study).                    |
|               |        |                |                            |
|               |        |                | **Toxicity Category IV**   |
+---------------+--------+----------------+----------------------------+
| Acute Dermal  |        | LD~50~ \> 2.0  | Symptoms: nasal discharge, |
| Tox           |        | g/kg/ b.w.     | soft stools, diarrhea,     |
| icity/Rabbit: |        |                | anorexia, decreased        |
| 2.0 g/kg/     |        |                | activity, paleness, mucus, |
| b.w. for 24   |        |                | and lacrimation. One       |
| hrs.          |        |                | animal died on day 15 of   |
| Accession No. |        |                | the study (this death was  |
| 073859        |        |                | deemed incidental).        |
|               |        |                | **Toxicity Category III**  |
+---------------+--------+----------------+----------------------------+
| Primary Eye   |        | Moderate eye   | Conjunctivae involvement   |
| Irrit         |        | irritant       | (moderate redness, slight  |
| ation/Rabbit: |        |                | chemosis, and minimal      |
|               |        |                | discharge) seen in all     |
| 0.1 ml of     |        |                | animals 1 hr. post-dose    |
| Manufacturing |        |                | but cleared after 72 hrs.  |
| Use Product   |        |                | Irridial irritation in 8/9 |
| (MUP).        |        |                | animals; cleared by 48 hrs |
| Accession No. |        |                | No corneal injury.         |
| 073859.       |        |                | **Toxicity Category II**   |
| **(Original   |        |                |                            |
| study was     |        |                |                            |
| unreadable    |        |                |                            |
| therefore     |        |                |                            |
| exact % a.i.  |        |                |                            |
| could not be  |        |                |                            |
| determined)** |        |                |                            |
+---------------+--------+----------------+----------------------------+
| Primary       |        | Very slight    | Very slight erythema and   |
| Dermal        |        | dermal         | eschar formation in 5/6    |
| Irrit         |        | irritant       | animals which persisted    |
| ation/Rabbit: |        |                | for 48 hrs. **Toxicity     |
|               |        |                | Category IV**              |
| 0.5 ml for 4  |        |                |                            |
| hrs.          |        |                |                            |
| Accession No. |        |                |                            |
| 073859        |        |                |                            |
+---------------+--------+----------------+----------------------------+
| Acute         |        | LC~50~         | Nasal discharge, ataxia,   |
| Inhalation    |        | Combined \>    | decreased activity and     |
| Toxicity/Rat: |        | 6.3 mg/L       | labored breathing seen     |
| Nominal       |        |                | within the first few hours |
| Concentration |        |                | post-dosing. All clinical  |
| of 52 mg/L    |        |                | signs had resolved by day  |
| (analytical   |        |                | 5 of the study. One animal |
| concentration |        |                | died on day 3 of the       |
| of 6.3 mg/L)  |        |                | study; this death was      |
| for 4 hrs.    |        |                | classified as incidental.  |
| Accession No. |        |                | **Toxicity Category IV**   |
| 073859        |        |                |                            |
+---------------+--------+----------------+----------------------------+
| Dermal        |        |                | Not a dermal sensitizer    |
| Se            |        |                |                            |
| nsitization - |        |                |                            |
| Guinea Pig    |        |                |                            |
|               |        |                |                            |
| 50% MUP.      |        |                |                            |
| Accession No. |        |                |                            |
| 073859        |        |                |                            |
+---------------+--------+----------------+----------------------------+
| Dermal        |        | 1-4% dermal    | No systemic toxicity was   |
| Penetration   |        | absorption at  | reported. ^14^C-PPG-844    |
| Study - RAT:  |        | the 4 and 10   | (lactofen) was observed in |
|               |        | hr. time       | the blood 2 hrs.           |
| 3.6, 18.1,    |        | points         | post-application. Levels   |
| and 72.3      |        |                | of compound continued to   |
| µg/cm^2^.     |        |                | rise over the next 24 hrs. |
| Extent of     |        |                | Plateaued and remained     |
| absorption    |        |                | constant up to 72 hrs.     |
| was           |        |                | (terminal sacrifice).      |
| determined at |        |                | After 72 hrs. \~ 8-10% of  |
| 0.5, 1, 2, 4, |        |                | test article is absorbed   |
| 10, and 72    |        |                | through the skin.          |
| hrs. after    |        |                |                            |
| exposure to   |        |                |                            |
| the test      |        |                |                            |
| article.      |        |                |                            |
| Accession No. |        |                |                            |
| 073843        |        |                |                            |
+---------------+--------+----------------+----------------------------+
| Dermal        |        | 4.6% dermal    | No systemic toxicity       |
| Penetration   |        | absorption     | reported.                  |
| Study -       |        | throughout the |                            |
| MONKEY        |        | duration of    |                            |
|               |        | the study.     |                            |
| 100 µg/cm^2^  |        |                |                            |
| (exposure     |        |                |                            |
| time 10 hrs.) |        |                |                            |
+---------------+--------+----------------+----------------------------+
| Metabolism    |        |                | Seventy two hours after    |
| and           |        |                | administration ≥ 97% of    |
| Pha           |        |                | the radiolabel was         |
| rmacokinetics |        |                | recovered in the excreta   |
| Study - RAT.  |        |                | (urine and feces). Urinary |
| Doses: 125 or |        |                | excretion comprised 39 -   |
| 1250 mg/kg    |        |                | 56% of the dose while the  |
| (gavage).     |        |                | fecal output totaled \~    |
| Accession No. |        |                | 43 - 67% of the dose.      |
| 071222        |        |                | While the parent compound, |
|               |        |                | lactofen, was the major    |
|               |        |                | metabolite in the feces,   |
|               |        |                | the major metabolite in    |
|               |        |                | urine was acifluorfen      |
|               |        |                | which accounted for \> 90% |
|               |        |                | of the radioactivity       |
|               |        |                | recovered in this          |
|               |        |                | fraction. The maximum      |
|               |        |                | percentage of administered |
|               |        |                | radioactivity that         |
|               |        |                | accumulated in a tissue    |
|               |        |                | sample was 0.55 - 0.75% in |
|               |        |                | the liver.                 |
+---------------+--------+----------------+----------------------------+
| Chronic       | 0.79   | 3.96 based on  | **Effects seen at the      |
| Feeding       |        | proteinaceous  | highest-dose tested        |
| Study/Dog: 0, |        | casts in the   | (19.78/59.3 mg/kg/day)**   |
| 40, 200, and  |        | kidneys (1/6   | included: 1) decreases in  |
| 1000/3000 ppm |        | \_), and       | body weight, body weight   |
| (0, 0.79,     |        | statistically  | gain, and food consumption |
| 3.96,         |        | significant    | in males only; 2)          |
| 19.78/59.33   |        | increases in   | decreases in the red blood |
| mg/kg/day) 1  |        | the absolute   | cell count (RBC),          |
| year          |        | weights of the | hematocrit and hemoglobin  |
|               |        | thyroid and    | levels as well as          |
| MRID          |        | adrenal glands | increases in the leukocyte |
| No.41967901   |        | in males.      | and lymphocyte counts      |
|               |        |                | (males and females)        |
|               |        |                | \[these changes in         |
|               |        |                | hematology and clinical    |
|               |        |                | chemistry parameters were  |
|               |        |                | first noted during the     |
|               |        |                | month 5 evaluation and     |
|               |        |                | persisted until the end of |
|               |        |                | the study period\]; 3)     |
|               |        |                | statistically significant  |
|               |        |                | decreases in the absolute  |
|               |        |                | weights of the heart,      |
|               |        |                | spleen, adrenals, thyroid, |
|               |        |                | and kidneys; 4)            |
|               |        |                | statistically significant  |
|               |        |                | increases in the relative  |
|               |        |                | weights of the liver and   |
|               |        |                | kidneys (organ/body        |
|               |        |                | weight); and 5) increase   |
|               |        |                | in the incidence of        |
|               |        |                | proteinaceous casts in the |
|               |        |                | kidneys (2/6 M, 1/6 F).    |
+---------------+--------+----------------+----------------------------+
| Carcinoge     | *      | 1.4 (LDT)      | **Effects seen at the 7.1  |
| nicity/Mouse: | *Could | based on       | mg/kg/day dose level       |
| 0, 1.4, 7.1,  | not be | hep            | included:** 1) increases   |
| and 35.7      | e      | atocytomegaly, | in liver weight; 2)        |
| mg/kg/day. 18 | stabli | increased      | increased incidence of     |
| months        | shed** | liver weight,  | dark colored and/or        |
|               |        | and increased  | enlarged livers; 3)        |
| Accession No. |        | sinusoidal     | hepatocytomegaly; 4)       |
| 073848        |        | cell           | increased incidences of    |
|               |        | pigmentation.  | focal cell alteration and  |
|               |        |                | sinusoidal cell            |
|               |        |                | pigmentation in the liver; |
|               |        |                | and 5) hepatocellular      |
|               |        |                | adenomas. **At the         |
|               |        |                | highest-dose tested (35.7  |
|               |        |                | mg/kg/day), the severity   |
|               |        |                | of these signs of toxicity |
|               |        |                | was increased. Other       |
|               |        |                | effects noted at the 35.7  |
|               |        |                | mg/kg/day dose level       |
|               |        |                | were:** 1) increase in the |
|               |        |                | incidence of               |
|               |        |                | non-neoplastic and         |
|               |        |                | neoplastic liver masses;   |
|               |        |                | 2) increase in kidney      |
|               |        |                | pigmentation and 3)        |
|               |        |                | increase in the incidence  |
|               |        |                | of cataracts.              |
+---------------+--------+----------------+----------------------------+
| Combined      | 2      | 19 based on    | **Effects seen at 38       |
| Chronic       |        | statistically  | mg/kg/day included**: 1)   |
| /Oncogenicity |        | significant    | decreased food             |
| Study/RAT: 0, |        | increases in   | consumption, 2) increased  |
| 2, 19, 38,    |        | the incidence  | incidence of mottled       |
| and 76        |        | of mottled or  | diffusely dark livers and  |
| mg/kg/day for |        | discolored     | kidneys, 3) increased      |
| 104 wks.      |        | livers and     | incidence of dark          |
|               |        | changes in     | discoloration of the       |
| MRID No.      |        | clinical       | testes, 4) decreases in    |
| 150329        |        | chemistry.     | hematocrit and hemoglobin  |
|               |        |                | levels, 5) increases in    |
|               |        |                | aspartate                  |
|               |        |                | aminotransferase, alanine  |
|               |        |                | aminotransferase and       |
|               |        |                | alkaline phosphatase       |
|               |        |                | levels, 6)decreases in     |
|               |        |                | cholesterol, blood urea    |
|               |        |                | nitrogen, and total        |
|               |        |                | protein globulin levels,   |
|               |        |                | and 7) increased incidence |
|               |        |                | in the pigmentation of     |
|               |        |                | hepatocytes, Kupffer cells |
|               |        |                | and renal cortical tubule  |
|               |        |                | cells. **Effects seen at   |
|               |        |                | the 76 mg/kg/day dose      |
|               |        |                | level (HDT)**[^1] **were   |
|               |        |                | similar to those seen at   |
|               |        |                | the 38 mg/kg/day but more  |
|               |        |                | severe. In addition other  |
|               |        |                | effects seen at this dose  |
|               |        |                | level were:** 1) decreased |
|               |        |                | body weight; 2) mortality; |
|               |        |                | and 3) increased incidence |
|               |        |                | in basophilic or           |
|               |        |                | eosinophilic foci of       |
|               |        |                | cellular alteration; and   |
|               |        |                | 4) increased incidence of  |
|               |        |                | neoplastic liver. nodules. |
+---------------+--------+----------------+----------------------------+
| Prenatal      | Mat    | Maternal: 150  |                            |
| Developmental | ernal: | based on signs |                            |
| Study/Rat: 0, | 50     | of toxicity    |                            |
| 15, 50, or    |        | (excessive     |                            |
| 150 mg/kg     | De     | salivation,    |                            |
| b.w. in GD    | velopm | lethargy,      |                            |
| 6-19.         | ental: | dried red      |                            |
| Accession No. | 50     | material       |                            |
| 071226        |        | around the     |                            |
|               |        | nares and      |                            |
|               |        | inguinal       |                            |
|               |        | regions) and   |                            |
|               |        | statistically  |                            |
|               |        | significant    |                            |
|               |        | decreases in   |                            |
|               |        | body weight    |                            |
|               |        | gain.          |                            |
|               |        |                |                            |
|               |        | Developmental: |                            |
|               |        | 150 based on   |                            |
|               |        | decreased      |                            |
|               |        | fetal weight   |                            |
|               |        | and skeletal   |                            |
|               |        | abnormalities  |                            |
|               |        | (increased     |                            |
|               |        | incidence of   |                            |
|               |        | bent ribs      |                            |
|               |        | and/or limb    |                            |
|               |        | bones) and     |                            |
|               |        | reduced        |                            |
|               |        | ossification   |                            |
|               |        | of vertebral   |                            |
|               |        | arches.        |                            |
+---------------+--------+----------------+----------------------------+
| Developmental |        | Maternal \> 20 | The only effect seen in    |
| Toxicity/     |        | (HDT)          | this study was a decrease  |
| Rabbit: 0, 1, |        |                | in food consumption by the |
| 4, 20         |        | Developmental  | does. This was not         |
| mg/kg/day. GD |        | \> 20 (HDT)    | accompanied by decreases   |
| 6 - 18.       |        |                | in body weight or body     |
|               |        |                | weight gain. **The HIARC   |
|               |        |                | considers this study as    |
|               |        |                | u                          |
|               |        |                | nacceptable/non-ungradable |
|               |        |                | based on the fact that the |
|               |        |                | dosing was inadequate.**   |
+---------------+--------+----------------+----------------------------+
| Developmental | Ma     | Maternal: 5    |                            |
| Toxicity/     | ternal |                |                            |
| Rabbit: 0, 5, | and    | Developmental: |                            |
| 15, 50        | De     | 5              |                            |
| mg/kg/day.    | velopm |                |                            |
|               | ental: |                |                            |
|               | *      |                |                            |
|               | *Could |                |                            |
|               | Not Be |                |                            |
|               | E      |                |                            |
|               | stabli |                |                            |
|               | shed** |                |                            |
+---------------+--------+----------------+----------------------------+
| Mu            | Par    | Parental: 26.2 | **For parental groups at   |
| ltigeneration | ental: | based on       | the high-dose level**, in  |
| Reproduction  | 2.6    | mortality and  | addition to death, there   |
| Study/Rat: 0, |        | decreased male | was: 1) decrease in body   |
| 50, 500, or   | Offs   | fertility.     | weight/gain; 2) increases  |
| 2000 ppm ( 0, | pring: |                | in spleen and liver        |
| F0 males 2.6  | 2.6    | Offspring:     | weights; 3) increase in    |
| /F0 females   |        | 26.2 based on  | the number of litters with |
| 3.1           | Reprod | reduced pup    | dead pups at birth \[both  |
| mg/kg/day; F1 | uctive | body weigh and | litterings\]; 4) increased |
| males 2.7/F1  | 2.6    | decreases in   | incidence of liver         |
| females 3.3   |        | the absolute   | \[hepatocytic              |
| mg/kg/day, F0 |        | and relative   | centrolobular degeneration |
| males 26.2/F0 |        | spleen weight  | and necrosis\] and spleen  |
| females 31.8  |        |                | \[extramedullary           |
| mg/kg/day; F1 |        | Reproductive:  | hematopoiesis\]            |
| males 26.7/F1 |        | 26.2 based on  | microscopic lesions; 5)    |
| females 32.9  |        | decreased male | increases in testis        |
| mg/kg/day,    |        | fertility.     | weight; 6) increased       |
| and F0 males  |        |                | incidence of bilateral     |
| 103.5/F0      |        |                | degeneration or maturation |
| females 121.3 |        |                | arrest of germinal         |
| mg/kg/day; F1 |        |                | epithelium in the testes,  |
| males         |        |                | hepatocytic centrolobular  |
| 115.4/F1      |        |                | degeneration, necrosis in  |
| females 138.9 |        |                | the liver, and             |
| mg/kg/day.    |        |                | extramedullary             |
| Accession     |        |                | hematopoiesis in the       |
| Nos. 072201,  |        |                | spleen.                    |
| 072202,       |        |                |                            |
| 072203        |        |                | **For offspring groups**   |
|               |        |                | **at the high-dose         |
|               |        |                | level,** in addition to    |
|               |        |                | decreased pup body weight, |
|               |        |                | there was: 1) decreased    |
|               |        |                | pup survival; and 2)       |
|               |        |                | decreased testes \[F1 and  |
|               |        |                | F2\], brain \[F1, both     |
|               |        |                | sexes\], spleen \[F1 and   |
|               |        |                | F2, both sexes\], and      |
|               |        |                | liver weights \[F1         |
|               |        |                | males\].                   |
+---------------+--------+----------------+----------------------------+
| Subchronic    | 14.1   | 73.7 based on  |                            |
| Oral Toxicity |        | decreased body |                            |
| Study/RAT: 0, |        | weight,        |                            |
| 2.9, 14.1, or |        | increased      |                            |
| 73.7          |        | incidence of   |                            |
| mg/kg/day for |        | anemia,        |                            |
| \_; 0, 3.5,   |        | increased      |                            |
| 17.0, and     |        | levels of      |                            |
| 84.5          |        | serum enzymes  |                            |
| mg/kg/day for |        | and bilirubin, |                            |
| \_. 13 weeks. |        | decreased      |                            |
| Accession No. |        | levels of      |                            |
| 071224.       |        | glucose,       |                            |
|               |        | increased      |                            |
|               |        | liver weights, |                            |
|               |        | and increased  |                            |
|               |        | incidence of   |                            |
|               |        | microscopic    |                            |
|               |        | liver lesions. |                            |
+---------------+--------+----------------+----------------------------+
| Subchronic    | *      | **28.6         | All animals at the two     |
| Oral Toxicity | *Could | mg/kg/day      | highest-doses tested died  |
| Study/MOUSE:  | not be | based on       | within the first 3 weeks   |
| 0, 5.7, 28.6, | e      | changes        | of the study. A myriad of  |
| 142.9, 714.3, | stabli | clinical       | effects including changes  |
| or 1,428.6    | shed** | chemistry      | in hematology, clinical    |
| mg/kg/day. 90 |        | parameters,    | chemistry, and organ       |
| days. MRID    |        | increases in   | weight parameters were     |
| No. 00132882  |        | organ weight   | noted at the 142.9         |
|               |        | and            | mg/kg/day dose level.      |
|               |        | his            | **During week 7 of the     |
|               |        | topathological | study period, the 5.7      |
|               |        | findings.**    | mg/kg/day dose level was   |
|               |        |                | increased to 285.7         |
|               |        |                | mg/kg/day to assess the    |
|               |        |                | maximum tolerated dose     |
|               |        |                | level (MTD). As a result,  |
|               |        |                | no NOAEL could be          |
|               |        |                | determined.**              |
+---------------+--------+----------------+----------------------------+
| *Salmonella   |        |                | No cytotoxicity evident at |
| typhiri       |        |                | ≥50 μg/plate in the        |
| um/*mammalian |        |                | absence or presence of     |
| microsome     |        |                | metabolic activation.      |
| mutagenicity  |        |                | **PPG-844 induced a        |
| assay. Doses  |        |                | dose-related increase in   |
| 50 - 5000     |        |                | revertant colonies of      |
| µg/plate ± S9 |        |                | strain TA1538 in the       |
| activation.   |        |                | absence of S9 activation;  |
| MRID          |        |                | however, no effect seen in |
| 00150346.     |        |                | strain TA98 (derived from  |
|               |        |                | TA1538).**                 |
+---------------+--------+----------------+----------------------------+
| *Salmonella   |        |                | Cytotoxicity was not       |
| typhiri       |        |                | evident for any strain up  |
| um/*mammalian |        |                | to the limit dose          |
| microsome     |        |                | (5000µg/plate). **No       |
| mutagenicity  |        |                | evidence of PPG-844        |
| assay. Doses  |        |                | induced mutagenic          |
| 50 - 5000     |        |                | effect.**                  |
| µg/plate ± S9 |        |                |                            |
| activation.   |        |                |                            |
| MRID 00150347 |        |                |                            |
+---------------+--------+----------------+----------------------------+
| *In vitro*    |        |                | No evidence of clastogenic |
| cytogenetic   |        |                | effect in the presence or  |
| assay with    |        |                | absence of S9 activation.  |
| Chinese       |        |                |                            |
| Hamster Ovary |        |                |                            |
| (CHO) cells.  |        |                |                            |
| Doses:        |        |                |                            |
| 31.25 - 500   |        |                |                            |
| µg/ml + S9    |        |                |                            |
| activation    |        |                |                            |
| and 15.63 -   |        |                |                            |
| 250 µg/ml -   |        |                |                            |
| S9            |        |                |                            |
| activation.   |        |                |                            |
| MRID No.      |        |                |                            |
| 00150626      |        |                |                            |
+---------------+--------+----------------+----------------------------+
| Mammalian     |        |                | No evidence of             |
| Cells in      |        |                | cytotoxicity at any dose   |
| Culture Gene  |        |                | tested. **No clear         |
| Mutation in   |        |                | indication of mutagenic    |
| Chinese       |        |                | effect in the presence or  |
| Hamster Ovary |        |                | absence of S9              |
| (CHO) cells.  |        |                | activation.**              |
| Doses: 25-150 |        |                |                            |
| µg/ml. MRID   |        |                |                            |
| No. 00150348  |        |                |                            |
+---------------+--------+----------------+----------------------------+
| Unscheduled   |        | Cytotoxicity   | No UDS                     |
| DNA           |        | at ≥ 5 x       |                            |
| Syn           |        | 10^-2^ mg/ml   |                            |
| thesis/1^ary^ |        |                |                            |
| mouse         |        |                |                            |
| hepatocytes:  |        |                |                            |
| 5 x 10^-6^ to |        |                |                            |
| 5 mg/ml for   |        |                |                            |
| 19 hrs.       |        |                |                            |
|               |        |                |                            |
| MRID No.      |        |                |                            |
| 00156064      |        |                |                            |
+---------------+--------+----------------+----------------------------+
| *In vivo* DNA |        |                | A covalent binding index   |
| covalent      |        |                | of 1.4 ± 0.6 was           |
| binding in    |        |                | determined for lactofen.   |
| mouse liver   |        |                | This suggests a low        |
| Dose:         |        |                | binding to mouse hepatic   |
| ^14^C-PPG-844 |        |                | DNA may occur. This        |
| at 3.8        |        |                | finding could not be       |
| mCi/mmole     |        |                | attributed solely to DNA   |
|               |        |                | binding since some         |
|               |        |                | protein-binding of the     |
|               |        |                | parent compound and/or     |
|               |        |                | metabolite could be        |
|               |        |                | occurring.                 |
+---------------+--------+----------------+----------------------------+

[^1]:
    > Abbreviations: HDT = Highest-dose tested; GD = Gestation day; LDT
    > = Lowest-dose tested; UDS = Unscheduled DNA Synthesis