![](media/image1.png){width="0.7993055555555556in" height="0.8in"}

> UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

**[MEMORANDUM]{.underline}**

Date: May 29, 2007

SUBJECT: Dimethenamid-P Human Health Risk Assessment for Proposed Use on
Grasses Grown for Seed, PC Codes: 120051 and 129051, Petition No:
0F6138, DP Num: 337887.

Regulatory Action: Section 3

FROM: Debra Rate, Ph.D., Biologist

Alternative Risk Integration Assessment (ARIA) Team

Risk Integration Minor Use and Emergency Response Branch (RIMUERB)

> Registration Division (RD) (7505P)

Karlyn J. Bailey, Toxicologist

Registration Action Branch 2 (RAB2)

Health Effects Division (HED) (7509P)

THROUGH: William Cutchin, Acting Branch Senior Scientist

ARIA/RIMUERB

RD (7505P)

Christina Swartz, Branch Chief

RAB2

HED (7509P)

TO: Jim Tompkins/Tobi Colvin-Schneider RM 25

Herbicide Branch (HB)

RD (7505P)

TABLE OF CONTENTS

[1.0 Executive Summary 4](#__RefHeading___Toc138551305)

[2.0 Ingredient Profile 7](#__RefHeading___Toc138551306)

[**2.1** **Summary of Registered/Proposed Uses**
8](#__RefHeading___Toc138551307)

[**2.2** **Structure and Nomenclature** 8](#__RefHeading___Toc138551308)

[**2.3** **Physical and Chemical Properties**
9](#__RefHeading___Toc138551309)

[3.0 Hazard Characterization/Assessmen**t**
10](#__RefHeading___Toc138551310)

[**3.1** **Hazard and Dose-Response Characterization**
10](#__RefHeading___Toc138551311)

[**3.2** **Adsorption, Distribution, Metabolism, Excretion (ADME)**
12](#refheading___toc138551312)

[**3.3** **Safety Factor for Infants and Children**
13](#__RefHeading___Toc138551313)

[**3.4** **Hazard Identification and Toxicity Endpoint Selection**
14](#refheading___toc138551315)

[**3.4.1** **Acute Reference Dose (aRfD) - Females age 13-49**
14](#__RefHeading___Toc138551316)

[**3.4.2** **Acute Reference Dose (aRfD) - General Population**
14](#__RefHeading___Toc138551317)

[**3.4.3** **Chronic Reference Dose (cRfD)**
14](#__RefHeading___Toc138551318)

[**3.4.4** **Incidental Oral Exposure (Short-term / 1-30 days, and
Intermediate-term / 1-6 months)** 15](#__RefHeading___Toc138551319)

[**3.4.5** **Dermal Absorption** 15](#__RefHeading___Toc138551320)

[**3.4.6** **Non-Occupational and Occupational Short-Term** **Dermal
Exposure (1-30 days)** 15](#__RefHeading___Toc138551321)

[**3.4.7** **Non-Occupational and Occupational Short-Term** **Inhalation
Exposure (1-30 days)** 15](#refheading___toc138551322)

[**3.4.8** **Classification of Carcinogenic Potential**
18](#__RefHeading___Toc138551323)

[**3.5** **Endocrine disruption** 18](#__RefHeading___Toc138551328)

[4.0 Public Health and Pesticide Epidemiology Data
18](#refheading___toc138551329)

[**4.1** **Incident Reports** 19](#__RefHeading___Toc138551330)

[5.0 Dietary Exposure/Risk Characterization
19](#__RefHeading___Toc138551331)

[**5.1** **Pesticide Metabolism and Environmental Degradation**
19](#__RefHeading___Toc138551332)

[**5.1.1** **Metabolism in Primary Crops**
19](#__RefHeading___Toc138551333)

[**5.1.2** **Metabolism in Animals** 20](#__RefHeading___Toc138551334)

[**5.1.3** **Metabolism in Rotational Crops**
21](#__RefHeading___Toc138551335)

[**5.1.4** **Metabolism in Livestock** 21](#__RefHeading___Toc138551336)

[**5.1.5** **Analytical Methodology** 21](#__RefHeading___Toc138551337)

[**5.1.6** **Multiresidue Methods** 22](#__RefHeading___Toc138551336)

[**5.1.7** **Magnitude in Plants** 22](#__RefHeading___Toc138551336)

[**5.1.8** **Environmental Degradation**
22](#__RefHeading___Toc138551338)

[**5.1.9** **Comparative Metabolic Profile**
22](#__RefHeading___Toc138551339)

[**5.1.10** **Toxicity Profile of Major Metabolites and Degradates**
23](#__RefHeading___Toc138551340)

[**5.1.11** **Drinking Water Residue Profile**
23](#__RefHeading___Toc138551341)

[**5.1.12** **Food Residue Profile** 24](#__RefHeading___Toc138551342)

[**5.1.13** **International Residue Limits**
25](#__RefHeading___Toc138551343)

[**5.2Dietary Exposure and Risk** 25](#__RefHeading___Toc138551344)

[6.0 Residential (Non-Occupational) Exposure/Risk Characterization
27](#__RefHeading___Toc138551345)

[**6.1** **Other (Spray Drift, etc.)** 27](#__RefHeading___Toc138551346)

[7.0 Aggregate Risk Assessments and Risk Characterization
27](#__RefHeading___Toc138551347)

[8.0 Cumulative Risk Characterization/Assessment
28](#__RefHeading___Toc138551348)

[9.0 Occupational Exposure/Risk Pathway
28](#__RefHeading___Toc138551349)

[**9.1** **Occupational Pesticide Handler Exposure**
29](#__RefHeading___Toc138551350)

[**9.2** **Postapplication Exposure to Agricultural Workers**
32](#__RefHeading___Toc138551353)

[**9.3** **Restricted Entry Interval (REI)**
33](#__RefHeading___Toc138551351)

[10.0 Data Needs and Label Requirements
33](#__RefHeading___Toc138551352)

[**10.1** **Toxicological Profile** 33](#__RefHeading___Toc138551353)

[**10.2** **Residue Chemistry** 33](#__RefHeading___Toc138551353)

[**10.3** **Occupational and Residential Exposure**
34](#__RefHeading___Toc138551353)

[References**:** 34](#__RefHeading___Toc138551354)

Appendix A: [International Residue Limit Status:
**33**](#__RefHeading___Toc138551352)

Appendix B: [Toxicity Profiles**: 33**](#__RefHeading___Toc138551352)

Appendix C: Review of Human Research 44

[]{#__RefHeading___Toc138551305 .anchor}**1.0 Executive Summary**

***Use Profile:***

Dimethenamid and dimethenamid-P are selective, preemergence,
chloroacetamide herbicides with existing tolerances for residues in
bean, dry, seed; beet, garden, roots; beet, garden, tops; beet, sugar,
dried pulp; beet, sugar, molasses; beet, sugar, roots; beet, sugar,
tops; corn, field, forage; corn, field, grain; corn, field, stover;
corn, pop, forage; corn, pop, grain; corn, pop, stover; corn, sweet,
forage; corn, sweet, kernel plus cob with husk removed; corn, sweet,
stover; garlic; horseradish; onion, dry bulb; onion, green; onion,
Welsh; peanut, hay; peanut, nutmeat; shallot, bulb; shallot, fresh
leaves; sorghum, grain; sorghum, grain, forage; sorghum, grain, stover;
soybean, seed; tuberous and corm vegetables; and winter squash.
Tolerances are established for residues of dimethenamid,
(*RS*)-2-chloro-*N*-\[(1-methyl-2-methoxy)ethyl\]-*N*-(2,4-dimethylthien-3-yl)acetamide
under 40 CFR §180.464(a) and (b). As the tolerance expression includes
both the R and S isomers, these tolerances also cover the registered
uses of dimethenamid-P. The current tolerances for all plant
commodities, listed above, are set at 0.01 ppm, which is the enforcement
method limit of quantitation (LOQ).

A pesticide tolerance petition (PP# 0F6138) has been submitted for the
use of dimethenamid-P on grasses grown for seed. Residue data have been
generated to establish tolerances for dimethenamid-P residues in/on
treated grass commodities in support of a regional US EPA registration
limited to Western and Northwest U.S.

OUTLOOK™ Herbicide (EPA Reg. No. 7969-156) is an emulsifiable
concentrate (EC) formulation containing 6.0 lb active ingredient
(ai)/gal of dimethenamid-P. The proposed use includes a single broadcast
foliar application made to established stands of bent grass, Kentucky
blue grass, fine fescue, tall fescue, orchard grass, and perennial
ryegrass at a maximum seasonal rate of 0.98 lb ai/A, [using ground
equipment.]{.mark} This product contains a chloroacetamide herbicide and
is active against annual grasses, broadleaf weeds, and sedges. The
petitioner, BASF Corporation, markets dimethenamid-P under the trade
names Frontier, Outlook, Optill, and Guardsman. Formulations can be
applied as banded or broadcast pre-plant, preemergence or as a
postemergence application using ground or aerial equipment.

***Human Health Risk Assessment:***

***Toxicity/Hazard:***

The toxicology database is adequate to characterize the toxicity of
dimethenamid-P and to assess risk. The acute toxicity data indicate that
\[S\]-dimethenamid-P is Category II via the oral route of exposure, and
Category III for exposure via the dermal and inhalation routes. It is
moderately irritating to the eye (Category III) and slightly irritating
to the skin (Category IV). Dimethenamid-P is a mild skin sensitizer. The
acute toxicity data for \[RS\]-dimethenamid is the same as
\[S\]-Dimethenamid-P for all exposures except acute oral (Category III).
In the 21-day dermal rabbit study, serum inorganic phosphorus decreases
were noted in males and females at the mid-dose and decreases in male
body weight at the high dose, but only mild skin irritation was noted.
Chronic studies in the rat, mouse and dog with \[RS\]-dimethenamid
showed decreases in body weight and food efficiency at the lowest effect
level. At higher dose levels, liver pathology, stomach hyperplasia, and
some indication of (unconfirmed) kidney effects were seen. In some of
the studies liver enzymes and cholesterol levels were increased at doses
resulting in liver pathology.

Metabolism studies with \[RS\]-dimethenamid showed extensive metabolism
(\> 30 metabolites). In the rat, dimethenamid-P parent was extensively
metabolized, being essentially complete within 3 days and over 90%
excreted in the urine, feces and bile within 7 days. No significant
differences in metabolism/excretion were seen between males and females
including biliary excretion. Up to 45 putative metabolites were reported
in the urine and up to 50 were reported in the feces. Of the
unidentified metabolites none exceeded 3% and most were less than 1% of
the administered dose. The developmental toxicity studies show increased
post-implantation loss and minor skeletal variations in the rat and late
resorptions and minor skeletal variations in the rabbit at the highest
doses tested. In the rabbit, the developmental effects occurred at the
same dose as maternal toxicity, whereas in the rat, the developmental
toxicity occurred at much higher doses than in the dams. The
reproduction study showed decreases in body weight in both pups and
parental animals at the same dose levels. The only other effects noted
were increases in liver weights in parental animals (both sexes).

\[RS\]-dimethenamid has been classified as group "C"-possible human
carcinogen, based on an increasing trend for liver tumors (males) seen
in the chronic rat study. There were no dose-related tumors seen in the
mouse carcinogenicity study. The chronic Point of Departure (cPOD)
chosen for human risk assessment is based on effects observed in the
chronic rat study; it is considered protective of the cancer effects.

HED has concluded that based on the proposed use pattern, the toxicology
database for dimethenamid is adequate for risk assessment. Adequate
toxicological information is available on dimethenamid-P for selecting
the doses needed to assess its occupational risks when used as a
pesticide (Tables 3.4.7.a and 3.4.7.b). The dose picked for short- term
dermal and short-term inhalation exposures is the lowest observed
adverse effect level (LOAEL) of 33.6mg/kg/day, from a toxicity study in
dogs. Lacking a clear cut no observed adverse effect level (NOAEL)
needed for risk assessment, a 4.72 mg/kg/day dose was derived from the
LOAEL using an uncertainty factor (UF) of 100. There were no data
available on dermal toxicity and dermal absorption on dimethenamid or
dimethenamid-P; therefore, a dermal absorption rate of 30% was used to
extrapolate from oral exposure to dermal exposure. An absorption rate of
100% was assumed for inhalation.

***Dietary Exposure (food/water):***

Product chemistry data, residue chemistry data relevant to food use, and
environmental fate data relevant to drinking water are adequate to
assess human exposure to dimethenamid-P and its metabolites. Magnitude
of the residue studies were submitted for regional registrations of the
use of dimethenamid-P on grasses grown for seed in the Western and
Northwest U.S. Dimethenamid-P residues in forage and hay ranged from
below limit of quantitation (LOQ) (0.01 ppm) to a maximum of 0.05 and
0.26 ppm, respectively (60 day preharvest interval (PHI)).
Dimethenamid-P residues were below the LOQ of 0.01 ppm in all seed
screening and straw samples collected at normal seed harvest (PHI of 217
to 314 days), with the exception of one treated seed screening sample
that had a residue value of 0.01 ppm, and one treated straw sample that
had a residue value of 0.02 ppm. Utilizing the maximum residue limit
(MRL) calculator and spreadsheet, the submitted data resulted in
tolerance recommendations of grass, forage at 0.15 ppm; grass, hay at
2.5 ppm; grass, straw at 0.01 ppm; and grass, seed screenings at 0.01
ppm. Due to low residue values and limited use in livestock feed, the
proposed use of dimethenamid-P on grasses grown for seed, will not
require the establishment of tolerances on livestock commodities at this
time.

Estimated Drinking Water Concentrations (EDWCs) were provided in a risk
assessment (DP Num: 326961, 326977, 327936, K. Moore, 23/JAN/2007) at
66.7 ug/L for acute [exposure and 20.2 ug/L for non-cancer chronic
exposure.]{.mark}

Dietary exposure and risk were calculated assuming tolerance level
residues and 100% crop treated (CT). The drinking water residues were
included in the respective acute (females age 13-49 years) and chronic
(all populations) analyses.

***Residential Exposure:***

Currently, there are no residential, or other non-agricultural uses of
dimethenamid-P. For these reasons, a residential assessment is not
included in this risk assessment.

***Aggregate Risk:***

Without residential exposure, the aggregate risk is based on
tolerance-level residues and an assumption of 100% CT for the food uses,
and on Tier 2 estimates for the drinking water contamination that may be
associated with crop uses. The 95^th^ percentile acute population
adjusted dose (aPAD) risk estimate for child-bearing females is less
than 1% of the aPAD. The chronic population adjusted dose (cPAD) risk
estimates for the general U.S. and specific population sub-groups are
[less than 3% of the cPAD. A]{.mark} determination of safety can be made
for aggregate dietary (food and water) exposure.

***Occupational Exposure/Risk:***

An occupational risk assessment was completed for dimethenamid-P for its
use on grasses grown for seed and for use on ornamental plantings (DP
Num: 339192, M. Dow, 08/MAY/2007). Based upon the proposed use patterns,
the most highly exposed occupational pesticide handlers will be
mixer/loaders using open-pour loading of liquid formulation and
applicators using low-pressure hand-wand sprayers. The margin of
exposure (MOE) must be \>100 for risks to be below ARIA's level of
concern. The MOE for a mixer/loader/applicator using low-pressure
hand-wand sprayers, wearing protective gloves and coveralls over a
single layer of work clothing is 67. This exceeds ARIA\'s level of
concern. The estimated MOE is based upon use of the highest rate of
application and the assumption that 40 acres are treated per day. If,
for this method of application, treatment is limited to 30 acres per
day, the MOE would be 90. Due to the conservative nature of the
assumptions used in the assessment and a limitation to 30 acres treated
per day using low-pressure hand-wand sprayers, the proposed use does not
exceed ARIA's level of concern. If the lower rate of application is used
(0.98 lb ai/A), the resulting MOE does not exceed ARIA's level of
concern for any of the mixer/loader/applicator scenarios. For
postapplication exposure, the calculated MOE is 103. The MOE for
postapplication exposure does not exceed ARIA's level of concern. Based
on the toxicity categories for dimethenamid-P (Table 3.1.1), a
restricted entry interval (REI) of 12 hours is adequate protection for
agricultural workers.

***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>).

***Review of Human Research:***

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical. These studies (listed in Appendix C) have been determined to
require a review of their ethical conduct, and have received that
review.

***Recommendations and Additional Data Needs:***

ARIA concludes that there is a reasonable certainty that no harm will
result to the U.S. Population, including infants and children, from
acute, short- and intermediate- term, and chronic aggregate exposure to
dimethenamid-P residues. ARIA recommends for tolerances for the residues
of dimethenamid-P on grass, forage at 0.15 ppm; grass, hay at 2.5 ppm;
grass, straw at 0.01 ppm; and grass, seed screenings at 0.01 ppm,
provided the following criteria are met.

1\) The petitioner must provide a revised Section F, amending the
proposed tolerances to correspond to the recommended tolerances (grass,
forage at 0.15 ppm; grass, hay at 2.5 ppm; grass, straw at 0.01 ppm; and
grass, seed screenings at 0.01 ppm).

2\) The petitioner must provide revised Section B and an amended label
to restrict the use for grasses grown for seed to the Western and
Northwest U.S. The revised Section B should also address the amended
label submission of 30 day PHI for warm-season grasses and 60 day PHI
for cool-season grasses.

3\) The label must be amended to include a restriction of 30 acres per
day for using the low-pressure hand-wand along with a requirement for
the use of gloves and coveralls. A general requirement for the use of
protective gloves is required on the product label.

[]{#__RefHeading___Toc138551306 .anchor}**2.0 Ingredient Profile**

OUTLOOK™ Herbicide (EPA Reg. No. 7969-156) is an emulsifiable
concentrate (EC) formulation containing 6.0 lb ai/gal of dimethenamid-P.
[This product contains a chloroacetamide herbicide and is active against
annual grasses, broadleaf weeds, and sedges. The Outlook™ proposed use
directions for grasses grown for seed are to apply at post-emergence, at
a maximum rate of 0.98 lb ai/A, per application and season, using ground
equipment.]{.mark}

[ ]{.mark}

[]{#__RefHeading___Toc138551307 .anchor}**2.1 Summary of
Registered/Proposed Uses**

+-----------+----------+-----------+-----------+-----------+-----------+
| **Table   |          |           |           |           |           |
| 2.1.      |          |           |           |           |           |
| Summary   |          |           |           |           |           |
| of        |          |           |           |           |           |
| D         |          |           |           |           |           |
| irections |          |           |           |           |           |
| for Use   |          |           |           |           |           |
| of        |          |           |           |           |           |
| Dimethen  |          |           |           |           |           |
| amid-P.** |          |           |           |           |           |
+===========+==========+===========+===========+===========+===========+
| Applic    | For      | Applic.   | Max. No.  | Max.      | PGI ^1^   |
| Timing,   | mulation | Rate      | Applic.   | Seasonal  |           |
| Type, and |          |           | per       | Applic.   | (days)    |
| Equip.    | \[EPA    | (lb ai/A) | Season    | Rate      |           |
|           | Reg.     |           |           |           |           |
|           | No.\]    |           |           | (lb ai/A) |           |
+-----------+----------+-----------+-----------+-----------+-----------+
| Grasses   |          |           |           |           |           |
| grown for |          |           |           |           |           |
| seed      |          |           |           |           |           |
+-----------+----------+-----------+-----------+-----------+-----------+
| Fall      | 6 lb ai  | 0.        | 1         | 0.984     | 60 for    |
| (prior to | /gal EC  | 656-0.984 | (implied) |           | co        |
| emergence |          |           |           |           | ol-season |
| of        | \[79     |           |           |           | grasses   |
| targeted  | 69-156\] |           |           |           | and 30    |
| weed)     |          |           |           |           | days for  |
|           |          |           |           |           | wa        |
| Broadcast |          |           |           |           | rm-season |
|           |          |           |           |           | grasses.  |
| Ground    |          |           |           |           |           |
+-----------+----------+-----------+-----------+-----------+-----------+
| Use       |          |           |           |           |           |
| D         |          |           |           |           |           |
| irections |          |           |           |           |           |
| and       |          |           |           |           |           |
| Rest      |          |           |           |           |           |
| rictions: |          |           |           |           |           |
| Ap        |          |           |           |           |           |
| plication |          |           |           |           |           |
| may be    |          |           |           |           |           |
| made to   |          |           |           |           |           |
| es        |          |           |           |           |           |
| tablished |          |           |           |           |           |
| stands of |          |           |           |           |           |
| b         |          |           |           |           |           |
| entgrass, |          |           |           |           |           |
| Kentucky  |          |           |           |           |           |
| blue      |          |           |           |           |           |
| grass,    |          |           |           |           |           |
| fine      |          |           |           |           |           |
| fescue,   |          |           |           |           |           |
| tall      |          |           |           |           |           |
| fescue,   |          |           |           |           |           |
| orchard   |          |           |           |           |           |
| grass,    |          |           |           |           |           |
| and       |          |           |           |           |           |
| perennial |          |           |           |           |           |
| ryegrass  |          |           |           |           |           |
| in a      |          |           |           |           |           |
| minimum   |          |           |           |           |           |
| of 10     |          |           |           |           |           |
| gal/A     |          |           |           |           |           |
| using     |          |           |           |           |           |
| ground    |          |           |           |           |           |
| e         |          |           |           |           |           |
| quipment. |          |           |           |           |           |
| Grass     |          |           |           |           |           |
| seed      |          |           |           |           |           |
| crops     |          |           |           |           |           |
| must have |          |           |           |           |           |
| been      |          |           |           |           |           |
| es        |          |           |           |           |           |
| tablished |          |           |           |           |           |
| for at    |          |           |           |           |           |
| least one |          |           |           |           |           |
| year or   |          |           |           |           |           |
| had at    |          |           |           |           |           |
| least one |          |           |           |           |           |
| seed crop |          |           |           |           |           |
| harvested |          |           |           |           |           |
| prior to  |          |           |           |           |           |
| app       |          |           |           |           |           |
| lication. |          |           |           |           |           |
| Ap        |          |           |           |           |           |
| plication |          |           |           |           |           |
| may be    |          |           |           |           |           |
| made in   |          |           |           |           |           |
| the fall  |          |           |           |           |           |
| prior to  |          |           |           |           |           |
| emergence |          |           |           |           |           |
| of        |          |           |           |           |           |
| targeted  |          |           |           |           |           |
| weeds or  |          |           |           |           |           |
| in a      |          |           |           |           |           |
| s         |          |           |           |           |           |
| equential |          |           |           |           |           |
| use       |          |           |           |           |           |
| program   |          |           |           |           |           |
| with      |          |           |           |           |           |
| other     |          |           |           |           |           |
| h         |          |           |           |           |           |
| erbicides |          |           |           |           |           |
| that      |          |           |           |           |           |
| control   |          |           |           |           |           |
| emerged   |          |           |           |           |           |
| weeds.    |          |           |           |           |           |
| Livestock |          |           |           |           |           |
| grazing   |          |           |           |           |           |
| in        |          |           |           |           |           |
| treated   |          |           |           |           |           |
| fields    |          |           |           |           |           |
| may occur |          |           |           |           |           |
| 60 days   |          |           |           |           |           |
| after     |          |           |           |           |           |
| app       |          |           |           |           |           |
| lication. |          |           |           |           |           |
| Tank mix  |          |           |           |           |           |
| use is    |          |           |           |           |           |
| pr        |          |           |           |           |           |
| ohibited. |          |           |           |           |           |
| The       |          |           |           |           |           |
| parent    |          |           |           |           |           |
| label     |          |           |           |           |           |
| specifies |          |           |           |           |           |
| that      |          |           |           |           |           |
| fa        |          |           |           |           |           |
| ll-seeded |          |           |           |           |           |
| cereal    |          |           |           |           |           |
| crops may |          |           |           |           |           |
| be        |          |           |           |           |           |
| planted 4 |          |           |           |           |           |
| months or |          |           |           |           |           |
| more      |          |           |           |           |           |
| following |          |           |           |           |           |
| t         |          |           |           |           |           |
| reatment. |          |           |           |           |           |
| There are |          |           |           |           |           |
| no        |          |           |           |           |           |
| r         |          |           |           |           |           |
| otational |          |           |           |           |           |
| crop      |          |           |           |           |           |
| res       |          |           |           |           |           |
| trictions |          |           |           |           |           |
| the       |          |           |           |           |           |
| spring    |          |           |           |           |           |
| following |          |           |           |           |           |
| the       |          |           |           |           |           |
| previous  |          |           |           |           |           |
| year's    |          |           |           |           |           |
| ap        |          |           |           |           |           |
| plication |          |           |           |           |           |
| of        |          |           |           |           |           |
| Outlook™. |          |           |           |           |           |
| If        |          |           |           |           |           |
| re        |          |           |           |           |           |
| -planting |          |           |           |           |           |
| of a crop |          |           |           |           |           |
| is        |          |           |           |           |           |
| n         |          |           |           |           |           |
| ecessary, |          |           |           |           |           |
| plant     |          |           |           |           |           |
| only      |          |           |           |           |           |
| crops     |          |           |           |           |           |
| where a   |          |           |           |           |           |
| soil      |          |           |           |           |           |
| ap        |          |           |           |           |           |
| plication |          |           |           |           |           |
| of        |          |           |           |           |           |
| Outlook™  |          |           |           |           |           |
| is        |          |           |           |           |           |
| re        |          |           |           |           |           |
| gistered. |          |           |           |           |           |
+-----------+----------+-----------+-----------+-----------+-----------+

^1^ PGI = pregrazing interval.

2.  []{#__RefHeading___Toc138551308 .anchor}**Structure and
    Nomenclature**

  ------------------------------------------------------------------------------------------------------
  **Table 2.2.a           
  Dimethenamid            
  Nomenclature.**         
  ----------------------- ------------------------------------------------------------------------------
  Chemical structure      ![](media/image2.wmf){width="2.2916666666666665in"
                          height="1.1666666666666667in"}

  Common name             Dimethenamid (50:50, R and S -isomers)

  Molecular Formula       C~12~H~18~ClNO~2~S

  Molecular Weight        275.8 g/mol

  IUPAC name              (*RS*)-2-chloro-*N*-(2,4-dimethyl-3-thienyl)-*N*-(2-methoxy-1-methylethyl)
                          acetamide

  CAS name                2-chloro-*N*-(2,4-dimethyl-3-thienyl)-*N*-(2-methoxy-1-methylethyl)acetamide

  CAS \#                  87674-68-8

  PC Code                 129051
  ------------------------------------------------------------------------------------------------------

  ------------------------------------------------------------------------------------------------------
  **Table 2.2.b           
  Dimethenamid-P          
  Nomenclature.**         
  ----------------------- ------------------------------------------------------------------------------
  Chemical structure      ![](media/image3.wmf){width="2.2916666666666665in" height="1.15625in"}

  Common name             Dimethenamid-P (90:10, S:R isomer ratio)

  Molecular Formula       C~12~H~18~ClNO~2~S

  Molecular Weight        275.8 g/mol

  IUPAC name              (*S*)-2-chloro-*N*-(2,4-dimethyl-3-thienyl)-*N*-(2-methoxy-1-methylethyl)
                          acetamide

  CAS name                2-chloro-*N*-(2,4-dimethyl-3-thienyl)-*N*-\[(1*S*)-2-methoxy-1-methylethyl\]
                          acetamide

  CAS \#                  163515-14-8

  PC Code                 120051

  Proposed End-use        OUTLOOK™ (6 lb ai/gal EC; EPA Reg. No. 7969-156)
  product (EP)            
  ------------------------------------------------------------------------------------------------------

Number range CHAPTER

**2.3 Physical and Chemical Properties**

+------------------+----------------------------+----------------------+
| **Table 2.3.a    |                            |                      |
| Physicochemical  |                            |                      |
| Properties of    |                            |                      |
| Dimethenamid     |                            |                      |
| (50:50, R and S  |                            |                      |
| -isomers).**     |                            |                      |
+==================+============================+======================+
| Parameter        | Value                      | Reference            |
+------------------+----------------------------+----------------------+
| Boiling          | 123°C at 0.1 mm Hg         | DP Num: 183774,      |
| point/range      |                            | 1/22/93, M. Flood    |
+------------------+----------------------------+----------------------+
| pH               | 8.4-6.9; continuously      | DP Num: 183774,      |
|                  | decreasing over a 45-      | 1/22/93, M. Flood    |
|                  | minute period; 1% aqueous  |                      |
|                  | solution                   |                      |
+------------------+----------------------------+----------------------+
| Density          | 1.19 g/mL at 25°C;         | DP Num: 183774,      |
|                  |                            | 1/22/93, M. Flood    |
|                  | 1.19 specific gravity at   |                      |
|                  | 25°C                       |                      |
+------------------+----------------------------+----------------------+
| Water solubility | 0.117 g/100 mL at 25°C     | DEB No. 7060,        |
|                  | (PAI)                      | 1/18/91, M. Flood    |
+------------------+----------------------------+----------------------+
| Solvent          | Soluble in all proportions | DP Num: 169997,      |
| solubility       | in acetone, n-octanol,     | 7/29/92, M. Flood    |
|                  | methylene chloride, and    |                      |
|                  | carbon disulfide at 25°C   |                      |
+------------------+----------------------------+----------------------+
| Vapor pressure   | 2.76 x 10^-4^ mm Hg at     | DEB No. 7060,        |
|                  | 25°C (PAI)                 | 1/18/91, M. Flood    |
+------------------+----------------------------+----------------------+
| Dissociation     | No dissociation between pH | DEB No. 7060,        |
| constant, pK~a~  | 1-11 at 25°C (PAI)         | 1/18/91, M. Flood    |
+------------------+----------------------------+----------------------+
| Octanol/water    | 141 (PAI)                  | DEB No. 7060,        |
| partition        |                            | 1/18/91, M. Flood    |
| coefficient,     |                            |                      |
| K~OW~            |                            |                      |
+------------------+----------------------------+----------------------+
| UV/visible       | Not available              |                      |
| absorption       |                            |                      |
+------------------+----------------------------+----------------------+

  ------------------------------------------------------------------------
  **Table 2.3.b                                        
  Physicochemical                                      
  Properties of                                        
  Dimethenamid-P.**                                    
  ---------------------- ----------------------------- -------------------
  Parameter              Value                         Reference

  Boiling point/range    123°C/0.07 torr               DP Num: 238349,
                                                       12/1/97, H. Podall

  pH                     3.3 at 25°C (1% aqueous       DP Num: 238349,
                         dispersion)                   12/1/97, H. Podall

  Density                1.19 g/mL at 20°C             DP Num: 238349,
                                                       12/1/97, H. Podall

  Water solubility       1.45 g/L at 25°C              DP Num: 238349,
                                                       12/1/97, H. Podall

  Solvent solubility     20.8 g / 100mL in hexane.     DP Num: 238349,
                         Soluble in tetrahydrofuran,   12/1/97, H. Podall
                         isopropyl alcohol, ACN, DMSO, 
                         DCM, toluene, and n-octanol   
                         in all proportions.           

  Vapor pressure         1.9 x 10-5 mm Hg at 25°C      DP Num: 238349,
                                                       12/1/97, H. Podall

  Dissociation constant, Bridging to dimethenamid was  DP Num: 217337,
  pK~a~                  approved                      7/26/95, M.
                                                       Rodriguez

  Octanol/water          Not applicable; soluble in    DP Num: 238349,
  partition coefficient, n-octanol in all proportions  12/1/97, H. Podall
  Log(K~OW~)                                           

  UV/visible absorption  Ε = 7560; 33 nm               MRID No. 46710201
  spectrum                                             
  ------------------------------------------------------------------------

**3.0 Hazard characterization**

**3.1 Toxicological Effects**

Based on the proposed use pattern, the toxicology database for
dimethenamid is adequate for risk assessment. The toxicity data base for
the \[RS\] mixture is complete and the bridging studies to the
\[S\]-dimethenamid toxicity data are complete. These bridging studies
include the 6 acute studies, a subchronic study in rats, a developmental
toxicity study in rats, and a battery of mutagenicity studies. There are
minor inconsistencies between the two sets of data. In the developmental
toxicity studies in the rat with \[S\]-dimethenamid-P, decreases in
maternal body weight were shown at 1/8 the LOAEL for dams dosed with
\[RS\]-dimethenamid. Since the toxicity in 90-day feeding studies in
rats with \[S\]-dimethenamid-P and \[RS\]-dimethenamid were very
similar, the finding of increased toxicity in pregnant dams may suggest
that \[S\]-dimethenamid-P is more toxic to pregnant rats. This
difference in doses resulting in decreased body weight may possibly be
due to strain drift in the Sprague Dawley rats used, since the studies
were conducted 9 years apart.

The acute toxicity data indicate that \[S\]-dimethenamid-P is Category
II via the oral route of exposure, and Category III via the dermal and
inhalation routes of exposure. It is moderately irritating to the eye
(Category III) and slightly irritating to the skin (Category IV); It is
a mild skin sensitizer. The acute toxicity data for \[RS\]-dimethenamid
is the same as \[S\]-Dimethenamid-P for all exposures except acute oral
(Category III).

There is no concern for increased qualitative and/or quantitative
susceptibility after exposure to dimethenamid in developmental toxicity
studies in rats and rabbits, and a reproduction study in rats. The
developmental toxicity studies show increased post-implantation loss and
minor skeletal variations in the rat and late resorptions and minor
skeletal variations in the rabbit at the highest doses tested. In the
rabbit, the developmental effects occurred at the same dose as maternal
toxicity, whereas in the rat, the developmental toxicity occurred at
much higher doses than in the dams. The reproduction study showed
decreases in body weight in both pups and parental animals at the same
dose levels. The only other effects noted were increases in liver
weights in parental animals (both sexes).

In the 21-day dermal rabbit study, serum inorganic phosphorus decreases
were noted in males and females at the mid-dose and decreases in male
body weight at the high dose, but only mild skin irritation was noted.
Chronic studies in the rat, mouse and dog with \[RS\]-dimethenamid
showed decreases in body weight and food efficiency at the lowest effect
level. At higher dose levels, liver pathology, stomach hyperplasia, and
some indication of (unconfirmed) kidney effects were seen. In some of
the studies liver enzymes and cholesterol levels were increased at doses
resulting in liver pathology.

\[RS\]-dimethenamid has been classified as group "C"-possible human
carcinogen, based on an increasing trend for liver tumors (males) seen
in the chronic rat study. There were no dose-related tumors seen in the
mouse carcinogenicity study. The cPOD chosen for human risk assessment
is based on effects observed in the chronic rat study; it is considered
protective of the cancer effects.

A battery of mutagenicity studies with \[S\]-dimethenamid-P are negative
for genetic mutations, including unscheduled DNA synthesis. However,
mutagenicity studies with \[RS\]-dimethenamid showed positive results
for unscheduled DNA synthesis and there were equivocal results in two
dominant lethal studies. (It is noted that late resorptions contributed
mostly to the positive dominant lethal effects; claimed not to be
characteristic of a dominant lethal effect). In some of the studies with
\[RS\]-dimethenamid, the studies were considered positive, but should
have been repeated because of equivocal results, such as precipitation
and positive responses not related to dose.

Metabolism studies with \[RS\]-dimethenamid showed extensive metabolism
(\> 30 metabolites). Thirty-one metabolites were identified and
quantified. The initial metabolite formed was the glutathione conjugate
of the parent at the active chlorine α to the carbonyl group, with
subsequent metabolism at the glutathione residue. The parent was
extensively metabolized, being essentially complete within 3 days and
over 90% being excreted in the urine, feces and bile within 7 days.
Excretion products with highest total concentration as a % of
administered multiple doses of 10 mg/kg to males and females,
respectively, were parent- 1.4% and 1.2%, M1- 3.3 & 7.2%, M2- 3.6% &
9.8%, M3- 0.6% & 0.4%, M14- 2.8% & 3.3%, M16- 5.1% & 3.3%, M17- 0.6% &
3.3%, M19-1.1% & 1.4%. Total excretion products in the urine, feces or
bile were less than 5% of the administered single (oral/intravenous)
dose of 10 mg/kg to males or females, except for M2 via the oral dose
(total female,-6.4%) and M1 via the intravenous dose (total
female,-6.1%). Most were less than 1% of the administered dose. No
significant differences in metabolism/excretion were seen between males
and females including biliary excretion. Up to 45 putative metabolites
were reported in the urine and up to 50 were reported in the feces. Of
the unidentified metabolites none exceeded 3 % and most were less than
1% of the administered dose. Saturation of the metabolic system was seen
at the 1,000 mg/kg dose.

*[Equivalence of Toxicity of \[RS\]-Dimethenamid and
\[S\]-Dimethenamid]{.underline}*

\[RS\]-dimethenamid and \[S\]-dimethenamid-P show similar toxicity. Both
products show similar toxicity and endpoints in the 90-day subchronic
studies, the acute studies and the mutagenicity studies. Both products
are likely to be extensively metabolized to the similar quantifiable
metabolites (about 30) and to the approximately 70 metabolites too low
to be quantified. The initial reaction in the rat is conjugation with
glutathione with most subsequent metabolic modification occurring at the
glutathione conjugate. The glutathione conjugation does not involve the
asymmetric \[RS\]-carbon of the pesticide structure, and thus there is
good reason to expect similar toxicities for both products.

However, \[S\]-dimethenamid-P apparently showed slight decrease in
maternal body weight gain at a lower dose than \[RS\]-dimethenamid in
developmental toxicity studies in the rat. This may suggest that
\[S\]-dimethenamid-P is possibly more toxic to the pregnant rat. This
apparent difference in toxicity of the two products is difficult to
compare because the two studies were conducted 9 years apart and the
dose selection in the two developmental studies with the two products
were different. In addition, a range-finding study conducted with
\[S\]-dimethenamid-P showed decreases in maternal body weight comparable
to the dose for the \[RS\] product, suggesting that the slight decreases
in maternal body weight gain at the lowest dose tested in the definitive
study could be incidental.

2.  []{#refheading___toc138551312 .anchor}**Adsorption, Distribution,
    Metabolism, Excretion (ADME)**

The rat metabolism study indicates that dimethenamid, at single doses
(low and high), is extensively metabolized to approximately 31
identified metabolites, and is essentially completely (90%) excreted in
the urine, feces, and bile within 7 days. Excretion products were
qualitatively independent of sex, but minor quantitative differences
were seen between males and females. In the urine, females excreted
about 47% to 63% and males about 31% to 35% at low and high oral doses,
i.v. doses, and multiple doses. In feces, females excreted 26% to 48%
and males 30% to 62% at low and high oral doses, i.v. doses, and
multiple doses.

The primary route of metabolism is the liver with less than 2.5% of the
dose being recovered as parent. None of the metabolites were more than
10% with most being less than 2% as free or conjugate. On the basis of
the metabolites identified in the urine and feces, the primary metabolic
pathways for dimethenamid involve glutathione conjugation via
displacement of the chlorine atom followed by (1) breakdown of the
glutathione to mercapturic acid, or (2) hydrolysis of the thio bond of
mercaptan, which is then methylated and oxidized to the methylsufoxide
and methylsulfone. Additional major metabolic reactions include
O-methylation of the 2-methoxyl-1-methylethyl moiety to form a
2-hydroxylated product and oxidation of the 2-methyl group on the
thiophene ring to produce a hydroxymethyl. Dimerization, cyclization,
and hydroxylation at the thiol also occur following hydrolysis of the
glutathione conjugate. Other minor pathways for dimethenamid involve
direct biotransformation reactions such as reductive chlorination,
oxidation of the sulfur on the thiophene ring to form a sulfoxide,
oxidation of the 2- or 4-methyl group on the thiophene ring, and
cyclization and hydroxylation of the thiol. Saturation of glutathione
pathway may have occurred at the higher dose.

There are no rat metabolism studies with \[S\]-dimethenamid-P, however,
consideration of the potential differences in metabolism of the \[R\]
and \[S\] enantiomer of dimethenamid indicates that few of the products
are likely to be affected by the orientation of the asymmetric carbon,
since most metabolism occurs at least 2 carbons and a nitrogen removed
from the asymmetric center. However, products including a nitrogen
containing ring structure may be preferentially formed depending on
possible steric hindrance in the ring.

**3.3 Special Considerations for Infants and Children (FQPA Safety
Determination)**

There is no concern for increased qualitative and/or quantitative
susceptibility following *in utero* (rats and rabbits) and pre-and
post-natal exposure (rats) to the \[RS\] or the \[S\] dimethenamid
technical products. However, it is noted that in the developmental
toxicity study in rats with \[S\]-dimethenamid-P, the maternal NOAEL was
not determined (LOAEL =25 mg/kg/day); whereas, in a similar study in
rats with \[RS\]-dimenthenamid, a maternal NOAEL of 50 mg/kg/day was
established (LOAEL=215 mg/kg/day). This would suggest that either the
\[S\] enantiomer is more toxic to the pregnant female rat than the
\[RS\] mixture, or that there was strain drift in the two studies
conducted 9 years apart. Both studies were conducted in the same rat
strain with 0.5% CMC, 10 ml/kg, and in the same laboratory with very
similar protocols.

There were clinical signs (decreased motor activity, ptosis, etc.)
observed in dams at the highest dose tested (HDT) (300 mg/kg/day) in the
developmental toxicity study in rats with dimethenamid-P \[S\]. The
observations were low in frequency and considered to be a result of
excessive toxicity. Decreased motor activity was noted 8 times in 6 rats
and ptosis (droopy eye lids) was noted 4 times in 4 rats (observations
were made 375 times on the 25 rats in the highest dose group during the
study with \[S\]-dimethenamid-P). Furthermore, these effects were not
seen in other developmental studies in rats or rabbits, or reproduction
and subchronic/chronic studies in rats. As a result, a developmental
neurotoxicity study is not required.

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

-   The toxicity data showed no increase in qualitative and/or
    quantitative susceptibility in fetuses and pups with *in utero* and
    pre- and post-natal exposure.

-   There is no evidence that dimethenamid is a neurotoxic chemical and
    there is no need for a developmental neurotoxicity study or
    additional uncertainty factors to account for neurotoxicity.

-   The dietary food exposure assessment utilizes proposed tolerance
    level residues and 100% crop treated information for all
    commodities, which results in very high-end estimates of dietary
    exposure.

-   The dietary drinking water assessment (Tier 2 estimates) utilizes
    values generated by model and associated modeling parameters which
    are designed to provide health protective, high-end estimates of
    water concentrations.

*Literature Sources:* There were no literature reports on the toxicity
of \[S\]-dimethenamid-P found. Structural analogues are acetochlor
\[Group B2 carcinogen\], metolachlor \[Group C carcinogen\], propachlor
\[evidence of thyroid tumors and ovarian tumors\] and alachlor
\[evidence of nasal, stomach and thyroid tumors\]. All are
chloroacetanilide pesticides and cause glutathione depletion. All
analogues can form the reactive quinone imine. Due to the thiophene
ring, \[S\]-dimethenamid-P can not.

[]{#refheading___toc138551315 .anchor}**3.4 Hazard Identification and
Toxicity Endpoint Dose Selection**

**3.4.1 Acute Point of Departure (aPOD) - Females age 13-49**

> Selected Study: Developmental toxicity in rabbits (MRID# 41706809).
>
> [Dose and Endpoint for Establishing an aPOD]{.underline}: NOAEL is 75
> mg/kg/day. LOAEL is 150 mg/kg/day based on developmental effects of
> increased resorptions, implantation loss and angulated hyoid alae. The
> resorptions and post implantation loss are presumed to be a single
> dose effect. The developmental endpoint is appropriate for females
> 13-49 and is of the appropriate duration. The endpoint is supported by
> a range-finding study in rats with \[S\]-dimethenamid-P, which showed
> increased resorptions at 400 mg/kg/day.
>
> [Uncertainty Factor (UF]{.underline}): 100 This includes 10x for
> interspecies extrapolation and 10x for intraspecies variation.

**3.4.2 Acute Point of Departure (aPOD)- General Population**

> An appropriate acute endpoint attributable to a single dose was not
> available in the toxicity data base including the developmental
> toxicity studies.

**3.4.3 Chronic Point of Departure (cPOD)**

> Selected Study: Chronic/carcinogenicity study in rats (MRID# 41706808
> & 42030102).
>
> [Dose and Endpoint for Establishing an cPOD]{.underline}: NOAEL is
> 5.1/6.8 mg/kg/day for male/female. The LOAEL is 36/49 mg/kg/day for
> male/female based on decreased body weight and body weight gain from
> week 1-10 and week 10-104 in both sexes, and increased microscopic
> hepatic lesions in both sexes.
>
> [Uncertainty Factor (UF]{.underline}): 100 This includes 10X for
> interspecies extrapolation and 10x for intraspecies variation.

4.  **Incidental Oral Exposure (Short Term, 1-30 days)**

> Selected Study: Subchronic Toxicity in Dogs (MRID# 41615902).
>
> [Dose and Endpoint for Establishing an aPOD]{.underline}: NOAEL is
> 4.72 mg/kg/day. LOAEL is 33.6 mg/kg/day based on decreases in body
> weight and body weight gain, and adverse liver effects (increased
> liver weight and periportal vacuolation, and dilation of the
> sinusoids).
>
> [Uncertainty Factor (UF]{.underline}): 100 This includes 10x for
> interspecies extrapolation and 10x for intraspecies variation.

**3.4.5 Dermal Absorption**

> There are no dermal absorption studies available for dimethenamid.
> Estimation of dermal absorption from the ratio of the LOAEL from a
> 21-day dermal study in rabbits and the rabbit developmental toxicity
> study show maximal dermal absorption of about 30%, i.e., \[(500
> mg/kg/day based on body weight change from the 21-day dermal rabbit
> study)/(150 mg/kg/day based on body weight change from the
> developmental toxicity rabbit study)\] x 100 = 30%.

**3.4.6 Non-Occupational and Occupational Short-Term Dermal Exposure
(1-30 days)**

> Selected Study: Subchronic Toxicity in Dogs (MRID# 41615902).
>
> [Dose and Endpoint for Establishing an aPOD]{.underline}: NOAEL is
> 4.72 mg/kg/day. LOAEL is 33.6 mg/kg/day based on decreases in body
> weight and body weight gain, and adverse liver effects (increased
> liver weight and periportal vacuolation, and dilation of the
> sinusoids).
>
> [Uncertainty Factor (UF]{.underline}): 100 This includes 10x for
> interspecies extrapolation and 10x for intraspecies variation.

[]{#refheading___toc138551322 .anchor}**3.4.7 Non-Occupational and
Occupational Short-Term Inhalation Exposure (1-30 days)**

> Selected Study: Subchronic Toxicity in Dogs (MRID# 41615902).
>
> [Dose and Endpoint for Establishing an aPOD]{.underline}: NOAEL is
> 4.72 mg/kg/day. LOAEL is 33.6 mg/kg/day based on decreases in body
> weight and body weight gain, and adverse liver effects (increased
> liver weight and periportal vacuolation, and dilation of the
> sinusoids).
>
> [Uncertainty Factor (UF]{.underline}): 100 This includes 10x for
> interspecies extrapolation and 10x for intraspecies variation.

+------------+-------------+---------------+-------------------------+
| **Table    |             |               |                         |
| 3.4.7.a.   |             |               |                         |
| Summary of |             |               |                         |
| Tox        |             |               |                         |
| icological |             |               |                         |
| Dose and   |             |               |                         |
| Endpoints  |             |               |                         |
| for        |             |               |                         |
| \[S\]-DIME |             |               |                         |
| THENAMID-P |             |               |                         |
| for Use in |             |               |                         |
| Dietary    |             |               |                         |
| and        |             |               |                         |
| Non-Oc     |             |               |                         |
| cupational |             |               |                         |
| Human      |             |               |                         |
| Health     |             |               |                         |
| Asse       |             |               |                         |
| ssments.** |             |               |                         |
+============+=============+===============+=========================+
| **         | **Dose Used | **FQPA SF\*   | **Study and             |
| Exposure** | in Risk     | and Level of  | Toxicological Effects** |
|            | Assessment, | Concern for   |                         |
| **         | UF**        | Risk          |                         |
| Scenario** |             | Assessment**  |                         |
+------------+-------------+---------------+-------------------------+
| Acute      | NOAEL = 75  | FQPA SF = 1X  | [Developmental Toxicity |
| Dietary    | mg/kg/day   |               | in rabbits]{.underline} |
|            |             | aPAD = [acute |                         |
| (Females   | UF = 100    | POD           | Maternal; LOAEL = 150   |
| 13-49      |             | ]{.underline} | mg/kg/day based on      |
| years of   | Acute POD=  |               | abortions and decreased |
| age)       | 0.75        | FQPA SF       | body weight gain and    |
|            | mg/kg/day   |               | food consumption.       |
| Based on   |             | = 0.75        |                         |
| \[RS\]     |             | mg/kg/day     | Developmental; LOAEL =  |
| data       |             |               | 150 mg/kg/day based on  |
|            |             |               | post-implantation loss  |
+------------+-------------+---------------+-------------------------+
| Acute      | No          |               |                         |
| Dietary    | appropriate |               |                         |
|            | endpoint    |               |                         |
| (General   | identified  |               |                         |
| population | for this    |               |                         |
| including  | population. |               |                         |
| infants    |             |               |                         |
| and        |             |               |                         |
| children)  |             |               |                         |
+------------+-------------+---------------+-------------------------+
| Chronic    | NOAEL= 5    | FQPA SF = 1X  | [                       |
| Dietary    | mg/kg/day   |               | Chronic/carcinogenicity |
|            |             | cPAD =        | rats]{.underline}       |
| (All       | UF = 100    |               |                         |
| po         |             | [chronic      | LOAEL = M/F; 36/49      |
| pulations) | Chronic POD | POD           | mg/kg/day based on      |
|            | =           | ]{.underline} | decreased body weight   |
| Based on   |             |               | and body weight gain in |
| \[RS\]     | 0.05        | FQPA SF       | both sexes, increased   |
| data       | mg/kg/day   |               | food conversion ratios  |
|            |             | = 0.05        | in females, and         |
|            |             | mg/kg/day     | increased microscopic   |
|            |             |               | hepatic lesions in both |
|            |             |               | sexes.                  |
+------------+-------------+---------------+-------------------------+
| Incidental | NOAEL= 4.72 | FQPA SF = 1X  | [Subchronic toxicity    |
| oral       | mg/kg/day   |               | study in                |
|            |             |               | dogs]{.underline}       |
| Based on   | UF = 100    |               |                         |
| \[RS\]     |             |               | LOAEL = M/F; 33.6/39.7  |
| data       |             |               | mg/kg/day, based on     |
|            |             |               | decreased body weight   |
|            |             |               | and body weight gain in |
|            |             |               | females and adverse     |
|            |             |               | liver effects           |
|            |             |               | (increased liver weight |
|            |             |               | and periportal          |
|            |             |               | vacuolation, and        |
|            |             |               | dilation of the         |
|            |             |               | sinusoids).             |
+------------+-------------+---------------+-------------------------+
| Dermal     | 30%         | No studies    |                         |
| Absorption |             | are           |                         |
|            |             | available.    |                         |
| Based on   |             | Value         |                         |
| \[RS\]     |             | estimated     |                         |
| data       |             | from the      |                         |
|            |             | ratio of the  |                         |
|            |             | LOAEL for     |                         |
|            |             | maternal      |                         |
|            |             | weight        |                         |
|            |             | decrement in  |                         |
|            |             | developmental |                         |
|            |             | study to      |                         |
|            |             | LOAEL for     |                         |
|            |             | male weight   |                         |
|            |             | decrement in  |                         |
|            |             | the 21-day    |                         |
|            |             | dermal study. |                         |
|            |             |               |                         |
|            |             | Ratio of      |                         |
|            |             | \[(           |                         |
|            |             | Developmental |                         |
|            |             | rabbit        |                         |
|            |             | maternal      |                         |
|            |             | LOAEL, body   |                         |
|            |             | we            |                         |
|            |             | ight)/(21-day |                         |
|            |             | Dermal rabbit |                         |
|            |             | LOAEL for     |                         |
|            |             | systemic      |                         |
|            |             | toxicity,     |                         |
|            |             | body          |                         |
|            |             | weight)\] X   |                         |
|            |             | 100 =         |                         |
|            |             | (150/500) x   |                         |
|            |             | 100 =30%      |                         |
+------------+-------------+---------------+-------------------------+
| Short-Term | Oral NOAEL= | Occupational  | [Subchronic toxicity    |
| Dermal (1  | 4.72        | = LOC for MOE | study in                |
| to 30      | mg/kg/day   | = 100         | dogs]{.underline}       |
| days)      |             |               |                         |
|            | Dermal      |               | LOAEL = M/F; 33.6/39.7  |
| Based on   | Absorption  |               | mg/kg/day, based on     |
| \[RS\]     | = 30%       |               | decreased body weight   |
| data       |             |               | and body weight gain in |
|            |             |               | females and adverse     |
|            |             |               | liver effects           |
|            |             |               | (increased liver weight |
|            |             |               | and periportal          |
|            |             |               | vacuolation, and        |
|            |             |               | dilation of the         |
|            |             |               | sinusoids).             |
+------------+-------------+---------------+-------------------------+
| Short-Term | Oral NOAEL= | Occupational  | [Subchronic toxicity    |
| Inhalation | 4.72        | LOC for MOE = | study in                |
| (1 to 30   | mg/kg/day   | 100           | dogs]{.underline}       |
| days)      |             |               |                         |
|            | Assume 100% |               | LOAEL = M/F; 33.6/39.7  |
| Based on   | absorption  |               | mg/kg/day, based on     |
| \[RS\]     |             |               | decreased body weight   |
| data       |             |               | and body weight gain in |
|            |             |               | females and adverse     |
|            |             |               | liver effects           |
|            |             |               | (increased liver weight |
|            |             |               | and periportal          |
|            |             |               | vacuolation, and        |
|            |             |               | dilation of the         |
|            |             |               | sinusoids).             |
+------------+-------------+---------------+-------------------------+
| Carci      | "C"         |               |                         |
| nogenicity | Possible    |               |                         |
|            | human       |               |                         |
| Based on   | carcinogen. |               |                         |
| \[RS\]     | (No         |               |                         |
| data       | Q~1~\*).    |               |                         |
|            | The cRfD is |               |                         |
|            | considered  |               |                         |
|            |             |               |                         |
|            | protective  |               |                         |
|            | of the      |               |                         |
|            | cancer      |               |                         |
|            | effects.    |               |                         |
+------------+-------------+---------------+-------------------------+

NOAEL = no observed adverse effect level. LOAEL = lowest observed
adverse effect level. UF = uncertainty factor. FQPA SF = FQPA Safety
Factor. PAD = population adjusted dose (a = acute, c = chronic). POD =
Point of Departure.

+------------+-------------+---------------+-------------------------+
| **Table    |             |               |                         |
| 3.4.7.b.   |             |               |                         |
| Summary of |             |               |                         |
| Tox        |             |               |                         |
| icological |             |               |                         |
| Dose and   |             |               |                         |
| Endpoints  |             |               |                         |
| for        |             |               |                         |
| \[S\]-DIME |             |               |                         |
| THENAMID-P |             |               |                         |
| for Use in |             |               |                         |
| Oc         |             |               |                         |
| cupational |             |               |                         |
| Human      |             |               |                         |
| Health     |             |               |                         |
| Asse       |             |               |                         |
| ssments.** |             |               |                         |
+============+=============+===============+=========================+
| **         | **Dose Used | **FQPA SF\*   | **Study and             |
| Exposure** | in Risk     | and Level of  | Toxicological Effects** |
|            | Assessment, | Concern for   |                         |
| **         | UF**        | Risk          |                         |
| Scenario** |             | Assessment**  |                         |
+------------+-------------+---------------+-------------------------+
| Short-Term | Oral NOAEL= | Occupational  | [Subchronic toxicity    |
| Dermal (1  | 4.72        | = LOC for MOE | study in                |
| to 30      | mg/kg/day   | = 100         | dogs]{.underline}       |
| days)      |             |               |                         |
|            | Dermal      |               | LOAEL = M/F; 33.6/39.7  |
| Based on   | Absorption  |               | mg/kg/day, based on     |
| \[RS\]     | = 30%       |               | decreased body weight   |
| data       |             |               | and body weight gain in |
|            |             |               | females and adverse     |
|            |             |               | liver effects           |
|            |             |               | (increased liver weight |
|            |             |               | and periportal          |
|            |             |               | vacuolation, and        |
|            |             |               | dilation of the         |
|            |             |               | sinusoids).             |
+------------+-------------+---------------+-------------------------+
| Short-Term | Oral NOAEL= | Occupational  | [Subchronic toxicity    |
| Inhalation | 4.72        | LOC for MOE = | study in                |
| (1 to 30   | mg/kg/day   | 100           | dogs]{.underline}       |
| days)      |             |               |                         |
|            | Assume 100% |               | LOAEL = M/F; 33.6/39.7  |
| Based on   | absorption  |               | mg/kg/day, based on     |
| \[RS\]     |             |               | decreased body weight   |
| data       |             |               | and body weight gain in |
|            |             |               | females and adverse     |
|            |             |               | liver effects           |
|            |             |               | (increased liver weight |
|            |             |               | and periportal          |
|            |             |               | vacuolation, and        |
|            |             |               | dilation of the         |
|            |             |               | sinusoids).             |
+------------+-------------+---------------+-------------------------+
| Carci      | "C"         |               |                         |
| nogenicity | Possible    |               |                         |
|            | human       |               |                         |
| Based on   | carcinogen. |               |                         |
| \[RS\]     | (No         |               |                         |
| data       | Q~1~\*).    |               |                         |
|            | The cPOD is |               |                         |
|            | considered  |               |                         |
|            |             |               |                         |
|            | protective  |               |                         |
|            | of the      |               |                         |
|            | cancer      |               |                         |
|            | effects     |               |                         |
+------------+-------------+---------------+-------------------------+

NOAEL = no observed adverse effect level. LOAEL = lowest observed
adverse effect level. UF = uncertainty factor. MOE = margin of exposure.
LOC = level of concern.

**3.4.8 Classification of Carcinogenic Potential**

The Carcinogenicity Peer Review of dimethenamid on 23/MAR/1995 (TXR#
012143) and 15/JUN/1992 (TXR# 012831) stated that the weight of evidence
classification was Group C - possible human carcinogen. The chronic
point of departure (cPOD) is protective for potential carcinogenic
effects. This decision was based on a statistically significant
increasing trend for liver cell tumors (benign and malignant combined)
in male rats and statistically significant increasing trend, and did not
show significance by pair wise comparison. Dimethenamid has shown
positive results in some genotoxicity tests and is structurally related
to other carcinogens. An acceptable study in mice showed no dose related
tumors.

5.  **Endocrine Disruption**

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) "may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate."
Following recommendations of its Endocrine Disruptor Screening and
Testing Advisory Committee (EDSTAC), EPA determined that there was a
scientific basis for including, as part of the program, the androgen and
thyroid hormone systems, in addition to the estrogen hormone system. EPA
also adopted EDSTAC's recommendation that the Program include
evaluations of potential effects in wildlife. For pesticide chemicals,
EPA will use FIFRA and, to the extent that effects in wildlife may help
determine whether a substance may have an effect in humans, FFDCA
authority to require the wildlife evaluations. As the science develops
and resources allow, screening of additional hormone systems may be
added to the Endocrine Disruptor Screening Program (EDSP).

In the available toxicity studies with \[RS\] and \[S\] dimethenamid
products, there was no estrogen, androgen, and/or thyroid mediated
toxicity.

[]{#refheading___toc138551329 .anchor}**4.0 Public Health and Pesticide
Epidemiology Data**

[]{#__RefHeading___Toc138551330 .anchor}**4.1 Incident Reports**

Available sources of incident data in humans were reviewed for
dimethenamid-P. These sources included the Incident Data System
consisting of reports submitted to EPA by registrants and the public
since 1992, California Pesticide Illness Surveillance Program which has
reports (primarily occupational) since 1982, seven states funded by
NIOSH provided data on occupational cases for 1998-2002, reports to the
nation\'s Poison Control Centers for 1993-2001, and reports in the
scientific literature reported on Medline. Among the above databases
only one had a single report of a spray drift victim who developed a
rash, eye irritation, and other symptoms. The dermal and eye effects
were considered consistent with the toxicity profile of dimethenamid-P,
but the systemic effects were not. No conclusions can be drawn from this
one incident, and no recommendations are warranted.

[]{#__RefHeading___Toc138551331 .anchor}**5.0 Dietary Exposure/Risk
Characterization**

[]{#__RefHeading___Toc138551332 .anchor}**5.1 Pesticide Metabolism and
Environmental Degradation**

The metabolism, or degradation of dimethenamid-P, has been adequately
studied in the rat, in plants, in ruminants and poultry, and in the
environment. Metabolism data for ruminants and poultry livestock is
presented essentially for qualitative purposes since the Agency does not
expect finite dimethenamid-P residue to occur in livestock commodities
even though dimethenamid-P may be used on animal feed stuff such as
field corn and sugar beets. Finite residues of dimethenamid-P are not
expected in livestock commodities due to the very low (less than
detection) levels of dimethenamid-P seen in residue field trial studies
on these feed items.

Based on an analysis of the structural relationship of metabolites to
parent dimethenamid-P, the toxicity of metabolites is not expected to
exceed the parent compound.

[]{#__RefHeading___Toc138551333 .anchor}**5.1.1 Metabolism in Primary
Crops**

The nature of the residue in plants is adequately understood. Soybean
and corn metabolism studies are available and have been reviewed by the
HED Metabolism Committee (M. Flood, 10/NOV/1992; and M. Bradley,
08/DEC/1993). The metabolism of dimethenamid-P in plants involves
conjugation with glutathione, with subsequent transformation of the
glutathione moiety to yield a variety of metabolites. The residue of
concern for purposes of the tolerance expression (and risk assessment)
was determined to be dimethenamid *per se.*

In addition, a sugar beet metabolism study was reviewed (DP Num: 288341,
D. Dotson, 14/APR/2004) in conjunction with various root, tuber, corm
and bulb vegetables. Following three early season foliar applications of
\[3-^14^C-thienyl\]dimethenamid to sugar beets at a total rate of 1.2 lb
ai/A, total radioactive residues (TRR) were 0.078 and 0.284 ppm in/on
sugar beet roots and tops harvested 126 days after the last treatment.
The metabolite profile was similar for roots and tops, and
dimethenamid-P was not detected in/on either commodity. For both roots
and tops, the majority of ^14^C-residues were characterized as minor
unknowns each present at ≤8% of the TRR. One unknown polar fraction
accounted for \>10% of the TRR in roots, but was present at \<0.01 ppm.
The metabolic pathway for \[^14^C\]dimethenamid in sugar beets is
complex, but proceeds *via* a pathway similar to that observed in corn
and soybeans. However, two metabolites not identified in corn or in
soybean were found in sugar beets. These are the sulfoxide of the
cysteine conjugate and the N-malonyl conjugate of the cysteine
conjugate, and together accounted for \<6 % of the TRR in sugar beets.

[]{#__RefHeading___Toc138551334 .anchor}**5.1.2 Metabolism in Animals**

The rat metabolism study indicates that dimethenamid-P, at single low
and high doses, is extensively metabolized to approximately 31
identified metabolites, and is essentially completely (90%) excreted in
the urine, feces, and bile within 7 days. Excretion products were
qualitatively independent of sex, but minor quantitative differences
were seen between males and females. In the urine, females excreted
about 47% to 63% and males about 31% to 35% at low and high oral doses,
i.v doses and multiple doses. In feces, females excreted 26% to 48% and
males 30% to 62% at low and high oral doses, i.v. doses and multiple
doses.

The primary route of metabolism is the liver with less than 2.5% of the
dose being recovered as parent. None of the metabolites were more than
10% with most being less than 2% as free or conjugate. On the basis of
the metabolites identified in the urine and feces, the primary metabolic
pathways for dimethenamid-P involve glutathione conjugation via
displacement of the chlorine atom followed by (1) breakdown of the
glutathione to mercapturic acid, or (2) hydrolysis of the thio bond of
mercaptan, which is then methylated and oxidized to the methylsufoxide
and methylsulfone. Additional major metabolic reactions include
O-methylation of the 2-methoxyl-1-methylethyl moiety to form a
2-hydroxylated product and oxidation of the 2-methyl group on the
thiophene ring to produce a hydroxymethyl. Dimerization, cyclization,
and hydroxylation at the thiol also occur following hydrolysis of the
glutathione conjugate. Other minor pathways for dimethenamid-P involve
direct biotransformation reactions such as reductive chlorination,
oxidation of the sulfur on the thiophene ring to form a sulfoxide,
oxidation of the 2- or 4-methyl group on the thiophene ring, and
cyclization and hydroxylation of the thiol. Saturation of glutathione
pathway may have occurred at the higher dose.

There are no rat metabolism studies with \[S\]-dimethenamid, however,
consideration of the potential differences in metabolism of the \[R\]
and \[S\] enantiomer of dimethenamid indicates that few of the products
are likely to be affected by the orientation of the asymmetric carbon,
since most metabolism occurs at least 2 carbons and a nitrogen removed
from the asymmetric center. However, products including a nitrogen
containing ring structure may be preferentially formed depending on
possible steric hindrance in the ring.

[]{#__RefHeading___Toc138551335 .anchor}**5.1.3 Metabolism in Rotational
Crops**

The requirements for confined accumulation in rotational crops are
satisfied. An adequate confined rotational crop study was reviewed by
the Agency. The study includes data on winter wheat planted 141 days
after treatment (DAT), lettuce planted 322 DAT, and carrots planted 332
DAT. The maximum concentration of any metabolite/degradate in harvested
wheat was 0.01 ppm for the sulfoxide of thiolactic acid conjugate. Based
on these data, HED concluded that a 4-month rotational interval is
adequate for fall-seeded cereal grains and other crops may be planted
the following spring. The current use directions specify that treated
areas may be replanted at any time with crops which have dimethenamid-P
tolerances.

[]{#__RefHeading___Toc138551336 .anchor}**5.1.4 Metabolism in
Livestock**

*Ruminant:* In the ruminant metabolism study, a dairy goat was dosed
orally for 4 days with \[^14^C\]dimethenamid at levels equivalent to 223
ppm (\>10,000x the maximum theoretical dietary burden (MTDB) of 0.019
ppm). Total radioactive residues were 16.6 ppm in liver, 9.9 ppm in
kidneys, 0.97 ppm in muscle and fat, and 0.98 ppm in milk.
\[^14^C\]Dimethenamid was extensively metabolized and identification of
metabolites was limited.

*Poultry:* In the poultry metabolism study, three hens were dosed orally
for 4 days with \[^14^C\]dimethenamid at levels equivalent to 167 ppm
(17,000x MTDB of 0.01 ppm). Total radioactive residues were 8.33 ppm in
liver, 0.58 ppm in muscle, 0.29 ppm in fat, 0.30 ppm in egg whites and
0.62 ppm in egg yolks. The metabolism of \[^14^C\]dimethenamid in hens
was extensive, with parent only being identified in fat (34.9% TRR).
Other than parent in fat, no one compound appears to account for more
than 10% of the TRR in any given tissue. Although only limited
identification of ^14^C-residues was achieved, the poultry metabolism
study was deemed adequate because the dosing level was highly
exaggerated compared to the MTDB and the extensive metabolism of
dimethenamid resulted in numerous minor metabolites (\<10% TRR).

Note that after considering the extensive metabolism of dimethenamid in
animals, the exaggerated dosing levels used in the animal metabolism
studies, and the expected low level of dietary exposure of livestock to
dimethenamid, the HED Metabolism Assessment Review Committee (MARC)
concluded that tolerances (enforcement and risk assessment) are not
required for livestock commodities (M. Flood, 10/NOV/1992).

[]{#__RefHeading___Toc138551337 .anchor}**5.1.5 Analytical Methodology**

An adequate enforcement method is available for determining
dimethenamid-P residues in plants and soil. The gas chromatography with
a nitrogen phosphorus detector (GC/NPD) method (AM-0884-0193-1) has been
validated by the Agency and submitted for publication in FDA's Pesticide
Analytical Manual, Volume II. The method does not separate the R and S
isomers of dimethenamid and the limit of quantitation (LOQ) is 0.01. As
tolerances are not required for animal commodities, no analytical
methods for livestock commodities are required.

**5.1.6 Multiresidue Methods**

Number range CHAPTERThe FDA PESTDATA database dated NOV/2001 (PAM Volume
I, Appendix I) indicates that dimethenamid is not recovered using
Multiresidue Methods Section 303 (Mills, Onley, and Gaither Method;
Protocol E, nonfatty food) or Section 304 (Mills Method; Protocol F,
fatty food). The gas chromatography with mass selective detection
(GC/MSD) method has been submitted for publication in FDA's PAM, Vol.
II.

**5.1.7 Magnitude in Plants**

Two sets of data were submitted for the regional registration of
dimethenamid-P for use on grasses grown for seed. One set of data is for
the Western U.S. (MRID 45649401), and the other is for the Northwest
U.S. (MRID 46710201).

[]{#__RefHeading___Toc138551338 .anchor}**5.1.8 Environmental
Degradation**

Dimethenamid-P is mobile (K~d~ = 1.4 to 3.0) and moderately persistent
in the environment. Dimethenamid-P is moderately susceptible to aerobic
biodegradation (mean half-life = 37 days at the 90% confidence
interval), and stable to hydrolysis. Photodegradation in aqueous media
is expected to be a minor route of dissipation. Dimethenamid-P is likely
to leach to ground water, and has the potential to contaminate drinking
water.

Based on an aerobic soil metabolism study conducted on both \[RS\] and
\[S\]-only dimethenamid, three minor degradates, M23 (oxalamide), M31
(STGA), and M27 (sulfonate sodium salt) were recovered at maximums of
less than or equal to 8% of the applied radioactivity. Three other
degradates M30 (STLA), M32 (TGA) and M11 (based on HPLC analysis) were
present at 3.8% of the applied radioactivity from 0 to 182 days
post-treatment. \[^14^C\]Residues associated with the fulvic acid, humic
acid and humin fractions were maximums of 8.6-8.9% (56 days), 23.0-25.1%
(84 days) and 9.6-10.4% (182 days) of the applied radioactivity,
respectively. Evolved ^14^CO~2~ accounted for 28.5-29.2% of the applied
radioactivity at 182 days post-treatment.

[]{#__RefHeading___Toc138551339 .anchor}**5.1.9 Comparative Metabolic
Profile**

Dimethenamid-P is readily absorbed through the rat gastro-intestinal
tract and is primarily excreted in the urine, with most of a dose being
excreted in 24 hours for low doses and 48 hours for higher doses.
Biliary excretion is significant but is a minor route. The tissue burden
is low, with up to only 3.3% of the dose remaining in the tissues. A
total of 10 fractions (nine metabolites and one isomer) were noted in
the urine and 5 fractions in the feces. The major urinary metabolites in
these fractions were sulfate and glucuronide conjugates and the major
fecal metabolite was a p-hydroxy derivative of dimethenamid-P. The
sulfate and glucuronide conjugates and p-hydroxy derivative of
dimethenamid-P were recognized as the biliary metabolites. Dimethenamid
per se, was detected only in small amounts in the urine and feces. Minor
quantitative differences related to gender were identified.

Metabolism of dimethenamid-P in other animals (poultry and ruminants)
appears to be similar to its metabolism in rats. The metabolism seems to
proceed by de-chlorination of the pyridazinone ring to yield a
dechlorinated dimethenamid-P or by hydroxylation of the phenyl ring to
yield a hydroxylated dimethenamid-P. The hydroxylated dimethenamid-P may
further degrade to form a sulfate conjugate of p-hydroxy dimethenamid-P.

The major residues found in plants include parent dimethenamid-P,
dephenylated dimethenamid-P and conjugates of each. Residues of parent
dimethenamid-P tend to predominate after post-emergent treatment of
sugar beets, while residues of desphenyl dimethenamid-P or its
conjugates predominate after pre-emergent treatment. Residues of
desphenyl dimethenamid-P or its conjugates also predominate in
rotational crops. Since the most significant route of soil degradation
of dimethenamid-P is microbial formation of desphenyl dimethenamid-P,
this pattern seems to suggest that the desphenyl metabolites are more
predominantly the result of soil metabolism and subsequent uptake by
plants than of plant metabolism itself.

[]{#__RefHeading___Toc138551340 .anchor}**5.1.10 Toxicity Profile of
Major Metabolites and Degradates**

Little information is available on the toxicity of the major
dimethenamid-P metabolites. The hydroxy dimethenamid-P metabolite formed
in livestock appears to also be formed in the rat, and is, therefore,
part of the total toxic exposure for these animals. It is unlikely to be
more toxic than the parent.

The desphenyl metabolite is also unlikely to be more toxic than the
parent. It is difficult to know, however, what effect the removal of the
entire benzene ring will have on the toxicology. This metabolite is not
formed in rats and, therefore, is not a part of the toxic profile to
which the rat is exposed when dosed with the parent. After correction
for molecular weight differences, the LD~50~ of the parent and of the
desphenyl metabolite are similar.

[]{#__RefHeading___Toc138551341 .anchor}**5.1.11 Drinking Water Residue
Profile**

Data relevant to dimethenamid-P residues in drinking water have been
evaluated by EFED, and EDWCs were provided in a risk assessment (DP Num:
326961, 326977, 327936, K. Moore, 23/JAN/2007). EDWCs have been
predicted using scenarios for green onions, grass for seed, and
ornamentals as surrogates for use on all crops, using acceptable
environmental fate and transport data submitted to the Agency. The
maximum proposed seasonal application rate is 3.0 lb ai/A for
ornamentals (maximum of 1.5 lb ai/A for individual applications), which
can be divided into 2 applications per year, made at 42-day intervals.

Dimethenamid-P is mobile (K~d~ = 1.4 to 3.0), moderately persistent in
the environment, moderately susceptible to aerobic biodegradation (mean
half-life = 37 days at the 90% confidence interval), and stable to
hydrolysis. Photodegradation in aqueous media is expected to be a minor
route of dissipation. Dimethenamid-P is likely to leach to ground water,
and has the potential to contaminate drinking water. In most cases, data
for both the racemic mixture and the resolved isomer were used to
generate model input values. Submitted aerobic soil metabolism
half-lives were not significantly different, and therefore not
distinguishable, between the resolved and the mixed isomers.

[Tier II surface water concentrations are predicted by the Pesticide
Root Zone Model/ Exposure Analysis Modeling System (PRZM/EXAMS at 66.7
ug/L for acute exposure and 20.2 ug/L for non-cancer chronic exposure.
Ground water concentrations of 0.34 ug/L and 1.0 ug/L were predicted by
the Tier I model,]{.mark} Screening Concentration In GROund Water
([SCIGROW). This assessment is for parent compound *only*.]{.mark}

[]{.mark}

+-----------------+-----------------+-------+---------+----------------+
| **Table 5.1.11  |                 |       |         |                |
| Summary of      |                 |       |         |                |
| EDWCs (ppb) for |                 |       |         |                |
| Proposed New    |                 |       |         |                |
| Uses for        |                 |       |         |                |
| Di              |                 |       |         |                |
| methenamid-P.** |                 |       |         |                |
+-----------------+-----------------+-------+---------+----------------+
| USE             | Modeled         | Su    |         | Ground Water   |
|                 | Scenario^c^     | rface |         | ^b^            |
|                 |                 | Water |         |                |
|                 | (Application    | ^a^   |         |                |
|                 | Method)         |       |         |                |
+-----------------+-----------------+-------+---------+----------------+
|                 |                 | Acute | Chronic | Acute and      |
|                 |                 |       |         | Chronic        |
+-----------------+-----------------+-------+---------+----------------+
| Grass for Seed  | OR grass seed   | 9.0   | 3.8     | 0.34           |
|                 | (Aerial Spray)  |       |         |                |
+-----------------+-----------------+-------+---------+----------------+
| Green Onions    | GA onion        | 66.7  | 8.4     | 0.34           |
|                 | (Ground spray)  |       |         |                |
+-----------------+-----------------+-------+---------+----------------+
| Ornamentals     | FL turf --      | 50.2  | 20.2    | 1.0            |
|                 | Acute           |       |         |                |
|                 |                 |       |         |                |
|                 | OR xmas --      |       |         |                |
|                 | Chronic (Aerial |       |         |                |
|                 | spray)          |       |         |                |
+-----------------+-----------------+-------+---------+----------------+

^a^ Generated using Tier 2 linked simulation models PRZM (3.12
beta)/(EXAMS (2.98.04)

^b^ Generated using Tier 1 model SCIGROW (2.3)

^c^ Only the scenarios and application methods with the highest EDWCs
are presented here. As appropriate, other scenarios and application
methods were modeled for characterization and are discussed in the
modeling section.

[]{#__RefHeading___Toc138551342 .anchor}**5.1.12 Food Residue Profile**

DP Num: 337885, D. Rate, 23/MAY/2007

Dimethenamid:
1(R,S)-2-chloro-*N*-\[(1-methyl-2-methoxy)ethyl\]-*N*-(2,4-dimethylthien-3-yl)-acetamide
is a synthetic herbicide for which permanent tolerances have been
established (40 CFR 180.464(a)) at 0.01 ppm in bean, dry, seed; beet,
garden, roots; beet, garden, tops; beet, sugar, dried pulp; beet, sugar,
molasses; beet, sugar, roots; beet, sugar, tops; corn, field, forage;
corn, field, grain; corn, field, stover; corn, pop, forage; corn, pop,
grain; corn, pop, stover; corn sweet, forage; corn, sweet, kernel plus
cobs with husk removed; corn, sweet, stover; garlic; horseradish; leek;
onion, dry bulb; onion, green; onion, Welsh; peanut, hay; peanut,
nutmeat; shallot, bulb; shallot, fresh leaves; sorghum, grain; sorghum,
grain, forage; sorghum, grain, stover; soybean, seed; and tuberous and
corm vegetables. A time-limited tolerance (Section 18) was established
for winter squash (40 CFR 180.464(b)). The residue of concern for
enforcement and risk assessment purposes is dimethenamid p*er se.* As
part of the current petition, ARIA recommends establishing permanent
tolerances for residues of dimethenamid in/on grass, forage at 0.15 ppm,
grass, hay at 2.5 ppm, grass, straw at 0.01 ppm, and grass, seed
screenings at 0.01 ppm. The maximum seasonal rate for the proposed use
on the requested crop, grasses grown for seed, is 0.98 lb ai/A.

*Residue in Crops*. The dietary risk assessment associated with the
proposed new use on grasses grown for seed, is based, in part, on the
following field trials conducted at the maximum labeled use rate (0.98
lb ai/A).

*Grasses grown for seed:* Trials were conducted with a single
application of dimethenamid-P EC at 0.98 lb ai/A (1x) as an early
post-emergence treatment (2-4 inches in height). Two sets of data were
submitted to the Agency (MRID Nos. 45649401 and 46710201) representing
studies on grasses grown in warm-season (Western U.S.) and cold-season
(Northwest U.S.) regions, respectively.

Dimethenamid-P residues in forage and hay ranged from below LOQ (0.01
ppm) to a maximum of 0.05 and 0.26 ppm, respectively (60 day PHI).
Dimethenamid-P residues were below the LOQ of 0.01 ppm in all seed
screening and straw samples collected at normal seed harvest (PHI of 217
to 314 days), with the exception of one treated seed screening sample
that had a residue value of 0.01 ppm, and one treated straw sample that
had a residue value of 0.02 ppm. Review of the submitted field trial
data and use of the MRL spreadsheet (DP Num: 326909, D. Rate,
04/MAY/2007) resulted in the recommended tolerances for residues of
dimethenamid in/on grass, forage at 0.15 ppm, grass, hay at 2.5 ppm,
grass, straw at 0.01 ppm, and grass, seed screenings at 0.01 ppm.

Due to low residue values and limited use in livestock feed, the
proposed use of dimethenamid-P on grasses grown for seed, will not
require the establishment of tolerances on livestock commodities at this
time. Therefore no new food residues will result from this proposed use.

[]{#__RefHeading___Toc138551343 .anchor}**5.1.13 International Residue
Limits**

An International Residue Limit (IRL) Status Sheet is appended to this
Risk Assessment Document. Codex has established maximum residue limits
(MRLs), expressed in terms of dimethenamid-P and its enantiomer, for
various crop commodities but not for grass commodities. Canada and
Mexico have also established MRLs for dimethenamid-P and its enantiomer
in/on various crop commodities but not for [grass, hay; grass, forage;
grass, straw; or grass, seed screenings]{.mark}.

[]{#__RefHeading___Toc138551344 .anchor}**5.2 Dietary Exposure and
Risk**

Aggregate dietary risk for dimethenamid-P is assessed by comparing acute
and chronic dietary (food and drinking water) exposure estimates to
their respective aPAD and cPAD, with risk expressed as a percent of the
PAD. The estimated acute (one day) aggregate dietary risk exposure for
females 13-49 years is less than 1% of the dimethenamid-P aPAD, and the
estimated aggregate chronic dietary (food + water) risk estimate for the
U.S. population as a whole is \<1% of the aPAD. The highest aggregate
chronic dietary (food + water) risk estimate is for the subpopulation
all infants (\<1 year) which utilizes \<3% of the dimethenamid-P cPAD
(0.05 mg/kg/day).

*Consumption Data/DEEM Software:* The acute and chronic aggregate (food
and drinking water) exposure assessment was conducted using the Dietary
Exposure Evaluation Model software with the Food Commodity Intake
Database (DEEM-FCID™, Version 1.3) which incorporates consumption data
from the USDA 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. Consumption data are averaged for the entire U.S.
population and within population subgroups for chronic exposure
assessment, but are retained as individual consumption "events" for
acute exposure assessment. Exposure estimates are expressed in mg/kg
body weight/day and risk as a percent of the aPAD/cPAD.

An upper-bound (Tier I) acute and chronic aggregate risk assessment was
conducted for dimethenamid-P food commodities and drinking water
*combined*. The residue estimate for each food commodity is based on the
tolerance for that crop and each crop is assessed as if 100% of the crop
has been treated with dimethenamid-P. The EDWC inputs (acute/chronic)
for drinking water are described as "Tier II", but are considered
upper-bound estimates for finished drinking water. It should also be
noted that, like the tolerance level inputs for foods, the residue
inputs for drinking water are point estimates rather than a residue
distribution (as seen in probabilistic assessments).

+-------------------+---+------------+---+------------------+---------------+
| **Table 5.2       |   |            |   |                  |               |
| Results of Acute  |   |            |   |                  |               |
| and Chronic       |   |            |   |                  |               |
| Dietary Exposure  |   |            |   |                  |               |
| and Risk          |   |            |   |                  |               |
| Estimates for     |   |            |   |                  |               |
| Dimethenamid-P.** |   |            |   |                  |               |
+===================+===+============+===+==================+===============+
| Population        |   | PAD,       |   | # DEEM-FCID      |               |
| Subgroup          |   | mg/kg/day  |   |                  |               |
+-------------------+---+------------+---+------------------+---------------+
|                   |   |            |   | Exposure,        | \% PAD        |
|                   |   |            |   | mg/kg/day        |               |
+-------------------+---+------------+---+------------------+---------------+
| Acute Dietary     |   |            |   |                  |               |
| Estimates (95^th^ |   |            |   |                  |               |
| Percentile of     |   |            |   |                  |               |
| Exposure)         |   |            |   |                  |               |
+-------------------+---+------------+---+------------------+---------------+
| Females 13-49 yrs |   | 0.75       |   | 0.003283         | \< 1          |
+-------------------+---+------------+---+------------------+---------------+
| Chronic Dietary   |   |            |   |                  |               |
| Estimates         |   |            |   |                  |               |
+-------------------+---+------------+---+------------------+---------------+
| Population        | P |            | D |                  |               |
| Subgroups         | A |            | E |                  |               |
|                   | D |            | E |                  |               |
|                   | , |            | M |                  |               |
|                   | m |            | - |                  |               |
|                   | g |            | F |                  |               |
|                   | / |            | C |                  |               |
|                   | k |            | I |                  |               |
|                   | g |            | D |                  |               |
|                   | / |            |   |                  |               |
|                   | d |            |   |                  |               |
|                   | a |            |   |                  |               |
|                   | y |            |   |                  |               |
+-------------------+---+------------+---+------------------+---------------+
|                   |   |            | E |                  | \% PAD        |
|                   |   |            | x |                  |               |
|                   |   |            | p |                  |               |
|                   |   |            | o |                  |               |
|                   |   |            | s |                  |               |
|                   |   |            | u |                  |               |
|                   |   |            | r |                  |               |
|                   |   |            | e |                  |               |
|                   |   |            | , |                  |               |
|                   |   |            | m |                  |               |
|                   |   |            | g |                  |               |
|                   |   |            | / |                  |               |
|                   |   |            | k |                  |               |
|                   |   |            | g |                  |               |
|                   |   |            | / |                  |               |
|                   |   |            | d |                  |               |
|                   |   |            | a |                  |               |
|                   |   |            | y |                  |               |
+-------------------+---+------------+---+------------------+---------------+
| U.S. Population   | 0 |            | 0 |                  | 0.9           |
|                   | . |            | . |                  |               |
|                   | 0 |            | 0 |                  |               |
|                   | 5 |            | 0 |                  |               |
|                   |   |            | 0 |                  |               |
|                   |   |            | 4 |                  |               |
|                   |   |            | 6 |                  |               |
|                   |   |            | 9 |                  |               |
+-------------------+---+------------+---+------------------+---------------+
| All infants (\< 1 | 0 |            | 0 |                  | 2.9           |
| yr)               | . |            | . |                  |               |
|                   | 0 |            | 0 |                  |               |
|                   | 5 |            | 0 |                  |               |
|                   |   |            | 1 |                  |               |
|                   |   |            | 4 |                  |               |
|                   |   |            | 6 |                  |               |
|                   |   |            | 0 |                  |               |
+-------------------+---+------------+---+------------------+---------------+
| Children 1-2 yrs  | 0 |            | 0 |                  | 1.5           |
|                   | . |            | . |                  |               |
|                   | 0 |            | 0 |                  |               |
|                   | 5 |            | 0 |                  |               |
|                   |   |            | 0 |                  |               |
|                   |   |            | 7 |                  |               |
|                   |   |            | 2 |                  |               |
|                   |   |            | 7 |                  |               |
+-------------------+---+------------+---+------------------+---------------+
| Children 3-5 yrs  | 0 |            | 0 |                  | 1.4           |
|                   | . |            | . |                  |               |
|                   | 0 |            | 0 |                  |               |
|                   | 5 |            | 0 |                  |               |
|                   |   |            | 0 |                  |               |
|                   |   |            | 6 |                  |               |
|                   |   |            | 9 |                  |               |
|                   |   |            | 1 |                  |               |
+-------------------+---+------------+---+------------------+---------------+
| Children 6-12 yrs | 0 |            | 0 |                  | 1.0           |
|                   | . |            | . |                  |               |
|                   | 0 |            | 0 |                  |               |
|                   | 5 |            | 0 |                  |               |
|                   |   |            | 0 |                  |               |
|                   |   |            | 4 |                  |               |
|                   |   |            | 8 |                  |               |
|                   |   |            | 0 |                  |               |
+-------------------+---+------------+---+------------------+---------------+
| Youth 13-19 yrs   | 0 |            | 0 |                  | 0.7           |
|                   | . |            | . |                  |               |
|                   | 0 |            | 0 |                  |               |
|                   | 5 |            | 0 |                  |               |
|                   |   |            | 0 |                  |               |
|                   |   |            | 3 |                  |               |
|                   |   |            | 5 |                  |               |
|                   |   |            | 8 |                  |               |
+-------------------+---+------------+---+------------------+---------------+
| Adults 20-49 yrs  | 0 |            | 0 |                  | 0.9           |
|                   | . |            | . |                  |               |
|                   | 0 |            | 0 |                  |               |
|                   | 5 |            | 0 |                  |               |
|                   |   |            | 0 |                  |               |
|                   |   |            | 4 |                  |               |
|                   |   |            | 3 |                  |               |
|                   |   |            | 3 |                  |               |
+-------------------+---+------------+---+------------------+---------------+
| Adults 50+ yrs    | 0 |            | 0 |                  | 0.9           |
|                   | . |            | . |                  |               |
|                   | 0 |            | 0 |                  |               |
|                   | 5 |            | 0 |                  |               |
|                   |   |            | 0 |                  |               |
|                   |   |            | 4 |                  |               |
|                   |   |            | 4 |                  |               |
|                   |   |            | 5 |                  |               |
+-------------------+---+------------+---+------------------+---------------+
| Females 13-49 yrs | 0 |            | 0 |                  | 0.9           |
| old               | . |            | . |                  |               |
|                   | 0 |            | 0 |                  |               |
|                   | 5 |            | 0 |                  |               |
|                   |   |            | 0 |                  |               |
|                   |   |            | 4 |                  |               |
|                   |   |            | 3 |                  |               |
|                   |   |            | 0 |                  |               |
+-------------------+---+------------+---+------------------+---------------+

[]{#__RefHeading___Toc138551345 .anchor}**6.0 Residential
(Non-Occupational) Exposure/Risk Characterization**

There are no non-agricultural (or residential) uses of dimethenamid-P.
Therefore, potential risk from such uses is not addressed in this risk
assessment.

[]{#__RefHeading___Toc138551346 .anchor}**6.1 Other (Spray Drift,
etc.)**

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 the ground application method employed for
dimethenamid-P. 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. On a chemical by chemical basis, the Agency is now requiring
interim mitigation measures for aerial applications that must be placed
on product 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 with specific products with significant risks
associated with drift.

[]{#__RefHeading___Toc138551347 .anchor}**7.0 Aggregate Risk Assessments
and Risk Characterization**

In accordance with the FQPA, ARIA must consider and aggregate 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.

Tier II surface water concentrations are predicted by the PRZM/EXAMS
model at 66.7 ug/L for the highest acute exposure, 20.2 ug/L for the
highest chronic exposure. Ground water concentrations of 0.34ug/L were
predicted by the less refined, Tier I model, SCIGROW. This drinking
water assessment is for the parent compound only (DP Num: 326961,
3326977, 327936, K. Moore, 23/JAN/2007).

Aggregate dietary risk for dimethenamid-P is assessed by comparing acute
and chronic dietary (food and drinking water) exposure estimates to
their respective aPAD and cPAD, with risk expressed as a percent of the
PAD. There are no residential, or other non-agricultural uses of
dimethenamid-P. An aggregate cancer risk analysis was not performed.
Aggregate risk is based on tolerance-level residues and an assumption of
100%CT for the food uses, and on Tier II estimates for the drinking
water contamination that may be associated with crop uses. Exposure
estimates that are less than 100% of the aPAD/cPAD are not of concern.
[]{.mark}The dietary aPAD risk estimate for child-bearing females is
less than 1% of the aPAD. The dietary cPAD risk estimates for the
general U.S. population and the most exposed population subgroup
(infants \< 1 year) are less than 3% of the cPAD. Since there are no
residential uses of exposure for dimethenamid-P, and water and food are
both included in the dietary exposure estimate, no further calculations
are necessary. Exposure estimates are less than 100% of the aPAD/cPAD;
therefore, risks are below ARIA's level of concern.

[]{#__RefHeading___Toc138551348 .anchor}**8.0 Cumulative Risk
Characterization/Assessment**

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

[]{#__RefHeading___Toc138551349 .anchor}**9.0 Occupational Exposure/Risk
Pathway**

An occupational risk assessment was completed for this Section 3
registration request of dimethenamid-P for its use on grasses grown for
seed and for use on ornamental plantings (DP Num: 339192, M. Dow,
08/MAY/2007).

For this submission, the Outlook^TM^ label specifies a maximum of 21 fl
oz/A/season that may be applied to grasses grown for seed. It should be
applied prior to weed emergence and must be moved into the upper soil
surface by rainfall or sprinkler irrigation. The draft label states that
it should be applied with ground equipment in 10 gallons of water/A.
Outlook^TM^ may be applied aerially to grasses grown for seed. There is
a 30 day pregrazing interval for warm-season perennial grasses and a 60
day pregrazing interval for cool-season perennial grasses. The label
directs applicators and other handlers to wear personal protective
equipment (PPE) consisting of long-sleeved shirt, long pants, shoes plus
socks, chemical resistant gloves and protective eyewear. There is a 12
hour restricted entry interval (REI).

Dimethenamid-P Ornamentals Herbicide (DOH) is not a currently registered
product. The proposed label indicates it is \"For Use as a Preemergence
Weed Control Herbicide in Landscape or Grounds Maintenance and
Ornamental Production\". It also contains 6.0 lb ai/gallon (63.9 % ai).
The product may only be applied by professional applicators. It may not
be \"privately\" applied by \"residents\". It may not be applied to any
type of improved or unimproved lawn or turfgrass. DOH may NOT be applied
aerially and it may NOT be applied through any type of irrigation
system, herbigation system or chemigation system. It may NOT be used
inside greenhouses, shade houses or other enclosed structures. The PPE
required and the REI are the same as noted above for Outlook^TM^. The
rate of application ranges from 21 - 32 fl oz/A (0.98 - 1.5 lb ai/A).
There is a seasonal maximum of 64 fl oz/A (3.0 lb ai/A/season). When
sequential applications are made, there is a re-application interval of
6 - 8 weeks.

A summary of the proposed use patterns used in the occupational risk and
exposure assessment are provided in below in Table 9.0.

  -----------------------------------------------------------------------
  **Table 9.0 Summary   
  of Proposed Use       
  Pattern for           
  Dimethenamid-P**      
  --------------------- -------------------------------------------------
  Formulation           Two products - 6.0 lb ai/gallon liquid, 63.9 %,
                        Outlook^TM^ EPA Reg. No. 7969-156; Dimethenamid-P
                        Ornamentals Herbicide (EPA Reg. No. 7969 - XXX).

  Crop/Site             perennial grasses grown for seed; containerized
                        ornamentals, commercial evergreen plantations,
                        maintained landscape ornamentals, general areas
                        that are maintained.

  Pest                  annual grasses, broadleaf weeds, sedges.

  Method of Applic.     aerial, ground boom, low-pressure handwand,
                        backpack

  Max. Applic. Rate     21 - 32 fl oz/A; (0.98 - 1.5 lb ai/A).

  Max. No. Applications 2 per season at the high rate of application for
                        a total of 64 fl oz/A/season

  Applic. Interval      6 - 8 weeks

  Preharvest Interval   N/A

  Restricted Entry      12 hours
  Interval              

  Manufacturer          BASF
  -----------------------------------------------------------------------

[]{#__RefHeading___Toc138551350 .anchor}**9.1 Occupational Pesticide
Handler Exposure**

Based upon the proposed use patterns, ARIA believes that the most highly
exposed occupational pesticide handlers will be mixer/loaders using
open-pour loading of liquid formulation, applicators using open-cab,
ground-boom sprayers, backpack sprayers, low-pressure hand-wand sprayers
and aerial applicators. Since dimethenamid-P is an herbicide, its use
around landscape plantings must be rather precise to minimize the
possibility of off-target spray. As such, low-pressure handwand sprayers
are more appropriate than high-pressure sprayers. There is no need for
canopy penetration or total foliar coverage as with other types of pest
control. Since the treatment blocks (*i.e*., areas treated) are
relatively small for the proposed new crop uses (as compared to typical
field crops such as cotton, corn, soybeans or wheat) and since repeat
applications are separated by 6 - 8 weeks, ARIA believes pesticide
handlers will be exposed to short-term duration (1 - 30 days) exposures
but not to intermediate-term (1 - 6 months) duration exposures.

Particularly for ground applications, private (*i.e.,* grower)
applicators may perform all functions, that is, mix, load and apply the
material. The HED ExpoSAC SOP Number 12 (29 March 2000) directs that
although the same individual may perform all those tasks, they shall be
assessed separately. The available exposure data for combined
mixer/loader/applicator scenarios are limited in comparison to the
monitoring of these two activities separately. These exposure scenarios
are outlined in the Pesticide Handler Exposure Database (PHED) Surrogate
Exposure Guide (August 1998). HED has adopted a methodology to present
the exposure and risk estimates separately for the job functions in some
scenarios and to present them as combined in other cases. Most exposure
scenarios for hand-held equipment (such as hand wands, backpack
sprayers, and push-type granular spreaders) are assessed as a combined
job function. With these types of hand held operations, all handling
activities are assumed to be conducted by the same individual. The
available monitoring data support this and HED presents them in this
way. Conversely, for equipment types such as fixed-wing aircraft,
groundboom tractors, or air-blast sprayers, the applicator exposures are
assessed and presented separately from those of the mixers and loaders.
By separating the two job functions, HED determines the most appropriate
levels of (PPE for each aspect of the job without requiring an
applicator to wear unnecessary PPE that might be required for a
mixer/loader (*e.g.,* chemical resistant gloves may only be necessary
during the pouring of a liquid formulation).

No chemical specific data were available with which to assess potential
exposure to pesticide handlers. The estimates of exposure to pesticide
handlers are based upon surrogate study data available in the PHED (v.
1.1, 1998).

Data are also taken from the Outdoor Residential Exposure Task Force\'s
(ORETF) LCO Exposure Study (MRID 449722-01). The ORETF data are
proprietary and only for use by members of the ORETF. BASF is a member
in good standing. For this assessment, ARIA cites the unit exposure data
for a professional lawn care operator (LCO) that mixes and loads a
liquid formulation and applies the material from a low-pressure
hand-wand type sprayer. Use of these unit exposures is appropriate given
the proposed use pattern and label restrictions. From this study for
purposes of risk assessment, the HED ExpoSAC directs that the geometric
mean be used for dermal exposure and the arithmetic mean be used for
inhalation exposure.

For pesticide handlers, it is HED standard practice to present estimates
of dermal exposure for "baseline" that is, for workers wearing a single
layer of work clothing consisting of a long sleeved shirt, long pants,
shoes plus socks and no protective gloves as well as for "baseline" and
the use of protective gloves or other PPE as might be necessary.

Relative to the review herein, the toxicology team identified a
short-term duration (1 - 30 days) dermal toxicological endpoint from a
subchronic toxicity study in the dog. The effects seen were decreased
body weight and decreased body weight gains in females and adverse liver
effects (increase liver weights and periportal vacuolation and dilation
of the sinusoids). The NOAEL is 4.72 mg ai/kg bw/day. The toxicology
team identified a 30 % dermal absorption factor for use in assessing
dermal exposure. A MOE of 100 is adequate for occupational exposures.

The RAB2 toxicology team also identified a short-term duration
inhalation toxicological endpoint. It is the same endpoint as identified
for dermal exposure, identified from the same subchronic toxicity study
in the dog and with the same NOAEL (4.72 mg ai/kg bw/day). HED and ARIA
assume 100% absorption via the inhalation route of exposure.

To calculate MOEs, dermal and inhalation exposures are summed since the
dermal and inhalation toxicological endpoints are the same and
identified from the same study.

Dimethenamid-P is classified as a group \"C\", possible human carcinogen
however no cancer potency factor was identified therefore an
occupational risk assessment for cancer effects is not necessary.

Applying these assumptions and parameters, the risks and exposures to
occupational pesticide handlers were estimated and presented in Table
9.1.

+-----------------+------+--------+---+------------+--------+------------+
| **Table 9.1     |      |        |   |            |        |            |
| Estimated       |      |        |   |            |        |            |
| Handler         |      |        |   |            |        |            |
| Exposure and    |      |        |   |            |        |            |
| Risk from the   |      |        |   |            |        |            |
| Proposed Uses   |      |        |   |            |        |            |
| of              |      |        |   |            |        |            |
| D               |      |        |   |            |        |            |
| imethenamid-P** |      |        |   |            |        |            |
+=================+======+========+===+============+========+============+
| **Unit          | *    | *      | * |            | **NOAE | **MOE^6^** |
| Exposure^1^**   | *App | *Units | * |            | L^5^** |            |
|                 | lic. | Treate | A |            |        | **SH       |
| **mg ai/lb      | R    | d^3^** | v |            | mg     | ORT-TERM** |
| handled**       | ate^ |        | e |            | ai/kg  |            |
|                 | 2^** | Per    | r |            | bw/day |            |
|                 |      | Day    | a |            |        |            |
|                 |      |        | g |            |        |            |
|                 |      |        | e |            |        |            |
|                 |      |        | D |            |        |            |
|                 |      |        | a |            |        |            |
|                 |      |        | i |            |        |            |
|                 |      |        | l |            |        |            |
|                 |      |        | y |            |        |            |
|                 |      |        | * |            |        |            |
|                 |      |        | * |            |        |            |
|                 |      |        |   |            |        |            |
|                 |      |        | * |            |        |            |
|                 |      |        | * |            |        |            |
|                 |      |        | D |            |        |            |
|                 |      |        | o |            |        |            |
|                 |      |        | s |            |        |            |
|                 |      |        | e |            |        |            |
|                 |      |        | * |            |        |            |
|                 |      |        | * |            |        |            |
|                 |      |        | ^ |            |        |            |
|                 |      |        | 4 |            |        |            |
|                 |      |        | ^ |            |        |            |
|                 |      |        |   |            |        |            |
|                 |      |        | * |            |        |            |
|                 |      |        | * |            |        |            |
|                 |      |        | m |            |        |            |
|                 |      |        | g |            |        |            |
|                 |      |        | a |            |        |            |
|                 |      |        | i |            |        |            |
|                 |      |        | / |            |        |            |
|                 |      |        | k |            |        |            |
|                 |      |        | g |            |        |            |
|                 |      |        | b |            |        |            |
|                 |      |        | w |            |        |            |
|                 |      |        | / |            |        |            |
|                 |      |        | d |            |        |            |
|                 |      |        | a |            |        |            |
|                 |      |        | y |            |        |            |
|                 |      |        | * |            |        |            |
|                 |      |        | * |            |        |            |
+-----------------+------+--------+---+------------+--------+------------+
| *Mixer/Loader - |      |        |   |            |        |            |
| Liquid -        |      |        |   |            |        |            |
| Open-pour       |      |        |   |            |        |            |
| Supporting      |      |        |   |            |        |            |
| Aerial          |      |        |   |            |        |            |
| Operations to   |      |        |   |            |        |            |
| Grasses Grown   |      |        |   |            |        |            |
| for Seed*       |      |        |   |            |        |            |
+-----------------+------+--------+---+------------+--------+------------+
| Dermal:         | 0.98 | 350    | S |            | 4.72   | SLNoGlove  |
|                 | lb   | A/day  | L |            |        |            |
| SLNoGlove 2.9   | ai/A |        | N |            |        | 1          |
| HC              |      |        | o |            |        |            |
|                 |      |        | G |            |        | SLWGlove   |
| SLWGloves 0.023 |      |        | l |            |        |            |
| HC              |      |        | o |            |        | 118        |
|                 |      |        | v |            |        |            |
| Inhal 0.0012 HC |      |        | e |            |        |            |
|                 |      |        | 4 |            |        |            |
|                 |      |        | . |            |        |            |
|                 |      |        | 2 |            |        |            |
|                 |      |        | 6 |            |        |            |
|                 |      |        |   |            |        |            |
|                 |      |        | S |            |        |            |
|                 |      |        | L |            |        |            |
|                 |      |        | W |            |        |            |
|                 |      |        | G |            |        |            |
|                 |      |        | l |            |        |            |
|                 |      |        | o |            |        |            |
|                 |      |        | v |            |        |            |
|                 |      |        | e |            |        |            |
|                 |      |        | 0 |            |        |            |
|                 |      |        | . |            |        |            |
|                 |      |        | 0 |            |        |            |
|                 |      |        | 3 |            |        |            |
|                 |      |        | 4 |            |        |            |
|                 |      |        |   |            |        |            |
|                 |      |        | I |            |        |            |
|                 |      |        | n |            |        |            |
|                 |      |        | h |            |        |            |
|                 |      |        | a |            |        |            |
|                 |      |        | l |            |        |            |
|                 |      |        | 0 |            |        |            |
|                 |      |        | . |            |        |            |
|                 |      |        | 0 |            |        |            |
|                 |      |        | 0 |            |        |            |
|                 |      |        | 5 |            |        |            |
|                 |      |        | 9 |            |        |            |
+-----------------+------+--------+---+------------+--------+------------+
| *Applicator -   |      |        |   |            |        |            |
| Ground-boom -   |      |        |   |            |        |            |
| Open Cab for    |      |        |   |            |        |            |
| Ornamentals*    |      |        |   |            |        |            |
+-----------------+------+--------+---+------------+--------+------------+
| Dermal:         | 1.5  | 200    | S |            | 4.72   | SLNoGlove  |
|                 | lb   | A/day  | L |            |        |            |
| SLNoGlove 0.014 |      |        | N |            |        | 222        |
| HC              | ai/A |        | o |            |        |            |
|                 |      |        | G |            |        | SLWGlove   |
| SLWGloves 0.014 |      |        | l |            |        |            |
| MC              |      |        | o |            |        | 222        |
|                 |      |        | v |            |        |            |
| Inhal 0.00074   |      |        | e |            |        |            |
| HC              |      |        | 0 |            |        |            |
|                 |      |        | . |            |        |            |
|                 |      |        | 0 |            |        |            |
|                 |      |        | 1 |            |        |            |
|                 |      |        | 8 |            |        |            |
|                 |      |        |   |            |        |            |
|                 |      |        | S |            |        |            |
|                 |      |        | L |            |        |            |
|                 |      |        | W |            |        |            |
|                 |      |        | G |            |        |            |
|                 |      |        | l |            |        |            |
|                 |      |        | o |            |        |            |
|                 |      |        | v |            |        |            |
|                 |      |        | e |            |        |            |
|                 |      |        | 0 |            |        |            |
|                 |      |        | . |            |        |            |
|                 |      |        | 0 |            |        |            |
|                 |      |        | 1 |            |        |            |
|                 |      |        | 8 |            |        |            |
|                 |      |        |   |            |        |            |
|                 |      |        | I |            |        |            |
|                 |      |        | n |            |        |            |
|                 |      |        | h |            |        |            |
|                 |      |        | a |            |        |            |
|                 |      |        | l |            |        |            |
|                 |      |        | 0 |            |        |            |
|                 |      |        | . |            |        |            |
|                 |      |        | 0 |            |        |            |
|                 |      |        | 0 |            |        |            |
|                 |      |        | 3 |            |        |            |
|                 |      |        | 1 |            |        |            |
|                 |      |        | 7 |            |        |            |
+-----------------+------+--------+---+------------+--------+------------+
| *Aerial         |      |        |   |            |        |            |
| Applicator for  |      |        |   |            |        |            |
| Grasses Grown   |      |        |   |            |        |            |
| for Seed*       |      |        |   |            |        |            |
+-----------------+------+--------+---+------------+--------+------------+
| Dermal:         | 0.98 | 350    | S |            | 4.72   | SLNoGlove  |
|                 | lb   |        | L |            |        |            |
| SLNoGlove 0.005 | ai/A | A/day  | N |            |        | 610        |
| MC              |      |        | o |            |        |            |
|                 |      |        | G |            |        |            |
| Inhal 0.000068  |      |        | l |            |        |            |
| MC              |      |        | o |            |        |            |
|                 |      |        | v |            |        |            |
|                 |      |        | e |            |        |            |
|                 |      |        | 0 |            |        |            |
|                 |      |        | . |            |        |            |
|                 |      |        | 0 |            |        |            |
|                 |      |        | 0 |            |        |            |
|                 |      |        | 7 |            |        |            |
|                 |      |        | 4 |            |        |            |
|                 |      |        |   |            |        |            |
|                 |      |        | I |            |        |            |
|                 |      |        | n |            |        |            |
|                 |      |        | h |            |        |            |
|                 |      |        | a |            |        |            |
|                 |      |        | l |            |        |            |
|                 |      |        | 0 |            |        |            |
|                 |      |        | . |            |        |            |
|                 |      |        | 0 |            |        |            |
|                 |      |        | 0 |            |        |            |
|                 |      |        | 0 |            |        |            |
|                 |      |        | 3 |            |        |            |
|                 |      |        | 3 |            |        |            |
+-----------------+------+--------+---+------------+--------+------------+
| *Mixer/Load     |      |        |   |            |        |            |
| er/Applicator - |      |        |   |            |        |            |
| Low-Pressure    |      |        |   |            |        |            |
| Hand-wand^7^    |      |        |   |            |        |            |
| for             |      |        |   |            |        |            |
| Ornamentals*    |      |        |   |            |        |            |
+-----------------+------+--------+---+------------+--------+------------+
| Dermal:         | 1.5  | 40     |   | SLWGlove   | 4.72   | SLWGlove   |
|                 | lb   | A/day  |   | 0.13       |        |            |
| SLWGlove 0.5    | ai/A |        |   |            |        | 36         |
|                 |      |        |   | SLWGlove   |        |            |
| SLWGloves **&   |      |        |   | **&        |        | SLWGlove   |
| coveralls**     |      |        |   | c          |        | **&        |
| 0.27 LC         |      |        |   | overalls** |        | c          |
|                 |      |        |   | 0.069      |        | overalls** |
| Inhal 0.0019    |      |        |   |            |        |            |
|                 |      |        |   | Inhal      |        | 67         |
|                 |      |        |   | 0.0016     |        |            |
+-----------------+------+--------+---+------------+--------+------------+
| *Mixer/Lo       |      |        |   |            |        |            |
| ader/Applicator |      |        |   |            |        |            |
| Using Backpack  |      |        |   |            |        |            |
| Sprayer (Liquid |      |        |   |            |        |            |
| Open Pour)^8^   |      |        |   |            |        |            |
| for             |      |        |   |            |        |            |
| Ornamentals*    |      |        |   |            |        |            |
+-----------------+------+--------+---+------------+--------+------------+
| Dermal:         | 1.5  | 40     |   | SLNoGlove  | 4.72   | SLNoGlove  |
|                 | lb   | g      |   | no data    |        |            |
| SLNoGlove no    | ai/A | al/day |   |            |        | no data    |
| data            |      |        |   | SLWGlove   |        |            |
|                 |      | (=     |   | 0.032      |        | SLWGlove   |
| SLWGloves 2.5   |      | 2      |   |            |        |            |
| LC              |      | A/day) |   | Inhal      |        | 127        |
|                 |      |        |   | 0.0051     |        |            |
| Inhal 0.12 LC   |      |        |   |            |        |            |
+-----------------+------+--------+---+------------+--------+------------+

1\. Unit Exposures are taken from "PHED SURROGATE EXPOSURE GUIDE",
Estimates of Worker Exposure from The Pesticide Handler Exposure
Database Version 1.1, August 1998. Dermal: SLNoGlove = Single layer work
clothing (long pants, long-sleeved shirt, shoes plus socks) No gloves;
SLWGloves = single layer work clothing WITH the use of protective
gloves; Inhal. = Inhalation. Units = mg ai/lb of ai handled. Data
Confidence: LC = Low Confidence, MC = Medium Confidence, HC = High
Confidence.

2\. Applic. Rate. = Taken from BASF proposed labels.

3\. Units Treated are taken from "Standard Values for Daily Acres
Treated in Agriculture"; SOP No. 9.1. ExpoSAC; Revised 5 July 2000;

4\. Average Daily Dose = Unit Exposure \* Applic. Rate \* Units Treated
\* absorption factor (30 % dermal absorption) ÷ Body Weight *(*70 kg).

5\. NOAEL = No Observable Adverse Effect Level 4.72 mg ai/kg bw/day for
short-term duration dermal and inhalation exposures.

6\. MOE = Margin of Exposure = NOAEL ÷ ADD.

7\. Unit Exposures taken from ORETF study (2a); MRID 449722-01.

8\. SOP No. 9.1 indicates 40 gallons per day may be applied via backpack
sprayer. 40 gal/day ÷ 20 gal/A = 2 A/day treated.

A MOE of 100 is adequate to protect occupational pesticide handlers from
short-term occupational exposures to dimethenamid-P. MOEs are \> 100 for
all occupational activities assessed except for mixer/loader/applicator
using low-pressure hand-wand sprayers. The MOE for a
mixer/loader/applicator wearing protective gloves AND coveralls over a
single layer of work clothing is 67 which exceeds ARIA\'s level of
concern. The estimated MOE is based upon use of the highest rate of
application and the assumption that 40 acres are treated per day. If,
for this method of application, treatment is limited to 30 acres per
day, the MOE would be 90. Due to the conservative nature of the
assumptions used in the assessment and a limitation to 30 acres treated
per day using low-pressure hand-wand sprayers, the proposed use does not
exceed ARIA's level of concern. If the lower rate of application is used
(0.98 lb ai/A), the resulting MOE does not exceed ARIA's level of
concern.

ARIA is not aware of any additional, practical means by which dermal
exposure may be adequately reduced for applicators using low-pressure
hand-wand sprayers. The use of protective gloves are required on the
product label.

[]{#__RefHeading___Toc138551351 .anchor}**9.2 Postapplication Exposure
to Agricultural Workers**

It is possible for agricultural workers to have post-application
exposures to pesticide residues as a result of typical agricultural
activities. For grasses grown for seed, ARIA does not expect significant
post-application exposure. Applications are intended for very early in
the season. There are no agricultural activities that require manual
labor or other reentry soon after application. Scouting for efficacy
would not take place for several days. Most, if not all, agricultural
activities including harvesting are accomplished mechanically.
Therefore, post-application exposure and risk was not assessed for
grasses grown for seed.

The situation for the uses on ornamentals as well as around and among
established ornamental plantings is somewhat different. Typically, when
materials are applied to ornamental plantings in residential settings,
post-application exposure is not assessed. ExpoSAC believes there is
typically negligible contact of residents with ornamental plants and
post-application exposure is expected to be negligible. This product is
prohibited from use on lawns or turf. Further, the ExpoSAC does not
assess post-application exposures for uses as \"spot treatments\" such
as around driveways or walkways etc. In ARIA's view, the proposed use
patterns for established plantings, would not result in any significant
exposure to \"residents\".

However, there may be post-application exposures to agricultural workers
who might \"handle\" potted or containerized ornamentals.

HED in conjunction with the Agricultural Re-entry Task Force (ARTF) has
identified a number of post-application agricultural activities that may
occur and which may result in post-application exposures to pesticide
residues. HED has also identified Transfer Coefficients (TC) (cm²/hr)
relative to the various activities which express the amount of foliar
contact over time, during each of the activities identified**.**

The ARTF conducted an exposure study (MRID 454695-02) of workers
\"harvesting\" potted ornamentals (in 5, 7, and 15 gallon containers).
The \"harvesting\" consisted of workers moving the containerized
ornamentals from the propagation area to a transport truck and then
loading them in the truck. The TC is 400 cm^2^/hr. The study data are
proprietary and only for use by members of the ARTF. BASF is a member of
the ARTF (membership list of 5 DEC 06) and therefore there is no issue
of data compensation for their use in this risk assessment.

The TCs used in this assessment are from an interim TC Standard
Operating Procedure (SOP) developed by HED's ExpoSAC using proprietary
data from the ARTF database (SOP \# 3.1). It is the intention of HED's
ExpoSAC that this SOP will be periodically updated to incorporate
additional information about agricultural practices in crops and new
data on transfer coefficients. Much of this information will originate
from exposure studies currently being conducted by the ARTF, from
further analysis of studies already submitted to the Agency, and from
studies in the published scientific literature.

Lacking compound specific dislodgeable foliar residue (DFR) data, HED
assumes 20 % of the application rate is available as DFR on day zero
after application. This is adapted from the ExpoSAC SOP No. 003 (7 May
1998 - Revised 7 August 2000).

Occupational and residential exposure memo (DP Num: 339192, M. Dow,
02/MAY/2007) shows the formula and calculations of post-application
exposure.

The calculated MOE is 103. A MOE of 100 is adequate to protect
agricultural workers from post-application exposures. The MOE is does
not exceed ARIA's level of concern.

**9.3 Restricted Entry Interval (REI)**

Dimethenamid-P is classified in Acute Toxicity Category III for acute
dermal toxicity, acute inhalation toxicity and acute eye irritation. It
is classified in Toxicity Category IV for dermal irritation. It is a
mild dermal sensitizer. The interim worker protection standard (WPS) REI
of 12 hours is adequate to protect agricultural workers.

[]{#__RefHeading___Toc138551352 .anchor}**10.0 Data Needs and Label
Requirements**

**10.1 Toxicological Profile**

There are no toxicology deficiencies at this time.

**10.2 Residue Chemistry**

A revised Section B is required to specify that the proposed use of
Outlook™ Herbicide (EPA Reg. No. 7969-156) on grasses grown for seed is
limited to the Western and Northwest U.S. The revised Section B should
also address the amended label submission of 30 day PGI for warm-season
grasses and 60 day PGI for cool-season grasses.

The petitioner is required to submit a revised Section F to amend the
proposed tolerances for dimethenamid in/on grass, forage at 0.15 ppm;
grass, hay at 2.5 ppm; grass, straw at 0.01 ppm; and grass, seed
screenings at 0.01 ppm

[]{#__RefHeading___Toc138551353 .anchor}**10.3 Occupational and
Residential Exposure**

The label must be amended to include a restriction of 30 acres per day
for using the low-pressure hand-wand along with a requirement for the
use of gloves and coveralls. A general requirement for the use of
protective gloves is required on the product label.

[]{#__RefHeading___Toc138551354 .anchor}**References:**

DP Num: 288341, D. Dotson, 14/APR/2004

DP Num: 326961, 326977, 327936, K. Moore, 23/JAN/2007

DP Num: 337885, D. Rate, 23/MAY/2007

DP Num: 326961, 3326977, 327936, K. Moore, 23/JAN/2007

DP Num: 339192, M. Dow, 08/MAY/2007

DP Num: 270174, T. Leighton, 01/NOV/2000

DP Num: 286237, S. Hanley, 04/NOV/2002

**Appendix A: International Residue Limit Status**

+-----------------+----------------+-------------------+-------------+
| INTERNATIONAL   |                |                   |             |
| RESIDUE LIMIT   |                |                   |             |
| STATUS          |                |                   |             |
+=================+================+===================+=============+
| Chemical Name:  | Common Name:   | X Proposed        | Date:       |
| 2-chloro-*N*-(  |                | tolerance         | 12/4/06     |
| 2,4-dimethyl-3- | Dimethenamid   |                   |             |
| thienyl)-*N*-\[ | (50:50, R and  |  Reevaluated     |             |
| (1S)-2-methoxy- | S --isomers    | tolerance         |             |
| 1-methylethyl\] |                |                   |             |
| acetamide       | Dimethenamid-P |  Other           |             |
|                 | (90:10, S:R    |                   |             |
|                 | isomer ratio)  |                   |             |
+-----------------+----------------+-------------------+-------------+
| Codex Status    |                | U. S. Tolerances  |             |
| (Maximum        |                |                   |             |
| Residue Limits) |                |                   |             |
+-----------------+----------------+-------------------+-------------+
| ⁯No Codex        |                | Petition Number:  |             |
| proposal step 6 |                | PP#0F6138         |             |
| or above        |                |                   |             |
|                 |                | DP Num: 326909    |             |
| √ Codex         |                |                   |             |
| proposal step 6 |                | Other Identifier: |             |
| or above for    |                |                   |             |
| the crops       |                |                   |             |
| requested       |                |                   |             |
+-----------------+----------------+-------------------+-------------+
| Residue         |                | Reviewer/Branch:  |             |
| definition      |                | C. Swartz/RAB2    |             |
| (step 8/CXL):   |                |                   |             |
| Dimethenamid-P  |                |                   |             |
| and its         |                |                   |             |
| enantiomer.     |                |                   |             |
+-----------------+----------------+-------------------+-------------+
|                 |                | Residue           |             |
|                 |                | definition:       |             |
|                 |                | dimethenamid,     |             |
|                 |                | 1(R,              |             |
|                 |                | S)-2-chloro-*N*-\ |             |
|                 |                | [(1-methyl-2-meth |             |
|                 |                | oxy)ethyl\]-*N*-( |             |
|                 |                | 2,4-dimethylthien |             |
|                 |                | -3-yl)-acetamide, |             |
|                 |                | applied as either |             |
|                 |                | the 90:10 or      |             |
|                 |                | 50:50 S:R         |             |
|                 |                | isomersNumber     |             |
|                 |                | range             |             |
|                 |                | CHAPTERNumber     |             |
|                 |                | range CHAPTER     |             |
+-----------------+----------------+-------------------+-------------+
| Crop (s)        | MRL (mg/kg)    | Crop(s)           | Tolerance   |
|                 |                |                   | (ppm)       |
+-----------------+----------------+-------------------+-------------+
| Bean fodder     | 0.01 (\*)      | Grass, forage     | 0.05        |
+-----------------+----------------+-------------------+-------------+
| Beans (dry)     | 0.01 (\*)      | Grass, hay        | 0.30        |
+-----------------+----------------+-------------------+-------------+
| Beetroot        | 0.01 (\*)      | Grass, straw      | 0.01        |
+-----------------+----------------+-------------------+-------------+
| Eggs            | 0.01 (\*)      | Grass, seed       | 0.01        |
|                 |                | screenings        |             |
+-----------------+----------------+-------------------+-------------+
| Fodder beet     | 0.01 (\*)      |                   |             |
+-----------------+----------------+-------------------+-------------+
| Garlic          | 0.01 (\*)      |                   |             |
+-----------------+----------------+-------------------+-------------+
| Maize           | 0.01 (\*)      |                   |             |
+-----------------+----------------+-------------------+-------------+
| Maize fodder    | 0.01 (\*)      |                   |             |
| (dry)           |                |                   |             |
+-----------------+----------------+-------------------+-------------+
| Meat (from      | 0.01 (\*)      |                   |             |
| mammals...)     |                |                   |             |
+-----------------+----------------+-------------------+-------------+
| Milks           | 0.01 (\*)      |                   |             |
+-----------------+----------------+-------------------+-------------+
| Onion, bulb     | 0.01 (\*)      |                   |             |
+-----------------+----------------+-------------------+-------------+
| Peanut          | 0.01 (\*)      |                   |             |
+-----------------+----------------+-------------------+-------------+
| Peanut fodder   | 0.01 (\*)      |                   |             |
+-----------------+----------------+-------------------+-------------+
| Potato          | 0.01 (\*)      |                   |             |
+-----------------+----------------+-------------------+-------------+
| Poultry meat    | 0.01 (\*)      |                   |             |
+-----------------+----------------+-------------------+-------------+
| Poultry, edible | 0.01 (\*)      |                   |             |
| offal of        |                |                   |             |
+-----------------+----------------+-------------------+-------------+
| Shallot         | 0.01 (\*)      |                   |             |
+-----------------+----------------+-------------------+-------------+
| Sorghum         | 0.01 (\*)      |                   |             |
+-----------------+----------------+-------------------+-------------+
| Sorghum straw   | 0.01 (\*)      |                   |             |
| and fodder, dry |                |                   |             |
+-----------------+----------------+-------------------+-------------+
| Soya bean (dry) | 0.01 (\*)      |                   |             |
+-----------------+----------------+-------------------+-------------+
| Sugar beet      | 0.01 (\*)      |                   |             |
+-----------------+----------------+-------------------+-------------+
| Sweet corn      | 0.01 (\*)      |                   |             |
| (c              |                |                   |             |
| orn-on-the-cob) |                |                   |             |
+-----------------+----------------+-------------------+-------------+
| Sweet potato    | 0.01 (\*)      |                   |             |
+-----------------+----------------+-------------------+-------------+
| Limits for      |                | Limits for Mexico |             |
| Canada          |                |                   |             |
+-----------------+----------------+-------------------+-------------+
|  No Limits     |                |  No Limits       |             |
|                 |                |                   |             |
| √ No Limits for |                | √ No Limits for   |             |
| the crops       |                | the crops         |             |
| requested       |                | requested         |             |
+-----------------+----------------+-------------------+-------------+
| Residue         |                | Residue           |             |
| definition      |                | definition:       |             |
| 2-chlor         |                | dimethenamid      |             |
| o-*N*-(2,4-dime |                |                   |             |
| thyl-3-thienyl) |                | \[Note: US is the |             |
| -*N*-(2-methoxy |                | source of the     |             |
| -1-methylethyl) |                | Mexican MRLs      |             |
| acetamide       |                | listed below, per |             |
|                 |                | USDA FAS          |             |
| Also registered |                | database, except  |             |
| (label) for use |                | as indicated by   |             |
| on corn, sweet  |                | \*\]              |             |
| corn, dry       |                |                   |             |
| common beans    |                |                   |             |
| (otebo, white,  |                |                   |             |
| kidney),        |                |                   |             |
| no-bearing      |                |                   |             |
| grape vines.    |                |                   |             |
+-----------------+----------------+-------------------+-------------+
| Crop(s)         | MRL (mg/kg)    | Crop(s)           | MRL (mg/kg) |
+-----------------+----------------+-------------------+-------------+
| Onion (dry      | 0.01           | Arracacha         | 0.01        |
| bulb)           |                |                   |             |
+-----------------+----------------+-------------------+-------------+
|                 |                | Arrowroot         | 0.01        |
+-----------------+----------------+-------------------+-------------+
|                 |                | Artichoke,        | 0.01        |
|                 |                | Chinese           |             |
+-----------------+----------------+-------------------+-------------+
|                 |                | Artichoke,        | 0.01        |
|                 |                | Jerusalem         |             |
+-----------------+----------------+-------------------+-------------+
|                 |                | Beet, Garden,     | 0.01        |
|                 |                | Roots             |             |
+-----------------+----------------+-------------------+-------------+
|                 |                | Beet, Garden,     | 0.01        |
|                 |                | Tops              |             |
+-----------------+----------------+-------------------+-------------+
|                 |                | Cassava, Roots    | 0.01        |
+-----------------+----------------+-------------------+-------------+
|                 |                | Chayote           | 0.01        |
+-----------------+----------------+-------------------+-------------+
|                 |                | Chufa             | 0.01        |
+-----------------+----------------+-------------------+-------------+
|                 |                | Corn, Sweet,      | 0.01        |
|                 |                | Kernels Plus Cob  |             |
|                 |                | With Husks        |             |
|                 |                | Removed           |             |
+-----------------+----------------+-------------------+-------------+
|                 |                | Dasheen, Corm     | 0.01        |
+-----------------+----------------+-------------------+-------------+
|                 |                | Garlic            | 0.01        |
+-----------------+----------------+-------------------+-------------+
|                 |                | Ginger            | 0.01        |
+-----------------+----------------+-------------------+-------------+
|                 |                | Horseradish       | 0.01        |
+-----------------+----------------+-------------------+-------------+
|                 |                | Leeks             | 0.01        |
+-----------------+----------------+-------------------+-------------+
|                 |                | Leren             | 0.01        |
+-----------------+----------------+-------------------+-------------+
|                 |                | Onion, Dry Bulb   | 0.01        |
+-----------------+----------------+-------------------+-------------+
|                 |                | Onion, Green      | 0.01        |
+-----------------+----------------+-------------------+-------------+
|                 |                | Onion, Welsh      | 0.01        |
+-----------------+----------------+-------------------+-------------+
|                 |                | Peanut            | 0.01        |
+-----------------+----------------+-------------------+-------------+
|                 |                | Potato            | 0.01        |
+-----------------+----------------+-------------------+-------------+
|                 |                | Shallots          | 0.01        |
+-----------------+----------------+-------------------+-------------+
|                 |                | Sugar, Beet,      | 0.01        |
|                 |                | Roots             |             |
+-----------------+----------------+-------------------+-------------+
|                 |                | Sugar, Beet, Tops | 0.01        |
+-----------------+----------------+-------------------+-------------+
|                 |                | Sweet Potato      | 0.01        |
+-----------------+----------------+-------------------+-------------+
|                 |                | Tanier            | 0.01        |
+-----------------+----------------+-------------------+-------------+
|                 |                | Tumeric           | 0.01        |
+-----------------+----------------+-------------------+-------------+
|                 |                | Vegetable,        | 0.01        |
|                 |                | Tuberous and      |             |
|                 |                | Corm, Subgroup 1C |             |
+-----------------+----------------+-------------------+-------------+
|                 |                | Yam Bean          | 0.01        |
+-----------------+----------------+-------------------+-------------+
|                 |                | Yam, True, Tuber  | 0.01        |
+-----------------+----------------+-------------------+-------------+
|                 |                | Maize (corn)      | 0.01\*      |
+-----------------+----------------+-------------------+-------------+
|                 |                | Sorghum           | 0.01\*      |
+-----------------+----------------+-------------------+-------------+
| Notes/Special   |                |                   |             |
| Instructions:   |                |                   |             |
| S. Funk,        |                |                   |             |
| 12/04/2006.     |                |                   |             |
+-----------------+----------------+-------------------+-------------+

**Appendix B: Toxicity Profiles:**

+----------+--------------+-------+-------------------+--------------+
| **Table  |              |       |                   |              |
| B.1.     |              |       |                   |              |
| Acute    |              |       |                   |              |
| Toxicity |              |       |                   |              |
| Profile  |              |       |                   |              |
| -\[R     |              |       |                   |              |
| S\]-dime |              |       |                   |              |
| thenamid |              |       |                   |              |
| \[PC     |              |       |                   |              |
| 12       |              |       |                   |              |
| 9051\]** |              |       |                   |              |
+----------+--------------+-------+-------------------+--------------+
| **G      | **Study      | *     | **Results**       | **Toxicity   |
| uideline | Type**       | *MRID |                   | Category**   |
| No.**    |              | (s)** |                   |              |
+----------+--------------+-------+-------------------+--------------+
| 870.1100 | Acute        | 416   | LD~50~ = 2140     | III          |
|          | oral/rats    | 62409 | mg/kg (males)     |              |
|          |              |       |                   | II-III       |
|          | \[Sprague    | \(1   | LD~50~ = 1297     |              |
|          | Dawley\]     | 989\) | mg/kg (females)   |              |
|          |              |       |                   |              |
|          | TXR# 008285  | 440   | LD~50~ = 1570     |              |
|          |              | 97602 | mg/kg mean for    |              |
|          |              |       | both sexes        |              |
|          |              | \(1   |                   |              |
|          |              | 992\) | LD~50~ = 500      |              |
+----------+--------------+-------+-------------------+--------------+
| 870.1200 | Acute        | 416   | LD~50~ = \>2000   | III          |
|          | de           | 62410 | mg/kg             |              |
|          | rmal/rabbits |       |                   |              |
|          |              | \(1   |                   |              |
|          | \[NZW\]      | 988\) |                   |              |
+----------+--------------+-------+-------------------+--------------+
| 870.1300 | Acute        | 416   | LC~50~ = 4.99     | III          |
|          | inh          | 62411 | mg/L              |              |
|          | alation/rats |       |                   |              |
|          |              | \(1   |                   |              |
|          | \[Wistar\]   | 986\) |                   |              |
|          |              |       |                   |              |
|          | TXR# 008285  |       |                   |              |
+----------+--------------+-------+-------------------+--------------+
| 870.2400 | Acute eye    | 416   | Minimally         | III          |
|          | irrita       | 62412 | irritating        |              |
|          | tion/rabbits |       |                   |              |
|          |              | \(1   |                   |              |
|          |              | 988\) |                   |              |
+----------+--------------+-------+-------------------+--------------+
| 870.2500 | Acute dermal | 416   | Minimally         | IV           |
|          | irritation/  | 62413 | irritating        |              |
|          | rabbits      |       |                   |              |
|          |              | \(1   |                   |              |
|          |              | 988\) |                   |              |
+----------+--------------+-------+-------------------+--------------+
| 870.2600 | Skin         | 416   | Mild skin         | Sensitizer   |
|          | s            | 62407 | sensitizer        |              |
|          | ensitization |       |                   |              |
|          | \[Guinea     | \(1   |                   |              |
|          | Pigs\]       | 987\) |                   |              |
+----------+--------------+-------+-------------------+--------------+

+----------+--------------+-------+--------------------+--------------+
| **Table  |              |       |                    |              |
| B.2.     |              |       |                    |              |
| Acute    |              |       |                    |              |
| Toxicity |              |       |                    |              |
| Profile  |              |       |                    |              |
| -\[S\]   |              |       |                    |              |
| dimeth   |              |       |                    |              |
| enamid-P |              |       |                    |              |
| \[PC     |              |       |                    |              |
| 12       |              |       |                    |              |
| 0051\]** |              |       |                    |              |
+==========+==============+=======+====================+==============+
| **G      | **Study      | *     | **Results \*values | **Toxicity   |
| uideline | Type**       | *MRID | for \[S\]**        | Category\*** |
| No.**    |              | (s)** |                    |              |
+----------+--------------+-------+--------------------+--------------+
| 870.1100 | Acute        | 440   | LD~50~ = 429 mg/kg | II           |
|          | oral/rats    | 97603 | for males LD50 =   |              |
|          |              |       | 531 mg/kg for      |              |
|          | \[Sprague    | \(1   | females            |              |
|          | Dawley\]     | 996\) |                    |              |
|          |              |       | LD50 =480 mg/kg    |              |
|          |              |       | for both sexes.    |              |
+----------+--------------+-------+--------------------+--------------+
| 870.1200 | Acute        | 443   | LD~50~ = \>2000    | III          |
|          | de           | 32234 | mg/kg              |              |
|          | rmal/rabbits |       |                    |              |
|          |              | \(1   |                    |              |
|          | \[NZW\]      | 996\) |                    |              |
+----------+--------------+-------+--------------------+--------------+
| 870.1300 | Acute        | 443   | LC~50~ = 2.2 mg/L  | III          |
|          | inhalation   | 32235 |                    |              |
|          | \[Sprague    |       |                    |              |
|          | Dawley\]     | \(1   |                    |              |
|          |              | 996\) |                    |              |
+----------+--------------+-------+--------------------+--------------+
| 870.2400 | Acute eye    | 443   | Minimally          | III          |
|          | irritation   | 32238 | irritating         |              |
|          | \[NZW\]      |       |                    |              |
|          |              | \(1   |                    |              |
|          |              | 996\) |                    |              |
+----------+--------------+-------+--------------------+--------------+
| 870.2500 | Acute dermal | 443   | Minimally          | IV           |
|          | irritation   | 32239 | irritating         |              |
|          | \[NZW\]      |       |                    |              |
|          |              | \(1   |                    |              |
|          |              | 996\) |                    |              |
+----------+--------------+-------+--------------------+--------------+
| 870.2600 | Skin         | 440   | Mild skin          | Sensitizer   |
|          | s            | 97604 | sensitizer         |              |
|          | ensitization |       |                    |              |
|          | \[Guinea     |       |                    |              |
|          | Pigs\]       |       |                    |              |
+----------+--------------+-------+--------------------+--------------+

+-------------+-----------------+--------------------------------------+
| **Table     |                 |                                      |
| B.3.        |                 |                                      |
| Subchronic, |                 |                                      |
| Chronic and |                 |                                      |
| Other       |                 |                                      |
| Toxicity    |                 |                                      |
| Profile for |                 |                                      |
| \[RS\]-dim  |                 |                                      |
| ethenamid** |                 |                                      |
+=============+=================+======================================+
| **Guideline | **MRID No.      | **Results**                          |
| No./ Study  | (year)/         |                                      |
| Type**      | Classification  |                                      |
|             | /Doses**        |                                      |
+-------------+-----------------+--------------------------------------+
| 870.3100    | 41615901 (1986) | NOAEL=33.5/40.1 mg/kg/day \[500      |
|             |                 | ppm\]                                |
| 90-Day      | Doses: 0, 50,   |                                      |
| Feed        | 150, 500, 1500, | LOAEL=98/119 mg/kg/day \[1500 ppm\]  |
| ing/Sprague | 3000 ppm \[M/F: | based on decreased body weight and   |
| Dawley rat  | 0/0/, 3.5/3.9,  | body weight gain, increased total    |
|             | 10.0/11.8,      | protein in males; in females,        |
|             | 33.5/40.1,      | increased cholesterol, increased adj |
|             | 98/119, 204/238 | liver weight and centrilobular       |
|             | mg/kg/day\]     | hepatocytic enlargement.             |
|             |                 |                                      |
|             | Acceptable in   |                                      |
|             | TXR# 008285     |                                      |
+-------------+-----------------+--------------------------------------+
| 870.3150    | 41615902 (1986  | NOAEL = 4.72/4.98 mg/kg/day \[100    |
|             | \[Doses: 0,     | ppm \]                               |
| 90-Day oral | 100, 750, 2000  |                                      |
| toxicity    | ppm\]\[M/F:     | LOAEL =33.6/39.7 mg/kg/day \[750     |
| (dog)       | 0/0, 4.72/4.98, | ppm\] based on decreased body weight |
|             | 33.6/39.7,      | and body weight gain in females,     |
|             | 89.6/87.4       | increased rel. liver wt in both      |
|             | mg/kg/day\]     | sexes, increased periportal          |
|             |                 | vacuolation in both sexes and        |
|             | \[From std      | dilation of liver sinusoids in       |
|             | tables(dry): 0, | females.                             |
|             | 2.5, 18.75, 50  |                                      |
|             | mg/kg/day\]     |                                      |
|             |                 |                                      |
|             | \[From std      |                                      |
|             | tables(wet): 0, |                                      |
|             | 7.5, 56.25, 150 |                                      |
|             | mg/kg/day\]     |                                      |
|             |                 |                                      |
|             | Acceptable TXR# |                                      |
|             | 008285          |                                      |
+-------------+-----------------+--------------------------------------+
| 870.3200    | 41662414 (1989) | NOAEL =50 mg/kg/day, by previous     |
|             |                 | reviewer                             |
| 21/28-Day   | Doses: 0, 50,   |                                      |
| dermal      | 150, 500        | LOAEL L=150 mg/kg/day based on       |
| toxicity    | mg/kg/day       | decreased blood phosphate in both    |
| (NZW        |                 | sexes \[15% at 150mkd and 15% at 500 |
| rabbit)     | Acceptable in   | mg/kg/day\] \[ p\<0.05\] {Possibly   |
|             | TXR# 010012     | incidental, but considered treatment |
|             |                 | related by previous reviewer, with   |
|             |                 | SS in both males and females; body   |
|             |                 | wt decrement occurring at 500        |
|             |                 | mg/kg/day in males.}                 |
+-------------+-----------------+--------------------------------------+
| 870.3700a   | 41615904 (1987) | Maternal NOAEL = 50 mg/kg/day        |
|             | \[Doses: 0, 50, |                                      |
| Prenatal    | 215, 425        | LOAEL =215 mg/kg/day based on body   |
| de          | mg/kg/day\]     | weight decrement on GD 12 (but not a |
| velopmental |                 | single dose effect) and body weight  |
| in (Sprague | Vehicle is 0.5% | dece and food consumption decrease,  |
| Dawley      | CMC, 10 ml/kg   | both GD 6-9 & 6-16                   |
| rats)       |                 |                                      |
|             | Acceptable in   | Developmental NOAEL = 215 mg/kg/day  |
|             | TXR# 008285     |                                      |
|             |                 | LOAEL=425 mg/kg/day based on         |
|             |                 | increased post implantation loss.    |
+-------------+-----------------+--------------------------------------+
| Prenatal    | 41706809 (1988) | Maternal NOAEL=75 mg/kg/day          |
| De          | Doses: 0, 37.5, |                                      |
| velopmental | 75, 150         | LOAEL=150 mg/kg/day based on slight  |
| (           | mg/kg/day       | body weight decrement (80g, GD       |
| NZW/Rabbit) |                 | 12-15), body weight loss (75g GD     |
|             | Acceptable TXR# | 15-19) and 2 abortions and in a 20   |
|             | 008469 N/L      | litter/group range-finding study,    |
|             | change from     | death (13/20) and abortions (7/20)   |
|             | previous        | at 250 mg/kg/day                     |
|             |                 |                                      |
|             |                 | Developmental NOAEL=75 mg/kg/day     |
|             |                 |                                      |
|             |                 | LOAEL=150 mg/kg/day based on SS      |
|             |                 | fetal incidence of irregular         |
|             |                 | parietals and hyoid angulated.       |
|             |                 | Litter incidence was nominally       |
|             |                 | elevated by 50% and 100%,            |
|             |                 | respectively, and nominally          |
|             |                 | increased post implantation loss     |
|             |                 | (double control).                    |
+-------------+-----------------+--------------------------------------+
| 870.3800    | 41615905 (1990) | Parental/Systemic NOAEL = 36/40      |
|             | Doses: 0, 100,  | mg/kg/day \[500 ppm\]                |
| R           | 500, 2000 ppm   |                                      |
| eproduction | \[M/F; 0/0,     | LOAEL =150/160 mg/kg/day \[2000      |
| and         | 7/8, 36/40,     | ppm\] based on decrease body weight, |
| fertility   | 150/160         | body weight gain, food consumption   |
| effects     | mg/kg/day\]     | and abs & relative liver weight      |
|             |                 | increase.                            |
| (Wistar     | Acceptable TXR# |                                      |
| rats)       | 008285          | Reproductive NOAEL = 150/160         |
|             |                 | mg/kg/day \[2000 ppm\]               |
|             |                 |                                      |
|             |                 | LOAEL = None                         |
|             |                 |                                      |
|             |                 | Offspring NOAEL = 40 mg/kg/day \[500 |
|             |                 | ppm\]                                |
|             |                 |                                      |
|             |                 | LOAEL = 160mg/kg/day \[2000 ppm\]    |
|             |                 | based on f1 pup weight decrement at  |
|             |                 | LD 21 and f2 pup weight decrease at  |
|             |                 | LD day 7and 21.                      |
+-------------+-----------------+--------------------------------------+
| 870.4100b   | 41615903 (1990) | NOAEL = 10.1/9.1 mg/kg/day           |
|             |                 | \[250ppm\]                           |
| Chronic     | 0, 25, 250,     |                                      |
| toxicity    | 1250 ppm \[M/F  | LOAEL =48.7/49.3 mg/kg/day           |
| (dog)       | 0/0, 1.95/2.1,  | \[1250ppm\] based on decreased body  |
|             | 10.1/9.1,       | wt & body wt gains \[43% to          |
|             | 48.7/49.3       | 60%,0-26wk\] both sexes 100% in      |
|             | mg/kg/day\]     | males wk 26-52\] alkaline Phos       |
|             |                 | increased in females 109-2185        |
|             | \[From std      | through out study and 80% in males.  |
|             | tables(dry): 0, | Portal vacuolation in males;         |
|             | 0.625, 6.25,    | vacuoles not lipid or glycogen       |
|             | 31.25           |                                      |
|             | mg/kg/day\]     |                                      |
|             |                 |                                      |
|             | \[From std      |                                      |
|             | tables(wet): 0, |                                      |
|             | 2.5, 18.75, 50  |                                      |
|             | mg/kg/day\]     |                                      |
|             |                 |                                      |
|             | Acceptable TXR# |                                      |
|             | 008285          |                                      |
+-------------+-----------------+--------------------------------------+
| 870.4200 b  | 41662415 (1990) | NOAEL = 300 ppm (M/F: 40.8/40.1      |
|             |                 | mg/kg/day)                           |
| Carc        | 0,30, 300,      |                                      |
| inogenicity | 1500, 3000 ppm  | LOAEL = 1500 ppm (M/F: 205/200       |
|             | \[M/F: 0/0,     | mg/kg/day) based on decreased body   |
| (mouse)     | 3.8/4.1,        | weight gain in both sexes.           |
|             | 40.8/40.1,      |                                      |
|             | 205/200,        | No treatment related tumors were     |
|             | 431/411         | seen at adequate doses.              |
|             | mg/kg/day       |                                      |
|             |                 |                                      |
|             | Acceptable TXR# |                                      |
|             | 008315          |                                      |
+-------------+-----------------+--------------------------------------+
| 870.4300    | 41706808 &      | NOAEL = 100 ppm \[M/F: 5.1/6.8       |
| Chronic/    | 42030102 (1990) | mg/kg/day\]                          |
|             | 0, 100,         |                                      |
| carc        | 700,1500 ppm    | LOAEL = 7000 ppm \[M/F: 36/49        |
| inogenicity | \[M/F: 0/0,     | mg/kg/day\] based on decreased body  |
| (Sprague    | 5.1/6.8, 36/49, | weight and body weight gain in both  |
| Dawley rat) | 80/109          | sexes and microscopic hepatic        |
|             | mg/kg/day\]     | lesions in both sexes.               |
|             |                 |                                      |
|             | Acceptable TXR# | A dose related increased incidence   |
|             | 008315 & 008975 | of liver tumors in males (benign and |
|             |                 | malignant combined) were seen at     |
|             |                 | 1500 ppm, both exceeding historical  |
|             |                 | controls.                            |
|             |                 |                                      |
|             |                 | Cancer Peer Rev (TXR# 012143 &       |
|             |                 | 012831) characterized                |
|             |                 | \[RS\]-dimethenamid as a Group C -   |
|             |                 | possible human carcinogen, and       |
|             |                 | recommended that for the purpose of  |
|             |                 | risk assessment the Reference dose   |
|             |                 | approach should be used for human    |
|             |                 | risk assessment)                     |
+-------------+-----------------+--------------------------------------+
| Gene        | 41596542 (1989) | Strains tested at 1000-10000         |
| Mutation    |                 | µg/plate, -S9 and 1000-6500          |
|             | Reverse         | µg/plate, +S9. Cytotoxicity and      |
| 870.5100    | mutation in *S. | precipitation were noted at higher   |
| Bacterial   | typhimurium*    | doses.                               |
| Reverse     | strains TA 98,  |                                      |
| mutation    | TA100, TA1535,  | Test was negative, +/-S9.            |
|             | TA1537, TA1538  |                                      |
|             |                 |                                      |
|             | Acceptable TXR# |                                      |
|             | 008285          |                                      |
+-------------+-----------------+--------------------------------------+
| C           | 43648401 (1993) | CD-1 mice dosed at 710 mg/kg in two  |
| ytogenetics |                 | daily doses. LD50 = 1417 mg/kg. Bone |
|             | *In vivo* Bone  | marrow erythrocytes harvested 24 and |
| 870.5395    | marrow          | 48 hours later.                      |
| Mouse       | erythrocyte     |                                      |
| erythrocyte | micronucleus    | Test negative.                       |
| m           | test            |                                      |
| icronucleus |                 |                                      |
| test        | Acceptable inn  |                                      |
|             | TXR# 011053     |                                      |
+-------------+-----------------+--------------------------------------+
| C           | 41822703 (1986) | Mice dosed 0-1000 mg/kg in single    |
| ytogenetics |                 | doses. Mice showed no toxicity; only |
|             | *In vivo* Bone  | one mouse died.                      |
| 870.5395    | marrow          |                                      |
| Mouse       | erythrocyte     | Test negative.                       |
| erythrocyte | micronucleus    |                                      |
| m           | test.           |                                      |
| icronucleus | Unacceptable in |                                      |
| test        | TXR# 008469     |                                      |
+-------------+-----------------+--------------------------------------+
| Chromosomal | 41596543 (1985) | Cells in 125-150 µg/mL, -S9 and 400  |
| aberration  |                 | to 500 µg/mL, +S9; all doses were    |
| test        | *In vitro*      | cytotoxic. Study needs repeating at  |
| 870.5375    | chromosomal     | none cytotoxic doses.                |
|             | aberration test |                                      |
|             | in chinese      | Test considered equivocally          |
|             | hamster ovaries | positive.                            |
|             | (CHO)           |                                      |
|             |                 |                                      |
|             | Unacceptable in |                                      |
|             | TXR# 008285 &   |                                      |
|             | acceptable in   |                                      |
|             | TXR# 009070     |                                      |
+-------------+-----------------+--------------------------------------+
| UDS in rat  | 41822702 (1986) | Cell in 1.0-100 nl/mL. No            |
| hepatocytes |                 | cytotoxicity was seen.               |
|             | *In vitro*      |                                      |
| 870.5550    | unscheduled DNA | Test was negative.                   |
|             | synthesis in    |                                      |
|             | rat hepatocytes |                                      |
|             |                 |                                      |
|             | Unacceptable in |                                      |
|             | TXR# 008469     |                                      |
+-------------+-----------------+--------------------------------------+
| UDS in rat  | 4364802 (1993)  | Fisher 344 rat administered SAN 582H |
| hepatocytes |                 | doses of 158 or 500 mg/kg. Sampled   |
|             | In vivo         | 2-4 and 12-14 hours after dosing.    |
| 870.5550    | unscheduled DNA | Only 0.2-3.6% cells in repair, but   |
|             | Synthesis in    | negative control was less than zero. |
|             | rat hepatocytes |                                      |
|             |                 | Test was negative for UDS at 158 and |
|             | Acceptable to   | 500 mg/kg.                           |
|             | EEC             |                                      |
|             | requirements    |                                      |
|             | TXR# 011053     |                                      |
+-------------+-----------------+--------------------------------------+
| UDS in rat  | 41596544 (1989) | SAN 582H administered at 0.01 to 50  |
| hepatocytes |                 | µg/mL. Unscheduled DNA synthesis was |
|             | *In vitro*      | seen well below cytotoxic doses.     |
| 870.5550    | unscheduled DNA | Unequivocally positive for UDS.      |
|             | synthesis in    |                                      |
|             | rat hepatocytes | Test positive.                       |
|             |                 |                                      |
|             | Acceptable in   |                                      |
|             | TXR# 008285     |                                      |
+-------------+-----------------+--------------------------------------+
| UDS in rat  | 41662416 (1990) | SAN 582H administered at 0.0128 to   |
| hepatocytes |                 | 1000 µg/mL to rat primary cultures   |
|             | *In vitro*      | of hepatocytes. Doses at 1000 µg/mL  |
| 870.5550    | unscheduled DNA | were cytotoxic. No UDS was noted.    |
|             | synthesis in    |                                      |
|             | rat             | Test negative for UDS.               |
|             | hepatocytes.    |                                      |
|             |                 |                                      |
|             | Acceptable in   |                                      |
|             | TXR# 008469     |                                      |
+-------------+-----------------+--------------------------------------+
| Dominant    | 43209201 (1994) | Male Charles River rats (40-55)      |
| Lethal      | (Hazleton)      | administered SAN 582H in single oral |
|             |                 | doses of 275, 550 or 1100 mg/kg were |
| 870.5450    | Dominant lethal | mated starting at 10 weeks to 40-55  |
|             | in CR rats      | female undosed CR rats. Increased    |
|             |                 | dead implants at week 1 and week 2   |
|             | Acceptable in   | may suggest a dominant lethal        |
|             | TXR# 011053     | effect. These were mostly late       |
|             |                 | implant deaths, which some           |
|             |                 | consultants claim are not            |
|             |                 | characteristic of a dominant lethal  |
|             |                 | effect. .                            |
+-------------+-----------------+--------------------------------------+
| Dominant    | 43814401 (1995) | Male Sprague Dawley rats (40-60)     |
| Lethal      |                 | administered SAN 582H in single oral |
|             | (               | doses of 275, 550 or 1100 mg/kg were |
| 870.5450    | Microbiological | mated starting the day after dosing  |
|             | Assoc.)         | in Trial 1 and 2 days after dosing   |
|             | Dominant lethal | in Trial 2 to 80-120 female undosed  |
|             | in Sprague      | Sprague Dawley rats . Each male was  |
|             | Dawley rats     | mated to 2 females over a five day   |
|             |                 | sequence. Results equivocal, but not |
|             |                 | considered to negate results from    |
|             |                 | MRID# 43209201.                      |
|             |                 |                                      |
|             |                 | Note: Both the high dose rabbit and  |
|             |                 | rat developmental studies showed     |
|             |                 | increased late and early             |
|             |                 | resorptions.                         |
+-------------+-----------------+--------------------------------------+
| BALB/3T3    | 41822701 (1986) | BALB/3T3 cells administered SAN 582H |
| cell        |                 | at 15.0 to 100 µg/mL. No transformed |
| tra         | per-1996 *in    | cells were noted, but several        |
| nsformation | vitro* cell     | inadequacies were noted in the test  |
|             | transformation  | report. Number of cells transformed. |
| NG          |                 | Cell transformation yields variable  |
|             | Unacceptable in | results and is not an acceptable     |
|             | TXR# 008469     | methodology.                         |
|             |                 |                                      |
|             |                 | Test negative                        |
+-------------+-----------------+--------------------------------------+
| 870.7485    | 41596545 (1989) | Extensively metabolized, being       |
|             | & 42289501      | essentially complete within 3 days   |
| Metabolism  | (1992)          | and over 90% being excreted in the   |
| and         |                 | urine, feces and bile within 7 days. |
| pharm       | Single low and  | Total excretion products with the    |
| acokinetics | high doses of   | highest concentrations (in % of      |
|             | \[^14^C\] SAN   | administered dose) in the male and   |
| (Wistar     | 582H and after  | female, respectively, were parent    |
| rats)       | repeat doses of | 1.4% and 1.2%, \*M1- 3.3 & 7.2%,     |
|             | SAN 582H were   | \*M2- 3.6% & 9.8%, M3- 0.6% & 0.4%,  |
|             | administered    | M14- 2.8% & 3.3%, \*M16- 5.1% &      |
|             |                 | 3.3%, M17- 0.6% & 3.3%, M19-1.1% &   |
|             | Unacceptable in | 1.4%. Parent was initially           |
|             | TXR# 008285     | conjugated with glutathione and most |
|             |                 | metabolism taking place with the     |
|             | Acceptable in   | glutathione conjugate. No            |
|             | TXR# 009867.    | significant differences in           |
|             |                 | metabolism were seen between males   |
|             |                 | and females. Up to 45 putative       |
|             |                 | metabolites were reported in the     |
|             |                 | urine and up to 50 were reported in  |
|             |                 | the feces. Of these metabolites, 31  |
|             |                 | were identified. Of the unidentified |
|             |                 | metabolites none exceeded 3.0% and   |
|             |                 | most being less than 1% of the       |
|             |                 | administered dose.                   |
+-------------+-----------------+--------------------------------------+
| Chemical    | M1 is           |                                      |
| name of     | N-(2,           |                                      |
| excretion   | 4-dimethyl-3-th |                                      |
| products    | ienyl)-N-(2-hyd |                                      |
| exceeding   | roxy-1-methylet |                                      |
| 5% in the   | hyl)-2-(methyl- |                                      |
| multidose   | thio)-acetamide |                                      |
| 10 mg/kg    |                 |                                      |
| study in    | M2 is           |                                      |
| males or    | N               |                                      |
| females.    | -(2,4-dimethyl- |                                      |
|             | 3-thienyl)-MN-( |                                      |
|             | 2-hydroxy-1-met |                                      |
|             | hylethyl)-2-(me |                                      |
|             | thyl-sulfinyl)- |                                      |
|             |                 |                                      |
|             | acetamide       |                                      |
|             |                 |                                      |
|             | M16 is          |                                      |
|             | N-(2-hyd        |                                      |
|             | roxymethyl-4-me |                                      |
|             | thyl-3-thienyl) |                                      |
|             | -N-(2-methoxy-1 |                                      |
|             | -metylethyl)-2- |                                      |
|             | (methylsulf     |                                      |
|             | inyl)-acetamide |                                      |
+-------------+-----------------+--------------------------------------+

+-------------+-----------------+--------------------------------------+
| **Table     |                 |                                      |
| B.4.        |                 |                                      |
| Subchronic, |                 |                                      |
| Chronic and |                 |                                      |
| Other       |                 |                                      |
| Toxicity    |                 |                                      |
| Profile for |                 |                                      |
| \[S\]-dim   |                 |                                      |
| ethenamid-P |                 |                                      |
| (PC         |                 |                                      |
| 120051)**   |                 |                                      |
+=============+=================+======================================+
| **Guideline | **MRID No.      | **Results**                          |
| No./ Study  | (year)/         |                                      |
| Type**      | Classification  |                                      |
|             | /Doses**        |                                      |
+-------------+-----------------+--------------------------------------+
| 870.3100    | 44332242 (1996) | NOAEL=37/40 mg/kg/day \[500 ppm\]    |
|             |                 |                                      |
| 90-Day      | Doses: 0, 500,  | LOAEL=110/125 mg/kg/day \[1500 ppm\] |
| Feed        | 1500, 3000 ppm  | based on decreased body weight and   |
| ing/Sprague | \[M/F: 0/0/,    | body weight gain in males and        |
| Dawley Rat  | 37/40, 110/125, | females, increased gamma-glutamyl    |
|             | 222/256         | transferase in both sexes, increased |
|             | mg/kg/day\]     | cholesterol in males, increased abs. |
|             |                 | and rel. liver weight and periportal |
|             | Acceptable in   | hepatocytic hypertrophy and          |
|             | TXR# 0050183    | periportal eosinophilic inclusions   |
|             |                 | in males, centrilobular hypertrophy  |
|             |                 | in females and liver necrosis in     |
|             |                 | females.                             |
+-------------+-----------------+--------------------------------------+
| 870.3700a   | 44332243 (1996) | Maternal NOAEL = None                |
|             | \[Doses: 0, 25, |                                      |
| Prenatal    | 150, 300        | LOAEL =25 mg/kg/day based on body    |
| de          | mg/kg/day\]     | weight decrement on GD 13-19 (no     |
| velopmental | Vehicle is 0.5% | single dose effect) and body weight  |
| in (Sprague | CMC, 10 ml/kg   | gain dece and food consumption       |
| Dawley      |                 | decrease GD 6-16 & 6-9, respectively |
| rats)       | Acceptable in   |                                      |
|             | TXR# 0050183    | Developmental NOAEL = 25 mg/kg/day   |
|             |                 |                                      |
|             |                 | LOAEL=150 mg/kg/day based on         |
|             |                 | ossification delays in the pubis and |
|             |                 | at 300 mg/kg/day ossification delays |
|             |                 | in the pubis, sternal centra,        |
|             |                 | incidences of microphthalmia,        |
|             |                 | umbilical hernia and at 400          |
|             |                 | mg/kg/day increased post             |
|             |                 | implantation loss in a range-finding |
|             |                 | study.                               |
+-------------+-----------------+--------------------------------------+
| Gene        | Reverse         | *S. typhimurium* exposed to 500-4000 |
| Mutation    | mutation        | µg/plate +/- S9.                     |
|             | 4332244 (1997)  |                                      |
| 870.5100    |                 | *E. coli* exposed to 20-5000         |
| Bacterial   | *S.             | µg/plate +/-S9 using the Std plate   |
| Reverse     | typhimurium*    | incorp method or 4-2500 µg/plate     |
| mutation    | TA1535; *E.     | +/-S9 using the preincubation        |
|             | coli* WP2uvrA   | modification to the std test.        |
|             |                 | Highest doses were cytotoxic.        |
|             | Acceptable in   |                                      |
|             | TRX# 0052635    | All assays were negative.            |
+-------------+-----------------+--------------------------------------+
| Gene        | Reverse         | Exposed to 20-5000 µg/plate in a     |
| Mutation    | mutation        | plate incorporation assay. Marginal  |
|             | 4332245 (1997)  | cytotoxicity at limit dose of 5000   |
| 870.5100    |                 | µg/plate +/- S9.                     |
| Bacterial   | *S. typhimurin* |                                      |
| Reverse     | TA1535, TA1537, | Assays were negative with both       |
| mutation    | TA 98, TA100;   | bacteria +/- S9.                     |
|             | *E. coli*       |                                      |
|             | WP2uvrA         |                                      |
|             |                 |                                      |
|             | Acceptable in   |                                      |
|             | TRX# 0052635    |                                      |
+-------------+-----------------+--------------------------------------+
| Gene        | Reverse         | Repeat of MRID# 44123502. *S.        |
| Mutation    | mutation        | typhimurium* TA100 was exposed to    |
|             | 4332246 (1997)  | 100-5000 µg/plate -S9.               |
| 870.5100    |                 |                                      |
| Bacterial   | *S. typhimurin* | Assay was negative.                  |
| Reverse     | TA100.          |                                      |
| mutation    |                 |                                      |
|             | Acceptable in   |                                      |
|             | TRX# 0052635    |                                      |
+-------------+-----------------+--------------------------------------+
| Gene        | Reverse         | Exposed to 100-5000 µg/plate, +/-S9, |
| Mutation    | mutation        | in a plate incorporation assay.      |
|             | 44123502 (1996) | Insolubility seen at 333 & 5000      |
| 870.5100    | & resubmitted   | µg/plate, but no toxicity at any     |
| Bacterial   | 44332250 (1996) | dose. +/- S9.                        |
| Reverse     |                 |                                      |
| mutation    | *S. typhimurin* | Assays were negative with both       |
|             | TA1535, TA1537, | bacteria + S9, however, -S9 induced  |
|             | TA 98, TA100;   | 1.5 fold increases at 333 µg/plate   |
|             | *E. coli*       | and 4.1 fold increases in reverents  |
|             | WP2uvrA         | in TA100 strain at 5000 µg/plate.    |
|             |                 | This mutagenic response was          |
|             | Acceptable in   | reproducible at 100 to 5000          |
|             | TRX# 0052636    | µg/plate.                            |
+-------------+-----------------+--------------------------------------+
| Mammalian   | In vitro        | Chinese hamster ovary (CHO) cells    |
| cell        | CHO/HGPRT       | were exposed to 100-400 µg/mL, -S9,  |
| mutation    | mutation assay  | and 100-450 µg/mL, +S9. Slight       |
|             |                 | cytotoxicity was seen at the highest |
| 870.5300    | 44123501 (1996) | dose and severe toxicity was seen at |
|             | & resubmission  | ≥500 µg/mL.                          |
|             | as 44332248     |                                      |
|             |                 | Test was negative for mutagenic      |
|             | Acceptable TXR# | effects, +/- S9.                     |
|             | 12312           |                                      |
+-------------+-----------------+--------------------------------------+
| C           | Chromosomal     | CHO cells were exposed to 2-120      |
| ytogenetics | aberrations *in | µg/mL -S9; cytotoxic at ≥120 µg/mL.  |
| in Chinese  | vitro*          | CHO cells were exposed to 15-120     |
| Hamster     |                 | µg/mL +S9; cytotoxic at ≥500 µg/mL.  |
| Ovary (CHO) | 44332247 (1996) |                                      |
| cells       |                 | Assay was negative +/-S9.            |
|             | Acceptable TXR# |                                      |
| 870.5375    | 0052635         |                                      |
+-------------+-----------------+--------------------------------------+
| Cy          | ICR mice *in    | Mice (5/sex) were exposed to i.p.    |
| togenetics; | vivo* test      | injections of 103, 205, 410 mg/kg.   |
| mouse       |                 |                                      |
| erythrocyte | 44332249 (1996) | Assay was negative, indicating no    |
| m           |                 | clastogenic or aneugenic response.   |
| icronucleus | Acceptable TRX# |                                      |
| test        | 0052635         |                                      |
|             |                 |                                      |
| 870.5395    |                 |                                      |
+-------------+-----------------+--------------------------------------+
| Other       | Rat hepatocyte  | Cells tested at 7.8-125 µg/mL.       |
| Effects     | cell *in vitro* | Cytotoxicity and insolubility were   |
|             | test            | seen at ≥250 µg/mL.                  |
| 870.5550    |                 |                                      |
|             | 44332251 (1996) | Test was negative for UDS.           |
| UDS in      |                 |                                      |
| mammalian   | Acceptable TRX# |                                      |
| cell        | 0052635         |                                      |
| culture     |                 |                                      |
+-------------+-----------------+--------------------------------------+

**Appendix C: Review of Human Research**

No MRID - PHED Surrogate Exposure Guide