Document ID: EPA-HQ-OPP-2006-0165-0012
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-08-08T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

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

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc138551305"  1.0	Executive
Summary	  PAGEREF _Toc138551305 \h  4  

  HYPERLINK \l "_Toc138551306"  2.0	Ingredient Profile	  PAGEREF
_Toc138551306 \h  7  

  HYPERLINK \l "_Toc138551307"  2.1	Summary of Registered/Proposed Uses	
 PAGEREF _Toc138551307 \h  8  

  HYPERLINK \l "_Toc138551308"  2.2	Structure and Nomenclature	  PAGEREF
_Toc138551308 \h  8  

  HYPERLINK \l "_Toc138551309"  2.3	Physical and Chemical Properties	9 

  HYPERLINK \l "_Toc138551310"  3.0	Hazard Characterization/Assessment
10 

  HYPERLINK \l "_Toc138551311"  3.1	Hazard and Dose-Response
Characterization	10 

  HYPERLINK \l "_Toc138551312"  3.2	Adsorption, Distribution,
Metabolism, Excretion (ADME)	12 

  HYPERLINK \l "_Toc138551313"  3.3	 Safety Factor for Infants and
Children	13 

  HYPERLINK \l "_Toc138551315"  3.4	Hazard Identification and Toxicity
Endpoint Selection	14 

  HYPERLINK \l "_Toc138551316"  3.4.1	Acute Reference Dose (aRfD) -
Females age 13-49	14 

  HYPERLINK \l "_Toc138551317"  3.4.2	Acute Reference Dose (aRfD) -
General Population	14 

  HYPERLINK \l "_Toc138551318"  3.4.3	Chronic Reference Dose (cRfD)	14 

  HYPERLINK \l "_Toc138551319"  3.4.4	Incidental Oral Exposure
(Short-term / 1-30 days, and Intermediate-term / 1-6 months)	15 

  HYPERLINK \l "_Toc138551320"  3.4.5	Dermal Absorption	15 

  HYPERLINK \l "_Toc138551321"  3.4.6	Non-Occupational and Occupational
Short-Term Dermal Exposure (1-30 days)	15 

  HYPERLINK \l "_Toc138551322"  3.4.7	Non-Occupational and Occupational
Short-Term Inhalation Exposure (1-30 days)	  PAGEREF _Toc138551322 \h 
15  

  HYPERLINK \l "_Toc138551323"  3.4.8	Classification of Carcinogenic
Potential	18   HYPERLINK \l "_Toc138551327"   

  HYPERLINK \l "_Toc138551328"  3.5	Endocrine disruption	18 

  HYPERLINK \l "_Toc138551329"  4.0	Public Health and Pesticide
Epidemiology Data	18 

  HYPERLINK \l "_Toc138551330"  4.1	Incident Reports	19 

  HYPERLINK \l "_Toc138551331"  5.0	Dietary Exposure/Risk
Characterization	  PAGEREF _Toc138551331 \h  19  

  HYPERLINK \l "_Toc138551332"  5.1 	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc138551332 \h  19  

  HYPERLINK \l "_Toc138551333"  5.1.1	Metabolism in Primary Crops	 
PAGEREF _Toc138551333 \h  19  

  HYPERLINK \l "_Toc138551334"  5.1.2	Metabolism in Animals	  PAGEREF
_Toc138551334 \h  20  

  HYPERLINK \l "_Toc138551335"  5.1.3	Metabolism in Rotational Crops	 
PAGEREF _Toc138551335 \h  21  

  HYPERLINK \l "_Toc138551336"  5.1.4	Metabolism in Livestock	  PAGEREF
_Toc138551336 \h  21  

  HYPERLINK \l "_Toc138551337"  5.1.5	Analytical Methodology	  PAGEREF
_Toc138551337 \h  21  

  HYPERLINK \l "_Toc138551336"  5.1.6	Multiresidue Methods	22 

  HYPERLINK \l "_Toc138551336"  5.1.7	Magnitude in Plants	22 

  HYPERLINK \l "_Toc138551338"  5.1.8	Environmental Degradation	 
PAGEREF _Toc138551338 \h  22  

  HYPERLINK \l "_Toc138551339"  5.1.9	Comparative Metabolic Profile	 
PAGEREF _Toc138551339 \h  22  

  HYPERLINK \l "_Toc138551340"  5.1.10	Toxicity Profile of Major
Metabolites and Degradates	  PAGEREF _Toc138551340 \h  23  

  HYPERLINK \l "_Toc138551341"  5.1.11	Drinking Water Residue Profile	 
PAGEREF _Toc138551341 \h  23  

  HYPERLINK \l "_Toc138551342"  5.1.12	Food Residue Profile	  PAGEREF
_Toc138551342 \h  24  

  HYPERLINK \l "_Toc138551343"  5.1.13	International Residue Limits	 
PAGEREF _Toc138551343 \h  25  

  HYPERLINK \l "_Toc138551344"  5.2Dietary Exposure and Risk	  PAGEREF
_Toc138551344 \h  25  

  HYPERLINK \l "_Toc138551345"  6.0	Residential (Non-Occupational)
Exposure/Risk Characterization	  PAGEREF _Toc138551345 \h  27  

  HYPERLINK \l "_Toc138551346"  6.1	Other (Spray Drift, etc.)	  PAGEREF
_Toc138551346 \h  27  

  HYPERLINK \l "_Toc138551347"  7.0	Aggregate Risk Assessments and Risk
Characterization	  PAGEREF _Toc138551347 \h  27  

  HYPERLINK \l "_Toc138551348"  8.0	Cumulative Risk
Characterization/Assessment	  PAGEREF _Toc138551348 \h  28  

  HYPERLINK \l "_Toc138551349"  9.0	Occupational Exposure/Risk Pathway	 
PAGEREF _Toc138551349 \h  28  

  HYPERLINK \l "_Toc138551350"  9.1	Occupational Pesticide Handler
Exposure	  PAGEREF _Toc138551350 \h  29  

  HYPERLINK \l "_Toc138551353"  9.2	Postapplication Exposure to
Agricultural Workers	32 

  HYPERLINK \l "_Toc138551351"  9.3	Restricted Entry Interval (REI)	33 

  HYPERLINK \l "_Toc138551352"  10.0	Data Needs and Label Requirements	 
PAGEREF _Toc138551352 \h  33  

  HYPERLINK \l "_Toc138551353"  10.1	Toxicological Profile	33 

  HYPERLINK \l "_Toc138551353"  10.2	Residue Chemistry	33 

  HYPERLINK \l "_Toc138551353"  10.3	Occupational and Residential
Exposure	  PAGEREF _Toc138551353 \h  34  

  HYPERLINK \l "_Toc138551354"  References:	  PAGEREF _Toc138551354 \h 
34  

Appendix A:   HYPERLINK \l "_Toc138551352"  International Residue Limit
Status:	  PAGEREF _Toc138551352 \h  33  	

Appendix B:   HYPERLINK \l "_Toc138551352"  Toxicity Profiles:	  PAGEREF
_Toc138551352 \h  33  

Appendix C: Review of Human Research	44

 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)ac
etamide 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
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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.  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.  

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 95th 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 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,"   HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
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
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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. 

 							

2.1	Summary of Registered/Proposed Uses

Table 2.1.  Summary of Directions for Use of Dimethenamid-P.

Applic Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate 

(lb ai/A)	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(lb ai/A)	PGI 1

(days)

Grasses grown for seed

Fall (prior to emergence of targeted weed)

Broadcast

Ground	6 lb ai /gal EC

[7969-156]	0.656-0.984	1 (implied)	0.984	60 for cool-season grasses and
30 days for warm-season grasses.

Use Directions and Restrictions:  Application may be made to established
stands of bentgrass, Kentucky blue grass, fine fescue, tall fescue,
orchard grass, and perennial ryegrass in a minimum of 10 gal/A using
ground equipment.  Grass seed crops must have been established for at
least one year or had at least one seed crop harvested prior to
application.  Application may be made in the fall prior to emergence of
targeted weeds or in a sequential use program with other herbicides that
control emerged weeds.  Livestock grazing in treated fields may occur 60
days after application.  Tank mix use is prohibited.  The parent label
specifies that fall-seeded cereal crops may be planted 4 months or more
following treatment.  There are no rotational crop restrictions the
spring following the previous year’s application of Outlook™.  If
re-planting of a crop is necessary, plant only crops where a soil
application of Outlook™ is registered.

1  PGI = pregrazing interval.

Structure and Nomenclature

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

Molecular Formula	C12H18ClNO2S

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

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

Molecular Formula	C12H18ClNO2S

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-[(1S)-2-methoxy-1-methylethyl]
acetamide

CAS #	163515-14-8

PC Code	120051

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

  SEQ CHAPTER \h \r 1 

2.3	Physical and Chemical Properties

Table 2.3.a	Physicochemical Properties of Dimethenamid (50:50, R and S
-isomers).

Parameter	Value	Reference

Boiling point/range	123°C at 0.1 mm Hg	DP Num: 183774, 1/22/93, M.
Flood

pH	8.4-6.9; continuously decreasing over a 45- minute period; 1% aqueous
solution 	DP Num: 183774, 1/22/93, M. Flood

Density	1.19 g/mL at 25°C;

1.19 specific gravity at 25°C	DP Num: 183774, 1/22/93, M. Flood

Water solubility	0.117 g/100 mL at 25°C (PAI)	DEB No. 7060, 1/18/91, M.
Flood

Solvent solubility	Soluble in all proportions in acetone, n-octanol,
methylene chloride, and carbon disulfide at 25°C	DP Num: 169997,
7/29/92, M. Flood

Vapor pressure	2.76 x 10-4 mm Hg at 25°C (PAI)	DEB No. 7060, 1/18/91,
M. Flood

Dissociation constant, pKa	No dissociation between pH 1-11 at 25°C
(PAI)	DEB No. 7060, 1/18/91, M. Flood

Octanol/water partition coefficient, KOW	141 (PAI)	DEB No. 7060,
1/18/91, M. Flood

UV/visible absorption 	Not available

	

Ε = 7560; 33 nm	MRID No. 46710201

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.

e 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

[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.  

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.

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:  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): 100 This includes 10x for interspecies
extrapolation and 10x for intraspecies variation.

3.4.2	Acute Point of Departure (aPOD)- General Population tc \l3 "Acute
Reference Dose (aRfD) - 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) tc \l3 "Chronic Reference Dose
(cRfD) 

Selected Study: Chronic/carcinogenicity study in rats (MRID# 41706808 &
42030102).  

Dose and Endpoint for Establishing an cPOD:  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): 100 This includes 10X for interspecies
extrapolation and 10x for intraspecies variation.

			

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

Selected Study: Subchronic Toxicity in Dogs (MRID# 41615902).

Dose and Endpoint for Establishing an aPOD:  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): 100 This includes 10x for interspecies
extrapolation and 10x for intraspecies variation.

3.4.5	Dermal Absorption tc \l3 "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:  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): 100 This includes 10x for interspecies
extrapolation and 10x for intraspecies variation.

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:  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): 100 This includes 10x for interspecies
extrapolation and 10x for intraspecies variation.

Table 3.4.7.a.  Summary of Toxicological Dose and Endpoints for
[S]-DIMETHENAMID-P for Use in Dietary and Non-Occupational Human Health
Assessments.

Exposure

Scenario	

Dose Used in Risk Assessment, UF 	

FQPA SF* and Level of Concern for Risk Assessment	

Study and Toxicological Effects

Acute Dietary

(Females 13-49 years of age)

Based on [RS] data	

NOAEL = 75 mg/kg/day

UF = 100

Acute POD= 0.75  mg/kg/day	

FQPA SF = 1X

aPAD = acute POD

              FQPA SF

= 0.75  mg/kg/day	

Developmental Toxicity in rabbits

Maternal; LOAEL = 150 mg/kg/day based on abortions and decreased body
weight gain and food consumption.

Developmental; LOAEL = 150 mg/kg/day based on post-implantation loss

Acute Dietary

(General population including infants and children)	

No appropriate endpoint identified for this population.

Chronic Dietary

(All populations)

Based on [RS] data	

NOAEL= 5 mg/kg/day

UF =  100 

Chronic POD = 

0.05 mg/kg/day	

FQPA SF = 1X  

cPAD = 

chronic POD

 FQPA SF

=  0.05  mg/kg/day	

Chronic/carcinogenicity rats

LOAEL = M/F; 36/49 mg/kg/day  based on decreased body weight and body
weight gain in both sexes, increased food conversion ratios in females,
and increased microscopic hepatic lesions in both sexes. 

Incidental oral

Based on [RS] data	NOAEL= 4.72 mg/kg/day

UF =  100	FQPA SF = 1X  	Subchronic toxicity study in dogs 

LOAEL = M/F; 33.6/39.7 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 Absorption

Based on [RS] data 	

30%	

No studies are available.  Value estimated 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 weight)/(21-day
Dermal rabbit LOAEL for systemic toxicity, body weight)] X 100 =
(150/500) x 100 =30% 

Short-Term Dermal (1 to 30 days) 

Based on [RS] data	

Oral NOAEL= 4.72 mg/kg/day

Dermal Absorption = 30%	

Occupational = LOC for MOE = 100	

Subchronic toxicity study in dogs 

LOAEL = M/F; 33.6/39.7 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).

Short-Term Inhalation (1 to 30 days)

Based on [RS] data	

Oral NOAEL= 4.72 mg/kg/day

Assume 100% absorption	

Occupational LOC for MOE = 100	

Subchronic toxicity study in dogs 

LOAEL = M/F; 33.6/39.7 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).

Carcinogenicity

Based on [RS] data 	

“C” Possible human carcinogen.  (No Q1*). The cRfD is considered 

protective of the cancer effects.   

  TC \l3 "3.5.10	Classification of Carcinogenic Potential 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 Toxicological Dose and Endpoints for
[S]-DIMETHENAMID-P for Use in Occupational Human Health Assessments.

Exposure

Scenario	

Dose Used in Risk Assessment, UF 	

FQPA SF* and Level of Concern for Risk Assessment	

Study and Toxicological Effects

Short-Term Dermal (1 to 30 days) 

Based on [RS] data	

Oral NOAEL= 4.72 mg/kg/day

Dermal Absorption = 30%	

Occupational = LOC for MOE = 100	

Subchronic toxicity study in dogs 

LOAEL = M/F; 33.6/39.7 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).

Short-Term Inhalation (1 to 30 days)

Based on [RS] data

	

Oral NOAEL= 4.72 mg/kg/day

Assume 100% absorption	

Occupational LOC for MOE = 100	

Subchronic toxicity study in dogs 

LOAEL = M/F; 33.6/39.7 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).

Carcinogenicity

Based on [RS] data 	

“C” Possible human carcinogen.  (No Q1*).  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.

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.

4.0	Public Health and Pesticide Epidemiology Data

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.

5.0	Dietary Exposure/Risk Characterization

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. 

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.  

≤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
[14C]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.

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. 

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.

5.1.4	Metabolism in Livestock

Ruminant:  In the ruminant metabolism study, a dairy goat was dosed
orally for 4 days with [14C]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.   [14C]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 [14C]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 [14C]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 14C-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).  

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

  SEQ CHAPTER \h \r 1 The 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).

5.1.8	Environmental Degradation

Dimethenamid-P is mobile (Kd = 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.  [14C]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 14CO2 accounted for 28.5-29.2% of the applied
radioactivity at 182 days post-treatment.

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.

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 LD50 of the parent and of the
desphenyl metabolite are similar.  

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 (Kd = 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, Screening Concentration In GROund Water (SCIGROW). 
This assessment is for parent compound only.

Table 5.1.11  Summary of EDWCs (ppb) for Proposed New Uses for
Dimethenamid-P.

USE	Modeled Scenarioc 

(Application Method)	Surface Water a	Ground Water b

Acute	Chronic	Acute and Chronic

Grass for Seed	OR grass seed (Aerial Spray)	9.0	3.8	0.34

Green Onions	GA onion (Ground spray)	66.7	8.4	0.34

Ornamentals	FL turf – Acute

OR xmas – Chronic (Aerial spray)	50.2	20.2	1.0

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.

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 per
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.

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.

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).   

ke 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 Subgroup	PAD, mg/kg/day	DEEM-FCID

Exposure, mg/kg/day	% PAD

Acute Dietary Estimates (95th Percentile of Exposure)

Females 13-49 yrs	0.75	0.003283	< 1

Chronic Dietary Estimates

Population Subgroups	PAD, mg/kg/day	DEEM-FCID

Exposure, mg/kg/day	% PAD

U.S. Population	0.05	0.000469	0.9

All infants (< 1 yr)	0.05	0.001460	2.9

Children 1-2 yrs	0.05	0.000727	1.5

Children 3-5 yrs	0.05	0.000691	1.4

Children 6-12 yrs	0.05	0.000480	1.0

Youth 13-19 yrs	0.05	0.000358	0.7

Adults 20-49 yrs	0.05	0.000433	0.9

Adults 50+ yrs	

0.05	0.000445	0.9

Females 13-49 yrs old	0.05	0.000430	0.9

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. 

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.

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. 
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.

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     HYPERLINK
"http://www.epa.gov/pesticides/cumulative/." 
http://www.epa.gov/pesticides/cumulative/. 

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 OutlookTM 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.  OutlookTM 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 OutlookTM. 
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 %, OutlookTM 
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 Interval	12 hours

Manufacturer	BASF

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
Dimethenamid-P

Unit Exposure1

mg ai/lb handled	

Applic. Rate2	

Units Treated3

Per Day	

Average Daily

Dose4

mg ai/kg bw/day	

NOAEL5

mg ai/kg bw/day	

MOE6

SHORT-TERM

Mixer/Loader - Liquid - Open-pour Supporting Aerial Operations to
Grasses Grown for Seed

Dermal:

SLNoGlove  2.9 HC

SLWGloves  0.023 HC

Inhal              0.0012 HC	

0.98 lb ai/A	

350 A/day	

SLNoGlove 4.26

SLWGlove 0.034

Inhal           0.0059	

4.72

	SLNoGlove

1

SLWGlove

118

Applicator - Ground-boom - Open Cab for Ornamentals

Dermal:

SLNoGlove   0.014 HC

SLWGloves   0.014 MC

Inhal              0.00074 HC	

1.5 lb 

ai/A	

200 A/day	

SLNoGlove 0.018

SLWGlove  0.018

Inhal          0.00317	

4.72	SLNoGlove

222

SLWGlove

222

Aerial Applicator for Grasses Grown for Seed

Dermal:

SLNoGlove  0.005 MC

Inhal           0.000068 MC	

0.98 lb ai/A	

350

A/day	

SLNoGlove 0.0074

Inhal          0.00033	

4.72	SLNoGlove

610

Mixer/Loader/Applicator - Low-Pressure Hand-wand7 for Ornamentals

Dermal:

SLWGlove  0.5 

SLWGloves & coveralls                              0.27 LC

Inhal              0.0019 	

1.5 lb ai/A	

40 A/day	

SLWGlove 0.13

SLWGlove & coveralls      0.069

Inhal           0.0016	

4.72	SLWGlove

36

SLWGlove & coveralls

67

Mixer/Loader/Applicator Using Backpack Sprayer (Liquid Open Pour)8 for
Ornamentals

Dermal:

SLNoGlove  no data

SLWGloves  2.5 LC

Inhal              0.12 LC	

1.5 lb ai/A	40 gal/day

(= 2A/day)

	SLNoGlove no data

SLWGlove 0.032

Inhal           0.0051	

4.72	SLNoGlove

no data

SLWGlove

127

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.  

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 cm2/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.

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  

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.

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: 
2-chloro-N-(2,4-dimethyl-3-thienyl)-N-[(1S)-2-methoxy-1-methylethyl]
acetamide	Common Name:

Dimethenamid (50:50, R and S –isomers

Dimethenamid-P (90:10, S:R isomer ratio)	X Proposed tolerance

( Reevaluated tolerance

⁯ No Codex proposal step 6 or above

√ Codex proposal step 6 or above for the crops requested	Petition
Number:  PP#0F6138

DP Num:  326909

      No Limits

 √   No Limits for the crops requested	   No Limits

√   No Limits for the crops requested

Residue definition 
2-chloro-N-(2,4-dimethyl-3-thienyl)-N-(2-methoxy-1-methylethyl)
acetamide

Also registered (label) for use on corn, sweet corn, dry common beans
(otebo, white, kidney), no-bearing grape vines.	Residue definition: 
dimethenamid

[Note:  US is the source of the Mexican MRLs listed below, per USDA FAS
database, except as indicated by *]

Crop(s)	MRL (mg/kg)	Crop(s)	MRL (mg/kg)

Onion (dry bulb)	0.01	Arracacha	0.01

Arrowroot	0.01

Artichoke, Chinese	0.01

Artichoke, Jerusalem	0.01

Beet, Garden, Roots	0.01

Beet, Garden, Tops	0.01

Cassava, Roots	0.01

Chayote	0.01

Chufa	0.01

Corn, Sweet, Kernels Plus Cob With Husks Removed	0.01

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, Roots	0.01

Sugar, Beet, Tops	0.01

Sweet Potato	0.01

Tanier	0.01

Tumeric	0.01

Vegetable, Tuberous and Corm, Subgroup 1C	0.01

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 -[RS]-dimethenamid [PC 129051] 

Guideline No.	

Study Type	

MRID(s)	

Results	

Toxicity Category

870.1100	

Acute oral/rats 

[Sprague Dawley]

TXR# 008285

	

41662409

(1989) 

44097602

(1992)	

LD50 = 2140 mg/kg (males)

LD50 = 1297 mg/kg (females)

LD50 = 1570 mg/kg mean for              both sexes 

LD50 = 500	

III

II-III

870.1200	

Acute dermal/rabbits

[NZW]	

41662410 

(1988)	

LD50 = >2000 mg/kg	

III

870.1300	

Acute inhalation/rats

[Wistar] 

TXR# 008285	

41662411

(1986)	

LC50 = 4.99 mg/L	

III

870.2400	

Acute eye irritation/rabbits	

41662412

(1988) 	

Minimally irritating 	

III

870.2500	

Acute dermal irritation/ rabbits	

41662413

(1988)	

Minimally irritating	

IV

870.2600	

Skin sensitization [Guinea Pigs]	

41662407

(1987) 	

Mild skin sensitizer 	

Sensitizer

Table  B.2.  Acute Toxicity Profile -[S] dimethenamid-P [PC 120051] 

Guideline No.	

Study Type	

MRID(s)	

Results *values for [S]	

Toxicity Category*

870.1100	

Acute oral/rats

[Sprague Dawley]

	

44097603

(1996)	

 LD50 = 429 mg/kg for males LD50 = 531 mg/kg for females

LD50 =480 mg/kg for both sexes.	

II

870.1200	

Acute dermal/rabbits

[NZW]	

44332234

(1996)	

LD50 = >2000 mg/kg	

III

870.1300	

Acute inhalation [Sprague Dawley]	

44332235

(1996)	

LC50 = 2.2 mg/L	

III

870.2400	

Acute eye irritation [NZW]	

44332238

(1996)	

Minimally irritating 	

III

870.2500	

Acute dermal irritation [NZW]	

44332239

(1996)	

Minimally irritating 	

IV

870.2600	

Skin sensitization [Guinea Pigs]	

44097604	

Mild skin sensitizer	

Sensitizer

Table B.3.  Subchronic, Chronic and Other Toxicity Profile for
[RS]-dimethenamid

Guideline No./ Study Type	

MRID No. (year)/ Classification /Doses	

Results

870.3100

90-Day Feeding/Sprague Dawley rat 

	

41615901 (1986)

Doses: 0, 50, 150, 500, 1500, 3000 ppm [M/F: 0/0/, 3.5/3.9, 10.0/11.8,
33.5/40.1, 98/119, 204/238 mg/kg/day]

Acceptable in TXR# 008285	

NOAEL=33.5/40.1 mg/kg/day [500 ppm]

 LOAEL=98/119 mg/kg/day [1500 ppm] based on decreased body weight and
body weight gain, increased total protein in males; in females,
increased cholesterol, increased adj liver weight and centrilobular
hepatocytic enlargement.

870.3150

90-Day oral toxicity (dog)

	

41615902 (1986 [Doses: 0, 100, 750, 2000 ppm][M/F: 0/0, 4.72/4.98,
33.6/39.7, 89.6/87.4 mg/kg/day]

[From std tables(dry): 0, 2.5, 18.75, 50 mg/kg/day]

[From std tables(wet): 0, 7.5, 56.25, 150 mg/kg/day]

Acceptable TXR# 008285	

NOAEL = 4.72/4.98 mg/kg/day [100 ppm ]

LOAEL =33.6/39.7 mg/kg/day [750 ppm] based on decreased body weight and
body weight gain in females, increased rel. liver wt in both sexes,
increased periportal vacuolation in both sexes and dilation of liver
sinusoids in females.

870.3200

21/28-Day dermal toxicity (NZW rabbit)

	

41662414 (1989)

Doses: 0, 50, 150, 500 mg/kg/day

Acceptable in TXR# 010012	

NOAEL =50 mg/kg/day, by previous reviewer

LOAEL L=150 mg/kg/day based on decreased blood phosphate in both sexes
[15% at 150mkd and 15% at 500 mg/kg/day] [ p<0.05]  {Possibly
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

Prenatal developmental in (Sprague Dawley rats)	

41615904 (1987) [Doses: 0, 50, 215, 425 mg/kg/day]

Vehicle is 0.5% CMC, 10 ml/kg

Acceptable in TXR# 008285	

Maternal NOAEL = 50 mg/kg/day

LOAEL =215 mg/kg/day based on body weight decrement on GD 12 (but not a
single dose effect) and body weight dece and food consumption decrease,
both  GD 6-9 & 6-16

Developmental NOAEL = 215 mg/kg/day

LOAEL=425 mg/kg/day based on increased post implantation loss.

Prenatal Developmental (NZW/Rabbit) 	

41706809 (1988) Doses: 0, 37.5, 75, 150 mg/kg/day

Acceptable TXR# 008469 N/L change from previous	

Maternal NOAEL=75 mg/kg/day

LOAEL=150 mg/kg/day based on slight body weight decrement (80g, GD
12-15), body weight loss (75g GD 15-19) and 2 abortions and in a 20
litter/group range-finding study, death (13/20) and abortions (7/20) 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

Reproduction and fertility effects

(Wistar rats)	

41615905 (1990) Doses: 0, 100, 500, 2000 ppm [M/F; 0/0, 7/8, 36/40,
150/160 mg/kg/day]  

Acceptable TXR# 008285	

Parental/Systemic NOAEL = 36/40  mg/kg/day [500 ppm]

LOAEL =150/160 mg/kg/day [2000 ppm] based on decrease body weight, body
weight gain, food consumption and abs & relative liver weight increase. 

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

Chronic toxicity (dog)

	

41615903 (1990)

0, 25, 250, 1250 ppm [M/F 0/0, 1.95/2.1, 10.1/9.1, 48.7/49.3 mg/kg/day]

[From std tables(dry): 0, 0.625, 6.25, 31.25 mg/kg/day]

[From std tables(wet): 0, 2.5, 18.75, 50 mg/kg/day]

Acceptable TXR# 008285	

NOAEL = 10.1/9.1 mg/kg/day [250ppm]

LOAEL =48.7/49.3 mg/kg/day [1250ppm] based on decreased body wt & body
wt gains [43% to 60%,0-26wk] both sexes 100% in males wk 26-52] alkaline
Phos increased in females 109-2185 through out study and 80% in males. 
Portal vacuolation in males;  vacuoles not lipid or glycogen  

870.4200 b

Carcinogenicity

(mouse)	

41662415 (1990)

0,30, 300, 1500, 3000 ppm [M/F: 0/0, 3.8/4.1, 40.8/40.1, 205/200,
431/411 mg/kg/day

Acceptable TXR# 008315	

NOAEL = 300 ppm (M/F: 40.8/40.1 mg/kg/day)

LOAEL = 1500 ppm (M/F: 205/200 mg/kg/day) based on decreased body weight
gain in both sexes. 

No treatment related tumors were seen at adequate doses.

870.4300 Chronic/

carcinogenicity (Sprague Dawley rat)	

41706808 & 42030102 (1990) 0, 100, 700,1500 ppm [M/F: 0/0, 5.1/6.8,
36/49, 80/109 mg/kg/day]

Acceptable TXR# 008315 & 008975	

NOAEL = 100 ppm [M/F: 5.1/6.8 mg/kg/day]

LOAEL = 7000 ppm [M/F: 36/49 mg/kg/day] based on decreased body weight
and body weight gain in both sexes and microscopic hepatic lesions in
both sexes.  

A dose related increased incidence 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 Mutation

870.5100 Bacterial Reverse mutation

	

41596542 (1989)

Reverse mutation in S. typhimurium strains TA 98, TA100, TA1535, TA1537,
TA1538

Acceptable TXR# 008285	

Strains tested at 1000-10000 µg/plate, -S9 and 1000-6500 µg/plate,
+S9.   Cytotoxicity and precipitation were noted at higher doses. 

Test was negative, +/-S9. 

Cytogenetics 

870.5395 Mouse erythrocyte micronucleus test	

43648401 (1993)

In vivo Bone marrow erythrocyte micronucleus test

Acceptable inn TXR# 011053 	

CD-1 mice dosed at 710 mg/kg in two daily doses.  LD50 = 1417 mg/kg. 
Bone marrow erythrocytes harvested 24 and 48 hours later.

Test negative. 

Cytogenetics 

870.5395 Mouse erythrocyte micronucleus test	

41822703 (1986)

In vivo Bone marrow erythrocyte micronucleus test.  Unacceptable in TXR#
008469	

Mice dosed 0-1000 mg/kg in single doses.  Mice showed no toxicity; only
one mouse died. 

Test negative. 

Chromosomal aberration test  870.5375	

41596543 (1985)

In vitro chromosomal aberration test in chinese hamster ovaries (CHO)

Unacceptable in TXR# 008285 & acceptable in TXR# 009070	

Cells in 125-150 µg/mL, -S9 and 400 to 500 µg/mL, +S9; all doses were
cytotoxic.  Study needs repeating at none cytotoxic doses. 

Test considered equivocally positive.    

UDS in rat hepatocytes

870.5550

	

41822702 (1986)

In vitro unscheduled DNA synthesis in rat hepatocytes

Unacceptable in TXR# 008469

	

Cell in 1.0-100 nl/mL.  No cytotoxicity was seen. 

Test was negative. 

UDS in rat hepatocytes

870.5550	

4364802 (1993)

In vivo unscheduled DNA Synthesis in rat hepatocytes

Acceptable to EEC requirements TXR# 011053	

Fisher 344 rat administered SAN 582H doses of 158 or 500 mg/kg.  Sampled
2-4 and 12-14 hours after dosing.  Only 0.2-3.6% cells in repair, but
negative control was less than zero.  

Test was negative for UDS at 158 and 500 mg/kg.

UDS in rat hepatocytes

870.5550	

41596544 (1989)

In vitro unscheduled DNA synthesis in rat hepatocytes

Acceptable in TXR# 008285  	

SAN 582H administered at 0.01 to 50 µg/mL.  Unscheduled DNA synthesis
was seen well below cytotoxic doses.  Unequivocally positive for UDS. 

Test positive.   

UDS in rat hepatocytes

870.5550	

41662416 (1990)

In vitro unscheduled DNA synthesis in rat hepatocytes.

Acceptable in TXR# 008469

	

SAN 582H administered at 0.0128 to 1000 µg/mL to rat primary cultures
of  hepatocytes.  Doses at 1000 µg/mL were cytotoxic.  No UDS was
noted.

Test negative for UDS.   

Dominant Lethal

870.5450	

43209201 (1994) (Hazleton)

Dominant lethal in CR rats

Acceptable in TXR# 011053	

Male Charles River rats (40-55) administered SAN 582H in single oral
doses of 275, 550 or 1100 mg/kg were mated starting at 10 weeks to 40-55
female undosed CR rats.  Increased dead implants at week 1 and week 2
may suggest a dominant lethal effect.  These were mostly late implant
deaths, which some consultants claim are not characteristic of a
dominant lethal effect. .

Dominant Lethal

870.5450	

43814401 (1995) 

(Microbiological Assoc.) Dominant lethal in Sprague Dawley rats	

Male Sprague Dawley rats (40-60) administered  SAN 582H in single oral
doses of 275, 550 or 1100 mg/kg were mated starting the day after dosing
in Trial 1 and  2 days after dosing in Trial 2 to 80-120 female undosed
Sprague Dawley rats .  Each male was 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 cell transformation 

NG	

41822701 (1986)

per-1996 in vitro cell transformation 

Unacceptable in TXR# 008469	

BALB/3T3 cells administered SAN 582H at 15.0 to 100 µg/mL.  No
transformed cells were noted, but several inadequacies were noted in the
test report.  Number of cells transformed.  Cell transformation yields
variable results and is not an acceptable methodology. 

Test negative 

870.7485

Metabolism and pharmacokinetics

(Wistar rats)	

41596545 (1989) & 42289501 (1992)

Single low and high doses of [14C] SAN 582H and  after repeat doses of
SAN 582H were administered

Unacceptable in TXR# 008285

Acceptable in TXR# 009867. 	

Extensively metabolized, being essentially complete within 3 days and
over 90% being excreted in the urine, feces and bile within 7 days.  
Total excretion products with the highest concentrations (in % of
administered dose) in the male and female, 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%.
Parent was initially conjugated with glutathione and most metabolism
taking place with the glutathione conjugate.  No 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. 
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ࠀM1 is
N-(2,4-dimethyl-3-thienyl)-N-(2-hydroxy-1-methylethyl)-2-(methyl-thio)-a
cetamide

M2 is
N-(2,4-dimethyl-3-thienyl)-MN-(2-hydroxy-1-methylethyl)-2-(methyl-sulfin
yl)-

acetamide

M16 is
N-(2-hydroxymethyl-4-methyl-3-thienyl)-N-(2-methoxy-1-metylethyl)-2-		
(methylsulfinyl)-acetamide

Table B.4.  Subchronic, Chronic and Other Toxicity Profile for
[S]-dimethenamid-P (PC 120051)

Guideline No./ Study Type	

MRID No. (year)/ Classification /Doses	

Results

870.3100

90-Day Feeding/Sprague Dawley Rat 

	

44332242 (1996)

Doses: 0, 500, 1500, 3000 ppm [M/F: 0/0/, 37/40, 110/125, 222/256
mg/kg/day]

Acceptable in TXR# 0050183	

NOAEL=37/40 mg/kg/day [500 ppm]

 LOAEL=110/125 mg/kg/day [1500 ppm] based on decreased body weight and
body weight gain in males and females, increased gamma-glutamyl
transferase in both sexes, increased cholesterol in males, increased
abs. and rel. liver weight and periportal hepatocytic hypertrophy and
periportal eosinophilic inclusions in males, centrilobular hypertrophy
in females  and liver necrosis in females.

870.3700a

Prenatal developmental in (Sprague Dawley rats)

	

44332243 (1996) [Doses: 0, 25, 150, 300 mg/kg/day] Vehicle is 0.5% CMC,
10 ml/kg 

Acceptable in TXR# 0050183	

Maternal NOAEL = None

LOAEL =25 mg/kg/day based on body weight decrement on GD 13-19 (no
single dose effect) and body weight gain dece and food consumption
decrease GD 6-16 & 6-9, respectively

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 Mutation

870.5100 Bacterial Reverse mutation

	

 Reverse mutation 4332244 (1997) 

S. typhimurium TA1535; E. coli WP2uvrA

Acceptable in TRX# 0052635	

S. typhimurium  exposed to 500-4000 µg/plate +/- S9.

E. coli exposed to 20-5000 µg/plate +/-S9 using the Std plate incorp
method or 4-2500 µg/plate +/-S9 using the preincubation modification to
the std test.  Highest doses were cytotoxic. 

All assays were negative.

Gene Mutation

870.5100 Bacterial Reverse mutation

	

 Reverse mutation 4332245 (1997) 

S. typhimurin TA1535, TA1537, TA 98, TA100; E. coli WP2uvrA

Acceptable in TRX# 0052635 	

Exposed to 20-5000 µg/plate in a plate incorporation assay.  Marginal
cytotoxicity at limit dose of 5000 µg/plate +/- S9. 

Assays were negative with both bacteria +/- S9.  

Gene Mutation

870.5100 Bacterial Reverse mutation

	

Reverse mutation 4332246 (1997) 

S. typhimurin TA100.

Acceptable in TRX# 0052635 	

Repeat of MRID# 44123502.  S. typhimurium TA100 was exposed to 100-5000
µg/plate -S9.  

Assay was negative.

Gene Mutation

870.5100 Bacterial Reverse mutation

	

 Reverse mutation 44123502 (1996) & resubmitted  44332250  (1996) 

S. typhimurin TA1535, TA1537, TA 98, TA100; E. coli WP2uvrA

Acceptable in TRX# 0052636 	

Exposed to 100-5000 µg/plate, +/-S9, in a plate incorporation assay. 
Insolubility seen at 333 & 5000 µg/plate, but no toxicity at any dose.
+/- S9. 

Assays were negative with both bacteria + S9, however, -S9 induced 1.5
fold increases at 333 µg/plate and 4.1 fold increases in reverents in
TA100 strain at 5000 µg/plate.  This mutagenic response was
reproducible at 100 to 5000 µg/plate. 

Mammalian cell mutation

870.5300

 	

In vitro CHO/HGPRT mutation assay

44123501 (1996) & resubmission as 44332248

Acceptable TXR# 12312	

Chinese hamster ovary (CHO) cells were exposed to 100-400 µg/mL, -S9,
and 100-450 µg/mL, +S9.  Slight cytotoxicity was seen at the highest
dose and severe toxicity was seen at (500 µg/mL. 

Test was negative for mutagenic effects, +/- S9. 

Cytogenetics in Chinese Hamster Ovary (CHO) cells 

870.5375

	

Chromosomal aberrations in vitro

44332247 (1996)

Acceptable TXR# 0052635	

CHO cells were exposed to 2-120 µg/mL -S9; cytotoxic at (120 µg/mL. 
CHO cells were exposed to 15-120 µg/mL +S9; cytotoxic at (500 µg/mL.  

Assay was negative +/-S9.

Cytogenetics; mouse erythrocyte micronucleus test  

870.5395

	

ICR mice in vivo test

44332249 (1996)

Acceptable TRX# 0052635

	

Mice (5/sex) were exposed to i.p. injections of 103, 205, 410 mg/kg.  

Assay was negative, indicating no clastogenic or aneugenic response.

Other Effects 

870.5550

UDS in mammalian cell culture 

 	

Rat hepatocyte cell in vitro test 

44332251 (1996)

Acceptable TRX# 0052635	

Cells tested at 7.8-125 µg/mL.  Cytotoxicity and insolubility were seen
at (250 µg/mL. 

Test was negative for UDS.   

Appendix C:  Review of Human Research

No MRID - PHED Surrogate Exposure Guide

  PAGE  44  of   NUMPAGES  44