Document ID: EPA-HQ-OPP-2007-0116-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-12-31T05:00Z

UNITED STAES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

 PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

DATE:		September 27November 6, 2007 

SUBJECT:	Dimethenamid-P.  AMENDED Human Health Risk Assessment for a
Proposal for the Establishment of Tolerances for Dimethenamid-P Use on
Winter Squash, Pumpkin, Radish (Roots and Tops), Rutabaga (Roots and
Tops), Turnip (Roots, Tops and Greens) and on Hops, Dried Cones.  

Petition #	6E7152	

PC Code:	120051

DP #:	336172346303	

Class:	Herbicide

Decision #:	372743	40 CFR:	§180.464

FROM:	Breann Hanson, Biologist 

		Alternative Risk Integration and Assessment (ARIA) Team

		Risk Integration Minor Use and Emergency Response Branch 		
(RIMUERB)/Registration Division (RD) (7505P)

THROUGH:	William Cutchin, Acting Branch Senior Scientist 

		ARIA Team

		RIMUERB/RD (7505P)

		AND

		

		Douglas Dotson Ph.D., Chemist 

		Christina Swartz, Branch Chief

		Registration Action Branch 2 (RAB 2)

		Health Effects Division (HED) (7509P)

TO:		Shaja Sidney JacksonBrothers, RM Team 05

		RIMUERB/RD (7505P)

This human health risk assessment is an amendment to the original
dimethenamid-p risk assessment, dated 9/27/2007 (B. Hanson, DP#:
336172).  Subsequent to the original occupational/residential assessment
(dated 3/8/2007), toxicological endpoints were changed.  This revision
herein utilizes the amended toxicological endpoints in the occupational
exposure sections.  

TABLE OF CONTENTS

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc182022566"  1.0	EXECUTIVE
SUMMARY	  PAGEREF _Toc182022566 \h  4  

  HYPERLINK \l "_Toc182022567"  2.0	INGREDIENT PROFILE	  PAGEREF
_Toc182022567 \h  10  

  HYPERLINK \l "_Toc182022568"  2.1	Proposed Use	  PAGEREF _Toc182022568
\h  11  

  HYPERLINK \l "_Toc182022569"  2.2	Identification of Active Ingredient	
 PAGEREF _Toc182022569 \h  12  

  HYPERLINK \l "_Toc182022570"  2.3	Physical and Chemical Properties	 
PAGEREF _Toc182022570 \h  13  

  HYPERLINK \l "_Toc182022571"  3.0	HAZARD CHARACTERIZATION	  PAGEREF
_Toc182022571 \h  14  

  HYPERLINK \l "_Toc182022572"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc182022572 \h  14  

  HYPERLINK \l "_Toc182022573"  3.2	Endocrine Disruption	  PAGEREF
_Toc182022573 \h  16  

  HYPERLINK \l "_Toc182022574"  3.3	Adsorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc182022574 \h  17  

  HYPERLINK \l "_Toc182022575"  3.4	Special Considerations for Infants
and Children (FQPA Safety Determination)	  PAGEREF _Toc182022575 \h  17 

  HYPERLINK \l "_Toc182022576"  4.0	PUBLIC HEALTH AND PESTICIDE
EPIDEMIOLOGY DATA	  PAGEREF _Toc182022576 \h  19  

  HYPERLINK \l "_Toc182022577"  4.1	Incident Reports	  PAGEREF
_Toc182022577 \h  19  

  HYPERLINK \l "_Toc182022578"  5.0	DIETARY EXPOSURE/RISK
CHARACTERIZATION	  PAGEREF _Toc182022578 \h  19  

  HYPERLINK \l "_Toc182022579"  5.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc182022579 \h  19  

  HYPERLINK \l "_Toc182022580"  5.1.1	Metabolism in Primary Crops	 
PAGEREF _Toc182022580 \h  19  

  HYPERLINK \l "_Toc182022581"  5.1.2	Metabolism in Animals	  PAGEREF
_Toc182022581 \h  20  

  HYPERLINK \l "_Toc182022582"  5.1.3	Metabolism in Rotational Crops	 
PAGEREF _Toc182022582 \h  21  

  HYPERLINK \l "_Toc182022583"  5.1.4	Metabolism in Livestock	  PAGEREF
_Toc182022583 \h  21  

  HYPERLINK \l "_Toc182022584"  5.1.5	Analytical Methodology	  PAGEREF
_Toc182022584 \h  21  

  HYPERLINK \l "_Toc182022585"  5.1.6	Multiresidue Methods	  PAGEREF
_Toc182022585 \h  22  

  HYPERLINK \l "_Toc182022586"  5.1.7	Environmental Degradation	 
PAGEREF _Toc182022586 \h  22  

  HYPERLINK \l "_Toc182022587"  5.1.8	Comparative Metabolic Profile	 
PAGEREF _Toc182022587 \h  22  

  HYPERLINK \l "_Toc182022588"  5.1.9	Toxicity Profile of Major
Metabolites and Degradates	  PAGEREF _Toc182022588 \h  23  

  HYPERLINK \l "_Toc182022589"  5.1.10   Drinking Water Residue Profile	
 PAGEREF _Toc182022589 \h  23  

  HYPERLINK \l "_Toc182022590"  5.1.11	Food Residue Profile	  PAGEREF
_Toc182022590 \h  24  

  HYPERLINK \l "_Toc182022591"  5.1.12	International Residue Limits	 
PAGEREF _Toc182022591 \h  26  

  HYPERLINK \l "_Toc182022592"  5.2	Dietary Exposure and Risk	  PAGEREF
_Toc182022592 \h  26  

  HYPERLINK \l "_Toc182022593"  5.2.1	Acute Dietary Exposure/Risk	 
PAGEREF _Toc182022593 \h  27  

  HYPERLINK \l "_Toc182022594"  5.2.2	Chronic Dietary Exposure/Risk	 
PAGEREF _Toc182022594 \h  27  

  HYPERLINK \l "_Toc182022595"  5.2.3	Cancer Dietary Risk	  PAGEREF
_Toc182022595 \h  28  

  HYPERLINK \l "_Toc182022596"  5.3	Anticipated Residue and Percent Crop
Treated (%CT) Information	  PAGEREF _Toc182022596 \h  28  

  HYPERLINK \l "_Toc182022597"  6.0	RESIDENTIAL (NON-OCCUPATIONAL)
EXPOSURE/RISK CHARACTERIZATION	  PAGEREF _Toc182022597 \h  28  

  HYPERLINK \l "_Toc182022598"  6.1	Other (Spray Drift, etc.)	  PAGEREF
_Toc182022598 \h  28  

  HYPERLINK \l "_Toc182022599"  7.0	AGGREGATE RISK ASSESSMENTS AND RISK
CHARACTERIZATION	  PAGEREF _Toc182022599 \h  29  

  HYPERLINK \l "_Toc182022600"  8.0	CUMULATIVE RISK
CHARACTERIZATION/ASSESSMENT	  PAGEREF _Toc182022600 \h  29  

  HYPERLINK \l "_Toc182022601"  9.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY	 
PAGEREF _Toc182022601 \h  29  

  HYPERLINK \l "_Toc182022602"  9.1	Proposed Uses	  PAGEREF
_Toc182022602 \h  30  

  HYPERLINK \l "_Toc182022603"  9.2	Non-Occupational/Residential
Exposure	  PAGEREF _Toc182022603 \h  31  

  HYPERLINK \l "_Toc182022604"  9.3	Occupational Pesticide Handler
Exposure	  PAGEREF _Toc182022604 \h  31  

  HYPERLINK \l "_Toc182022605"  9.4	Occupational Post-Application Worker
Exposure and Risk	  PAGEREF _Toc182022605 \h  33  

  HYPERLINK \l "_Toc182022606"  9.5	Restricted Entry Interval	  PAGEREF
_Toc182022606 \h  35  

  HYPERLINK \l "_Toc182022607"  10.0	DATA NEEDS AND LABEL
RECOMMENDATIONS	  PAGEREF _Toc182022607 \h  35  

  HYPERLINK \l "_Toc182022608"  10.1	Toxicology	  PAGEREF _Toc182022608
\h  35  

  HYPERLINK \l "_Toc182022609"  10.2	Residue Chemistry	  PAGEREF
_Toc182022609 \h  35  

  HYPERLINK \l "_Toc182022610"  10.3	Occupational and Residential
Exposure	  PAGEREF _Toc182022610 \h  35  

  HYPERLINK \l "_Toc182022611"  Appendix A: International Residue Limits
Status	  PAGEREF _Toc182022611 \h  37  

  HYPERLINK \l "_Toc182022612"  Appendix B:  TOXICOLOGY ASSSESSMENT	 
PAGEREF _Toc182022612 \h  38  

  HYPERLINK \l "_Toc182022613"  B.1	Toxicity Profiles	  PAGEREF
_Toc182022613 \h  38  

  HYPERLINK \l "_Toc182022614"  Appendix C:	REFERENCES (in MRID order)	 
PAGEREF _Toc182022614 \h  45  

  HYPERLINK \l "_Toc182022615"  Appendix D:	REVIEW OF HUMAN RESEARCH	 
PAGEREF _Toc182022615 \h  49  

 1.0	EXECUTIVE SUMMARY

The Interregional Research Project No. 4 (IR-4) has submitted a petition
for use of dimethenamid-P,
(RS)-2-chloro-N-[(1-methyl-2-methoxy)ethyl]-N-(2,4-dimethylthien-3-yl)ac
etamide, on winter squash, pumpkin, radish, rutabaga, turnip and hops,
dried cones (PP# 6E7152).  Dimethenamid-P, which is a form of
dimethenamid that is enriched in the biologically active S-isomer
(90:10, S:R), is a selective, preemergence herbicide registered for the
control of annual broadleaf and grass weeds in a variety of field and
vegetable crops.  The most recent human health risk assessment for
dimethenamid-P was conducted for these commodities, but included
outdated toxicological endpoints in the occupational exposure assessment
(B. Hanson, DP #: 336172, 9/27/2007).  Prior to this, tThhe most recent
human health risk assessment for dimethenamid-P was conducted in
conjunction with a request for the establishment of tolerances for
residues on grasses grown for seed (D. Rate, DP #: 337887, 5/29/2007).

Use Profile

Dimethenamid is currently registered to BASF Corporation for use on a
variety of food/feed crops as a 6 lb/gal emulsifiable concentrate (EC,
Outlook® Herbicide; EPA Reg. No. 7969-156).  The Interregional Research
Project No. 4 (IR-4) is proposing new uses for dimethenamid-P on
radishes, turnips, rutabagas, pumpkins, winter squash, and hops. 
Dimethenamid (6 lb/gal EC) is being proposed for a single broadcast
postemergence application at up to 0.98 lb ai/A to radishes at the 2- to
4-leaf stage and to turnips and rutabagas at the 2- to 8-leaf stage. 
The specified preharvest intervals (PHIs) are 21 days for radishes
(roots and tops), 14 days for turnip and rutabaga tops, and 40 days for
turnip and rutabaga roots.  The proposed use on winter squash and
pumpkins is restricted to OR and WA and is for single preemergence
application at up to 0.98 lb ai/A, with a PHI of 90 days.  The proposed
use for hops is restricted to ID, OR and WA and is for a single
soil-directed or banded application between rows at up to 0.98 lb ai/A,
when hops are at the vegetative or early bloom stages.  The proposed PHI
for hops is 60 days.  All applications are to be made using ground
equipment; the use of aerial applications and chemigation are
prohibited.  

Current Tolerances

Tolerances are established for residues of dimethenamid in/on numerous
raw agricultural commodities at 0.01 ppm, which is the lowest limit of
method validation (LLMV).  Tolerances are established in 40 CFR
§180.464(a) and (b) for both dimethenamid (50:50, S:R) and
dimethenamid-P (90:10, S:R).  As a result, tolerances that are
established for the proposed commodities will apply to both dimethenamid
and dimethenamid-P.  

Proposed Tolerances

Under PP# 6E7152, IR-4 requests the establishment of new tolerances for
dimethenamid-P in/on the following raw agricultural commodities (RACs): 
winter squash; pumpkin; radish, roots; radish, tops; rutabaga, roots and
turnip, roots at 0.01 ppm and rutabaga, tops; turnip, tops and turnip,
greens at 0.1 ppm and hops, dried cones at 0.05 ppm.

Human Health Risk Assessment

Toxicology/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 are the same
as those for [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.  The dose picked for short- term dermal and short-term
inhalation exposures is the lowest observed adverse effect level (LOAEL)
of 33.6 mg/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 and Risk

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.  Adequate
residue data are available to support the proposed tolerances.  With the
exception of turnip tops, residues of dimethenamid were < the lower
limit of method validation (LLMV) in/on all samples of radish roots and
tops (<0.01 ppm), dried hop cones (<0.05 ppm), winter squash (<0.01 ppm)
and turnip roots (<0.01 ppm).  Residues in/on turnip tops were
<0.01-0.093 ppm, with only 3 of 16 samples having residues above the
LLMV.  Based on data from the ruminant and poultry metabolism studies
and the calculated MDB for livestock to dimethenamid residues,
tolerances for livestock commodities are not required at the present
time.

  SEQ CHAPTER \h \r 1 The nature of dimethenamid residues in plants is
understood based on adequate soybean, corn and sugar beet metabolism
studies.  The residue of concern for purposes of the tolerance
expression and risk assessment is dimethenamid per se.  The qualitative
nature of the residue in livestock is also understood based on adequate
goat and hen metabolism studies.

  SEQ CHAPTER \h \r 1 An adequate gas chromatograph/nitrogen-phosphorus
detection method (GC/NPD) AM-0884-0193-1 is available for enforcing
tolerances on plant commodities.  This method does not separate the R
and S isomers of dimethenamid, and is therefore adequate for both
dimethenamid and dimethenamid-P.  

Based on the current and proposed uses of dimethenamid,   SEQ CHAPTER \h
\r 1 requirements for confined/field accumulation in rotational crops
are satisfied based on the acceptable confined rotational crop study. 
The submitted study includes data on winter wheat, lettuce planted, and
carrots.  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 determined that a 4-month
rotational interval is adequate for fall-seeded cereal grains, and other
crops may be planted the following spring.  These recommendations are
consistent with the rotational crop restrictions on the current label
for the 6 lb/gal EC formulation of dimethenamid-P

There are no established or proposed Codex, Canadian or Mexican maximum
residue limits (MRLs) for dimethenamid on any of the crops/commodities
being proposed in this petition (see attached international residue
limit (IRL) status sheet).  Therefore, there is no question about
compatibility of the proposed tolerances.

Water Exposure and Risk

The drinking water residues used in the dietary risk assessment were
provided by EFED and summarized in the following memoranda: “Drinking
water Exposure Assessment for the Section 3 IR-4 Proposed New Uses of
S-Dimethenamid on Squash, Pumpkin, Rutabaga, Turnip, Radish and Hops.”
(P. Mastradone, 8/28/2007) and incorporated directly into this dietary
assessment.  Water residues were incorporated in the DEEM-FCID into the
food categories “water, direct, all sources” and “water, indirect,
all sources.” 

Considering all currently registered uses as well as the proposed new
uses, the highest acute estimated drinking water concentration (EDWC) is
from the green onion use (66.7 ppb) while the highest chronic EDWC is
from the ornamental use (20.2 ppb)..  

Acute and Chronic Dietary Exposure Results and Characterization

Dietary exposure and risk were calculated assuming tolerance level
residues, DEEM( default processing factors, and 100% assumed CT for all
RACs  The drinking water residues were included in the respective acute
(females age 13-49 years) and chronic (all populations) analyses.  An
appropriate acute endpoint attributable to a single dose was not
identified for the general population in the toxicity data base
including the developmental toxicity studies.   

The results of the analysis indicate that acute risk from the dietary
(food + drinking water) exposure to dimethenamid-P will not exceed
HED’s level of concern (i.e. <100% acute population adjusted doses
(cPAD)) for females age 13-49 years.  

The results of the analysis indicate that chronic risk from the dietary
(food + drinking water) exposure to dimethenamid-P will not exceed
HED’s level of concern (i.e. <100% chronic population adjusted doses
(cPAD)) for the general U.S. population, and all population subgroups.  

Non-Occupational and Residential Exposure/Risks

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 Exposure/Risks

Acute and chronic aggregate risk estimates do not exceed HED's level of
concern.  Since the acute and chronic aggregate risk exposures include
only food and water, and the acute and chronic dietary analyses included
both, no further calculations are necessary.  Since both the acute and
chronic dietary risks do not exceed HED’s level of concern, the acute
and chronic aggregate risks do not exceed HED’s level of concern.

Occupational Exposure/Risks

An occupational risk assessment was completed for dimethenamid-P for its
use on winter squash, pumpkin, radish, rutabaga, turnip, turnip greens
and hops (M. Dow, DP#: 336589, 35/8/2007).  Subsequently, an amended
risk assessment was completed 11/2/2007 due to changes in toxicological
endpoints used for risk assessments (M. Dow, DP#: 346234).  Based upon
the proposed use patterns RD believes that for the proposed new uses,
the most highly exposed occupational pesticide handlers will be
mixer/loaders using open-pour loading of liquid formulations and
applicators using open-cab, ground-boom sprayers.  The level of concern
is a Margin of Exposure (MOE) of< 300100.  An additional 3X uncertainty
factor was added due to use of a LOAEL.  The proposed use patterns do
not exceed RDs level of concern provided the mixer/loaders wear
protective gloves as directed on the product label.

It is possible for agricultural workers to have post-application
exposures to pesticide residues during the course of typical
agricultural activities.  For the proposed new crop use sites, the
post-application agricultural activity that may occur and which may
result in the highest post-application exposures to pesticide residues
results from hand harvesting turnips.  The MOE is < 100 for hand
harvesting turnips on day 0 of treatment.  There is a 14 day PHI for
hand harvesting tops and a 30 day PHI for hand harvesting roots.  Due to
the use patterns (timing of application) for crops other than turnips
and rutabagas, and due to the PHI for turnips and rutabagas, the
proposed use patterns do not exceed RD’s level of concern.

The MOE is < 300 and in some other cases would be of concern to RD.  In
this case, there is only one application at or near the time of weed
emergence.  At this time, the only agricultural activity expected is
scouting for treatment efficacy.  Scouting at this time does not involve
foliar contact or manual activity that results in contact with treated
materials.  There is a 12 hour REI.  The MOE calculated is a
conservative estimate.   In this case, the proposed use does not exceed
RDs level of concern.

Based on the toxicity categories for dimethenamid-P,A a restricted entry
interval (REI) of 12 hours is adequate protection for the proposed new
use patterns.  

for agricultural workers.

Environmental Justice Consideration

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 ).

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

Review of Human Research

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.

 

Additional Data Needs

Residue Chemistry

No deficiencies were noted in the subject petition that would preclude
establishing permanent tolerances for dimethenamid on the proposed crops
provided the petitioner addresses the deficiencies noted below:

1.	A revised Section B must be provided.  This should be revised so that
uses on rutabagas (roots and tops) are associated with the proposed uses
on turnips (tops and roots).  

2.	Although the proposed label directions for turnips and rutabagas
specify a 40-day PHI for roots, ARIA notes that the available turnip
field trial data would support lowering the PHI for roots to 30 days,
which matches the proposed use in the submitted Section B.

Recommendations for Tolerances/Registration

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.  It should be noted that the data submitted for
radish, turnip and rutabaga, while adequate for individual crop
tolerances, are not sufficient for a crop group tolerance.  All of the
recommended tolerances should be placed in 40 CFR §180.464(a), without
restriction, except for the tolerances for pumpkins and winter squash
which should be placed in 40 CFR §180.464(c), as the use on these crops
is restricted to OR and WA.  The data submitted for hops support a
national tolerance placing it in 40 CFR §180.464(a), even though the
labeled use submitted by the petitioner restricts distribution to ID, OR
and WA (>95% of US hops production). 

ARIA recommends for tolerances for the residues of dimethenamid-P in/on
the following RACs, noted in table 1.0, below, provided the deficiencies
noted above are addressed.

Table 1.0. 	Tolerance Summary for Dimethenamid

Commodity	Proposed Tolerance (ppm)	Recommended Tolerance (ppm)	Comments;

Correct Commodity Definition

40 CFR §180.464(a)

Hop, dried cones	0.05	0.05	Adequate hops residue data are available for
a national registration.

Radish, tops	0.01	0.01	Adequate radish residue data are available.

Radish, roots	0.01	0.01

	Rutabaga, roots	0.01	0.01	The available turnip residue data will
support the equivalent tolerances on rutabaga roots and tops.

Rutabaga, tops	0.1	0.1

	Turnip, greens	0.1	0.1	Adequate residue data are available on turnip
roots and tops.

Turnip, roots	0.01	0.01

	Turnip, tops	0.1	0.1

	40 CFR §180.464(c)

Pumpkin	0.01	0.01	Adequate winter squash residue data are available to
support regionally restricted tolerances on both Pumpkin and Squash,
winter

Winter squash	0.01	0.01

	

2.0	INGREDIENT PROFILE

Dimethenamid is currently registered to BASF Corporation for use on a
variety of food/feed crops (EC, Outlook® Herbicide; EPA Reg. No.
7969-156).  Dimethenamid (6 lb/gal EC) is being proposed for a single
broadcast postemergence application at up to 0.98 lb ai/A to radishes at
the 2- to 4-leaf stage and to turnips and rutabagas at the 2- to 8-leaf
stage.  The specified PHIs are 21 days for radishes (roots and tops), 14
days for turnip and rutabaga tops, and 40 days for turnip and rutabaga
roots.  The proposed use on winter squash and pumpkins is restricted to
OR and WA and is for single preemergence application at up to 0.98 lb
ai/A, with a PHI of 90 days.  The proposed use for hops is restricted to
ID, OR and WA and is for a single soil-directed or banded application
between rows at up to 0.98 lb ai/A, when hops are at the vegetative or
early bloom stages.  The proposed PHI for hops is 60 days.  All
applications are to be made using ground equipment; the use of aerial
applications and chemigation are prohibited.  

2.1	Proposed Use

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

Applic. Timing, Type, and Equip. 1	Formulation

[EPA Reg. No.]	Applic. Rates 

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

(lb ai/A)	PHI

(days)	Use Directions and Limitations 2

Hops (only in ID, OR and WA)

Directed or banded post-emergence application from vegetative to early
bloom stages, using ground equipment 	6.0 lb/gal EC

[7969-156]	0.56-0.98	1	0.98	60	This use is restricted to the states of
ID, OR and WA.

Radish

Broadcast post-emergence application when plants are at 2- to 4-leaf
stage, using ground equipment 	6.0 lb/gal EC

[7969-156]	0.56-0.98	1	0.98	21

	Turnip and Rutabaga

Broadcast post-emergence application when plants are at 2- to 8-leaf
stage, using ground equipment 	6.0 lb/gal EC

[7969-156]	0.56-0.98	1	0.98	tops - 14

roots - 40

	Winter Squash and Pumpkins (only in OR and WA)

Broadcast preemergence application using ground equipment	6.0 lb/gal EC

[7969-156]	0.56-0.98	1	0.98	90	This use is restricted to the states of
OR and WA

1	Do not apply by air or through any irrigation systems.

2	Crops listed on the main label may be replanted at anytime, and
fall-seeded cereal grains may be planted 4 months after application.  
All other crops may be planted the following spring.

2.2	Identification of Active Ingredient

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

OUTLOOK™ (6 lb ai/gal EC; EPA Reg. No. 7969-156)

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#: 183774, 1/22/93, M. Flood

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

Density	1.19 g/mL at 25°C;

1.19 specific gravity at 25°C	DP#: 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#: 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

	

Table 2.3.b	Physicochemical Properties of Dimethenamid-P.

Parameter	Value	Reference

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

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

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

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

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

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

Dissociation constant, pKa	No dissocitation between pH 1 and 11 at 25°C
(PAI)	DP#: 217337, 7/26/95, M. Rodriguez

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

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

3.0	HAZARD CHARACTERIZATION  TC \l1 "3.0  HAZARD CHARACTERIZATION 

3.1	Hazard and Dose-Response Characterization

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. 

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.

 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 excretion products 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.

The Carcinogenicity Peer Review of dimethenamid on 3/23/1995 (TXR#
012143) and 6/15/1992 (TXR# 012831) classified dimethenamid as Group C -
possible human carcinogen, based on benign liver tumors in male rats. 
The tumors were slightly above historical control levels, only showed
statistical significance as increased trends and not by pairwise between
control and treated animals, only evidenced a statistically significant
trend when benign and malignant tumors were combined, and were only seen
in one species.  An acceptable study in mice showed no dose-related
tumors.  There were positive results in some genotoxicity tests with
dimethenamid and it is structurally related to other carcinogens.  The
chronic reference dose (cRfD) of 0.05 mg/kg/day used for risk assessment
is based on non-cancer precursor effects in the liver; therefore, the
cRfD is considered protective of both cancer and non-cancer effects. 

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 a slight decrease in
maternal body weight gain at a lower dose than did [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 selections 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.  

3.2	Endocrine Disruption

EPA is required under the Federal Food Drug and Cosmetic Act (FFDCA), as
amended by FQPA, to develop a screening program to determine whether
certain substances (including all pesticide active and other
ingredients) "may have an effect in humans that is similar to an effect
produced by a naturally occurring estrogen, or other such endocrine
effects as the Administrator may designate."  Following the
recommendations of its Endocrine Disruptor Screening and Testing
Advisory Committee (EDSTAC), EPA determined that there was 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 has 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.

3.3	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, intravenous 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. 

3.4	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 (i.e.,
droopy eye lids), 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 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 recommended 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:  No literature reports on the toxicity of
[S]-dimethenamid-P were 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.

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  TC \l1 "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 are
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 feedstuff 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 that of 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, 11/10/1992; and M. Bradley,
12/8/1993).  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.  

C-residues were characterized as minor unknowns each present at ≤8% of
the TRR.  One unknown polar fraction accounted for >10% of the TRR in
roots, but was present at <0.01 ppm.  The metabolic pathway for [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,
intravenous doses and multiple doses.  In feces, females excreted 26% to
48% and males 30% to 62% at low and high oral doses, intravenous 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% of the dose 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.  These recommendations are consistent with the
rotational crop restrictions on the current label for the 6 lb/gal EC
formulation of dimethenamid-P.

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).

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, 11/10/1992).  

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 11/2001 (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).  

5.1.7	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.

5.1.8	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.

5.1.9	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 be formed in the rat also, 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.  

  TC \l3 "5.1.5	Environmental Degradation 

5.1.10   Drinking Water Residue Profile

The drinking water residues used in the dietary risk assessment were
provided by EFED and summarized in the following memoranda: “Drinking
water Exposure Assessment for the Section 3 IR-4 Proposed New Uses of
S-Dimethenamid on Squash, Pumpkin, Rutabaga, Turnip, Radish and Hops.”
(P. Mastradone, 8/28/2007) and incorporated directly into this dietary
assessment.  Water residues were incorporated in the DEEM-FCID into the
food categories “water, direct, all sources” and “water, indirect,
all sources.” 

   

Considering all currently registered uses as well as the proposed new
uses, the highest acute EDWC is from the green onion use (66.7 ppb)
while the highest chronic EDWC is from the ornamental use (20.2 ppb), as
presented in Table 5.1.10.

Table 5.1.10.  Maximum EDWC’S (ppb) from all Current and Proposed Uses
of S-Dimethenamid.

Use	Surface Water a	Ground Water b

	Modeled scenario c

(App. Method)	Acute

[1-in-10 year peak]	Chronic

[1-in-10 year average]	Acute and Chronic

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

5.1.11	Food Residue Profile

As part of the current petition, ARIA recommends establishing permanent
tolerances for residues of dimethenamid at 0.01 ppm on radish roots and
tops, turnip roots, rutabaga roots, pumpkins and winter squash. 
Tolerances should also be established at 0.1 ppm on turnip tops and
rutabaga tops, and at 0.05 ppm on hops, dried cones.

It should be noted that the data submitted for radish, turnip and
rutabaga, while adequate for individual crop tolerances, are not
sufficient for a crop group tolerance.  All of the recommended
tolerances should be placed in 40 CFR §180.464(a), without restriction,
except for the tolerances for pumpkins and winter squash which should be
placed in 40 CFR §180.464(c), as the use on these crops is restricted
to OR and WA.  The data submitted for hops support a national tolerance
placing it in 40 CFR §180.464(a), even though the labeled use submitted
by the petitioner restricts distribution to ID, OR and WA (>95% of US
hops production).

If IR-4 wants to continue with the Section 3 registration, then the
following deficiencies need to be addressed: 

1.	A revised Section B must be provided.  This should be revised so that
uses on rutabagas (roots and tops) are associated with the proposed uses
on turnips (tops and roots).  

2.	Although the proposed label directions for turnips and rutabagas
specify a 40-day PHI for roots, ARIA notes that the available turnip
field trial data would support lowering the PHI for roots to 30 days,
which matches the proposed use in the submitted Section B.

For a more detailed explanation of deficiencies/issues with this
petition, please see the residue chemistry data review memorandum (D.
Rate, DP#: 341886, 9/25/2007).

 

  SEQ CHAPTER \h \r 1 The nature of dimethenamid residues in plants is
understood based on the adequate soybean, corn and sugar beet metabolism
studies.  The residue of concern for purposes of the tolerance
expression and risk assessment is dimethenamid per se.  The qualitative
nature of the residue in livestock is also understood based on the
adequate goat and hen metabolism studies.    SEQ CHAPTER \h \r 1
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,
ARIA has concluded that livestock feeding studies and tolerances for
animal commodities are not required at the present time.  

  SEQ CHAPTER \h \r 1 An adequate GC/NPD Method AM-0884-0193-1 is
available for enforcing tolerances on plant commodities.  The LLMV is
0.01 ppm for the requested plant commodities, except hops (which has an
LLMV of 0.05 ppm).  This method does not separate the R and S isomers of
dimethenamid, and is therefore adequate for both dimethenamid and
dimethenamid-P.  As tolerances are not required for animal commodities,
no analytical methods for animal commodities are required.

The residue data from the submitted turnip and radish field trials were
collected using the above GC/NPD enforcement method, and residue data
from the squash and hops field trials were collected using methods which
were derived from the enforcement method.  In each case, the method used
for data collection was adequately validated in conjunction with the
analysis of field trial samples.  In the turnip and radish field trials,
the statistically calculated LOQs for dimethenamid are 0.008 ppm for
turnip tops, 0.004 for radish tops and 0.005 for turnip and radish
roots.

In the squash field trials, residues of dimethenamid were determined
using a gas chromatography with electron capture detection (GC/ECD)
method (Method SAM 3002.01) that is a modification of the above
enforcement method.  The calculated LOQ for dimethenamid in squash is
0.005 ppm.

In the hops field trials,   SEQ CHAPTER \h \r 1 residues of dimethenamid
were determined using a gas chromatography with a mass selective
detector (GC/MSD)   SEQ CHAPTER \h \r 1 method.  Residues are analyzed
by GC/MSD using an external standard and the m/z 230 ion of
quantitation.  The statistically calculated LOQ is 0.034 ppm for
dimethenamid in hops.

The available turnip, radish, winter squash and hops field trial data
are adequate and support the proposed use patterns.  The number and
geographic distribution of the field trials are adequate and the
appropriate samples were collected at the proposed PHIs.  Samples were
analyzed for the residues of concern using adequate methods, and the
sample storage conditions and intervals are supported by the available
storage stability data.

In the eight adequate turnip field trials, dimethenamid (6 lb/gal EC)
was applied to turnips during vegetative development as a single
post-emergence broadcast application at 0.94-1.03 lb ai/A (1x rate)
using ground equipment.  Residues of dimethenamid were non-detectable
in/on all 16 root samples harvested at 28-40 days after treatment (DAT),
and <0.01-0.093 ppm in/on 16 samples of tops harvested at 14-16 DAT. 
Average residues were 0.018 ppm in tops and <0.01 ppm in roots.  The
field trial data on turnips will support the equivalent use on
rutabagas.  Because the radish, top and turnip, top data are over 10x
difference (0.01 ppm and 0.1 ppm, respectively) not the 5x defined in
OPP policy, the data do not support a crop group tolerance.

In the six radish field trials, dimethenamid (6 lb/gal EC) was applied
to radishes at the 2- to 4-leaf stage as a single post-emergence
broadcast application at 0.96-1.03 lb ai/A (1x rate) using ground
equipment.  Residues of dimethenamid were <0.01 ppm in/on all 12 samples
of radish tops and <0.01 ppm in/on all 12 samples of radish roots
harvested at 15-21 DAT.

In the three winter squash field trials conducted in EPA growing Region
12, dimethenamid (6 lb/gal EC) was applied to winter squash as a single
preemergence broadcast application at 0.95-1.00 lb ai/A (1x rate) using
ground equipment.  Residues of dimethenamid were <0.01 ppm in/on all 6
samples of winter squash harvested at normal crop maturity, 108-131 DAT.
 ARIA determined that the field trial data on winter squash will support
the equivalent use on pumpkins (D. Rate, DP#: 341886, 9/25/2007).

In the three hops field trials, dimethenamid (6 lb/gal EC) was applied
to hops during vegetative development through early bloom as a single
soil directed application at 0.97-1.02 lb ai/A (1x rate) using ground
equipment.  Residues of dimethenamid were <0.05 ppm in/on all 6 samples
of dried hop cones harvested at 60-61 DAT.

No processing studies were submitted with the current petition as none
of the proposed uses include crops having regulated processed
commodities.  An adequate confined rotational crop study is available
which supports the current label restrictions for rotational crops. 

5.1.12	International Residue Limits

There are no established or proposed Codex, Canadian or Mexican maximum
residue limits (MRLs) for dimethenamid on any of the crops/commodities
being proposed in this petition.  Therefore, there is no question about
compatibility of the proposed tolerances.

5.2	Dietary Exposure and Risk

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

The dietary exposure analysis was performed by ARIA (B. Hanson, DP #:
341975, 9/25/2007).

 TC \l2 "5.2  Dietary Exposure and Risk 

5.2.1	Acute Dietary Exposure/Risk

An appropriate acute endpoint attributable to a single dose was not
identified for the general population in the toxicity data base
including the developmental toxicity studies.  However, an endpoint was
selected for the population subgroup females 13-49.  The acute dietary
analysis was conducted for dimethenamid-p assuming tolerance level
residues, default processing factors, and 100%CT information.  The
highest drinking water estimate for acute exposure, 66.7 ppb, was used
in the analysis.  The results of the analysis indicate that acute risk
from the dietary (food + drinking water) exposure to dimethenamid-p will
not exceed HED’s level of concern (i.e. <100% acute population
adjusted dose (aPAD)) for the population subgroup females 13-49.  The
risk estimate due to acute dietary exposure from food and water for this
population subgroup is less than 1% of the aPAD.  

Table 5.2.1.  Results of Acute Dietary Exposure Analysis at the 95th
Percentile of Exposure.

Population Subgroup	

aPAD

(mg/kg/day)	

Exposure (mg/kg/day)	

% aPAD

Females 13-49	

0.75	0.003285	<1

5.2.2	Chronic Dietary Exposure/Risk

The chronic dietary risk assessment was conducted for dimethenamid-p
assuming tolerance level residues, default processing factors, and
100%CT information.  The highest drinking water estimate for chronic
exposure, 20.2 ppb, was used in the analysis.  The results of the
analysis indicate that chronic risk from the dietary (food + drinking
water) exposure to dimethenamid-p will not exceed HED’s level of
concern (i.e. <100% chronic population adjusted doses (cPAD)) for the
general U.S. population, and all population subgroups.  The chronic
dietary risk estimate for the highest reported exposed population
subgroup, all infants (<1 year old), was <3% of the cPAD.  The general
US population utilizes <1% of the cPAD.

Table 5.2.2  Summary of Chronic Dietary (Food and Drinking Water)
Exposure Risk for Dimethenamid-P

Population Subgroup	Chronic Dietary

	Dietary Exposure (mg/kg/day)	% cPAD

General U.S. Population	0.000471	<1

All Infants (< 1 year old)	0.001460	2.9

Children 1-2 years old	0.000728	1.5

Children 3-5 years old	0.000692	1.4

Children 6-12 years old	0.000480	1.0

Youth 13-19 years old	0.000359	<1

Adults 20-49 years old	0.000434	<1

Adults 50+ years old	0.000447	<1

Females 13-49 years old	0.000431	<1

5.2.3	Cancer Dietary Risk

Dimethenamid-P is a category “C” possible human carcinogen;
therefore, quantification of human cancer risk is not required and a
cancer dietary assessment was not performed.

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

No anticipated residues or %CT information was used in these dietary
analyses.

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 non-occupational sources, including; food,
drinking water, and residential pathways.  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, ARIA considers both the route and duration of exposure.

Since the acute and chronic aggregate risk exposures include only food
and water and the acute and chronic dietary analyses included both, no
further calculations are necessary.  Since the acute and chronic dietary
risk estimates do not exceed HED’s level of concern, the acute and
chronic aggregate risk estimates do not exceed HED’s level of concern.
 There are no residential uses associated with dimethenamid-P;
therefore, short and intermediate-term aggregate risk assessments were
not performed.

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, and 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 amended occupational risk assessment was completed for this IR-4
registration request of dimethenamid-P for its use on winter squash,
pumpkin, radish, rutabaga, turnip, turnip greens and hops (M. Dow, DP#:
336589346234, 3/811/2/2007).

9.1	Proposed Uses

The use pattern summary is taken primarily from the Sections B of the IR
4 submissions and from the supplemental labels submitted by BASF.  The
registered product suggested for amendment is Outlook® Herbicide (Reg.
No. 7969-156).  Outlook® is formulated as a 6.0 lb active ingredient
(ai)/gal (63.9 %) dimethenamid-P liquid formulation.  The product label
directs applicators and other handlers to wear personal protective
equipment (PPE) consisting of: long-sleeved shirt, long pants, chemical
resistant gloves, shoes plus socks and protective eyewear.  

The target pests for all proposed crop sites are annual grasses, annual
broadleaf weeds and sedges.  

WINTER SQUASH AND PUMPKIN

The rate of application is 0.98 lb ai/A.  A single broadcast ground
application is to be made pre-emergence after planting but prior to crop
emergence.  It should be applied in 10 - 40 gal water/A.  The
supplemental label indicates it is only for distribution and use in
Oregon and Washington.  There is a 90 day preharvest interval (PHI).  

RADISH 

The rate of application is 0.98 lb ai/A.  One broadcast ground
application is to be made when the radish plants are at the 2 - 4 leaf
stage of growth.  Applications should be made in 10 - 40 gallons of
water/A.  There is a 21 day PHI.  It may not be applied aerially or
through any type of irrigation system.  

TURNIP AND RUTABAGA

The rate of application is 0.98 lb ai/A.  One post-emergence, broadcast,
ground application in 10 - 40 gallons of water/A should be made 14 days
(± 1 day) prior to harvesting tops of turnip, rutabaga and turnip
greens and 30 days (± 2 days) prior to harvesting roots of turnips and
rutabaga.  T.   he supplemental label lists a 40 day PHI for roots. The
PHI for tops is 14 days and the PHI for roots is 40 days.  It may not be
applied aerially or through any type of irrigation system.  

HOPS

The rate of application is 0.98 lb ai/A.  It should be applied by ground
only in 10 - 40 gallons water/A.  One application should be made as a
directed spray to the ground, prior to weed emergence.  Sufficient
rainfall (1/8") and/or irrigation (1/2") is necessary within 3 days of
application to move herbicide into the soil (1 - 2 inches). 
Applications may not be made by air or through any type of irrigation
system.  The supplemental label states that for hops it is for
distribution and use only in Idaho, Oregon and Washington.  The PHI is
60 days.  

For all proposed new crop sites, sufficient rainfall (1/8") and/or
irrigation (1/2") is necessary within 3 days of application to move
herbicide into the soil (1 - 2 inches).  Applications may not be made
aerially or through any type of irrigation system.

See Table 9.0.a for a summary of the proposed use pattern.

Table 9.0.a Summary of Proposed Use Pattern for Dimethenamid - P

Crop/Site	Winter Squash, Pumpkin, Radish, Rutabaga, Turnips and Turnip
Greens and Hops

Pest	annual grasses, annual broadleaf weeds, sedges

Method of Applic.	ground only

Max. Applic. Rate	0.98 lb ai/A

Max. No. Applications	1/season

Applic. Interval	N/A

Preharvest Interval	Winter Squash and Pumpkin 90 days

Radish and Rutabaga 21 days

Turnips 14 days for tops and 40 days for roots

Hops 60 days

Restricted Entry Interval	12 hours listed on the product label

Manufacturer	BASF

9.2	Non-Occupational/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.

9.3	Occupational Pesticide Handler Exposure

Based upon the proposed label instructions, the only method of
application will be by ground spray machinery.   For hops, the
directions indicate application as a directed spray to the soil.  Label
directions indicate only ground applications are permitted.

RD further believes that for the proposed new uses, the most highly
exposed occupational pesticide handlers will be mixer/loaders using
open-pour loading of liquid formulations and applicators using open-cab,
ground-boom sprayers.  

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 there is only one application
per year, RD 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 (3/29/2000) 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).   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.   

The revised toxicological endpoints for dimethanamid-P were transmitted
(via e-mail) to John Redden (RIMUERB/RD) from K. Bailey (Registration
Action Branch 2 (RAB2)/Health Effects Division) on 4/18/2007.  The RAB 2
toxicological 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 gain and decreased body weight
in females and adverse liver effects (increased 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 from an oral
study.  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 RD assume 100 % absorption via the inhalation route of
exposure.  

As was indicated in the original assessment, to calculate the MOE the
dermal and inhalation exposures were summed since the dermal and
inhalation toxicological endpoints were the same and identified from the
same study.

The toxicological database for dimethenamid-P was most recently
evaluated by HED on 8/12/2004 (Memo, R. Griffin et.al., DP#: 304790,
"Dimethenamid / Dimethenamid-P.  Human Health Risk Assessment.")  The
toxicological endpoints used herein for purposes of risk assessment are
taken from the document cited above.  Pertinent to this assessment, a
dermal LOAEL was identified from a developmental toxicity study in the
rat.  The maternal effects seen were maternal body weight decrement. 
The LOAEL is 25 mg ai/kg bw/day.  For exposure assessment, a 30 % dermal
absorption factor was identified.  The level of concern is a MOE < 300. 
An additional 3X uncertainty factor was added due to use of a LOAEL. 
Since the toxic effects cited are maternal effects, a 70 kg body weight
is used to calculate exposure.

The short-term duration inhalation toxicological endpoint was identified
from the same rat developmental study and the same maternal effects
(body weight decrements) were noted.  The LOAEL is identified as 25 mg
ai/kg bw/day.  HED and RD assume 100 % absorption via the inhalation
route of exposure.  The level of concern is for MOEs < 300.  An
additional 3X uncertainty factor was identified due to use of a LOAEL
for risk assessment.

To calculate the MOE the dermal and inhalation exposures were summed
since the dermal and inhalation toxicological endpoints were the same
and identified from the same study.

 

Table 9.0.b   Estimated Handler Exposure and Risk from the Proposed Uses
of Dimethenamid-P

Unit Exposure1

mg a.i./lb handled	

Applic. Rate2	

Units Treated3

Per Day	

Average Daily

Dose4

mg a.i./kg bw/day	

LOAEL5

mg a.i./kg bw/day	

MOE6

SHORT-TERM

Mixer/Loader - Liquid - Open-pour

Dermal:

SLNoGlove  2.9 HC

SLWGloves  0.023 HC

Inhal              0.0012 HC	

0.98 lb ai/A	

80 A/day	

SLNoGlove 0.97

SLWGlove 0.0077

Inhal           0.0013	

4.72	SLNoGlove

5

SLWGlove

524

Applicator - Ground-boom - Open Cab

Dermal:

SLNoGlove   0.014 HC

SLWGloves   0.014 MC

Inhal              0.00074 HC	

0.98 lb ai/A	

80 A/day	

SLNoGlove 0.0047

SLWGlove  0.0047

Inhal          0.00083	

4.72	SLNoGlove

850

SLWGlove

850

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 a.i./pound of
active ingredient handled.  Data Confidence: LC = Low Confidence, MC =
Medium Confidence, HC = High Confidence.

2.  Applic. Rate. = Taken from Sections B of the IR-4 submissions and
from BASF supplemental 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.  LOAEL = Lowest  Observable Adverse Effect Level 25 mg a.i./kg bw/day
for short-term  dermal and inhalation

6.  MOE = Margin of Exposure = LOAEL  ( ADD.  

A MOE of 1300 is adequate to protect occupational pesticide handlers
from short-term exposures to dimethenamid-P.  The proposed use patterns
do not exceed RD’s level of concern provided mixer/loaders wear
protective gloves as directed on the product label.

9.4	Occupational Post-Application Worker Exposure and Risk

It is possible for agricultural workers to have post-application
exposures to pesticide residues during the course of typical
agricultural activities.  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.   For the proposed new crop use
sites, the highest TC is 2,500 cm²/hr which results from hand
harvesting turnips.  One might typically expect high exposures in late
season hops however the directions for application to hops indicate a
directed spray soil application.  Under those conditions, scouting in
hops has a TC of 100 cm2/hr.   Therefore, as a conservative,
“screening” level assessment, RD herein uses a TC of 2,500 cm²/hr.

For the proposed new crop use sites, the highest TC is 1,500 cm²/hr
which results from "scouting" (i.e., crop advisors) in squash and
pumpkin.  One might typically expect high exposures in late season hops
however the directions for application to hops indicate a directed spray
soil application.  Under those conditions, scouting in hops has a TC of
100 cm2/hr.   Therefore, as a conservative, “screening” level
assessment, RD herein uses a TC of 1,500 cm²/hr.

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 TCs.  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
(5/7/1998 - Revised 8/7/2000).  

The following convention may be used to estimate post-application
exposure.  

Average Daily Dose (ADD) (mg a.i./kg bw/day) = DFR µg/cm2 * TC cm2/hr *
hr/day * 0.001 mg/µg * 1/70 kg bw 

 and where:

Surrogate Dislodgeable Foliar Residue (DFR) = application rate * 20%
available as dislodgeable residue * (1-D)t * 4.54 x 108 µg/lb * 2.47 x
10-8 A/cm2 .  

0.98 lb a.i./A * 0.20 * (1-0)0 * 4.54 x 108 µg/lb *  2.47 x10-8 A/cm²
= 2.198 µg/cm2 , therefore,

2.198 µg/cm2 * 2,500 cm2/hr * 8 hr/day * 0.001 mg/µg * 0.30 (% dermal
absorption) ( 70 kg bw = 0.188 mg ai/kg bw/day.

MOE = NOAEL ( ADD then 4.72 mg/kg bw/day ( 0.188 mg/kg bw/day = 25.

A MOE of 100 is adequate to protect agricultural workers from
post-application exposures.  The MOE is < 100 for hand harvesting
turnips on day 0 of treatment.

There is a 14 day PHI for hand harvesting tops and a 30 day PHI for hand
harvesting roots.  

Based on numerous dislodgeable foliar residue studies, HED and RD assume
pesticide foliar residue dissipates at the rate of 10.0 % per day.  As
such, the original dislodgeable foliar residue on day 0 of treatment
(i.e., 2.198 µg/cm2) is reduced to 0.557 µg/cm2 by Day After Treatment
(DAT) 13 which results in a MOE of 98.  By DAT 14 the dislodgeable
foliar residue is 0.501 µg/cm2 which results in a MOE of 110.   

Therefore, due to the use patterns (timing of application) for crops
other than turnips and  rutabagas, and due to the PHI for turnips and
rutabagas, the proposed use patterns do not exceed ARIA/RD’s level of
concern. 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 TCs.  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
(5/7/1998 - Revised 8/7/2000).  

The following convention may be used to estimate post-application
exposure.  

Average Daily Dose (ADD) (mg a.i./kg bw/day) = DFR µg/cm2 * TC cm2/hr *
hr/day * 0.001 mg/µg * 1/70 kg bw 

 and where:

Surrogate Dislodgeable Foliar Residue (DFR) = application rate * 20%
available as dislodgeable residue * (1-D)t * 4.54 x 108 µg/lb * 2.47 x
10-8 A/cm2 .  

0.98 lb a.i./A * 0.20 * (1-0)0 * 4.54 x 108 µg/lb *  2.47 x10-8 A/cm²
= 2.198 µg/cm2 , therefore,

2.198 µg/cm2 * 1,500 cm2/hr * 8 hr/day * 0.001 mg/µg * 0.30 (% dermal
absorption) ( 70 kg bw = 0.113 mg/kg bw/day.

MOE = NOAEL ( ADD then 25.0 mg/kg bw/day ( 0.113 mg/kg bw/day =  221.

A MOE of 300 is adequate to protect agricultural workers from
post-application exposures.  The MOE is < 300 and in some other cases
would be of concern to RD.  In this case, there is only one application
at or near the time of weed emergence.   At this time, the only
agricultural activity expected is scouting for treatment efficacy. 
Scouting at this time does not involve foliar contact or manual activity
that results in contact with treated materials.  There is a 12 hour REI.
 The MOE calculated is a conservative estimate.   In this case, the
proposed use does not exceed RDs level of concern.

9.5	Restricted Entry Interval

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 not
a dermal sensitizer.  The interim worker protection standard (WPS) REI
of 12 hours is adequate to protect agricultural workers.   In light of
discussion in the preceding paragraph, RD believes a 12 hr REI is
adequate for the proposed new use patterns.  

10.0	DATA NEEDS AND LABEL RECOMMENDATIONS

10.1	Toxicology

None.

10.2	Residue Chemistry

1.	A revised Section B must be provided.  This should be revised so that
uses on rutabagas (roots and tops) are associated with the proposed uses
on turnips (tops and roots).  

2.	Although the proposed label directions for turnips and rutabagas
specify a 40-day PHI for roots, ARIA notes that the available turnip
field trial data would support lowering the PHI for roots to 30 days,
which matches the proposed use in the submitted Section B.

10.3	Occupational and Residential Exposure

None.

REFERENCES:

Dietary Exposure Memorandum

	Dimethenamid-p.  Acute and Chronic Dietary Exposure Assessments for the
Interregional Research Project No. 4 (IR-4) Petition Proposing
Tolerances Residues on Winter Squash, Pumpkin, Radish (Roots and Tops),
Rutabaga (Roots and Tops), Turnip (Roots, Tops and Greens) and on Hops,
Dried Cones (PP#: 6E7152), B. Hanson, DP#: 341975, 9/26/2007.

Drinking Water Memorandum

	Drinking Water Exposure Assessment for the Section 3 IR-4 Proposed New
Uses of S-Dimethenamid on Squash, Pumpkin, Rutabaga, Turnip, Radish and
Hops.  P. Mastradone, 8/28/2007.  

Residue Chemistry Data Review Memorandum

	Dimethenamid-P.  Petition for Registration for Uses on Turnips,
Rutabagas, Radishes, Winter Squash, Pumpkins, and Hops.  Summary of
Analytical Chemistry and Residue Data.  Petition Number 6E7152. D. Rate;
DP #: 341886; 9/25/2007.

Occupational and Residential Exposure Memorandum

	Revision to: Human, Non-Dietary Exposure/Risk Assessment for Proposed
Use of Dimethenamid-P on Winter Squash, Pumpkin, Radish, Rutabaga,
Turnips and Turnip Greens and Hops.  M. Dow, DP#: 346234; 11/2/2007.

	Human, Non-Dietary Exposure/Risk 	Assessment for Proposed Use of
Dimethenamid-P on Winter Squash, Pumpkin, Radish, Rutabaga, Turnips and
Turnip Greens and Hops.  M. Dow, DP#: 336589; 3/8/2007.

Risk Assessment Document

	Dimethenamid-P Human Health Risk Assessment for Proposed Use on Grasses
Grown for Seed, PC Codes: 120051 and 129051, Petition No: 0F6138. D.
Rate, DP#:: 337887, 5/29/2007. 

Appendix A: International Residue Limits 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

⁯ Other	Date: 01/AUG/2007

Codex Status (Maximum Residue Limits)	U. S. Tolerances

⁯ No Codex proposal step 6 or above

√No  Codex proposal step 6 or above for the crops requested	Petition
Number:  PP#6E7152

DP Num:  341886

/Other Identifier:  

Residue definition (step 8/CXL):

Dimethenamid –P and its enantiomer..  The definition applies to
residues arising from the use of either dimethenamid-p or dimethenamid. 
	Reviewer/Branch:  D. Rate / ARIA/RIMUERB

	Residue definition:  dimethenamid,
1(R,S)-2-chloro-N-[(1-methyl-2-methoxy)ethyl]-N-(2,4-dimethylthien-3-yl)
-acetamide, applied as either the 90:10 or 50:50 S:R isomers  SEQ
CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 

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

Hop, dried cones	0.05

Pumpkin	0.01

Radish, tops	0.01

Radish, roots	0.01

Rutabaga, roots	0.01

Rutabaga, tops	0.1

Squash, winter	0.01

Turnip, roots	0.01

Turnip, tops	0.1

	Limits for Canada	Limits for Mexico

      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	Residue definition:  dimethenamid

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

	Notes/Special Instructions:  

S.Funk, 08/01/2007.

Appendix B:  TOXICOLOGY ASSSESSMENT

B.1	Toxicity Profiles

	

Table B.1.a  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.1.b  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.1.c  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 no 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	

43648402 (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.  Of these metabolites, 31 were identified.  Of the unidentified
metabolites none exceeded 3.0% and most being less than 1% of the
administered dose.

Chemical name of excretion products exceeding 5% in the multidose 10
mg/kg study in males or females.	

M1 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.1.d.  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 44332244 (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 44332245 (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 44332246 (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:	REFERENCES (in MRID order)

41596542	Haworth, L.; Lawlor, T. (1989) Mutagenicity Test on SAN 582H in
the Ames Salmonella/Microsome Reverse Mutation Assay: Lab Project
Number: 10767-0-401. Unpublished study prepared by Hazleton Laboratories
America, Inc. 31 p.

41596543	Taalman, R. (1985) SAN 582H: In vitro Chromosome Aberration
Assay using Chinese Hamster Ovary (CHO) Cells: Lab Project Number:
E-9428. Unpublished study prepared by Hazleton Biotechnologies Corp. 22
p.

41596544	Cifone, M. (1989) Mutagenicity Test on SAN 582H in the Rat
Primary Hepatocyte Unscheduled DNA Synthesis Assay: Final Report: Lab
Project Number: 10767-0-447. Unpublished study prepared by Hazleton
Laboratories America, Inc. 24 p.

41596545	Vollin, S. (1989) SAN 582H Metabolism in the Rat: Lab Project
Num- ber: 12726/89. Unpublished study prepared by Sandoz Ltd. 153 p.

41615901	Ruckman, S.; Anstey, M.; Heywood, R. et al. (1986) SAN 582 H:
Toxi- city to Rats by Repeated Dietary Administration for 13 Weeks
Followed by a 4-Week Withdrawal Period: Final Report: Lab Proj- ect
Number: SDZ/327/87318. Unpublished study prepared by Hunt- ingdon
Research Center Ltd. 332 p.

41615902	Greenough, R.; Goburdhun, R. (1986) SAN 582H: 13 Week Oral
Toxicity Study in Dogs: Lab Project Number: IRI/635563. Unpublished
study prepared by Inveresk Research International. 180 p.

41615903	Greenough, R.; Goburdhun, R.; Macnaughtan, F. (1988) SAN 582H:
52 Week Oral Toxicity Study in Dogs: Lab Project Number: 635579.
Unpublished study prepared by Inveresk Research International. 167 p.

41615904	Lochry, E. (1987) Developmental Toxicity (Embryo/Fetal Toxicity
and Teratogenic Potential) Study of SAN H Administered Orally Via Gavage
to Crl: COBS CD (SD)BR Presumed Pregnant Rats. Lab Project Number:
1319/001. Unpublished study prepared by Argus Research Laboratories,
Inc. 280 p.

41615905	Suter, P.; Biedermann, K.; Wilson, J. et al. (1989) SAN 582 H:
Two Generation Reproduction Study in the Rat: Lab Project Number:
201205. Unpublished study prepared by RCC Research and Consul- ting
Company. 662 p.

41662407	Yu, C.; Ekdawi, M.; Fostiak, W. (1989) Photodegradation Study
of SAN 582 H on Soil: Lab Project Number: 414105: 8. Unpublished study
prepared by Sandoz Crop Protection Corp. 41 p.

41662409	Lemen, J. (1989) Acute Oral Toxicity Study in Rats with SAN
582H Technical: Final Report: Lab Project Number: HLA 686-171. Un-
published study prepared by Hazleton Laboratories America, Inc. 21 p.

41662410	Lemen, J. (1988) Acute Dermal Toxicity Study in Rabbits with
SAN 582H Technical: Final Report: Lab Project Number: HLA 686-172.
Unpublished study prepared by Hazleton Laboratories America, Inc. 9 p.

41662411	Ullmann, L. (1986) 4-Hour Acute Inhalation Toxicity Study with
SAN 582 H in Rats: Lab Project Number: RCC 075510. Unpublished study
prepared by Researching & Consulting Co., Ag. 39 p. 

41662412	Lemen, J. (1988) Primary Eye Irritation Study in Rabbits with
SAN 582H Technical: Lab Project Number: HLA 686-174. Unpublished study
prepared by Hazleton Laboratories America, Inc. 14 p.

41662413	Lemen, J. (1988) Primary Dermal Irritation Study in Rabbits
with SAN 582H Technical: Final Report: Lab Project Number: HLA 686-173.
Unpublished study prepared by Hazleton Laboratories America, Inc. 11 p.

41662414	Hopley, J.; Muller, F.; Chevalier, H. (1989) SAN 582H: 3-Week
Dermal Study in Rabbits: Lab Project Number: 416-RB: II.7099/88: LMP
416-RB. Unpublished study prepared by Sandoz Agro Div., Dept. of
Toxicology. 217 p.

41662415	Hooks,W.; Chambers, P.; Majeed, S.; et al. (1990) SAN 582 H:
Potential Tumorigenic Effects in Prolonged Dietary Administration to
Mice: Final Report (Weeks 1 to 94): Lab Project Number: SDZ 346/ 90189.
Unpublished study prepared by Huntingdon Research Centre Ltd. 1352 p.

41662416	Dean, S. (1990) Study to Evaluate the Potential of SAN 582H to
Induce Unscheduled DNA Systhesis in Isolated Rat Hepatocytes In vitro:
Lab Project Number: RHURESAD/005. Unpublished study pre- pared by
Hazleton Microtest. 28 p.

41706808	Ruckman, S.; Waterson, L.; Crook, D.; et al. (1990) SAN 582 H:
Potential Tumorigenic and Toxic Effects in Prolonged Dietary
Administration to Rats: Lab Project Number: SDZ 335/891445. Unpublished
study prepared by Huntingdon Research Centre Ltd. 1407 p.

41706809	Hoberman, A. (1988) Developmental Toxicity (Embryo/Fetal
Toxicity and Teratogenic Potential) Study of SAN 582 H Administered
Orally (Stomach Tube) to New Zealand White Rabbits: Lab Project Number:
1319-003. Unpublished study prepared by Argus Research Laboratories,
Inc. 371 p.

41822701	DenBoer, W. (1986) SAN 582H: In vitro Transformation of
BALB/3T3 Cells with S9 Activation: Lab Project Number: E-9428. Unpub-
lished study prepared by Hazleton Biotechnologies Corp. 18 p.

41822702	Muller, E. (1986) SAN 582H (300-069): UDS in Rat Hepatocytes in
vitro: Lab Project Number: LMP 170. Unpublished study prepared by
Technical University Darmstadt. 22 p.

41822703	Volkner, W. (1986) SAN 582H: Micronucleus Test in Bone Marrow
Cells of the Mouse: Lab Project Number: LMP 173. Unpublished study
prepared by Technical University Darmstadt. 29 p.

42030102	Sandoz Crop Protection Corp. (1990) Potential Tumorigenic and
Toxic Effects Study of SAN 582H in Prolonged Dietary Administration to
Rats: Historical Control Data...: Lab Project Number: SDZ 335/891445.
Unpublished study. 55 p.

42289501	Vollmin, S. (1992) Absorption, Distribution, Metabolism and
Excretion of ?carbon 14| SAN 582H in Rats after Single and Multiple
Doses: Lab Project Number: BS-2261. Unpublished study prepared by Sandoz
Agro Ltd. 315 p.

43209201	Murli, H. (1994) Mutagenicity Test on Dimethenamid (SAN 582 H)
in the Dominant Lethal Assay in Rats: Lab Project Number: 15675-0-472:
22203: 472. Unpublished study prepared by Hazleton Washington, Inc. 89
p.

43648401	Marshall, R. (1993) Study to Evaluate the Potential of SAN 582
H Technical to Induce Micronuclei in the Polychromatic Erythrocytes of
CD-1 Mice: Lab Project Numbers: 252/100: SAD 24/MNT: ECMRESAD.024.
Unpublished study prepared by Hazleton Microtest. 46 p.

43648402	Ward, P. (1993) Study to Evaluate the Potential of SAN 582 H to
Induce Unscheduled DNA Synthesis in Rat Liver Using an in vivo/in vitro
Procedure: Lab Project Numbers: 252/101: SAD 24/ILU: ILURESAD.024.
Unpublished study prepared by Hazleton Microtest. 58 p.

43814401	Putman, D. (1995) Acute Dominant Lethal Mutation Assay in Rats:
Modified Confirmatory Study: Dimethenamid Technical (SAN 582 H): Final
Report: Lab Project Number: G95AD95.112001. Unpublished study prepared
by Microbiological Associates, Inc. 48 p.

44097603	Blaszcak, D. (1996) Acute Oral Toxicity Study with SAN 1289 H
Technical in Rats: Final Report: Lab Project Number: 96-1404.
Unpublished study prepared by Huntingdon Life Sciences. 42 p.

44097604	Blaszcak, D. (1996) Closed-Patch Repeated Insult Dermal
Sensitization Study with SAN 1289 H Technical in Guinea Pigs (Buehler
Method): Final Report: Lab Project Number: 96-1408. Unpublished study
prepared by Huntingdon Life Sciences. 27 p.

44123501	San, R.; Clarke, J. (1996) CHO/HGPRT Mutation Assay: SAN 1289 H
Technical: Final Report: Lab Project Number: G95CB09.782: DP 302059:
SPGT782. Unpublished study prepared by Microbiological Associates, Inc.
27 p. (Relates to L0000089).

44123502	Wagner, V.; Coffman, N. (1996) Salmonella/Escherichia coli
Plate Incorporation Mutagenicity Assay: SAN 1289 H Technical: Final
Report: Lab Project Number: G95CB09.502: DP 302037: SPGT502. Unpublished
study prepared by Microbiological Associates, Inc. 41 p. (Relates to
L0000089).

44332234	Blaszcak, D. (1996) Acute Dermal Toxicity Study with SAN 1289 H
Technical in Rabbits: Final Report: Lab Project Number: 96-1405:
96/5395. Unpublished study prepared by Huntingdon Life Sciences. 20 p.

44332235	Hoffman, G. (1996) An Acute (4-Hour) Inhalation Toxicity Study
of SAN 1289 H Technical in the Rat via Nose-Only Exposure: Final Report:
Lab Project Number: 96-5279: 96-5397. Unpublished study prepared by
Huntingdon Life Sciences. 67 p.

44332238	Blaszcak, D. (1996) Primary Eye Irritation Study with SAN 1289
H Technical in Rabbits: Final Report: Lab Project Number: 96-1407:
96/5396. Unpublished study prepared by Huntingdon Life Sciences. 25 p.

44332239	Blaszcak, D. (1996) Primary Dermal Irritation Study with SAN
1289 H Technical in Rabbits: Final Report: Lab Project Number: 96-1406:
96/5406. Unpublished study prepared by Huntingdon Life Sciences. 18 p.

44332242	Blanset, D. (1996) A Subchronic (3-Month) Toxicity Study of SAN
1289 H in the Rat via Dietary Administration: Final Report: Lab Project
Number: 95-2401: 96/5420. Unpublished study prepared by Huntingdon Life
Sciences. 368 p.

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by Argus Research Labs, Inc. 337 p.

44332244	Engelhardt, G.; Hoffmann, H. (1997) Salmonella
typhimurium/Escherichia coli Reverse Mutation Assay (Standard Plate Test
and Preincubation Test) with s-Dimethenamid: Lab Project Number:
40M0073/974028: 97/10621. Unpublished study prepared by BASF
Aktiengesellschaft. 48 p.

44332245	Engelhardt, G.; Hoffmann, H. (1997) Salmonella
typhimurium/Escherichia coli Reverse Mutation Assay (Standard Plate Test
and Preincubation Test) with s-Dimethenamid Technical: Lab Project
Number: 40M0071/974027: 97/10622. Unpublished study prepared by BASF
Aktiengesellschaft. 51 p.

44332246	Wagner, V.; Klug, M. (1997) Bacterial Reverse Mutation Assay
(with) SAN 1289 H Technical: Final Report: Lab Project Number:
G97BB92.502099: 97/5271: SPGT502099. Unpublished study prepared by MA
BioServices, Inc. 25 p.

44332247	Curry, P.; Schadly, E. (1996) Chromosome Aberrations in Chinese
Hamster Ovary (CHO) Cells: SAN 1289 H Technical: Final Report: Lab
Project Number: G95CB09.330: 96/5400: SPGT330. Unpublished study
prepared by Microbiological Associates, Inc. 38 p.

44332248	San, R.; Clarke, J. (1996) CHO/HGPRT Mutation Assay: SAN 1289 H
Technical: Final Report: Lab Project Number: G95CB09.782: 96/5404: DP
302059. Unpublished study prepared by Microbiological Associates, Inc.
27 p. (Relates to L0000089)

44332249	Puman, D.; Gudi, R.; Poris, S. (1996) Micronucleus Cytogenetic
Assay in Mice: SAN 1289 H Technical: Final Report: Lab Project Number:
G95CB09.122: 96/5401: SPGT122. Unpublished study prepared by
Microbiological Associates, Inc. 37 p.

44332250	Wagner, V.; Coffman, N. (1996) Salmonella/Escherichia coli
Plate Incorporation Mutagenicity Assay: SAN 1289 H Technical: Final
Report: Lab Project Number: G95CB09.502: 96/5403: DP 302037. Unpublished
study prepared by Microbiological Associates, Inc. 41 p. (Relates to
L0000089).

44332251	San, R.; Sly, J. (1996) Unscheduled DNA Synthesis Assay in Rat
Primary Hepatocytes: SAN 1289 H Technical: Final Report: Lab Project
Number: G95CB09.380: 96/5399: SPGT380. Unpublished study prepared by
Microbiological Associates, Inc. 25 p.

Appendix D:	REVIEW OF HUMAN RESEARCH 

No MRID - PHED Surrogate Exposure Guide

Page   PAGE  40  of 49

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