Document ID: EPA-HQ-OPP-2008-0876-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-09-09T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, DC  20460

OFFICE OF PREVENTION,

PESTICIDES, AND TOXIC SUBSTANCES

MEMORANDUM

Date:		June 30, 2009

Subject:	REVISED Pendimethalin: Human Health Risk and Exposure
Assessment for Proposed Section 3 Registration for Use on Olive  

		

PC Code:  108501	DP Barcode:  366768

MRID No.: NA	Registration No.: 241-418

Petition No.:  8E7404	Regulatory Action: Proposed New Use

Assessment Type:  Single Chemical	Reregistration Case No.:  NA

TXR No.:  NA	CAS No.: 40487-42-1

 

FROM:	Shalu Shelat, Industrial Hygienist

		Risk Assessment Branch VI

		Health Effects Division (7509P)

			AND

		Judy Facey, Ph.D., Toxicologist

		P.Yvonne Barnes, Chemist

		Risk Assessment Branch VI

		Health Effects Division (7509P)

		Office of Pesticide Programs

THRU:	Felecia Fort, Branch Chief

		Risk Assessment Branch VI

		Health Effects Division (7509P) 

		Office of Pesticide Programs

TO:		Sidney Jackson/ Barbara Madden, RM Team 5

Risk Integration Minor Use, and Emergency Response Branch

		Registration Division (7505P)

		Office of Pesticide Programs

A Section 3 registration has been requested for three new agricultural
uses of the herbicide, pendimethalin, formulated as PROWL ® H2O to
control weeds on olive.  A summary of the findings and an assessment of
human health risk resulting from the proposed and registered uses of
pendimethalin are provided in this document.  



  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc231206322"  1.0	Executive
Summary	  PAGEREF _Toc231206322 \h  4  

  HYPERLINK \l "_Toc231206323"  2.0	Ingredient Profile	  PAGEREF
_Toc231206323 \h  8  

  HYPERLINK \l "_Toc231206324"  2.1	Summary of Proposed Uses	  PAGEREF
_Toc231206324 \h  8  

  HYPERLINK \l "_Toc231206325"  2.2	Structure and Nomenclature	  PAGEREF
_Toc231206325 \h  8  

  HYPERLINK \l "_Toc231206326"  2.3	Physical and Chemical Properties	 
PAGEREF _Toc231206326 \h  9  

  HYPERLINK \l "_Toc231206327"  3.0	Hazard Characterization/Assessment	 
PAGEREF _Toc231206327 \h  10  

  HYPERLINK \l "_Toc231206328"  3.1	Summary of Toxicological Doses and
Endpoints	  PAGEREF _Toc231206328 \h  10  

  HYPERLINK \l "_Toc231206329"  3.2	FQPA Considerations	  PAGEREF
_Toc231206329 \h  13  

  HYPERLINK \l "_Toc231206330"  3.2.1	Adequacy of the Toxicity Data Base
  PAGEREF _Toc231206330 \h  13  

  HYPERLINK \l "_Toc231206331"  3.2.2	Evidence of Neurotoxicity	 
PAGEREF _Toc231206331 \h  13  

  HYPERLINK \l "_Toc231206332"  3.2.3	Developmental Toxicity Studies	 
PAGEREF _Toc231206332 \h  13  

  HYPERLINK \l "_Toc231206333"  3.2.4	Reproductive Toxicity Study	 
PAGEREF _Toc231206333 \h  14  

  HYPERLINK \l "_Toc231206334"  3.2.5	Additional Information from
Literature Sources	  PAGEREF _Toc231206334 \h  14  

  HYPERLINK \l "_Toc231206335"  3.2.6	Pre-and/or Postnatal Toxicity	 
PAGEREF _Toc231206335 \h  14  

  HYPERLINK \l "_Toc231206336"  3.2.7	Determination of Susceptibility	 
PAGEREF _Toc231206336 \h  14  

  HYPERLINK \l "_Toc231206337"  3.2.8	Degree of Concern Analysis and
Residual Uncertainties	  PAGEREF _Toc231206337 \h  14  

  HYPERLINK \l "_Toc231206338"  3.3	Endocrine disruption	  PAGEREF
_Toc231206338 \h  15  

  HYPERLINK \l "_Toc231206339"  4.0	Public Health and Pesticide
Epidemiology Data	  PAGEREF _Toc231206339 \h  15  

  HYPERLINK \l "_Toc231206340"  5.0	Dietary Exposure/Risk
Characterization	  PAGEREF _Toc231206340 \h  15  

  HYPERLINK \l "_Toc231206341"  5.1	Summary of Residues and Degradates
of Concern	  PAGEREF _Toc231206341 \h  15  

  HYPERLINK \l "_Toc231206342"  5.2	Residue Profile	  PAGEREF
_Toc231206342 \h  16  

  HYPERLINK \l "_Toc231206343"  5.2.1	Drinking Water Residue Profile	 
PAGEREF _Toc231206343 \h  16  

  HYPERLINK \l "_Toc231206344"  5.2.2	Food Residue Profile	  PAGEREF
_Toc231206344 \h  16  

  HYPERLINK \l "_Toc231206345"  5.3	International Residue Limits	 
PAGEREF _Toc231206345 \h  17  

  HYPERLINK \l "_Toc231206346"  5.4	Dietary Exposure and Risk	  PAGEREF
_Toc231206346 \h  17  

  HYPERLINK \l "_Toc231206347"  5.4.1	Acute Dietary Exposure/Risk	 
PAGEREF _Toc231206347 \h  17  

  HYPERLINK \l "_Toc231206348"  5.4.2	Chronic Dietary Exposure/Risk	 
PAGEREF _Toc231206348 \h  17  

  HYPERLINK \l "_Toc231206349"  5.4.3	Cancer Dietary Risk	  PAGEREF
_Toc231206349 \h  18  

  HYPERLINK \l "_Toc231206350"  6.0	Residential (Non-Occupational)
Exposure/Risk Characterization	  PAGEREF _Toc231206350 \h  18  

  HYPERLINK \l "_Toc231206351"  6.1	Residential Exposure	  PAGEREF
_Toc231206351 \h  18  

  HYPERLINK \l "_Toc231206352"  6.2	Other (Spray Drift, etc.)	  PAGEREF
_Toc231206352 \h  19  

  HYPERLINK \l "_Toc231206353"  7.0	Aggregate Risk Assessments and Risk
Characterization	  PAGEREF _Toc231206353 \h  20  

  HYPERLINK \l "_Toc231206354"  7.1	Acute Aggregate Risk	  PAGEREF
_Toc231206354 \h  20  

  HYPERLINK \l "_Toc231206355"  7.2	Short-Term Aggregate Risk	  PAGEREF
_Toc231206355 \h  20  

  HYPERLINK \l "_Toc231206356"  7.3	Intermediate-Term Aggregate Risk	 
PAGEREF _Toc231206356 \h  21  

  HYPERLINK \l "_Toc231206357"  7.4	Long-Term Aggregate Risk	  PAGEREF
_Toc231206357 \h  21  

  HYPERLINK \l "_Toc231206358"  7.5	Cancer Aggregate Risk	  PAGEREF
_Toc231206358 \h  21  

  HYPERLINK \l "_Toc231206359"  8.0	Cumulative Risk
Characterization/Assessment	  PAGEREF _Toc231206359 \h  21  

  HYPERLINK \l "_Toc231206360"  9.0	Occupational Exposure/Risk
Characterization	  PAGEREF _Toc231206360 \h  22  

  HYPERLINK \l "_Toc231206361"  9.1	Short-/Intermediate - Term Handler
Risk	  PAGEREF _Toc231206361 \h  22  

  HYPERLINK \l "_Toc231206362"  9.2	Short-/Intermediate -Term
Postapplication Risk	  PAGEREF _Toc231206362 \h  23  

  HYPERLINK \l "_Toc231206363"  10.0	Data Needs and Label
Recommendations	  PAGEREF _Toc231206363 \h  24  

  HYPERLINK \l "_Toc231206364"  10.1	Toxicology	  PAGEREF _Toc231206364
\h  24  

  HYPERLINK \l "_Toc231206365"  10.2	Residue Chemistry	  PAGEREF
_Toc231206365 \h  24  

  HYPERLINK \l "_Toc231206366"  10.3	Occupational and Residential
Exposure	  PAGEREF _Toc231206366 \h  24  

  HYPERLINK \l "_Toc231206367"  References:		  PAGEREF _Toc231206367 \h 
25  

  HYPERLINK \l "_Toc231206368"  Appendix A:	Toxicology Assessment	 
PAGEREF _Toc231206368 \h  26  

  HYPERLINK \l "_Toc231206369"  Appendix B: 	Tolerance Assessment
Summary And Table	  PAGEREF _Toc231206369 \h  31  

  HYPERLINK \l "_Toc231206371"  Appendix C:  Review of Human Research	 
PAGEREF _Toc231206371 \h  32  

  HYPERLINK \l "_Toc231206372"  Appendix D: 	DCI Table	  PAGEREF
_Toc231206372 \h  33  

   SEQ CHAPTER \h \r 1 1.0	Executive Summary

A human health risk assessment has been conducted to support the
Interregional Research Project No. 4 (IR-4) submission of a petition for
the establishment of permanent tolerances for residues of the herbicide
pendimethalin in/on olives.  The proposed tolerance for the combined
residues of the herbicide pendimethalin
[N-(1-ethylpropyl)-3,4-dimethyl-2,6-dinitrobenzenamine] , including its
metabolites and degradates, in or on olive is 0.1 ppm.   Compliance with
the tolerance levels specified is to be determined by measuring only
pendimethalin [N-(1-ethylpropyl)-3,4-dimethyl-2,6-dinitrobenzenamine]
and its metabolite 4-[(1-ethylpropyl)amino]-2-methyl-3,5-dinitrobenzyl
alcohol expressed as the stoichiometric equivalent of pendimethalin, in
or on the commodity.  Pendimethalin is a selective herbicide registered
for control of broadleaf weeds and grassy weed species on a variety of
agricultural crops, turf and ornamentals.  It is a meristematic
inhibitor that interferes with the plant’s cellular division of
mitosis, and is generally applied early in the growing season.

Since the completion of the Revised HED Human Health Risk Assessment
document dated March 3, 2006 (D3125176); Human health risk assessment
for the Proposed uses of the herbicide on artichoke, Globe; asparagus;
Brassica head and stem vegetables, subgroup 5A; and grapes (PP#6E7129)
(D334062, August 22, 2007); Human health risk assessment for the
Proposed  Tolerance in/on Crayfish (D350493, March 31, 2008); and Human
health risk assessment for the proposed food/feed use of the herbicide
(associated with Section 18 Registration) on Bermuda grass pastures and
hay fields in Texas (D349723, May 20, 2008) the Agency has not received
any new toxicity studies.  This current risk assessment document reviews
and addresses changes in the dietary (food and drinking water) and
occupational assessments.  Modifications to the previous residential
exposure assessments for the use of pendimethalin on turf are not
required.  

Hazard Characterization

The toxicology database is adequate to support the proposed uses for
pendimethalin. The thyroid is a target organ for pendimethalin.  The
toxicity data show that with repeated dosing pendimethalin affects the
thyroid at doses as low as 31 mg/kg/day. A developmental thyroid study
has been requested to provide additional information to evaluate thyroid
toxicity in the developing fetus following pre- and post-natal exposure.
The lack of this study does not prohibit us from making a safety
finding. Neurotoxicity has not been observed in subchronic or chronic
toxicity studies.  Developmental toxicity was not observed in either rat
or rabbit developmental toxicity studies.  At doses of 125 mg/kg/day and
above, a reduced number of live births was observed in the two
generation reproduction study, but there was no indication of increased
susceptibility in the pups.

No appropriate endpoint attributable to a single exposure was identified
from the oral toxicity studies and developmental toxicity studies in
rats and rabbits.  Therefore, an acute point of departure (aPOD) was not
selected.    SEQ CHAPTER \h \r 1 Three studies (a 92-day thyroid
function study in rats, a 56-day thyroid function study in rats, and a
14-day intra-thyroid metabolism study in rats), all demonstrating
thyroid effects induced by pendimethalin and were considered together to
select the dose and endpoint for establishing the chronic population
adjusted dose (cPAD) of 0.03 mg/kg/day. The cPAD is derived from the
NOAEL of 10 mg/kg/day for thyroid effects, and a combined uncertainty
factor of 300.  

The same three studies mentioned above were used for dose and endpoint
selection for all durations of dermal and inhalation exposure.  A dermal
absorption factor of 3% has been determined, and inhalation toxicity is
assumed to be equivalent to oral toxicity.  Since both dermal and
inhalation endpoints were based on the same toxicological effects, these
route-specific margins of exposure (MOEs) were combined into a total
MOE.  

  SEQ CHAPTER \h \r 1 Dietary Exposure

The nature of the residue in plants, livestock, and rotational crops is
adequately understood.  The residues of concern in plants (for both
tolerance expression and risk assessment purposes) are the parent,
pendimethalin, and its 3,5-dinitrobenzyl alcohol metabolite (CL202,347);
in peanut hulls, the residues of concern also include the
2,4-dinitrobenzyl alcohol metabolite.  The residue of concern in
drinking water is pendimethalin, per se.  HED has determined that there
is no reasonable expectation of finite pendimethalin residues in animal
commodities (40CFR §180.6[a][3]).  Tolerances for pendimethalin
residues in animal commodities are therefore not needed at this time.  

FCID™), which uses food consumption data from the USDA’s Continuing
Surveys of Food Intakes by Individuals (CSFII) from 1994 to 1996, and
1998.  Tolerance-level residues were assumed for all food commodities
which included both current and proposed pendimethalin tolerances, and
it was assumed that all of the crops included in the analysis were
treated (100% crop treated).  The estimated drinking water concentration
(EDWC) of 0.006 ppm was directly entered into the exposure model to
assess the contributions from drinking water.  Acute dietary exposure
estimates were not generated, because of the lack of an acute dietary
endpoint and dose for risk assessment.  

The most highly exposed population subgroup is children 1-2 years old. 
The chronic exposure estimate of 0.004582 mg/kg/day corresponds to
approximately 15% of the cPAD.  Risk estimates for the general US
population and all other population subgroups are lower.  Therefore,
chronic dietary exposure to pendimethalin is not of concern.

  SEQ CHAPTER \h \r 1 Residential Exposure

The level of concern for oral, dermal and inhalation exposure is an MOE
of less than 300.  No additional residential exposure is anticipated
from the proposed new use on olives and therefore was not conducted. 
The previous residential exposure and risk estimates based on the
currently registered uses for adults (consisting of dermal exposure
only) resulted in a total MOE of 740, and was therefore, not of concern.
 The residential exposure for children resulted in a total MOE (dermal +
oral) of 410 at an application rate of 2 lb ai/acre, and an MOE of 400
at an application rate of 3 lb ai/acre.  Residential aggregate exposure
is not of concern.  

  SEQ CHAPTER \h \r 1 Aggregate Exposure 

HED has combined chronic dietary (food and water) and non-dietary
(residential) sources of exposure to pendimethalin.  The resulting MOEs
are all greater than 300 and, therefore, indicate that risk estimates
for all population subgroups do not exceed HED’s level of concern.  

Occupational   SEQ CHAPTER \h \r 1 Exposure Handler

No chemical-specific data for assessing handler exposures were submitted
to the Agency in support of the proposed uses; therefore, surrogate data
from the Pesticide Handlers Exposure Data Base (PHED) Version 1.1, the
Outdoor Residential Exposure Task Force (ORETF) and standard values
established by the Health Effects Division (HED) Science Advisory
Council for Exposure were used for acres treated per day, body weight
and the level of personal protective equipment worn by handlers.

Since both dermal and inhalation toxicological endpoints were the same
for short-term duration, the route specific MOEs were combined and
compared to the NOAEL (10 mg/kg/day).   The total MOE for short- and
intermediate-term mixing/loading scenarios was 1,200 using PPE (single
layer and gloves), and did not exceed HED’s level of concern (MOEs <
30). The total MOEs for short- and intermediate-term applicator
scenarios, at baseline level of mitigation were 1,900 and do not exceed
HED’s level of concern (MOEs < 30).

Postapplication

Since these products are herbicides used mainly to control pre-emergent
weeds, and not applied directly to foliage, postapplication exposure is
expected to be minimal.  Based on this information an occupational
postapplication exposure assessment was not required. 

Restricted Entry Interval (REI)

The restricted entry interval (REI) is based on the acute toxicity of
pendimethalin technical material which is classified as Category III and
IV for acute dermal, dermal irritation and eye irritation (HIARC Doc.
No. 014116, April 18, 2000).  Acute toxicity Category III and IV
chemicals for these potential hazards require a 12-hour REI, therefore,
the 24 hour REI stated on the current PROWL®H2O label is adequate. 

Environmental Justice Considerations

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

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 Intake 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
postapplication are evaluated.  Further considerations are currently in
development as OPP has committed resources and expertise to the
development of specialized software and models that consider exposure to
bystanders and farm workers as well as lifestyle and traditional dietary
patterns among specific subgroups.

Review of Human Research

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.

Regulatory Recommendations and Proposed Tolerances

HED recommends in favor of the proposed uses of pendimethalin on olives.
The proposed tolerance (0.1ppm) for the combined residues of the
herbicide pendimethalin
[N-(1-ethylpropyl)-3,4-dimethyl-2,6-dinitrobenzenamine] , including its
metabolites and degradates, in or on olive based on the existing stone
fruit residue data is acceptable. Compliance with the tolerance levels
specified is to be determined by measuring only pendimethalin
[N-(1-ethylpropyl)-3,4-dimethyl-2,6-dinitrobenzenamine] and its
metabolite 4-[(1-ethylpropyl)amino]-2-methyl-3,5-dinitrobenzyl alcohol
expressed as the stoichiometric equivalent of pendimethalin, in or on
the commodity. The registration is conditional based on fulfillment of
the following data gaps and deficiencies.

Data Gaps and Deficiencies

Toxicology

HED has requested the submission of developmental thyroid toxicity data
for adult rats and young rats following pre- and post-natal exposure to
pendimethalin. Guidance for conducting developmental thyroid assays has
been developed by HED (Guidance for Thyroid Assays in Pregnant Animals,
Fetuses and Postnatal Animals, and Adult animals, dated October 24,
2005) in cooperation with the registrant. Currently, BASF is in the
process of conducting the requested thyroid study.

Also, an immunotoxicity and acute and subchronic neurotoxicity studies
are required as part of the revised Part 158 toxicology data
requirements for pendimethalin. The available studies do not indicate
potential immunotoxicity and pendimethalin does not belong to the class
of compounds (e.g., the organotins, heavy metals, or halogenated
aromatic hydrocarbons) that would be expected to be toxic to the immune
system. Based on available data, the immunotoxicity study is not
expected to provide a Point of Departure (PoD) lower than that currently
used for overall risk assessments. In addition, there is no evidence of
neurotoxicity for pendimethalin in the toxicology database. Therefore,
the Agency determined that an additional factor (UFDB) for database
uncertainties is not needed to account for lack of these data. 

Residue Chemistry

There are no additional residue chemistry data requirements that would
preclude the conditional registration of pendimethalin in/on olives.
However, HED has previously requested a limited field accumulation study
(OPPTS 860.1900) to determine the amount of pesticide residue uptake
into rotational crops.  The limited field trials should reflect the
maximum label use rate on crops (that may be rotated) of 4.0 lb ai/A,
and should be conducted on a representative crop (as defined in 40CFR
§180.41), at two trial sites per crop, for the following three crop
groups:  (1) root and tuber vegetables, (2) leafy vegetables, and (3)
small grains (wheat, barley, oats, rye), for a total of six trials.  The
six trials should be conducted on crops which the petitioner intends to
have as rotational crops on the label.  Samples should be analyzed for
pendimethalin and its 3,5-dinitrobenzyl alcohol metabolite.  

Occupational and Residential Exposure

The Agency reiterates the recommendation that agricultural handlers
should wear chemical-resistant gloves when mixing/loading liquids.

2.0	Ingredient Profile

  SEQ CHAPTER \h \r 1 2.1	Summary of Proposed Uses

Pendimethalin (N-(1-ethylpropyl)-3,4-dimethyl-2,6-dinitrobenzenamine),
an herbicide used to control annual grass and broadleaf weeds, belongs
to the dinitroaniline class of herbicides.  As with other chemicals in
this class, pendimethalin is a meristematic inhibitor that interferes
with the plant’s cellular division or mitosis, and it is applied early
in the growing season as an aqueous capsule suspension.  

The petitioner is currently proposing use of pendimethalin on olives by
groundboom application for the end -use product PROWL ® H2O (EPA Reg.
No. 241-418) with the 3.8 lbs/gal aqueous capsule suspension (CS)
formulation. The proposed amended use directions for pendimethalin are
presented in Table 2.1.

Table 2.1	Summary of Directions for Use of Pendimethalin.

Applic. Timing, Type, and Equipment	Formulation

[EPA Reg. No.]	Applic. Rate 

(lbs a.i/A)	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(lbs a.i/A)	PGI/

PHI1

(days)

I.  Olives

Early in the planting process

Groundboom  	3.8 lbs/gal CS

[241-418]	2.0 to 4.0 	1/2	4.0	60

Use Limitations:  The product may be applied as a single application or
in two split at half the seasonal rate.  

2.2	  SEQ CHAPTER \h \r 1 Structure and Nomenclature

The chemical structure and nomenclature for pendimethalin and its
regulated plant metabolite are presented in Table 2.2.  

Common name	Pendimethalin

Company experimental name	BAS 455H (old CL 92533)

IUPAC name	N-(1-ethylpropyl)-2,6-dinitro-3,4-xylidine

CAS name	N-(1-ethylpropyl)-3,4-dimethyl-2,6-dinitrobenzenamine

CAS registry number	40487-42-1

End-use product (EP)	Prowl® H2O Herbicide (EPA Reg. No 241-418)

Chemical structure of metabolite CL 202347

(3,5-dinitrobenzyl alcohol metabolite)	

4-[(1-ethylpropyl)amino]-2-methyl-3,5-dinitrobenzyl alcohol

  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 2.3	Physical and Chemical
Properties   TC \l2 "2.3	Physical and Chemical Properties 

The physicochemical properties of the technical grade of pendimethalin
are presented in Table 2.3. 

Table 2.3		Physicochemical Properties of Pendimethalin. 

Parameter	Value	Reference

Melting point/range	54-58 °C (TGAI)	Product Chemistry Chapter of
Pendimethalin RED, DP# 221531, 12/8/1995, B. Cropp-Kohlligian

pH	4.7 (TGAI)	CB# 789, 06/13/1986, G. Makhijani

Density	1.461 g/cm3 (at room temperature)	DP#s 271502 and 317053, 
07/12/2006, W. Drew

Water solubility of PAI	0.275 ppm at 25 °C	CB# 789, 06/13/1986, G.
Makhijani

Solvent solubility of TGAI	Solvent	g/100 mL at 25 ºC

n-Heptane	11.2 

2-Propanol	6.1 

Acetone	161.0

Toluene	128.4 

Methyl alcohol	5.5

Dimethyl sulfoxide	21.4 

Methylene chloride	232.0	CB# 789, 06/13/1986, G. Makhijani

Vapor pressure	1.24 x 10-8 Pa at 20 °C 	DP#s 271502 and 317053,
07/12/2006, W. Drew

Dissociation constant, pKa	Too small to measure	CB# 789, 06/13/1986, G.
Makhijani

Octanol/water partition coefficient, Log(KOW)	5.18	DP#s 271502 and
317053, 07/12/2006, W. Drew

UV/visible absorption spectrum	UV molecular extinction = 

3.81 x 104 at 234 nm,

1.93 x 104 at 280 nm.  	DP#s 271502 and 317053, 07/12/2006, W. Drew

3.0	Hazard Characterization/Assessment tc "4.0  Hazard
Characterization/Assessment" 

3.1	Summary of Toxicological Doses and Endpoints

The toxicity database for pendimethalin is adequate for the purpose of
characterizing potential toxic effects following acute, short-term and
long-term exposures via oral, dermal and inhalation routes of exposure.

The database adequately characterizes pendimethalin as having low acute
oral, dermal, and inhalation toxicity. Pendimethalin is classified in
Toxicity Category IV for acute dermal toxicity, acute inhalation
toxicity, and primary dermal irritation; Toxicity Category III for acute
oral and primary eye irritation; it is not a dermal sensitizer. The
acute toxicity is summarized in Table A.1 (Appendix A).

The thyroid is a target organ for pendimethalin. Thyroid toxicity in
chronic and subchronic rat and mouse studies was manifested as
alterations in thyroid hormones (decreased Total T4, and T3, increased
percent of free T4 and T3), increased thyroid weight, and microscopic
thyroid lesions (including increased thyroid follicular cell height,
follicular cell hyperplasia, as well as follicular cell adenomas).

The toxicology database for pendimethalin is complete with regard to
pre-natal developmental toxicity in rats and rabbits; the studies are
both classified as acceptable. However, a developmental thyroid study
has been requested to provide additional information to evaluate thyroid
toxicity in the developing fetus following pre- and post-natal exposure.
The lack of this study does not prohibit HED from making a safety
finding. The available data provided no indication of qualitative or
quantitative susceptibility following pre-natal and postnatal exposure
in a 2-generation reproduction studies in rats (MRIDs 41725203,
00026671, 0040304, 00059470).

In a combined chronic/carcinogenicity study in rats (MRID 40174401), the
LOAEL of 250 mg/kg/day is based on decreased survival, body weight gain
and food consumption, increased gamma glutamyl transferase and
cholesterol, increase in absolute and/or relative liver weight,
generalized icterus, dark adipose tissue in females, diffusely dark
thyroids and follicular cell hyperplasia of the thyroid. Thyroid tumors
were observed in both male and female rats. In the carcinogenicity study
in mice (MRID 40909901), the LOAEL of 622.1/806.99 mg/kg/day (M/F) is
based on increased mortality in females, decreased body weight in
females, increased absolute thyroid, liver and gall bladder weights
and/or relative body and brain weight ratios in males and females as
well as amyloidosis in males. There were no tumors observed in mice.

Pendimethalin is classified as “Group C”, possible human carcinogen,
based on a statistically significant increased trend and pair-wise
comparison between the high dose group and controls for thyroid
follicular cell adenomas in male and female rats. A non-quantitative
approach (i.e., non-linear, RfD approach) was recommended by the Cancer
Peer Review Committee since mode of action studies are available that
demonstrate that the thyroid tumors are due to a thyroid-pituitary
imbalance, and also since pendimethalin was shown to be non-mutagenic in
mammalian somatic cells and germ cells. The chronic risk assessment is
considered to be protective of any cancer effects; therefore, a separate
quantitative cancer aggregate risk assessment is not required.  

Based on concern for the hormonal changes (alterations in thyroid
weights and histopathological lesions) seen in several studies following
oral administration of pendimethalin for 14, 28, 92 days as well as
following chronic exposure and the likelihood that pendimethalin may
cause disruption in the thyroid, HED has previously recommended for a
developmental thyroid study to further characterize these effects. This
study has not been submitted.

An immunotoxicity and acute and subchronic neurotoxicity studies are
required as part of the revised Part 158 toxicology data requirements
for pendimethalin. The available studies do not indicate potential
immunotoxicity and pendimethalin does not belong to the class of
compounds (e.g., the organotins, heavy metals, or halogenated aromatic
hydrocarbons) that would be expected to be toxic to the immune system.
Based on available data, the immunotoxicity study is not expected to
provide a Point of Departure (PoD) lower than that currently used for
overall risk assessments. In addition, there is no evidence of
neurotoxicity for pendimethalin in the toxicology database. Therefore,
the Agency determined that an additional factor (UFDB) for database
uncertainties is not needed to account for lack of these data. 

A summary of the levels of concern for risk assessment may be found in
Table 3.1 and a summary of the hazard endpoints selected may be found in
Table 3.2.

Table 3.1  Summary of Levels of Concern for Risk Assessment.

Route of Exposure	Duration of Exposure

	Short-Term 

(1 – 30 Days)	Intermediate-Term 

(1 - 6 Months)	Long-Term 

(> 6 Months)

Residential Exposure

Dermal	300	300	300

Inhalation	300	300	300

Incidental Oral	300	300	N/A

Table 3.2 Toxicological Doses and Endpoint for Pendimethalin Human
Health Risk Assessment

Exposure/Scenario	Point of Departure	Uncertainty/FQPA Safety Factors
RfD, PAD, Level of Concern for Risk Assessment	Study and Toxicological 
Effects

Acute Dietary             (Females 13-49) 

General US Pop.)	NA	NA	NA	No appropriate acute endpoint identified for
these groups.  There were no toxic effects attributable to a single
dose.

Chronic Dietary (all populations) 	NOAEL = 10 mg/kg/day	UFA  = 10X 

UFH = 3X 

UFDB  = 10X

FQPA SF = 1X

 

Total UF = 300X

	

cPAD = Chronic RfD

               FQPA SF

cPAD = 0.03 mg/kg/day	92- day thyroid function study in rats (MRID
42054601); 56- day thyroid study in rats (MRID 43135001); 14- day intra
thyroid metabolism study in rats (MRID 43135003).

LOAEL = 31 mg/kg/day based on hormonal and histopathological changes in
the thyroid. 

Incidental Oral Exposure

Incidental Oral

Short- Term (1- 30 days)

Intermediate – Term

(1-6 months)	NOAEL = 10 mg/kg/day	UFA  = 10X 

UFH = 3X 

UFDB  = 10X

FQPA SF = 1X

Total UF = 300X

 

	

Residential LOC = 300

Occupational LOC = 30	92- day thyroid function study in rats (MRID
42054601); 56- day thyroid study in rats (MRID 43135001); 14- day intra
thyroid metabolism study in rats (MRID 43135003).

LOAEL = 31 mg/kg/day based on hormonal and histopathological changes in
the thyroid. 

Dermal Exposure

Dermal 

Short- Term (1- 30 days) 

Intermediate – Term

(1-6 months)

Long – Term

(>6 months)	NOAEL = 10 mg/kg/day	UFA  = 10X 

UFH = 3X 

UFDB  = 10X

FQPA SF = 1X

Total UF = 300X 

Dermal Absorption = 3%	

Residential LOC = 300

Occupational LOC = 30	92- day thyroid function study in rats (MRID
42054601); 56- day thyroid study in rats (MRID 43135001); 14- day intra
thyroid metabolism study in rats (MRID 43135003).

LOAEL = 31 mg/kg/day based on hormonal and histopathological changes in
the thyroid.

Inhalation Exposure

Inhalation 

Short- Term (1- 30 days) 

Intermediate – Term

(1-6 months)

Long – Term

(>6 months)

	NOAEL = 10 mg/kg/day	UFA  = 10X 

UFH = 3X 

UFDB  = 10X

FQPA SF = 1X

Total UF = 300X

 

Inhalation Absorption = 100%	

Residential LOC = 300

Occupational LOC = 30	92- day thyroid function study in rats (MRID
42054601); 56- day thyroid study in rats (MRID 43135001); 14- day intra
thyroid metabolism study in rats (MRID 43135003).

LOAEL = 31 mg/kg/day based on hormonal and histopathological changes in
the thyroid

Cancer

Cancer (oral, dermal, inhalation)	Pendimethalin is considered to be a
possible human carcinogen; quantitative estimate of cancer risk is not
required.	2- year chronic/ carcinogenicity study in rats. 

UF = uncertainty factor, FQPA SF =  FQPA safety factor, NOAEL = no
observed adverse effect level, LOAEL = lowest observed adverse effect
level, PAD = population adjusted dose (a = acute, c = chronic) RfD =
reference dose, MOE = margin of exposure, LOC = level of concern, NA =
Not Applicable. UFA= extrapolation from animal to human (intraspecies),
UFH = potential variation in sensitivity among members of the human
population (interspecies). UFDB = to account for the absence of key data
(i.e., lack of a critical study). 

3.2	FQPA Considerations  tc "4.2	FQPA Hazard Considerations " \l 2 

3.2.1	Adequacy of the Toxicity Data Base  tc "4.2.1	Adequacy of the
Toxicity Data Base " \l 3 

The toxicology database for pendimethalin is adequate for purposes of
risk assessment.  Based on concern for the hormonal changes (alterations
in thyroid weights and histopathological lesions) seen in several
studies following oral administration of pendimethalin for 14, 28, 92
days as well as following chronic exposure, and the likelihood that
pendimethalin may cause disruption in the thyroid, HED has previously
recommended for a developmental thyroid study to further characterize
these effects.  HED has recommended that the 10X database uncertainty
factor (UFDB) be retained pending receipt of the developmental thyroid
study.

3.2.2	Evidence of Neurotoxicity  tc "4.2.2	Evidence of Neurotoxicity "
\l 3 

The acute and subchronic neurotoxicity studies are required as part of
the revised Part 158 toxicology data requirements for pendimethalin. 
However, since there was no evidence of neurotoxic clinical signs,
changes in brain weight, or histopathology of the nervous system in any
study with pendimethalin., the Agency determined that an additional
factor (UFDB) for database uncertainties is not needed to account for
lack of these data.

3.2.3	Developmental Toxicity Studies  tc "4.2.3	Developmental Toxicity
Studies " \l 3 

In the rat toxicity study (MRID 00025752), the pendimethalin NOAELs for
developmental and maternal toxicity are both 500 mg/kg/day (highest dose
tested). There were no maternal or developmental effects noted at any
dose level tested. Although a true NOAEL was not determined, the study
is considered adequate. A new study is not required because in other rat
studies, thyroid toxicity was seen at significantly lower doses (31
mg/kg/day) than the highest dose tested in this study, and if thyroid
parameters had been measured, maternal toxicity would likely have been
demonstrated.

In a rabbit toxicity study (MRID 00117444) with pendimethalin no
maternal toxicity was seen at the highest dose tested. The NOAEL for
developmental toxicity was 60 mg/kg/day (HDT). Since neither maternal
nor developmental toxicity was seen at the highest dose tested,
potential for increased sensitivity of the offspring could not be
determined.

3.2.4	Reproductive Toxicity Study  tc "4.2.4	Reproductive Toxicity Study
" \l 3 

A 2-generation reproduction study (MRID 41725203) with pendimethalin was
reviewed by HED. The pendimethalin RED and the Data Evaluation Report
(DER), concluded that the parental systemic NOAEL was 172 mg/kg/day [M]
and 216 mg/kg/day [F] (2500 ppm), based on decreased body weight gain
and food consumption at the LOAEL of 346 mg/kg/day [M] and 436 mg/kg/day
[F] (5000 ppm). The reproductive/offspring NOAEL was 172 mg/kg/day [M]
and 216 mg/kg/day [F] (2500 ppm), based on decreased pup weight at the
LOAEL of 346 mg/kg/day [M] and 436 mg/kg/day [F] (5000 ppm). The
mg/kg/day doses were calculated from actual intake of chemical specific
data in the DER.

3.2.5	Additional Information from Literature Sources  tc "4.2.5
Additional Information from Literature Sources " \l 3 

There was no additional information available from the literature.

3.2.6	Pre-and/or Postnatal Toxicity  tc "4.2.6  Pre-and/or Postnatal
Toxicity " \l 3 

HED has concluded there is potential for pre- and/or post-natal toxicity
(thyroid) in developing offspring resulting from exposure to
pendimethalin.

3.2.7	Determination of Susceptibility  tc "4.2.6.1	Determination of
Susceptibility " \l 4 

There was no indication of pre- and/or post-natal qualitative or
quantitative increased susceptibility in the developmental studies in
rats and rabbits or the 2-generation reproduction studies in rats. 
However, because developmental LOAELs could not be determined in the
developmental studies, HED has requested developmental thyroid toxicity
data, in order to determine potential thyroid toxicity following pre-
and/or post-natal exposure to pendimethalin.

3.2.8	Degree of Concern Analysis and Residual Uncertainties  tc "4.2.6.2
Degree of Concern Analysis and Residual Uncertainties for Pre and/or
Post-natal Susceptibility " \l 4 

HED performed a Degree of Concern Analysis because the developmental
studies were not adequate to fully address the potential for
susceptibility. The purpose of the Degree of Concern analysis is (1) to
determine the level of concern for the effects observed when considered
in the context of all available toxicity data; and (2) identify any
residual uncertainties after establishing toxicity endpoints and
traditional uncertainty factors to be used in the risk assessment. 

There are no residual uncertainties identified in the exposure
databases.  The chronic food exposure assessments are considered to be
highly conservative, as they assume that all crops consumed in the US
bear tolerance-level residues.  The drinking water estimates were
derived from conservative screening models.  The residential exposure
assessment utilizes reasonable high-end variables set out in EPA's
Residential Exposure SOPs (Standard Operating Procedures).  The
aggregate assessment is based upon reasonable high end residential
exposure assumptions, and is also not likely to underestimate exposure
to any subpopulation, including those comprised of infants and children.

In the case of pendimethalin, the developmental studies in rats and
rabbits were acceptable but not adequate to determine the potential for
thyroid toxicity during development.  Consequently, there is concern for
potential increased sensitivity or susceptibility in offspring regarding
thyroid effects.  A developmental thyroid toxicity study has been
required, and the registrant has met with the Agency to discuss the
conduct of the ongoing study.  Pending receipt of the study, a 10X
database uncertainty factor (UFDB) has been retained.

3.3	Endocrine disruption  TC \l2 "3.6	Endocrine disruption 	

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) “may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate.” 
Following recommendations of its Endocrine Disruptor and Testing
Advisory Committee (EDSTAC), EPA determined that there was a scientific
basis for including, as part of the program, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system.  EPA also
adopted EDSTAC’s recommendation that the Program include evaluations
of potential effects in wildlife. When the appropriate screening and/or
testing protocols being considered under the Agency’s Endocrine
Disruptor Screening Program (EDSP) have been developed and vetted,
pendimethalin may be subjected to additional screening and/or testing to
better characterize effects related to endocrine disruption.  

	

Public Health and Pesticide Epidemiology Data

Please refer to DP Num: 325176; M. Collantes; 3/3/2006.   At this time
there is no information in the incident reports that affects this risk
assessment.

5.0	Dietary Exposure/Risk Characterization  tc "3.0	Metabolism
Assessment" 

5.1	Summary of Residues and Degradates of Concern

Please refer to D325176; M. Collantes; 3/3/2006 for detailed
information.  

Table 5.1.  Summary of Metabolites and Degradates included in the
Pendimethalin Risk Assessment and Tolerance Expression

Matrix	Residues included in

Risk Assessment	Residues included in

Tolerance Expression

Plants	Primary Crop	Pendimethalin and
4-[(1-ethylpropyl)amino]-2-methyl-3,5-dinitrobenzyl alcohol (CL 202347)
Pendimethalin and (CL 202347)

	Rotational Crop	N/A	N/A

Livestock	Ruminant	Not applicable - there is no reasonable expectation
of finite residues in livestock.

	Poultry

	Drinking Water	Pendimethalin	Not Applicable

5.2	Residue Profile

	

Drinking Water Residue Profile

Please refer to DP Num.: D356491, D355650; W. Eckel; 2/06/2009 for
detailed information.

Pendimethalin dissipates in the environment by binding to soil,
metabolizing by microbes, and by volatilizing into air.  Persistence
decreased with increased temperature, increased moisture and decreased
soil organic carbon.  Pendimethalin residues in laboratory and field
studies are tightly bound to soil and sediment particles, which is
consistent with the laboratory mobility studies.

EFED estimated concentrations in drinking water using Tier II screening
level surface water modeling (PRZM-EXAMS) for surface water and Tier I
modeling (SCI-GROW2) for ground water.  These Estimated Drinking Water
Concentrations (EDWCs) may be used for acute, chronic (non-cancer), and
chronic (cancer) exposure assessments.  The PRZM-EXAMS  concentrations
to be used for drinking water ranged from 2.5 to 77.7 ug/L for peak
values, 0.2 to 6.0 ug/L for chronic (non-cancer), and 0.1 to 4.8 ug/L
for chronic (cancer) exposures as summarized in Table 5.1.8.

The 1 in 10 year annual peak (acute), 1 in 10 year annual mean
(non-cancer chronic), and 36-year annual mean concentrations (cancer
chronic) were derived from modeling pendimethalin on the New York grape
scenario. Since no degradates have been identified in the metabolism
studies at significant ( 10% of applied) levels, no degradates of
pendimethalin were modeled in this assessment. 

n SCI-GROW modeling, the acute and chronic pendimethalin concentrations
are not expected to exceed 0.036 μg/L (ppb) from one application of 6
lbs a.i./A.  The estimated concentrations of up to 0.036 ug/L were
actually lower than the detected concentrations in ground water, ranging
from 0.2 to 0.9 ppb.  However, EFED does not consider pendimethalin to
be a likely ground water contaminant in most environments based on its
environmental fate property of tight sorption to soil.

Table 5.2	Summary of Estimated Surface Water and Groundwater
Concentrations for Pendimethalin.

Scenario	Surface Water Conc., ppb a	Groundwater Conc., ppb b

Acute	77.7	0.036c

Chronic (non-cancer)	6.0	0.036c

Chronic (cancer)	4.8	NA

a From the Tier II PRZM-EXAMS - Index Reservoir model.  Input parameters
are based on grapes in New York state (See May 8, 2007 DWA, DP Barcode
334061, J. Breithaupt, EFED to D. Rosenblatt, RD).

b From the SCI-GROW model assuming a maximum seasonal use rate of 6 lb
a.i./A, a Koc of 19768 L/g-oc, and a half-life of 172 days.

5.2.2	Food Residue Profile

Please refer to DP Num.: D356045; M. Negussie; 9/09/2008 for detailed
information. 

The residue chemistry database to support registration of agricultural
uses of pendimethalin, with respect to the nature of the residue in
plants, livestock and rotational crops; residues to be regulated in
plants for both risk assessment and tolerance enforcement; storage
stability; processing studies and residue analytical methods were
summarized in the 1996 residue chemistry chapter of the pendimethalin
RED.

The residue chemistry data submitted to support the proposed uses (and
associated tolerances) on olive are generally adequate as translated
from stone fruit. Though stone fruit is not typically a suitable
surrogate for olive, primarily due to differences in oil content, HED is
recommending that the use on olives be permitted.  Based on the proposed
pendimethalin use pattern, application is only to the soil surface, in
the row middles or the orchard floor, to prevent weedy grasses and some
broadleaves from germinating.   There is very limited translocation of
pendimethalin (Herbicide Handbook, Weed Science Society of America,
1998).  The only way this chemical would have residues in the fruit is
by misuse of a foliar application or drift.  Based on the stone fruit
data showing residue levels below the LOQ following a similar use
pattern, an LOQ-level tolerance (0.1 ppm combined residues of concern)
is appropriate.

International Residue Limits

There are currently no Codex or Canadian MRLs for pendimethalin.  Mexico
has established MRLs (expressed as pendimethalin per se) for several
crops but none for olives.  Therefore, there are no harmonization issues
with respect to the proposed uses on olives.

Dietary Exposure and Risk

Please refer to DP Num.: D356045; P. Y. Barnes; 4/14/09 for detailed
information.

5.4.1	Acute Dietary Exposure/Risk  TC \l3 "5.2.1  Acute Dietary
Exposure/Risk 

No acute endpoint was identified for pendimethalin, so a quantitative
assessment of risk was not conducted. 

5.4.2	Chronic Dietary Exposure/Risk  TC \l3 "5.2.2  Chronic Dietary
Exposure/Risk 

A chronic dietary risk assessment was conducted using the Dietary
Exposure Evaluation Model (DEEM-FCID, Version 2.00), which uses food
consumption data from the US Department of Agriculture’s Continuing
Surveys of Food Intakes by Individuals (CSFII) from 1994 to 1996, and
1998.  The analysis was performed in order to determine the exposure and
risk estimates that result from the addition of a tolerance in/on
olives.  

The chronic dietary exposure analysis was based on the following
assumptions:  (1) tolerance-level residues of pendimethalin in/on all
current RACs (e-CFR 40 §180.361, Updated November 16, 2007) and
proposed RACs.  (2) 	empirical processing factors obtained from
processing studies.  (3) maximum theoretical concentration factors of
8.0 for the processed commodities of wheat bran and wheat germ and 1.4
for wheat flour.  (4) DEEM 7.81 default-processing factors were used for
the remaining processed commodities.   (5) 100% crop treated (CT), and  
(6) 0.006 ppm pendimethalin estimated drinking water concentration
(EDWC).  

Tolerance-level residues were assumed for all food commodities with
current and proposed pendimethalin tolerances, and it was assumed that
all of the crops included in the analysis were treated (i.e., 100 % crop
treated).  These assumptions result in highly conservative estimates of
dietary exposure and risk.  In calculating dietary risk estimates, HED
has compared the chronic population-adjusted dose (cPAD) to the
estimated dietary exposure from DEEM-FCID.  Typically, HED has concerns
regarding dietary risk when the exposure estimates exceed 100% of the
cPAD.  Even with the conservative assumptions noted above, risk
estimates associated with dietary exposure to pendimethalin are below
HED’s level of concern.

In the chronic dietary assessment, the most highly exposed population
subgroup is children 1-2 years old, with an estimated chronic exposure
of 0.004584 mg/kg/day, corresponding to approximately 15% of the cPAD. 
Exposure and risk estimates for the general US population (0.001528
mg/kg/day, 5% of the cPAD) and all other population subgroups were
lower.

The summarized results of the chronic dietary exposure analysis are
listed in Table 5.3.  

Table 5.3	Summary of Chronic Dietary Exposure and Risk Estimates for
Pendimethalin.  

Population Subgroup*

[Years of Age]	DEEM Chronic Dietary Analysis – Food and Drinking Water

	cPAD (mg/kg/day)	Exposure Estimate (mg/kg/day)	% cPAD

General US Population	0.03	0.001528	5

All Infants [<1]	0.03	0.003037	10

Children [1-2]	0.03	0.004584	15

Children [3-5]	0.03	0.003726	12

Children  [6-12]	0.03	0.002272	8

Youths    [13-19]	0.03	0.001406	5

Adults     [20-49]	0.03	0.001159	4

Adults     [50+]	0.03	0.001054	4

Females  [13-49]	0.03	0.001157	4

* Values for the population with the highest risk are in bold type.  

5.4.3	Cancer Dietary Risk  TC \l3 "5.2.3  Cancer Dietary Risk 

The HED Cancer Peer Review Committee classified pendimethalin as a
“Group C” (possible human) carcinogen, based on thyroid follicular
cell adenomas in rats. The chronic dietary risk assessment is considered
to be protective of any cancer effects; therefore, a separate
quantitative cancer dietary risk assessment is not required. 

6.0	Residential (Non-Occupational) Exposure/Risk Characterization

Residential Exposure

Please refer to DP Num.: D325175; M. Collantes and Z. Figueroa; 4/02/07
for detailed information.

As there are no new residential exposures as a result of the newly
proposed tolerance, please refer to previously reviewed residential
exposure in memorandum DP Num: 325175; M. Collantes; 4/2/2007.  With
regard to residential pendimethalin uses previously reviewed, HED
combined all non-dietary sources of handler and post-application
exposure to obtain an estimate of potential aggregate exposure.  The
scenarios used were short-term in duration and consisted of dermal (for
adults and children) and oral (hand-to-mouth, object-to-mouth, and soil
ingestion, for children only) exposure.  

The level of concern for oral, dermal and inhalation exposure is an MOE
of less than 300.  The residential exposure estimate for adults
(consisting of dermal exposure only) results in a total MOE of 740, and
is therefore not of concern.  The residential exposure for children
results in a total MOE (dermal + oral) of 410 at an application rate of
2 lb ai/acre, and an MOE of 400 for an application rate of 3 lb ai/acre.
 Residential exposure is not of concern.  

  SEQ CHAPTER \h \r 1 Table 6.1	Aggregate Risk Resulting from
Residential Exposure to Pendimethalin (Tier 1).  

Exposure Scenario	Popu-lation	TTR 1 (µg/cm2)	Dermal Dose (mg/kg/day)
Dermal MOE 2

	Total Oral Dose 3 (mg/kg/day)	Oral

MOE 4	Total Dose	Total MOE 5

Turf Grass	Adults	1.1	0.0136	740	NA	NA	0.0136	740

	Children

0.0228	440	0.0015	6800	0.0243	410

	0.0022	4600	0.0250	400

  SEQ CHAPTER \h \r 1 1 Total transferable residue (TTR) values are
based on Pendulum WDG TTR study (MRID #44969901).  

2 Dermal MOE = average of dermal MOEs for adults and children
(calculated from TTR data in CA, PA, and FL).  

3 Oral Dose = hand-to-mouth dose + object-to-mouth dose + soil ingestion
dose.  

4   SEQ CHAPTER \h \r 1 Oral MOE = 1/ (  SEQ CHAPTER \h \r 1
hand-to-mouth MOE + object-to-mouth MOE + soil ingestion MOE).  

5   SEQ CHAPTER \h \r 1 Total MOE = 1/[(1/  SEQ CHAPTER \h \r 1 dermal
MOE) + (1/  SEQ CHAPTER \h \r 1 oral MOE)]

6.2	Other (Spray Drift, etc.) TC \l2 "6.3	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
pendimethalin.  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 labels/labeling.  The Agency has completed its evaluation of
the new database 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.

It is noted that the 3.0 lb ai/acre application rate for turf was
modeled to estimate postapplication residential exposure of toddlers. 
As this rate is equal to or higher than many of agricultural application
rates, this scenario is protective of any exposure of farm children via
spray drift from agricultural pendimethalin applications.

  SEQ CHAPTER \h \r 1 7.0	Aggregate Risk Assessments and Risk
Characterization

In an aggregate assessment, exposures from relevant sources are
combined, and compared to quantitative estimates of hazard (such as a
NOAEL or PAD).  When aggregating exposures and risks from various
sources, HED considers both the route and duration of exposure.  

In evaluating the proposed uses of pendimethalin, HED has combined
dietary (food and drinking water) and non-dietary (turf grass) sources
of exposure to obtain an estimate of potential aggregate exposure.  The
non-dietary scenarios in the aggregate assessment include dermal
exposure for adults and children, as well as incidental oral exposures
(hand- and object-to-mouth transfer of residues and ingestion of soil)
for children only.  

HED acknowledges that the aggregate exposure and risk estimates for
children are likely to overestimate actual exposures since our estimates
assume simultaneous, constant exposures from dietary and non-dietary
sources.  An assessment that takes into account the timing of
source-specific exposures and the likelihood of their co-occurring would
be expected to produce more realistic and lower exposure and risk
estimates.  

  SEQ CHAPTER \h \r 1 7.1	Acute Aggregate Risk

No toxic effects attributable to a single dose were identified for
pendimethalin.  Therefore, a quantitative acute risk assessment was not
conducted for pendimethalin.  

  SEQ CHAPTER \h \r 1 7.2	Short-Term Aggregate Risk

In estimating short-term aggregate risk, HED combines the chronic
dietary (food and drinking water) exposure estimate and the total
non-dietary (residential) exposure estimate for adults and children. 
The chronic dietary exposure estimate reflects average dietary exposure,
and serves as an estimate of dietary exposure that co-occurs with
potential short-term non-dietary exposure to adults and children. 
Short-term aggregate risk estimates for pendimethalin are summarized in
Table 7.2, below.  The level of concern for oral, dermal, and inhalation
exposure is an MOE of less than 300.  The short-term aggregate exposure
estimate for adult males results in an aggregate MOE of 650, while the
short-term aggregate exposure estimate for adult females results in an
aggregate MOE of 580.  The aggregate exposure estimate for children
results in a total MOE of 350 at an application rate (to residential
turf) of 2 lb ai/acre, and a total MOE of 340 for an application rate of
3 lb ai/acre.  Aggregate exposure is therefore not of concern for any of
the population subgroups.  

  SEQ CHAPTER \h \r 1 Table 7.2	Short-Term Aggregate Risk Calculations. 

Population	Short-Term Scenario

	NOAEL

(mg/kg/day)	Target

MOE 1	Average

Dietary Exposure Estimate 2

(mg/kg/day)	Residential Exposure Estimate 3

(mg/kg/day)	Aggregate MOE 4

(Dietary and

Residential)

Adult Male

(US Population)	10	300	0.0015	0.014	650

Adult Female

(Females 13+)	10	300	0.0012	0.016	580

Child

(Children 1-2 yrs)	10	300	0.0046	0.024 5	350

0.025 6	340

  SEQ CHAPTER \h \r 1 1. Target MOE = 300, based on a total UF of 100
(10X intraspecies, 3X interspecies, 10X Database).  

2. Dietary exposure = [food exposure + drinking water exposure].  

3. Residential exposure = [oral exposure + dermal exposure + inhalation
exposure].  

4. Aggregate MOE = [NOAEL ÷ (average dietary exposure + residential
exposure)].  

5. Based on an application rate of 2 lb ai/A.  

6. Based on an application rate of 3 lb ai/A.  

7.3	Intermediate-Term Aggregate Risk  tc "7.3	Intermediate-Term
Aggregate Risk " \l 2 

Based on the currently registered uses, there are no scenarios that are
likely to result in intermediate-term exposure (30 to 180 days,
continuous).  Therefore, HED has not conducted a quantitative
intermediate-term risk assessment for pendimethalin.  

7.4	Long-Term Aggregate Risk  tc "7.4	Long-Term Aggregate Risk " \l 2 

The dietary exposure (food and drinking water) pathway is the only
source of exposure to pendimethalin that is expected to be of long term
(180 to 365 days).  Therefore, the long-term aggregate exposure and risk
estimates are equivalent to the chronic dietary exposure and risk
estimates discussed in Section 5.4.2, and do not exceed HED’s level of
concern.  

7.5	Cancer Aggregate Risk

The HED Cancer Peer Review Committee classified pendimethalin (3/18/1992
and re-affirmed 11/1/1999) as a “Group C” (possible human)
carcinogen based on a statistically significant increased trend and
pair-wise comparison between the high dose group and controls for
thyroid follicular cell adenomas in male and female rats.  The committee
recommended a non-quantitative approach since mode of action studies are
available that demonstrate that the thyroid tumors are due to a
thyroid-pituitary imbalance, and also since pendimethalin was shown to
be non-mutagenic in mammalian somatic cells and germ cells.  The chronic
risk assessment is considered to be protective of any cancer effects;
therefore, a separate quantitative cancer aggregate risk assessment is
not required.  

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 pendimethalin and any other
substances and pendimethalin 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 pendimethalin 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 Characterization

Please refer to DP Num.: D356574; N. Tsaur; 9/17/08 for detailed
information.

PROWL ® H2O Herbicide contains 38.7% active ingredient.  The product is
formulated as a liquid and proposed for use as an agricultural herbicide
olive applied by ground equipment.  The maximum seasonal application
rate is specified as 4 lb a.i./A per season for the proposed new use
assessed in this document. Based on the number of seasonal applications
indicated on the product label, and information provided by the
registrant, handler and post-application exposures are expected to be
short-term in duration.

Chemical-specific data for assessing exposure during pesticide handling
activities were not submitted to the Agency in support of this Section 3
application.  It is HED policy to use data from the Pesticide Handlers
Exposure Database (PHED) Version 1.1 to assess handler exposures for
regulatory actions when chemical-specific data are not available (HED
Science Advisory Council for Exposure, SOP Number .007, January 1999).

Occupational handler exposure assessments were completed by HED using
baseline and single layer of personal protective equipment (PPE).  The
baseline clothing level for occupational exposure scenarios is generally
an individual wearing long pants, a long-sleeved shirt, no
chemical-resistant gloves, and no respirator.  The first level of
mitigation generally applied is PPE.  As reflected in the calculations
included herein, PPE may involve the use of single layer of clothing,
chemical-resistant gloves, and no respirator.

9.1	Short-/Intermediate - Term Handler Risk  TC \l2 "9.1
Short-/Intermediate-/Long-Term/Cancer (if needed) Handler Risk 

Summaries of the non-cancer (MOEs) short-term risks for handlers at the
baseline and PPE levels are included in Table 9.1. Calculations for
handler exposure were performed for the highest application rate per
crop to represent the worst case scenario.  Since both dermal and
inhalation toxicological endpoints were the same for the short-term
duration, the route-specific MOEs were combined and compared to the
NOAEL (10 mg/kg/day).  The total MOEs for short-and intermediate-term
mixing/loading scenario is 1,200 using PPE (single layer and gloves),
and does not exceed HED’s level of concern (MOEs < 30). The total MOEs
for short- and intermediate-term applicator scenario, at baseline level
of mitigation, is 1,900 and does not exceed HED’s level of concern
(MOEs < 30).

The handler exposure estimates in this assessment are based on a central
tendency estimate of unit exposure and an upper-percentile assumption
for the application rate, and are assumed to be representative of
high-end exposures.  The uncertainties associated with this assessment
stem from the use of surrogate exposure data (e.g., differences in use
scenario and data confidence) and assumptions regarding the amount of
chemical handled.  The estimated exposures are believed to be reasonable
high-end estimates based on observations from field studies and
professional judgment.  It should be noted that for mixing/loading
scenarios, gloves are recommended.

Table 9.1.  Short/ Intermediate- Term Occupational Exposure and Risk
Estimates for Pendimethalin. All estimates are at baseline and single
layer with gloves PPE mitigation.  The dermal NOAEL is 10 mg/kg/day; the
inhalation NOAEL is 10 mg/kg/day.

Exposure Scenario	Crop	Daily

Dermal

Dosea

( mg/kg/day)	Daily

Inhalation

Doseb

(mg/kg/day)	Total Dosec (mg/kg/day)	Total

MOEd

Mixer/Loadere

Mixing Loading Liquids for Groundboom Applications	Olives	0.0031	0.0055
0.0086	1200

Applicatorf

Sprays for Groundboom Applications	Olives	0.0019	0.0034	0.0053	1900

a. Dermal Dose  (mg/kg/day)  =   Rate (lb a.i./A) x  UE (mg /lb a.i. ) 
x  DA (0.03)  x  Acres Treated (A/day)			

 	                          					BW (70 kg)																			

b. Inhalation Dose  (mg/kg/day)  =   Rate (lb a.i./A) x UE (mg /lb a.i.
) x  Acres Treated (A/day)								

									BW  (70 kg)			

c. Total Dose (mg/kg/day)  =   Dermal Dose (mg/kg/day) + Inhalation Dose
	

d. Total MOE =  NOAEL (10  mg/kg/day) / Total Dose  (mg/kg/day) 

e. All Mixer/Loader scenarios are represented with Single Layer with
Gloves level of  PPE mitigation.

f. All applicator scenarios are represented with baseline level of PPE.

9.2	Short-/Intermediate -Term Postapplication Risk  TC \l2 "9.2
Short-/Intermediate-/Long-Term/Cancer (if needed) Postapplication Risk 

No postapplication data were submitted in support of this registration
action.  Based on the number of seasonal applications indicated on the
proposed product labels, and information provided by the registrant,
postapplication exposures are expected to be short-term in duration for
all agricultural crops.  Furthermore, since these products are
herbicides used to mainly control pre-emergent weeds, and not applied
directly to foliage, postapplication exposure is expected to be minimal.
 Based on this information a postapplication exposure assessment was not
required.

The restricted entry interval (REI) is based on the acute toxicity of
pendimethalin technical material which is classified as Category III and
IV for acute dermal, dermal irritation and eye irritation (HIARC Doc.
No. 014116, April 18, 2000).  Acute toxicity Category III and IV
chemicals for these potential hazards require a 12-hour REI, therefore,
the 24 hour REI stated on the current PROWL®H2O label is protective.

10.0	Data Needs and Label Recommendations  TC \l1 "10.0	Data Needs and
Label Recommendations 

Toxicology

  TC \l2 "10.1	Toxicology 

HED has requested the submission of developmental thyroid toxicity data
for adult rats and young rats following pre- and post-natal exposure to
pendimethalin. In addition, an immunotoxicity and acute and subchronic
neurotoxicity studies are required as part of the revised Part 158
toxicology data requirements for pendimethalin. The available studies do
not indicate potential immunotoxicity and pendimethalin does not belong
to the class of compounds (e.g., the organotins, heavy metals, or
halogenated aromatic hydrocarbons) that would be expected to be toxic to
the immune system. Based on available data, the immunotoxicity study is
not expected to provide a Point of Departure (PoD) lower than that
currently used for overall risk assessments. In addition, there is no
evidence of neurotoxicity for pendimethalin in the toxicology database.
Therefore, the Agency determined that an additional factor (UFDB) for
database uncertainties is not needed to account for lack of these data. 

10.2	Residue Chemistry

  TC \l2 "10.2	Residue Chemistry 

No data deficiencies have currently been identified for the
establishment of the proposed tolerance on olives are translated from
stone fruits. However, HED has previously requested a limited field
accumulation study (OPPTS 860.1900) to determine the amount of pesticide
residue uptake into rotational crops.  The limited field trials should
reflect the maximum label use rate on crops (that may be rotated) of 4.0
lb ai/A, and should be conducted on a representative crop (as defined in
40CFR §180.41), at two trial sites per crop, for the following three
crop groups:  (1) root and tuber vegetables, (2) leafy vegetables, and
(3) small grains (wheat, barley, oats, rye), for a total of six trials. 
The six trials should be conducted on crops which the petitioner intends
to have as rotational crops on the label.  Samples should be analyzed
for pendimethalin and its 3,5-dinitrobenzyl alcohol metabolite.  

Occupational and Residential Exposure

  TC \l2 "10.3	Occupational and Residential Exposure 

The Agency reiterates the recommendation that agricultural handlers
should wear chemical-resistant gloves when mixing and loading.

References:

  TC \l1 "References: 

Toxicology:

Thyroid Disrupting Pesticides: Use of Rat Thyroid Data Application of
Uncertainty Factors for RfD Derivation (Interim Guidance: Hazard Science
Policy Council). 11/1/05.

Dietary Exposure Memo:

Pendimethalin:  Chronic Dietary (Food and Drinking Water) Analysis and
Risk Assessment to Support a Tolerance in/on Olives. Y. Barnes,
4/14/2009; PC Code: 108501; DP Number: D356906.

Residue Chemistry Memoranda

Pendimethalin: IR-4 Tolerance Petition for use of Prowl® H2O Herbicide
(EPA Reg. No. 241-418) on Olives.  Summary of existing data for the
stone fruit crop group 12 tolerance; M. Negussie, 9/19/2008; PC Code:
108501, DP Number 356045.

Occupational and Residential Exposure Memo:

REVISED: Occupational and Residential Exposure for the Use of
Pendimethalin  Proposed Section 3 Registration for Use on Mint, Citrus
Fruits, Tree Nuts, and Carrots; PC Code: 108501; DP Barcode D325176; M.
Collantes and Z. Figueroa; 3/03/06

REVISED: Occupational and Residential Exposure for the Use of
Pendimethalin  Proposed Section 3 Registration for Use on Mint, Citrus
Fruits, Tree Nuts, and Carrots; PC Code: 108501; DP Barcode D325175; M.
Collantes and Z. Figueroa; 4/2/07

Pendimethalin: Occupational and Residential Exposure Assessment for
Proposed Section 3 Registration for Use on Olive Trees; PC Code 108501;
DP Barcode 356574; N. Tsaur; 9/17/08 tc \l1 "9.0	Occupational
Exposure/Risk Pathway 

Risk Assessment Document:

Pendimethalin. Human Health Assessment for the Proposed Food Uses of the
Herbicide on Artichoke, Globe; Asparagus; Brassica Head and Stem
Vegetables, Subgroup 5A; and Grape (PP#6E7129). PC Code 108501; DP
Barcode D334062; D. Rate; 08/22/07.

Pendimethalin. Human Health Risk Assessment for the Proposed Food/Feed
Use of the Herbicide (Associated with Section 18 Registration) on
Bermuda Grass and Hay Fields in Texas. PC Code 108501; DP Barcode
D349723; W. Drew; 05/20/08. 

Pendimethalin. Human Health Risk Assessment for the Proposed Tolerance
in/on Crayfish. PC Code 108501; DP Barcode D350493; C. Olinger;
03/31/08.

Reregistration Eligibility Document

Pendimethalin Reregistration Eligibility Document; D221532; J. Leahy;
02/20/96

Appendix A:	Toxicology Assessment  TC \l1 "Appendix A:	Toxicology
Assessment 

Toxicity Profiles TC \l2 "A.2	Toxicity Profiles 

Table A.1 Acute Toxicity Profile- Pendimethalin

Guideline No.	Study Type	MRID(s)	Results	Toxicity Category

870.1100	Acute oral [Rat]	00026657	LD50=1250 mg/kg (m)

=1050 mg/kg (f)	III

870.1200	Acute dermal [Rabbit]	00026657	LD50= >1250 mg/kg	IV

870.1300	Acute inhalation [Rat]	00073342	LC50= 32 mg/L	IV

870.2400	Acute eye irritation [Rabbit]	00026657	Slight conjunctival
irritation	III

870.2500	Acute dermal irritation [Rabbit]	00026657	No dermal irritation
IV

870.2600	Skin sensitization [Guinea pig]	00153767	Non- sensitizer	-

Table A.2	Subchronic, Chronic and Other Toxicity Profile for
Pendimethalin.

Guideline Number	Study Type	MRID Number & Classification	Dose Levels
Results

870.3100	Subchronic oral [Rat] (30-day)	000106754 Supplementary	ppm = 0,
800, 1600, 3200 

mg/kg/day =

0, 80, 160, 320	NOAEL = 160 mg/kg/day.

LOAEL = 320 mg/kg/day, based on increased liver weight.

870.3100	Subchronic oral [Rat] (13-week)	00156081	ppm = 0, 100, 500,
5000

mg/kg/day =

 0, 10, 50, 500	NOAEL = 50 mg/kg/day.

LOAEL = 500 mg/kg/day, based on decreased body weight gain and food
consumption, decreased hematocrit and hemoglobin with increases in
platelets in males, increased liver weight, red thyroids, and
hypertrophy of the liver.

870.3100	Subchronic oral [Rat] (13-week)	00059468

Supplementary	ppm = 0, 25, 50, 100, 500, 2500

mg/kg/day =

0, 2.5, 5, 10, 50,  250	NOAEL = 250 mg/kg/day.

LOAEL was not determined.

870.3100	Subchronic oral [Rat] (13 week)	00059469

Supplementary	ppm = 0, 2500

mg/kg/day = 0, 250	NOAEL = 250 mg/kg/day.

LOAEL was not determined.

870.3100	Subchronic oral [Rat] (92-day)	42054601	ppm = 0, 100, 5000

mg/kg/day =

0, 4.98, 245.4	NOAEL = 4.98 mg/kg/day.

LOAEL = 245.4 mg/kg/day, based on thyroid effects.

870.3100	Subchronic oral [Rat] (56-day)	43135001	ppm = 0, 500, 5000

mg/kg/day =

0, 31, 292	NOAEL was not determined.

LOAEL = 31 mg/kg/day, based on thyroid effects.

870.3100	Subchronic oral [Rat] (14-day)	43135003	ppm = 0, 100, 500

mg/kg/day =

0, 10, 500	NOAEL = 10 mg/kg/day.

LOAEL = 500 mg/kg/day, based on thyroid effects.

870.3100	Subchronic oral [Dog] (90-day)	00026672

Supplementary	mg/kg/day =

0, 62.5, 250, 1000	NOAEL = 62.5 mg/kg/day.

LOAEL = 250 mg/kg/day, based on body weight loss.

870.3150	Subchronic oral [Mouse] (30-day)	000106754

Supplementary	ppm = 0, 500, 1000, 2000

mg/kg/day =

0, 75, 150, 300	NOAEL = 300 mg/kg/day.

LOAEL was not determined.

870.3200	21-Day dermal toxicity [Rat]	00026663	mg/kg/day = 

0, 250, 500, 1000	NOAEL = 1000 mg/kg/day.

LOAEL was not determined.

870.3700a	Prenatal developmental toxicity [Rat]	00025752

Supplementary, but satisfactory when considered with the rabbit
developmental.	mg/kg/day = 

0, 125, 250, 500	Maternal NOAEL = 500 mg/kg/day (highest dose tested).

Developmental NOAEL = 500 mg/kg/day  (highest dose tested).

870.3700b

	Prenatal developmental toxicity [Rabbit)]	00117444

Supplementary, upgradeable.	mg/kg/day =

 0, 15, 30,  60	Maternal NOAEL = 60 mg/kg/day (highest dose tested).

Developmental NOAEL = 60 mg/kg/day (highest dose tested).

Note: a range finding study indicated doses ≥125 mg/kg/day associated
with increased mortality.

870.3800	Reproduction and fertility effects [Rat]

(2-generation reproduction)	41725203

	ppm = 0, 500, 2500, 5000

mg/kg/day (M/F) = 

0, 34/43, 172/216, 346/436

HED RED

mg/kg/day =

0, 25, 125, 250

HIARC Document

Note: Doses were obtained from an HED pendimethalin RED, and a HIARC
document (4/18/2000) which resulted in different dose calculations for
mg/kg/day.  Consequently, doses 

are given as a range, based on calculations from actual chemical intake,
and a generic ratio (1:20) of dietary intake.	Parental/Systemic NOAEL =
25-34/43 (M/F) mg/kg/day (500 ppm).

Parental /Systemic LOAEL = 125-172/216 (M/F) mg/kg/day (2500 ppm), based
on decreased body weight gain and food consumption.

Reproductive/Offspring NOAEL = 25-34/43 (M/F) mg/kg/day (500 ppm).

Reproductive/Offspring LOAEL = 125-172/216 (M/F) mg/kg/day (2500 ppm),
based on decreases in the number of pups born, and pup weights.

870.3800	Reproduction and fertility effects [Rat]

(3-generation reproduction)	00026671, 0040304, 00059470	ppm = 0, 500,
5000

mg/kg/day =

0, 25, 250	Parental/Systemic NOAEL = 25 mg/kg/day.

Parental/Systemic LOAEL = 250 mg/kg/day, based on decreased body weight.

Reproductive/Offspring NOAEL = 25 mg/kg/day.

Reproductive/Offspring LOAEL = 250 mg/kg/day, based on decreased pup
body weight gain, and possible decreased pups born alive and pup
survival.

870.4100a	Chronic toxicity

[Mouse]	40909901	ppm = 0, 100, 500, 5000

mg/kg/day (M/F) =

0, 12.3/15.6, 62.3/78.3, 622.1/806.9	NOAEL = 62.3/78.3 mg/kg/day.

LOAEL = 622.1/806.99 mg/kg/day, based on mortality, body weight
decrease, organ weight changes, and amyloidosis.

870.4100b	Chronic toxicity [Dog] (2-year oral)	00058657	mg/kg/day =

0, 12.5, 50, 200	NOAEL = 200 mg/kg/day.

LOAEL was not established. 

870.4200	Chronic toxicity/carcino-genicity [Rat]

(2-year oral)	40174401	ppm = 0, 100, 500, 5000

mg/kg/day = 

0, 5, 25, 250	NOAEL = 25 mg/kg/day.

LOAEL = 250 mg/kg/day, based on decreased survival and body weight gain,
decreased food consumption, increased gamma glutamyl transferase,
cholesterol and liver weights, and thyroid effects.

870.4200	Chronic toxicity  [Rat] (2-year oral)	42027802	ppm = 0, 1250,
2500, 3750, 5000

mg/kg/day =

0, 51, 103, 154, 213	NOAEL was not determined.

LOAEL = 51 mg/kg/day, based on non-neoplastic thyroid follicular cell
changes.

870.4300

	Carcinogenicity [Mouse] (18-month oral)	40909901	ppm = 0, 100, 500,
5000

mg/kg/day (M/F) =

0, 12.3/15.6, 62.3/78.3, 622.1/806.9	NOAEL = 62.3/78.3 mg/kg/day. 

LOAEL = 622./806.9 mg/kg/day, based on mortality, body weight decrease,
organ weight changes, and amyloidosis.

870.5100	Reverse gene mutation assay [Bacterial strains of S.
typhimurium]	00153768	µg/plate = 50, 158, 500, 1581, 5000	Positive 

Evidence of a 2-fold increase in the number of induced mutant colonies
over background (at all doses from 50 to 5000 µg/plate).

870.5100	Reverse gene mutation assay [Escherichia coli WP2]	43177801
µg/plate = 25, 50, 100, 250, 500, 750	Negative

870.5100	Reverse gene mutation assay [Escherichia coli WP2]	43135005	50,
158, 500, 1581, 5000 µg/plate or 1000 µg/paper disk/plate 	Negative

870.5100	Reverse gene mutation assay [Escherichia coli WP2]	43135006
µg/plate = 50, 100, 250, 500, 750	Negative

870.5300	Mammalian cell gene mutation [Chinese hamster ovary]	43177802
µg/plate = 1, 5, 7.5, 10, 20, 30, 40, 50 (-S9)

µg/plate = 10, 25, 50, 75, 100, 125, 150, 175 (+S9)	Negative

870.5375	Chromosomal aberration [Chinese hamster ovary]	00153770	Doses
ranging from 5-50 µg/ml	Negative

870.5395	Micronucleus study [Mouse]	42027801	mg/kg = 313, 625, 1250
Negative

870.5550	Alkaline elution assay [Rat]	43135007	mg/kg/bw = 1250, 2500,
5000	Negative

870.7485	Metabolism and pharmacokinetics [Rat]	00046275	NA*
Pendimethalin is eliminated from the body within 24 hours, with 70%
being excreted in feces (primarily the parent compound), and 20% in
urine.

* NA = Not Applicable.  

Note:  Some of the LOAELs/NOAELS were previously denoted as LOELs/NOELS
in Data Evaluation Records 	(DERs).  The language was updated to comply
with current standards without re-examining effects.  As 	new uses for
pendimethalin are submitted, DERs will be re-reviewed and updated.  

Appendix B: Tolerance Assessment Summary And Table

(DP Numbers: D356905 and 350492; Y. Barnes; 4/02/2009 and D356045; M.
Negussie ; 9/19/2008)

Tolerances for pendimethalin on raw agricultural commodities are
currently established under 40 CFR §180.361 and are expressed in terms
of the combined residues of the herbicide pendimethalin
[N-(1-ethylpropyl)-3,4-dimethyl-2,6-dinitrobenzenamine] and its
metabolite 4-[(1-ethylpropyl)amino]-2-methyl-3,5-dinitrobenzyl alcohol. 
The tolerance expression must be revised in accordance with the most
current guidance as follows: Tolerances for pendimethalin on raw
agricultural commodities are currently established under 40 CFR
§180.361 and are expressed in terms of the combined residues of the
herbicide pendimethalin
[N-(1-ethylpropyl)-3,4-dimethyl-2,6-dinitrobenzenamine] , including its
metabolites and degradates, in or on olive.   Compliance with the
tolerance levels specified below is to be determined by measuring only
pendimethalin [N-(1-ethylpropyl)-3,4-dimethyl-2,6-dinitrobenzenamine]
and its metabolite 4-[(1-ethylpropyl)amino]-2-methyl-3,5-dinitrobenzyl
alcohol expressed as the stoichiometric equivalent of pendimethalin, in
or on the commodity.  

There are currently no Codex MRLs for pendimethalin.  Mexico has
established MRLs (expressed as pendimethalin per se) for several crops
but none for olives.  No Canadian MRLs have been established for
pendimethalin. 

The proposed tolerances for olives are presented in Table B-1.  The
available field trial data support the proposed tolerance on olives at a
level of 0.1 ppm.  

Table B.1 Tolerance Summary for Pendimethalin

Commodity	

Recommended Tolerance (ppm)	

Petition

Olive	

0.1	

0.1

Appendix C:  Review of Human Research

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database,
Version 1.1. Electronic Database. Task Force members Health Canada, U.
S. Environmental Protection Agency, and the National Agricultural
Chemicals Association, released February, 1995.

 

Appendix D: DCI Table

Guideline Number: 870.7800

Study Title:  Immunotoxicity

Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the
data requirements for registration of a pesticide (food and non-food
uses). 

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional
immunotoxicity testing and is designed to evaluate the potential of a
repeated chemical exposure to produce adverse effects (i.e.,
suppression) on the immune system. Immunosuppression is a deficit in the
ability of the immune system to respond to a challenge of bacterial or
viral infections such as tuberculosis (TB), Severe Acquired Respiratory
Syndrome (SARS), or neoplasia.  Because the immune system is highly
complex, studies not specifically conducted to assess immunotoxic
endpoints are inadequate to characterize a pesticide’s potential
immunotoxicity.  While data from hematology, lymphoid organ weights, and
histopathology in routine chronic or subchronic toxicity studies may
offer useful information on potential immunotoxic effects, these
endpoints alone are insufficient to predict immunotoxicity.  

Practical Utility of the Data

How will the data be used?

Immunotoxicity studies provide critical scientific information needed to
characterize potential hazard to the human population on the immune
system from pesticide exposure. Since epidemiologic data on the effects
of chemical exposures on immune parameters are limited and are
inadequate to characterize a pesticide’s potential immunotoxicity in
humans, animal studies are used as the most sensitive endpoint for risk
assessment.  These animal studies can be used to select endpoints and
doses for use in risk assessment of all exposure scenarios and are
considered a primary data source for reliable reference dose
calculation. For example, animal studies have demonstrated that
immunotoxicity in rodents is one of the more sensitive manifestations of
TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental,
reproductive, and endocrinologic toxicities.  Additionally, the EPA has
established an oral reference dose (RfD) for tributyltin oxide (TBTO)
based on observed immunotoxicity in animal studies (IRIS, 1997).

How could the data impact the Agency's future decision-making? 

If the immunotoxicity study shows that the test material poses either a
greater or a diminished risk than that given in the interim decision’s
conclusion, the risk assessments for the test material may need to be
revised to reflect the magnitude of potential risk derived from the new
data.

 

If the Agency does not have this data, a 10X database uncertainty factor
may be applied for conducting a risk assessment from the available
studies.

Guideline Number:  870.6200

Study Title:  Neurotoxicity Screening Battery

Rationale for Requiring the Data

Acute and subchronic neurotoxicity studies with pendimethalin were not
conducted, pendimethalin showed no indication of being a neurotoxicant
in the provided studies and there was no evidence of neurotoxicity in
open literature searches, however, the submitted studies did not examine
neurotoxicity endpoints.  These data are now required under the revised
CFR 158.340 and will be needed if new uses are petitioned for with
pendimethalin.  

Practical Utility of the Data

How did the Agency make its re-registration decision without this data?

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瑹祺nఀcomplete toxicity database. In fact, the Agency was able to
select doses and endpoints for conducting a risk assessment from the
available studies. However, the toxicity database for pendimethalin does
not include any neurotoxicity studies and there is uncertainty of the
neurotoxicity potential of pendimethalin as none of the submitted
studies measured neurotoxicity endpoints.

How will the data be used?

After the review and evaluation of the acute and subchronic
neurotoxicity studies, it is possible that the RfD could change and that
Agency could choose a dose and endpoint from either the acute or
subchronic neurotoxicity study for the deriving the acute RfD.

How could the data impact the Agency’s future decision-making?

If the acute RfD changes, then the pendimethalin acute dietary risk
assessment would need to be done. At present there is no hazard
identified based on the submitted study. The risk would then be
identified for the acute RfD. 

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