UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

	OFFICE OF PREVENTION, PESTICIDE

	AND TOXIC SUBSTANCES

  SEQ CHAPTER \h \r 1 MEMORANDUM

	Date:	3 December 2009

	SUBJECT:	Clopyralid – Human Health Risk Assessment to Evaluate New
Uses on Swiss Chard, Bushberry Subgroup (13-07B), and Strawberry
(Regional Restriction).

PC Code:  117401 (alkanolamine salts), 117403 (acid)	DP Barcode:
D361316

Decision No.:  403248	Registration Nos.:  62719-80, 62719-81, and
62719-84

Petition No.:  8E7481	Regulatory Action:  Section 3 and 24(c)
Registrations

Risk Assessment Type:  NA	Case No.:  NA

TXR No.:  NA	CAS Nos.:	1702-17-6 (acid)

	57754-85-5 (monoethanolamine salt)

MRID Nos.:  47604401, 47604402, 47604403	40 CFR:  180.431

	FROM:	Michael A. Doherty, Ph.D., Senior Chemist

		Linnea Hansen, Ph.D., Toxicologist

		Suku Oonnithan, Biologist

		Risk Assessment Branch II

		Health Effects Division (7509P)  SEQ CHAPTER \h \r 1

	THROUGH:	Edward Scollon, Ph.D., Toxicologist

		Zaida Figueroa, Industrial Hygenist

		William Drew, Environmental Scientist

		Richard A. Loranger, Ph.D., Senior Scientist

		Christina Swartz, Branch Chief

		Risk Assessment Branch II

		Health Effects Division (7509P)

	TO:	Barbara Madden, RM 05

		Risk Integration, Minor Use, and Emergency Response Branch

		Registration Division (7505P)  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r
1

Table of Contents

  TOC \f  1.0	Executive Summary	  PAGEREF _Toc244409539 \h  4

2.0	Ingredient Profile	  PAGEREF _Toc244409540 \h  5

2.1	Summary of Proposed Uses	  PAGEREF _Toc244409541 \h  5

2.2	Structure and Nomenclature	  PAGEREF _Toc244409542 \h  6

2.3	Physical and Chemical Properties	  PAGEREF _Toc244409543 \h  7

3.0	Hazard Characterization/Assessment	  PAGEREF _Toc244409544 \h  7

3.1	Hazard and Dose-Response Characterization	  PAGEREF _Toc244409545 \h
 7

3.1.1	Database Summary	  PAGEREF _Toc244409546 \h  7

<IP_ADDRESS>	Studies available and considered (animal, human, general
literature)	  PAGEREF _Toc244409547 \h  7

<IP_ADDRESS>	Mode of action, metabolism, toxicokinetic data	  PAGEREF
_Toc244409548 \h  7

<IP_ADDRESS>	Sufficiency of studies/data	  PAGEREF _Toc244409549 \h  8

3.1.2	Toxicological Effects	  PAGEREF _Toc244409550 \h  8

3.1.3	Dose-response	  PAGEREF _Toc244409551 \h  9

3.1.4	FQPA	  PAGEREF _Toc244409552 \h  10

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)	  PAGEREF
_Toc244409553 \h  10

3.3	FQPA Considerations	  PAGEREF _Toc244409554 \h  10

3.3.1	Adequacy of the Toxicity Database	  PAGEREF _Toc244409555 \h  10

3.3.2	Evidence of Neurotoxicity	  PAGEREF _Toc244409556 \h  10

3.3.3	Developmental Toxicity and Developmental Neurotoxicity Studies
PAGEREF _Toc244409557 \h  11

3.3.4	Reproductive Toxicity Study	  PAGEREF _Toc244409558 \h  11

3.3.5	Additional Information from Literature Sources	  PAGEREF
_Toc244409559 \h  11

3.3.6	Pre-and/or Postnatal Toxicity	  PAGEREF _Toc244409560 \h  11

<IP_ADDRESS>	Determination of Susceptibility	  PAGEREF _Toc244409561 \h  12

<IP_ADDRESS>	Degree of Concern Analysis and Residual Uncertainties for Pre-
and/or Postnatal Susceptibility	  PAGEREF _Toc244409562 \h  12

3.3.7	Recommendation Regarding a Developmental Neurotoxicity Study
PAGEREF _Toc244409563 \h  12

3.4	Safety Factor for Infants and Children	  PAGEREF _Toc244409564 \h
13

3.5	Hazard Identification and Toxicity Endpoint Selection	  PAGEREF
_Toc244409565 \h  13

3.5.1	Acute Reference Dose (aRfD)	  PAGEREF _Toc244409566 \h  13

3.5.3	Chronic Reference Dose (cRfD)	  PAGEREF _Toc244409567 \h  13

3.5.3	Incidental Oral Exposure (Short-Term)	  PAGEREF _Toc244409568 \h
14

3.5.4	Incidental Oral Exposure (Intermediate-Term)	  PAGEREF
_Toc244409569 \h  14

3.5.5	Dermal Absorption	  PAGEREF _Toc244409570 \h  14

3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term)	  PAGEREF
_Toc244409571 \h  14

3.5.7	Inhalation Exposure (Short-Term)	  PAGEREF _Toc244409572 \h  15

3.5.8	Inhalation Exposure (Intermediate-Term)	  PAGEREF _Toc244409573 \h
 15

3.5.9	Level of Concern for Margin of Exposure	  PAGEREF _Toc244409574 \h
 15

3.5.10	Recommendation for Aggregate Exposure Risk Assessments	  PAGEREF
_Toc244409575 \h  16

3.5.11	Classification of Carcinogenic Potential	  PAGEREF _Toc244409576
\h  16

3.5.12	Summary of Toxicological Doses and Endpoints for Use in Human
Risk Assessments	  PAGEREF _Toc244409577 \h  16

3.6	Endocrine disruption	  PAGEREF _Toc244409578 \h  18

4.0	Public Health and Pesticide Epidemiology Data	  PAGEREF
_Toc244409579 \h  18

5.0	Dietary Exposure/Risk Characterization	  PAGEREF _Toc244409580 \h
18

5.1	Pesticide Metabolism and Environmental Degradation	  PAGEREF
_Toc244409581 \h  18

5.2	Analytical Methodology	  PAGEREF _Toc244409582 \h  19

5.3	Food Residue Profile	  PAGEREF _Toc244409583 \h  19

5.3.1 Anticipated Residue and Percent Crop Treated (%CT) Information
PAGEREF _Toc244409584 \h  20

5.3.2	International Residue Limits	  PAGEREF _Toc244409585 \h  20

5.4	Drinking Water Residue Profile	  PAGEREF _Toc244409586 \h  20

5.5	Dietary Exposure and Risk	  PAGEREF _Toc244409587 \h  20

6.0	Residential (Non-Occupational) Exposure/Risk Characterization
PAGEREF _Toc244409588 \h  21

6.1	Residential Handler Exposure	  PAGEREF _Toc244409589 \h  21

6.2.	Residential Postapplication Exposure	  PAGEREF _Toc244409590 \h  21

6.3	Other (Spray Drift, etc.)	  PAGEREF _Toc244409591 \h  22

7.0	Aggregate Risk Assessments and Risk Characterization	  PAGEREF
_Toc244409592 \h  22

7.1	Acute Aggregate Risk	  PAGEREF _Toc244409593 \h  22

7.2	Short- and Intermediate-Term Aggregate Risk	  PAGEREF _Toc244409594
\h  22

7.3	Long-Term Aggregate Risk	  PAGEREF _Toc244409595 \h  23

7.4	Cancer Risk	  PAGEREF _Toc244409596 \h  23

8.0	Cumulative Risk Characterization/Assessment	  PAGEREF _Toc244409597
\h  23

9.0	Occupational Exposure/Risk Pathway	  PAGEREF _Toc244409598 \h  23

10.0	Data Needs and Label/Regulatory Recommendations	  PAGEREF
_Toc244409599 \h  23

10.1	Toxicology	  PAGEREF _Toc244409600 \h  23

10.2	Residue Chemistry	  PAGEREF _Toc244409601 \h  24

10.3	Occupational and Residential Exposure	  PAGEREF _Toc244409602 \h
24

References:	  PAGEREF _Toc244409603 \h  24

Appendix A:  Toxicology Assessment	  PAGEREF _Toc244409604 \h  26

A.1	Toxicology Data Requirements	  PAGEREF _Toc244409605 \h  26

A.2	Toxicity Profiles	  PAGEREF _Toc244409606 \h  26

A.3	Rationale for Toxicology Data Requirements	  PAGEREF _Toc244409607
\h  31

 1.0	Executive Summary  TC \l1 "1.0	Executive Summary

The Interregional Research Project No.4 (IR-4) has petitioned the Agency
to register clopyralid, a pyridinoxy acid herbicide, for use on Swiss
chard and the bushberry crop subgroup (Subgroup 13-07B), and to grant a
regional registration (Florida and North Carolina) for use on strawberry
in an annual crop production system.  A use on strawberry grown as a
perennial crop has already been established.  HED has reviewed the
available toxicological and residue chemistry studies for clopyralid and
is recommending that the requested uses be conditionally registered and
that permanent tolerances be established.

No mammalian target organ was identified in the clopyralid toxicological
studies submitted to the Agency.  Effects were noted in various organs
and systems, including increases in liver weight, changes in clinical
chemistry and blood cell parameters, skin lesions, and decreases in body
weight gain.  There is no evidence of increased pre- or post-natal
sensitivity to clopyralid as effects in offspring were only observed at
doses that caused severe toxicity in the maternal animals.  There are no
indications of neurotoxic or immunotoxic activity and clopyralid has
been classified as not likely to be carcinogenic to humans.  No adverse
dermal effects were noted, even at the highest dose tested.

Studies with rats, goats, hens, various crops, and environmental
conditions show clopyralid to be relatively stable.  In animals, the
compound is rapidly absorbed and essentially completely excreted as the
parent compound, although some conjugation to glycine was observed in
the livestock studies.  Field trials with Swiss chard, blueberry, and
strawberry resulted in quantifiable residues in all three crops.  The
residue data are adequate to support the establishment of tolerances at
3.0 ppm on Swiss chard, 4.0 ppm on strawberry, and 0.5 ppm on bushberry
(Subgroup 13-07B).

HED has used conservative assumptions to assess the risk from exposure
to clopyralid from dietary and non-dietary sources.  Risk estimates are
below our level of concern for all population subgroups for all exposure
durations.  Based on the previous assessment from 2002, occupational
exposures to clopyralid, assuming baseline personal protective
equipment, are also below HED’s level of concern for all scenarios.  A
new occupational risk assessment is being developed.

Provided the label is modified to prohibit application to low-bush
varieties of bushberry, HED recommends that the requested uses be
conditionally granted and that permanent tolerances, as listed above, be
established.  Submission of acceptable toxicity studies (870.3465 –
28- or 90-Day Inhalation Toxicity; 870.6200 – Acute and Subchronic
Neurotoxicity; and 870.7800 – Immunotoxicity) should be made a
condition of registration.

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, "Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations" http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).
As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures.
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Survey of Food Intakes by Individuals (CSFII) and are used in pesticide
risk assessments for all registered food uses of a pesticide.  These
data are analyzed and categorized by subgroups based on age, season of
the year, ethnic group, and region of the country.  Whenever
appropriate, 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.

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, which comprise the Pesticide Handlers Exposure
Database (PHED), have been determined to require a review of their
ethical conduct, and have received that review.  The studies in PHED are
considered appropriate (ethically conducted) for use in risk
assessments.

2.0	Ingredient Profile  TC \l1 "2.0	Ingredient Profile

Clopyralid [3,6-dichloro-2-pyridinecarboxylic acid]  is a pyridine
herbicide registered for use on a variety of food and feed crops in the
U.S. for the postemergence control of broadleaf weeds, particularly
thistles and clover.  Permanent tolerances are established for residues
of clopyralid in/on a wide variety of plant commodities at levels
ranging from 0.5 ppm in/on stone fruits to 500 ppm in/on grass forage
and hay [40 CFR §180.431(a)], including a tolerance of 1.0 ppm on
strawberry.  Permanent tolerances are also established for residues of
clopyralid in livestock commodities at levels ranging from 0.1 ppm in
eggs to 36 ppm in meat byproducts, except liver, of cattle, goats,
horses and sheep.  There are currently no tolerances for inadvertent or
indirect residues of clopyralid.

2.1	Summary of Proposed Uses  TC \l2 "2.1	Summary of Proposed Uses

In the current petition (PP#8E7481), IR-4 is proposing to expand the use
of clopyralid to include applications to Swiss chard and bushberries for
the postemergence control of various weeds.  In addition, IR-4 is
proposing a regionally restricted use on strawberries grown only in FL
and NC under an annual-type production system.  There is currently a use
on strawberries grown as a perennial crop (DP# 270507, 8/6/2002, D.
Dotson).  The proposed end-use product is an emulsifiable concentrate
containing 3 pounds acid equivalent (ae) clopyralid per gallon.

Table 2.1.  Summary of Directions for Use of Clopyralid.

Applic. Timing, Type, and Equip. 1	Formulation

[EPA Reg. No.]	Applic. Rate

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

(lb ae/A)	PHI

(days)	Use Directions and Limitations 2

Swiss Chard

Broadcast foliar application when crop is at the cotyledon to 8-leaf
stage of growth; ground equipment.	3.0 lb ae/gal EC [62719-73]
0.094-0.187	1	0.187	30	Apply in a minimum of 10 gal/A.

Bushberry subgroup 13-07B

Directed applications to row middles beginning 1 week after bloom;
ground equipment 	3.0 lb ae/gal EC [62719-73]	0.06-0.25	2	0.5	30	Apply
in a minimum of 10 gal/A, with a minimum RTI of 14 days.  Do not apply
by aircraft.

Strawberry (annual fields only in FL and NC)

Broadcast foliar application to well-established plantings; ground
equipment	3.0 lb ae/gal EC [62719-73]	0.113-0.25	1	0.25	7	Apply in a
minimum of 20 gal/A.  Do not use with a surfactant.

Do not apply by aircraft

1	Do not apply through any type of irrigation system.

2	The label for the 3 lb ae/gal EC contains the following rotational
crop restrictions:  barley, canola, cole crops, flax, garden beets,
grasses, corn (field, pop and sweet), oats, spinach, sugar beets,
turnips and wheat may be planted at anytime following a treated crop.
Depending on the amount of soil organic matter, rainfall and location
(state), the plant-back intervals for all other crops range from 10.5 to
18 months.

2.2	Structure and Nomenclature  TC \l2 "2.2	Structure and Nomenclature

Table 2.2.  Clopyralid Nomenclature.

Compound

Common name	Clopyralid, monoethanolamine salt

Company experimental name	Dowco 290

IUPAC name	3,6-dichloropyridine-2-carboxylic acid, monoethanolamine salt

CAS name	3,6-dichloro-2-pyridinecarboxylic acid, monoethanolamine salt

CAS registry number	1702-17-6 (acid)

 ™ herbicide; EPA Reg. No. 62719-73)

2.3	Physical and Chemical Properties  TC \l2 "2.3	Physical and Chemical
Properties

Table 2.3.  Physicochemical Properties of Technical Grade Clopyralid
Acid.

Parameter	Value	Reference

Melting point/range	149.6	Data were obtained from the FOOTPRINT
Pesticide Properties DataBase, (  HYPERLINK
"http://www.eu-footprint.org/ppdb.html"
http://www.eu-footprint.org/ppdb.html ).

pH	Not available

	Density (specific gravity)	1.76 g/mL

	Water solubility (g/L) at 20°C	143

	Solvent solubility (g/L) at 20°C	Acetone – 250

Ethyl acetate – 102

Xylene – 4.6

Hexane – 6.0

	Vapor pressure at 25°C, mPa	1.36

	Dissociation constant, pKa, at 25°C	2.01

	Octanol/water partition coefficient, Log(KOW), at 20°C	-2.63

	UV/visible absorption spectrum	Not available

3.0	Hazard Characterization/Assessment  TC \l1 "3.0	Hazard
Characterization/Assessment

This hazard characterization updates the previously prepared assessment
of September 26, 2002 (D270885).  No additional toxicology studies have
been received since that time.  Additional data requirements in this
assessment reflect the recently revised 40 CFR Part 158 guidelines.

3.1	Hazard and Dose-Response Characterization  TC \l2 "3.1	Hazard and
Dose-Response Characterization

3.1.1	Database Summary  TC \l3 "3.1.1	Database Summary

<IP_ADDRESS>	Studies available and considered (animal, human, general
literature)  TC \l4 "<IP_ADDRESS>	Studies available and considered (animal,
human, general literature)

The following studies have been considered for this hazard
characterization: subchronic toxicity in mice; chronic
toxicity/carcinogenicity in rats; carcinogenicity in mice; chronic
toxicity in dogs; developmental toxicity in rats and rabbits;
two-generation reproduction toxicity in rats; mutagenicity battery;
metabolism (rats) and 21-day rabbit dermal toxicity.

<IP_ADDRESS>	Mode of action, metabolism, toxicokinetic data  TC \l4 "<IP_ADDRESS>
Mode of action, metabolism, toxicokinetic data

Clopyralid is an herbicide of the pyridinoxy acid chemical group that is
used to control broadleaf weeds.  It is structurally similar to plant
auxins and acts as an “auxin imitator”, disrupting plant growth by
binding to auxin receptors.

The mode of action for mammalian toxicity has not been characterized.
The rat metabolism study indicates rapid and essentially complete
absorption and excretion, but essentially no metabolism; only the
unchanged parent compound was recovered.

<IP_ADDRESS>	Sufficiency of studies/data  TC \l4 "<IP_ADDRESS>	Sufficiency of
studies/data

The toxicology database for clopyralid is incomplete at this time.
Based on the toxicology data requirements outlined in the recently
revised 40 CFR Part 158, there are additional requirements for acute and
subchronic neurotoxicity studies in the rat (§870.6200a and b), and an
immunotoxicity study (§870.7800).  In addition, a 28-day inhalation
toxicity study in the rat (§870.3465) is required.  The rationales for
requiring these studies are provided in the attached DCI Tables (see
Appendix A.3).

3.1.2	Toxicological Effects  TC \l3 "3.1.2	Toxicological Effects

The acute toxicity of clopyralid is low (Toxicity Category IV) via oral,
inhalation and dermal exposure and it is not a dermal irritant or
sensitizer.  In its acid form, clopyralid is a severe eye irritant
(Category I).

Subchronic data were available only for the mouse, where decreased body
weight was observed in a 90-day oral study in males and females at
dietary levels exceeding the limit dose (1000 mg/kg/day).  No systemic
toxicity or local dermal irritation was observed in rabbits following
dermal exposure to the limit dose for 21 days.  Subchronic inhalation
data are not available.

Toxicity was observed in the rat and dog following chronic exposure, but
consistent target organs were not identified.  In a one year dog study,
reductions in red blood cell parameters, increased liver weight (males),
and vacuolated adrenal cortical cells (females) were reported.  Skin
lesions and clinical chemistry changes (decreased serum glucose,
protein, albumin) were observed at the highest dose.  In the rat,
epithelial hyperplasia and thickening of the limiting ridge of the
stomach were observed at the LOAEL and decreased body weight at the
highest dose.  Only decreased body weight/weight gain and food
efficiency in males were observed in the mouse carcinogenicity study
above the limit dose.

There was no indication of increased pre- and/or postnatal
susceptibility.  No developmental toxicity was observed in the rat at
doses that caused maternal mortality and decreased maternal body weight
gain.  Decreased fetal body weight and hydrocephalus were observed in
the rabbit but at a dose that caused severe maternal toxicity, including
mortality, clinical signs of toxicity, decreased body weight gain and
gastric mucosal lesions.  Reproductive toxicity was not observed in the
rat, but mean pup weights (Day 28) were reduced and relative liver
weights increased at doses that caused parental toxicity (decreased body
weight/weight gain and food consumption; gastric lesions).

Acute and subchronic neurotoxicity studies and an immunotoxicity study
have not been submitted.  However, there were no clinical or
histopathological indications of neurotoxicity, nor indications of
immunotoxicity, in the subchronic or chronic toxicity studies at doses
up to or beyond the limit dose.

No evidence for carcinogenicity was observed in rat and mouse 2-year
bioassays at doses exceeding the limit dose.  No positive findings for
mutagenicity or clastogenicity were observed in a battery of
mutagenicity studies (bacterial reverse gene mutation, in vitro and in
vivo host mediated assays in Salmonella and Saccharomyces, in vivo
chromosomal aberrations, unscheduled DNA synthesis, dominant lethal
activity).  Clopyralid is therefore classified as “not likely to be
carcinogenic to humans.”

Clopyralid is rapidly absorbed and excreted, predominantly as parent
compound, primarily in the urine with very low fecal excretion.  It is
not retained in tissues.

3.1.3	Dose-response  TC \l3 "3.1.3	Dose-response

The endpoints selected for this human health risk assessment of
clopyralid are presented and discussed in greater detail in Section 3.5
of this document.

An acute dietary exposure endpoint was selected based on decreased
maternal body weight gain/food consumption in the rat developmental
study during the first three days of dosing (gestation days 6-9).  This
endpoint was selected because the maternal body weight gain changes
could have resulted from a single exposure, but only the day 6-9
interval data were available.  There were no other endpoints of an
appropriate duration for this risk assessment.

For chronic dietary exposure, the lowest NOAEL identified in the
database was 15 mg/kg/day, based on stomach histopathology in the rat at
150 mg/kg/day in the chronic toxicity/carcinogenicity feeding study.
Although the effects were observed in the limiting ridge of the rat
stomach, they were considered relevant to human risk assessment because
they were most likely the result of irritation.  Body weight effects
were observed at the highest dose tested (1500 mg/kg/day), a dose that
exceeded the limit dose.

For short-term incidental oral exposure to young children, assessment
was based on the developmental toxicity NOAEL of 75 mg/kg/day from the
rat developmental study, in which decreased maternal body weight gain
and food consumption were observed at the LOAEL of 250 mg/kg/day.  This
was the lowest available NOAEL for exposure of this duration:  the
rabbit developmental NOAEL was 110 mg/kg/day (250 mg/kg/day LOAEL) and
the mouse subchronic study exceeded the limit dose.

For incidental oral intermediate-term exposure to young children, the
assessment was based on the rat chronic toxicity NOAEL of 15 mg/kg/day
due to stomach lesions at the LOAEL of 150 mg/kg/day.  The finding was
reported by 6 months’ dosing and is therefore the result of an
appropriate duration of exposure.  Both short- and intermediate-term
endpoints are protective of postnatal effects, based on the reproductive
toxicity offspring NOAEL of 500 mg/kg/day.

A dermal risk assessment is not required for clopyralid.  No toxicity
was observed in the rabbit 21-day dermal toxicity study, which tested up
to the limit dose of 1000 mg/kg/day.   Because there was no toxicity
observed, and developmental toxicity in the rabbit was only observed in
the presence of maternal toxicity (maternal/developmental LOAEL = 250
mg/kg/day), no pre-and/or postnatal toxicity would be expected from
dermal exposure up to the limit dose.

There are no inhalation toxicity data on clopyralid; therefore, oral
studies were selected with an assumption of 100% absorption (relative to
oral).  The rat developmental toxicity study NOAEL of 75 mg/kg/day was
selected for short-term inhalation exposure and the rat chronic toxicity
NOAEL of 15 mg/kg/day was selected for intermediate-term exposure.

3.1.4	FQPA  TC \l3 "3.1.4	FQPA

HED recommends reduction of the FQPA special factor to 1X.  There was no
evidence of increased pre- and/or postnatal qualitative or quantitative
susceptibility in the developmental rat or rabbit studies, or the rat
2-generation reproduction study.  In the developmental rat study, no
developmental effects were seen at doses that caused maternal toxicity.
 Although acute and subchronic neurotoxicity studies and an
immunotoxicity study have not been submitted and are required under the
revised 40 CFR Part 158 guidelines, the available subchronic and chronic
studies show no evidence of either neurotoxicity or immunotoxicity at
doses up to or exceeding the limit dose.  The endpoints selected for
risk assessment are therefore considered adequately protective of pre-
and/or postnatal toxicity.  Furthermore, exposure estimates in the risk
assessment are health-protective and likely overestimate exposures.

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)  TC \l2 "3.2
Absorption, Distribution, Metabolism, Excretion (ADME)

Metabolism of clopyralid was evaluated in the rat.  Clopyralid was
essentially completely absorbed at both a low (5 mg/kg/day) and a high
(150 mg/kg/day) dose (95-115% of administered dose recovered).
Excretion was primarily in the urine (91-113% of the administered dose
at 72 hrs postdosing, with 74-98% excreted within 6-12 hrs postdosing),
whether by oral or intravenous dosing.  Less than 4% of the excretion
was via feces.  Radioactivity was not retained in tissues (<0.01% of
administered dose at 72 hrs postdosing).   There was no evidence of
metabolism; only parent compound was identified in the urine and feces.

3.3	FQPA Considerations  TC \l2 "3.3	FQPA Considerations

3.3.1	Adequacy of the Toxicity Database  TC \l3 "3.3.1	Adequacy of the
Toxicity Database

Acceptable developmental toxicity studies in rats and rabbits and a
two-generation reproduction study in rats are available for FQPA
assessment.   However, acute and subchronic neurotoxicity in rats and
immunotoxicity studies have not been submitted and represent data gaps
for clopyralid under the revised 40 CFR Part 158 guidelines.  A 28-day
inhalation toxicity study in rats is also required for assessment of
inhalation exposure risk, but the selected oral endpoints, with an
assumption of 100% absorption relative to oral absorption, are
considered adequately protective of pre- and/or postnatal toxicity.

3.3.2	Evidence of Neurotoxicity  TC \l3 "3.3.2	Evidence of Neurotoxicity

There are no clinical or micropathological indications of neurotoxicity
in the available subchronic and chronic studies in multiple species.
Acute and subchronic neurotoxicity studies in the rat have not been
submitted but are required under the revised 40 CFR Part 158 guidelines.

In the rabbit developmental toxicity study, hydrocephalus was observed
at the highest dose tested, 250 mg/kg/day.  However, this finding
occurred at a dose that caused severe maternal toxicity, including
mortality and decreased body weight gain and food consumption.  No
evidence of neurodevelopmental toxicity was observed in the rat
developmental toxicity study or in the rat two-generation reproductive
toxicity study.

3.3.3	Developmental Toxicity and Developmental Neurotoxicity Studies  TC
\l3 "3.3.3	Developmental Toxicity and Developmental Neurotoxicity
Studies

In a developmental toxicity study in the rat (MRID 00127279), pregnant
Fischer 344 rats were administered clopyralid (97.0% a.i.) by gavage at
0, 15, 75 or 250 mg/kg/day from gestation days 6 through 15.  A repeat
study evaluating control and high doses was conducted to assess a low
level of malformations in the initial study at the high dose.  Maternal
toxicity was observed at the LOAEL of 250 mg/kg/day, based on mortality,
decreased body weight gains and decreased food consumption.  The
maternal NOAEL was 75 mg/kg/day.  No developmental toxicity was
observed; the NOAEL was 250 mg/kg/day and the LOAEL was not established
(>250 mg/kg/day).

In a second developmental toxicity study (MRID 41649801), pregnant New
Zealand White rabbits were administered clopyralid (96.1-96.4% a.i.) by
gavage at doses of 0, 50, 110 or 250 mg/kg/day from gestation days 7
through 19.  Maternal toxicity was observed at the LOAEL of 250
mg/kg/day, based on mortality, clinical signs of toxicity, decreased
mean body weight gain and gastric mucosal lesions at the LOAEL of 110
mg/kg/day.  Developmental toxicity was observed at the LOAEL of 250
mg/kg/day based on decreased mean fetal body weight and hydrocephalus.
The NOAEL was 110 mg/kg/day.

A developmental neurotoxicity study is not available and is not
required.

3.3.4	Reproductive Toxicity Study  TC \l3 "3.3.4	Reproductive Toxicity
Study

In a 2-generation rat reproduction study (MRID 00138155), clopyralid
(96.7% a.i.) was administered in the diet to Fischer 344 rats at 0, 150,
500 or 1500 mg/kg/day for two mating generations (two litters per
generation).   Parental toxicity was observed at the LOAEL of 1500
mg/kg/day as decreased body weights, body weight gains and food
consumption in F0 and F1 males and females, and slight focal
hyperkeratotic changes in the gastric squamous mucosa of 1 F0 male and 2
F1 males.  The parental toxicity NOAEL was 500 mg/kg/day.  Offspring
toxicity was observed at the LOAEL of 1500 mg/kg/day based on decreased
Day 28 male pup body weight in both F1 litters and increased relative
liver weights of male and female F1a pups and male F1b pups.
Reproductive toxicity was not observed; the NOAEL was 1500 mg/kg/day and
a LOAEL was not identified (>1500 mg/kg/day).

3.3.5	Additional Information from Literature Sources  TC \l3 "3.3.5
Additional Information from Literature Sources

Additional information from the published literature was not identified
for clopyralid.

3.3.6	Pre-and/or Postnatal Toxicity  TC \l3 "3.3.6	Pre-and/or Postnatal
Toxicity

<IP_ADDRESS>	Determination of Susceptibility  TC \l4 "<IP_ADDRESS>	Determination
of Susceptibility

There was no evidence of increased pre- and/or postnatal qualitative or
quantitative susceptibility.  In the rat developmental study, no
developmental toxicity was observed at a maternally toxic dose and in
the two-generation reproduction study, decreased pup weight (post-natal
Day 28) and increased relative liver weights were observed at the
parental LOAEL.  In the rabbit, hydrocephalus and decreased mean fetal
weight were observed at a dose that caused severe maternal toxicity,
including mortality.

<IP_ADDRESS>	Degree of Concern Analysis and Residual Uncertainties for Pre-
and/or Postnatal Susceptibility  TC \l4 "<IP_ADDRESS>	Degree of Concern
Analysis and Residual Uncertainties for Pre- and/or Postnatal
Susceptibility

There is low concern for increased pre- and/or postnatal qualitative or
quantitative susceptibility.  Increased susceptibility was not observed
in the developmental toxicity studies, or in the rat reproduction study.
 There are residual uncertainties due to lack of acute and subchronic
neurotoxicity studies and an immunotoxicity study; however there was no
evidence of neurotoxicity or immunotoxicity in the available subchronic
and chronic studies, which tested up to doses exceeding the limit dose.
Although hydrocephalus was observed in the rabbit developmental toxicity
study, it was only observed at a dose that also caused severe maternal
toxicity, including mortality.  In the rat, there were no fetal effects
observed in the developmental study; in the reproduction study, pup
weights (post-natal Day 28) were decreased and relative liver weights
increased at a maternally toxic dose that exceeded the limit dose.  The
endpoints selected for risk assessment provide adequate protection to
offspring.  Based on these findings, there is low concern for increased
pre- and/or postnatal susceptibility.

3.3.7	Recommendation Regarding a Developmental Neurotoxicity Study  TC
\l3 "3.3.7	Recommendation Regarding a Developmental Neurotoxicity Study

A developmental neurotoxicity study is not recommended at this time,
based on low concern for neurotoxicity.   Neuropathology (hydrocephalus)
was only observed in the rabbit developmental study at a dose that
caused severe maternal toxicity, and no evidence of neurotoxicity was
observed in the rat developmental or reproduction studies or in the
available subchronic or chronic studies.

3.4	FQPA Safety Factor for Infants and Children

HED recommends reduction of the 10X FQPA safety factor for protection of
infants and children to 1X.  Increased qualitative or quantitative pre-
and/or postnatal susceptibility was not observed in the developmental or
2-generation reproduction studies.  A rat developmental neurotoxicity
study is not required at this time, based on lack of evidence of
neurotoxicity in subchronic and chronic exposure studies and in the rat
developmental and reproduction studies; hydrocephalus in the rabbit
developmental study occurred only in one species and in the presence of
severe maternal toxicity, including death.  Exposure estimates are based
on conservative, health-protective assumptions and further support
reducing the FQPA safety factor.

Data gaps include acute and subchronic neurotoxicity studies.  An
immunotoxicity study is also required; however, there was no indication
in the submitted toxicity studies that there were effects on the immune
system.  Based on the lack of concerns for neurotoxicity and
immunotoxicity in the existing database and selection of endpoints which
are adequately protective of pre- and/or postnatal toxicity, an
additional factor for data gaps is not required.

  TC \l2 "3.4	Safety Factor for Infants and Children

3.5	Hazard Identification and Toxicity Endpoint Selection  TC \l2 "3.5
Hazard Identification and Toxicity Endpoint Selection

3.5.1	Acute Reference Dose (aRfD)   TC \l3 "3.5.1	Acute Reference Dose
(aRfD)

Study Selected:  Developmental Toxicity Study - rat

MRID Nos.:   00127279

Dose and Endpoint for Establishing cRfD: maternal NOAEL = 75 mg/kg/day,
based on decreased body weight gains and reduced food consumption at the
LOAEL of 250 mg/kg/day.

Uncertainty Factor(s):  An UF of 100 was applied to account for
inter-species extrapolation (10X) and intra-species variation (10X).

Comments on Study/Endpoint/Uncertainty Factors:  The rat developmental
toxicity study with a maternal toxicity NOAEL of 75 mg/kg/day is of an
appropriate route of administration (gavage).  The body weight effects
in the maternal animals are believed to be due to one or a few doses
given at the initiation of the dosing period (gestation days 6-15).  The
first calculation of maternal weight gain and food consumption was
conducted for days 6 through 9 of gestation (days 1-3 of dosing).  The
selected dose is also protective of developmental effects seen in the
rabbit at 250 mg/kg/day in the presence of severe maternal toxicity
(developmental toxicity NOAEL of 110 mg/kg/day).

	Acute RfD =    75 mg/kg/day (NOAEL)   = 0.75 mg/kg/day

			              100 (UF)

3.5.2	Chronic Reference Dose (cRfD)  TC \l3 "3.5.3	Chronic Reference
Dose (cRfD)

Study Selected:  Combined Chronic/Carcinogenicity - rat (OPPTS 870.4300)

MRID Nos.:   00162393, 00162434

Dose and Endpoint for Establishing cRfD: NOAEL = 15 mg/kg/day, based on
histopathology in the stomach (epithelial hyperplasia and thickening of
the limiting ridge) at the LOAEL of 150 mg/kg/day:

Uncertainty Factor(s):  An UF of 100 was applied to account for
inter-species extrapolation (10X) and intra-species variation (10X).

Comments on Study/Endpoint/Uncertainty Factors:  The 2-year rat chronic
toxicity/carcinogenicity study with a NOAEL of 15 mg/kg/day is via an
appropriate route of administration (diet) and is the lowest NOAEL for
all chronic studies in the dog, rat and mouse.  The limiting ridge is
the structure between the forestomach (nonglandular) and glandular
portions of the rodent stomach.  Although the limiting ridge is absent
in dogs and primates, the histological effects are believed to be due to
the irritating properties of the chemical and, therefore, may be of
potential toxicity in humans.  Stomach lesions were also observed in the
developmental rabbit study and rat reproduction study.  The NOAEL is
lower than all endpoints for developmental and reproductive effects and
therefore protective of potential pre- and/or postnatal toxicity.

	Chronic RfD =    15 mg/kg/day (NOAEL)   = 0.15 mg/kg/day

 (UF)

3.5.3	Incidental Oral Exposure (Short-Term)   TC \l3 "3.5.3	Incidental
Oral Exposure (Short-Term)

Study Selected:  Developmental Toxicity Study – rat (OPPTS 870.3700a)

MRID No.:  00127279

Dose and Endpoint for  Risk Assessment:  NOAEL = 75 mg/kg/day, based on
maternal mortality and decreased body weight gain and food consumption
during days 6-9 of gestation at the LOAEL of 250 mg/kg/day.

Uncertainty Factor(s): An UF of 100 was applied to account for
inter-species extrapolation (10X) and intra-species variation (10X).

Comments on Study/Endpoint:  This endpoint is based on an oral study of
an appropriate duration.  Effects in the maternal animal are believed to
be due to one or a few doses given at the initiation of the dosing
period (gestation days 6 through 15).  The first calculation of maternal
weight gain and food consumption was determined for gestation days 6-9.
The selected dose is protective of potential postnatal toxicity based on
the offspring NOAEL of 500 mg/kg/day in the rat reproduction study.

3.5.4	Incidental Oral Exposure (Intermediate-Term)   TC \l3 "3.5.4
Incidental Oral Exposure (Intermediate-Term)

Study Selected:  Combined Chronic/Carcinogenicity - rat (OPPTS 870.4300)

MRID Nos.:   00162393, 00162434

Dose and Endpoint for Establishing cRfD: NOAEL = 15 mg/kg/day, based on
histopathology in the stomach (epithelial hyperplasia, thickening of the
limiting ridge) at the LOAEL of 150 mg/kg/day:

Uncertainty Factor(s):  An UF of 100 was applied to account for
inter-species extrapolation (10X) and intra-species variation (10X).

Comments on Study/Endpoint/Uncertainty Factors:  See 3.5.2.  Stomach
lesions in the rat were observed at 6 months of oral dosing and are
therefore an appropriate endpoint for this risk assessment.  The
selected dose is protective of potential postnatal toxicity based on the
offspring NOAEL of 500 mg/kg/day in the rat reproduction study.

3.5.5	Dermal Absorption  TC \l3 "3.5.5	Dermal Absorption

Dermal absorption data are not available for clopyralid.  A 21-day
dermal toxicity is available and was considered for dermal exposure
endpoints of all durations (see below).

3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term)  TC \l3
"3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term)

Dermal absorption data are not available for clopyralid.  No toxicity
was observed in a rabbit 21-day dermal study up to the limit dose of
1000 mg/kg/day (MRID 41790701).  In the rabbit, the more sensitive
species for developmental effects, fetal toxicity was observed only in
the presence of severe maternal toxicity (decreased maternal body
weight, clinical signs of toxicity and mortality).  Therefore, since no
body weight or other effects were observed following dermal exposure in
the same species, developmental effects would not be expected at the
limit dose.  The 21-day study indicates that dermal absorption is low;
based on comparison of the two studies, risk from exposure via the
dermal route is not a concern.

3.5.7	Inhalation Exposure (Short-Term)  TC \l3 "3.5.7	Inhalation
Exposure (Short-Term)

Study Selected:  Developmental toxicity in rat

MRID No.:  00127276

Dose and Endpoint for Risk Assessment:  Maternal NOAEL = 75 mg/kg/day
based on mortality, decreased body weight gain and food consumption at
the LOAEL of 250 mg/kg/day.

Uncertainty Factor(s): An UF of 100 was applied to account for
inter-species extrapolation (10X) and intra-species variation (10X).

Comments about the Study/Endpoint:  This endpoint is based on an oral
study because no inhalation studies are available.  Therefore, an oral
study is selected to estimate risk using a route-to-route extrapolation.
 The rat developmental study and endpoint were selected because they are
protective of effects observed in all the available studies, including
hydrocephalus as observed in the rabbit developmental study at 250
mg/kg/day (maternal and developmental NOAEL = 110 mg/kg/day).  The
observed effects are a result of short-term exposure.  Absorption via
inhalation is assumed to be equivalent to absorption via the oral route,
i.e., 100% inhalation absorption is assumed in risk assessment.

3.5.8	Inhalation Exposure (Intermediate-Term)  TC \l3 "3.5.8	Inhalation
Exposure (Intermediate-Term)

Study Selected:  Chronic toxicity/carcinogenicity in rats

MRID No.:  00162393, 00162434

Dose and Endpoint for Risk Assessment:  The NOAEL = 15 mg/kg/day, based
on epithelial hyperplasia and thickening of the limiting ridge of the
stomach in both sexes.

Uncertainty Factor(s): An UF of 100 was applied to account for
inter-species extrapolation (10X) and intra-species variation (10X).

Comments about the Study/Endpoint:  No inhalation studies are available.
 Therefore, an oral study is selected to estimate risk using
route-to-route extrapolation.  The study and endpoint were selected
because they are protective of effects observed in all available
studies, including developmental effects in the rabbit (hydrocephalus,
decreased fetal weight), which were seen at a dose that caused severe
maternal effects including mortality (250 mg/kg/day).  The endpoint is
of appropriate duration, as the effect may be a result of intermediate-
or longer-term exposure.  Absorption via inhalation is assumed to be
equivalent to absorption via the oral route, i.e., 100% inhalation
absorption is assumed in risk assessment.

3.5.9	Level of Concern for Margin of Exposure  TC \l3 "3.5.9	Level of
Concern for Margin of Exposure

Table 3.5.9.  Summary of Levels of Concern for Risk Assessment.

Route	Short-Term

(1 - 30 Days)	Intermediate-Term

(1 - 6 Months)	Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	100	100	N/A

Inhalation	100	100	N/A

Residential Exposure

Dermal	100	100	N/A

Inhalation	100	100	N/A

Incidental Oral	100	100	N/A

3.5.10	Recommendation for Aggregate Exposure Risk Assessments  TC \l3
"3.5.10	Recommendation for Aggregate Exposure Risk Assessments

According to FQPA (1996), when there are potential residual exposures to
a pesticide, an aggregate risk assessment must consider exposures from 3
major routes: oral, dermal and inhalation.  Although dermal exposure is
anticipated from residential use of clopyralid, a dermal assessment was
not performed, and therefore dermal exposure is not included in the
aggregate assessment, because an appropriate endpoint was not identified
(no toxicity up to the limit dose of 1000 mg/kg/day).

Exposures to clopyralid may be aggregated as follows:  (1) for acute
dietary exposure, drinking water and dietary exposures may be combined;
(2) for short-term exposure, drinking water and dietary exposures may be
combined with inhalation exposure for adult applicators and residential
incidental oral exposures for young children; and (3) for
intermediate-term exposure, drinking water and dietary exposures may be
combined with residential incidental oral exposures for young children.
An adult aggregate exposure estimate for intermediate exposure is not
required because intermediate-term inhalation exposure is not
anticipated from residential uses and a dermal assessment is not
required.

3.5.11	Classification of Carcinogenic Potential  TC \l3 "3.5.11
Classification of Carcinogenic Potential

There was no evidence of treatment-related increases in tumor incidence
in the 2-year rat and mouse dietary studies.  Both studies included a
high dose that exceeded the limit dose.  Genotoxicity studies were
negative.  In accordance with the EPA’s Final Guidelines for
Carcinogen Risk Assessment (March, 2005), clopyralid is classified as
“not likely to be carcinogenic to humans.”

3.5.12	Summary of Toxicological Doses and Endpoints for Use in Human
Risk Assessments  TC \l3 "3.5.12	Summary of Toxicological Doses and
Endpoints for Use in Human Risk Assessments

Table 3.5.12a.  Toxicological Doses and Endpoints for Clopyralid for Use
in Dietary and Residential  Human Health Risk Assessments.

Exposure/

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

Acute Dietary (All populations including infants and children) 	NOAEL =
75 mg/kg	UFA= 10X

UFH= 10X

SFFQPA=1	aRfD=0.75 mg/kg/day

aPAD=0.75 mg/kg/day	Developmental Toxicity (oral) – rat

Maternal LOAEL = 250 mg/kg/day, based on decreased body weight gain and
food consumption during GD 6-9.

Chronic Dietary

(All populations including infants and children)	NOAEL= 15 mg/kg/day
UFA= 10X

UFH= 10X

SFFQPA=1	cRfD=0.15 mg/kg/day

cPAD=0.15 mg/kg/day	2-Year Combined Chronic Toxicity/Carcinogenicity
(oral) – rat

LOAEL = 150 mg/kg/day, based on increased epithelial hyperplasia and
thickening of the limiting ridge of the stomach in both sexes.

Incidental Oral, Short-term (1-30 days)

	NOAEL= 75 mg/kg/day	UFA= 10X

UFH= 10X

SFFQPA=1	Residential LOC for MOE= 100

	Developmental Toxicity (oral) – rat

Maternal LOAEL = 250 mg/kg/day, based on decreased body weight gain and
food consumption during GD 6-9.

Incidental Oral, Intermediate-term (1-6 months)	NOAEL = 15 mg/kg/day
UFA= 10X

UFH= 10X

SFFQPA=1	Residential LOC for MOE = 100 	2-Year Combined Chronic
Toxicity/Carcinogenicity (oral) – rat

LOAEL = 150 mg/kg/day, based on increased epithelial hyperplasia and
thickening of the limiting ridge of the stomach in both sexes.

Dermal, Short-and Intermediate-term (1-30 days and 1-6 months,
respectively) 	No dermal or systemic toxicity was observed at the limit
dose (1000 mg/kg/day) in a rabbit 21-day dermal toxicity study and there
are no developmental or reproductive concerns.  No quantification of
risk is required.

Inhalation, Short-term (1-30 days)	Oral study

NOAEL = 75 mg/kg/day

(inhalation absorption rate = 100% of oral)	UFA= 10X

UFH= 10X

SFFQPA=1	Residential LOC for MOE = 100	Developmental Toxicity (oral) –
rat

Maternal LOAEL = 250 mg/kg/day, based on decreased body weight gain and
food consumption during GD 6-9.

Inhalation Intermediate-term (1-6 months)

	Oral study NOAEL=  15 mg/kg/day

(inhalation absorption rate = 100% of oral)	UFA= 10X

UFH= 10X

SFFQPA=1	Residential LOC for MOE= 100 	2-Year Combined Chronic
Toxicity/Carcinogenicity (oral) – rat

LOAEL 150 mg/kg/day, based on increased epithelial hyperplasia and
thickening of the limiting ridge of the stomach in both sexes.

Cancer (all routes)	 “Not likely to be carcinogenic to humans”.
Cancer risk is not of concern.

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

Table 3.5.12b.  Summary of Toxicological Doses and Endpoints for
Clopyralid for Use in Occupational Human Health Risk Assessments.

Exposure/

Scenario	Point of Departure	Uncertainty Factors	Level of Concern for
Risk Assessment	Study and Toxicological Effects

Dermal, Short- and Intermediate-term (1-30 days and 1-6 months,
respectively)	No dermal or systemic toxicity was observed at the limit
dose (1000 mg/kg/day) in a 21-day dermal toxicity study and there are no
developmental or reproductive concerns.  No quantification of risk is
required.

Inhalation, Short-term

(1-30 days)	NOAEL = 75 mg/kg/day (default inhalation absorption rate =
100% of oral absorption)	UFA= 10X

UFH= 10X

SFFQPA=1	Occupational LOC for MOE = 100	Developmental Toxicity (oral)
– rat

Maternal LOAEL = 250 mg/kg/day, based on decreased body weight gain and
food consumption during GD 6-9.

Inhalation, Intermediate- term

(1-6 months)	NOAEL = 15 mg/kg/day (default inhalation absorption rate =
100% of oral absorption)	UFA = 10X

UFH = 10X

SFFQPA = 1	Occupational LOC for MOE = 100	2-Year Combined Chronic
Toxicity/Carcinogenicity (oral) – rat

LOAEL = 150 mg/kg/day, based on increased epithelial hyperplasia and
thickening of the limiting ridge of the stomach in both sexes.

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

3.6	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 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
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).

When the appropriate screening and/or testing protocols being considered
under the Agency’s EDSP have been developed, clopyralid may be
subjected to additional screening and/or testing to better characterize
effects related to possible endocrine disruption.  To the extent that
new or revised tests are developed in connection with the EDSP that can
provide more information on endocrine effects, EPA will consider whether
further testing of clopyralid is appropriate.

4.0	Public Health and Pesticide Epidemiology Data  TC \l1 "4.0	Public
Health and Pesticide Epidemiology Data

Public health and pesticide epidemiology data were not used for this
risk assessment.

5.0	Dietary Exposure/Risk Characterization  TC \l1 "5.0	Dietary
Exposure/Risk Characterization

5.1	Pesticide Metabolism and Environmental Degradation  TC \l2 "5.1
Pesticide Metabolism and Environmental Degradation

The nature of the residue in plants is adequately understood for
purposes of this petition based on the acceptable cabbage, grass, barley
and wheat metabolism studies.  In each of these studies, the major
14C-residue was determined to be only parent compound.  Although the
available crop metabolism data all indicate that the parent compound is
the only major residue, the data are from only two dissimilar crops
(leafy vegetable and cereal grain).  Therefore, HED concludes that the
residue of concern in plants for purposes of this petition is
clopyralid.  Additional metabolism studies may be required in the future
should the petitioner request the establishment of clopyralid tolerances
for additional crops.

In livestock, the major residues are the parent clopyralid as well as
its glycine conjugate (3,6-DCPA-glycine).  HED notes that the current
petition does not involve livestock feed items.

In the environment, clopyralid has a low rate of soil sorption, is
stable to photolysis and anaerobic metabolism and is moderately stable
to aerobic metabolism.  Due to its stability and high mobility,
clopyralid is likely to persist in groundwater.  Based on the available
information, OPP has determined that the residue of concern in drinking
water is the parent compound only.

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

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants	Primary Crop	Clopyralid	Clopyralid

	Rotational Crop	Clopyralid	Clopyralid

Livestock	Ruminant	Clopyralid + Glycine Conjugate	Clopyralid

	Poultry	Clopyralid + Glycine Conjugate	Clopyralid

Drinking Water	Clopyralid	Not Applicable

5.2	Analytical Methodology  TC \l2 "5.2	Analytical Methodology

An adequate gas chromatography/electron-capture detection (GC/ECD)
method (Method ACR 75.6) is available for enforcing the proposed
tolerances and collecting data on residues of clopyralid in Swiss chard,
blueberries and strawberries.  Residues are extracted with 0.5% NaOH and
centrifuged.  The resulting extract is acidified with HCl and salinized
with NaCl; the residues are then partitioned into ethyl ether.  Residues
are then methylated using diazomethane, concentrated to dryness,
re-dissolved in toluene, cleaned up using an activated Alumina A column,
and eluted with toluene.  The methylated residues are analyzed by GC/ECD
using external standards.  Residues are expressed in terms of parent
clopyralid using a conversion factor of 0.93.  The lowest level of
method validation (LLMV) for clopyralid in each commodity is 0.05 ppm.

5.3	Food Residue Profile  TC \l2 "5.3	Food Residue Profile

Adequate supervised crop field trials have been conducted to support
tolerances for clopyralid in/on swiss chard, bushberry, and strawberry.
The trials resulted in quantifiable residues of clopyralid in all three
crops, with maximum values of 1.9 ppm (swiss chard), 0.42 ppm
(blueberry), and 3.0 ppm (strawberry) at the 1X use rate.  Residue data
at the 0.5X use rate for Swiss chard and strawberry show a proportionate
relationship between application rate and residue levels.

5.3.1	Anticipated Residue and Percent Crop Treated (%CT) Information TC
\l3 "5.3.1 Anticipated Residue and Percent Crop Treated (%CT)
Information

This assessment is based on tolerance-level residues and assumes 100%
crop treated for all crops with registered or proposed uses on
clopyralid labels.

5.3.2	International Residue Limits TC \l3 "5.3.2	International Residue
Limits

There are no Codex or Mexican maximum residue limits (MRLs) for residues
of clopyralid in/on the requested commodities (Appendix I).  However,
there are Canadian MRLs for residues of clopyralid at 1.0 mg/kg on
strawberry and 0.1 mg/kg on blueberry.  The Canadian MRL for strawberry
harmonizes with the existing tolerance for strawberry.  Based on the
proposed use on strawberry and bushberries, and the available residue
data, the recommended tolerances on strawberry and bushberries (subgroup
13-07B) cannot be harmonized with the Canadian MRLs.

5.4	Drinking Water Residue Profile TC \l2 "5.4	Drinking Water Residue
Profile

The Environmental Fate and Effects Division (EFED) provided a Tier I
drinking water assessment that uses modeling and available monitoring
data to estimate the ground water and surface water concentrations of
pesticides in drinking water source water (pre-treatment) resulting from
clopyralid use on sites that are highly vulnerable (D361314, A. Shelby,
9 September 2009).  Of the requested uses, bushberry had the greatest
single application rate and was used to model estimated drinking water
concentrations (EDWCs) of clopyralid.  Non-crop uses of clopyralid have
greater application rates than those of bushberry and were also used to
obtain EDWCs (Table 5.4).  HED has used the maximum acute and chronic
EDWCs (45.0 and 11.9 ppb, respectively) from non-crop uses of clopyralid
in its dietary assessment.

Table 5.4.  Maximum Tier I Estimated Drinking Water Concentrations
(EDWCs) for drinking water assessment based on ground application of
Clopyralid.

Drinking Water Source (Model Used)	Use (Rate Modeled)	Maximum Estimated
Drinking Water Concentration (EDWC) (ppb)

Groundwater (SCIGROW)	Bushberry (0.25 lbs a.i./A)	Acute and Chronic	0.39

Groundwater (monitoring)	NAWQA, Alabama	Acute	13

Surface water (FIRST)

	Bushberry (0.25 lbs a.i./A)	Acute	41.1

	Bushberry (0.25 lbs a.i./A)	Chronic	10.8

	Non-crop (0.5 lbs a.i./ A)	Acute	45.0

	Non-crop (0.5 lbs a.i./ A)	Chronic	11.9

5.5	Dietary Exposure and Risk TC \l2 "5.5	Dietary Exposure and Risk

Acute and chronic combined dietary (food + drinking water) exposure and
risk assessments were conducted using the Dietary Exposure Evaluation
Model DEEM-FCID™, Version 2.03 which use food consumption data from
the U.S. Department of Agriculture’s Continuing Surveys of Food
Intakes by Individuals (CSFII) from 1994-1996 and 1998.

The acute and chronic assessments are highly conservative with regard to
protecting human health.  Both assessments assume 100% crop treated and
are based on tolerance-level residues for all commodities.  Modeled
estimates of clopyralid residues in drinking water have been
incorporated into the analyses.  Children 1-2 years old are estimated to
have the highest dietary exposure to clopyralid.  The screening-level
estimates for that subpopulation are 9% of the acute population-adjusted
dose (aPAD) and 23% of the chronic population-adjusted dose (cPAD).
Generally, HED is concerned about dietary risk when the exposure
estimate exceeds 100% of the PAD.  Therefore, the combined dietary risk
from residues of clopyralid in food and drinking water are below HED’s
level of concern for all population groups (Table 5.5).

Table 5.5.  Summary of the Combined Dietary (Food + Drinking Water)
Exposure and Risk Estimates for Clopyralid.

Population Subgroup	Acute (95th Percentile)	Chronic	Cancer

	Dietary Exposure (mg/kg/day)	% aPAD*	Dietary Exposure

(mg/kg/day)	% cPAD*	Dietary Exposure

(mg/kg/day)	Risk

General U.S. Population	0.035084	5	0.013212	9	N/A	N/A

All Infants (< 1 year old)	0.043768	6	0.012778	9

Children 1-2 years old	0.070616	9	0.035056	23

Children 3-5 years old	0.060428	8	0.031908	21

Children 6-12 years old	0.042390	6	0.021317	14

Youth 13-19 years old	0.025842	3	0.012669	8

Adults 20-49 years old	0.022783	3	0.010403	7

Adults 50+ years old	0.019576	3	0.008967	6

Females 13-49 years old	0.021362	3	0.009685	7

The % PAD values for the highest exposed population for each type of
risk assessment are bolded.

6.0	Residential (Non-Occupational) Exposure/Risk Characterization  TC
\l1 "6.0	Residential (Non-Occupational) Exposure/Risk Characterization

There are no new residential uses for clopyralid associated with the
subject petition and HED has used the previous residential exposure
estimates (D270507, W. G. Sproat, 26 September 2002) to assess
non-occupational risk as well as aggregate risk (Section 7).
Residential exposure and risk estimates from the 2002 assessment are
summarized below.  Note that risks via the dermal route of exposure are
not of concern for clopyralid; therefore, residential risks result
solely from incidental oral and inhalation exposures.

6.1	Residential Handler Exposure TC \l2 "6.1	Residential Handler
Exposure

Inhalation exposures were estimated for homeowners using push-type
granular spreaders, low-pressure hand sprayers and garden hose-end
sprayers.  The maximum exposure estimate from these scenarios is
0.000034 mg/kg/day (garden hose-end sprayers), with an associated MOE of
2.2×106.  The level of concern for residential risk is an MOE of less
than 100; therefore, the MOE for garden hose-end sprayers represents a
risk below HED’s level of concern.

6.2.	Residential Postapplication Exposure TC \l2 "6.2.	Residential
Postapplication Exposure

Short-term hand-to-mouth exposure of clopyralid by toddlers from turf
treated with Lontrel Turf and Ornamental (EPA Reg. No. 62719-305) at an
application rate of 0.5 lb ae/A amounted to 0.0075 mg/kg/day with an MOE
of 10,000.   Additionally, there is a potential for toddlers to ingest
granular formulations of clopyralid directly from treated turf.  The
incidental oral ingestion of granules from turf treated with Lawn
Fertilizer Plus Confront Weed Control (EPA Reg. No. 62719-263) resulted
in a dose of 0.024 mg/kg/day and a corresponding MOE of 3,100.  All of
these MOEs are greater than 100 and represent risks below HED’s level
of concern.  Note that due to the episodic nature of granule ingestion,
it is not appropriate to include this source of exposure in aggregate
assessments.

6.3	Other (Spray Drift, etc.) TC \l2 "6.3	Other (Spray Drift, etc.)

Spray drift is always a potential source of exposure to residents living
in close proximity to spraying operations.  This situation is
particularly the case with aerial application.  However, to a lesser
extent, spray drift resulting from the ground application of clopyralid
could also be a potential source of exposure.  The Agency has been
working with the Spray Drift Task Force (a membership of U.S. pesticide
registrants), EPA Regional Offices, State Lead Agencies for pesticide
regulation, and other parties to develop the best spray drift management
practices.  The Agency is now requiring interim mitigation measures for
aerial applications that must be placed on product labels/labeling.  The
Agency has completed its evaluation of the new database submitted by the
Spray Drift Task Force, and is developing a policy on how to apply
appropriately 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 risks associated with pesticide application.

7.0	Aggregate Risk Assessments and Risk Characterization  TC \l1 "7.0
Aggregate Risk Assessments and Risk Characterization

7.1	Acute Aggregate Risk TC \l2 "7.1	Acute Aggregate Risk

There are no non-dietary exposure scenarios appropriate for assessing
via an acute risk assessment; therefore, acute aggregate risk estimates
are equivalent to the acute dietary risk estimates discussed in Section
5.5 and are below HED’s level of concern.

7.2	Short- and Intermediate-Term Aggregate Risk TC \l2 "7.2	Short- and
Intermediate-Term Aggregate Risk

Residential risks associated with short-term exposures were discussed in
Section 6.  These residential exposures may coincide with dietary
exposure to clopyralid, resulting in aggregate exposure.  HED has
evaluated short- and intermediate-term aggregate risk by combining the
short- or intermediate-term MOEs for residential exposures with dietary
MOEs (based on chronic exposures from food plus water as measures of
background dietary exposure).  The aggregate MOEs are summarized in
Table 7.2 and represent risks that are below HED’s level of concern.

Table 7.2.  Summary of Short- and Intermediate-Term Aggregate Risks for
Clopyralid.

Population	NOAEL, mg/kg/day	LOC	Dietary Exposure, mg/kg/day	Dietary MOE
Residential

Activity	Residential

MOE	Aggregate MOE*

Short-Term

Adult Handler	75	100	0.013212	5,600	Application (Inhalation)	2,200,000
5,500

Children 1-2 years old	75	100	0.035056	2,100	Incidental Oral
(Hand-to-Mouth)	10,000	1,700

Intermediate-Term

Children 1-2 years old	15	100	0.035056	420	Incidental Oral
(Hand-to-Mouth)	5,800	390

* Aggregate MOE = 1÷ [(1÷MOEDietary) + (1÷MOEResidential)]

7.3	Long-Term Aggregate Risk TC \l2 "7.3	Long-Term Aggregate Risk

There are no non-dietary exposure scenarios appropriate for assessing
via a chronic risk assessment; therefore, chronic aggregate risk
estimates are equivalent to the chronic dietary risk estimates discussed
in Section 5.5 and are below HED’s level of concern.

7.4	Cancer Risk TC \l2 "7.4	Cancer Risk

Clopyralid has been classified as “Not Likely to be Carcinogenic to
Humans.”  Therefore, cancer risk is not a concern for this chemical.

8.0	Cumulative Risk Characterization/Assessment  TC \l1 "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 clopyralid and any other
substances and clopyralid 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 clopyralid 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  TC \l1 "9.0	Occupational
Exposure/Risk Pathway

An occupational risk assessment to address the requested uses of
clopyralid is being developed (D367967, S. Oonnithan, in preparation).
Based on the previous assessment (D270885, D. Dotson, 26 September
2002), in which occupational MOEs ranged from 17,000 to 470,000 assuming
baseline personal protective equipment (PPE), occupational risk
estimates are expected to be below HED’s level of concern.

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

10.1	Toxicology  TC \l2 "10.1	Toxicology

In order to satisfy recently revised pesticide registration data
requirements (40 CFR Part 158), the following toxicity studies are
required (see Appendix A3):

870.3465 – 28- or 90-Day Inhalation Toxicity

870.6200 – Acute and Subchronic Neurotoxicity

870.7800 – Immunotoxicity

10.2	Residue Chemistry  TC \l2 "10.2	Residue Chemistry

No data deficiencies were noted in the submission or in the residue
chemistry database for clopyralid.  Prior to registration, the label
should be modified to prohibit application of clopyralid to low-bush
varieties of bushberry.

The tolerance definition for clopyralid should be revised to read as
follows:

Tolerances are established for residues of the herbicide clopyralid,
including its metabolites and degradates, in or on the commodities in
the table below from its application in the acid form or in the form of
its salts.  Compliance with the tolerance levels specified below is to
be determined by measuring only clopyralid
[3,6-dichloro-2-pyridinecarboxylic acid] in or on the commodity.

HED is recommending that tolerances for residues of clopyralid be
established as summarized in Table 10.

Table 10.  Tolerance Summary for Clopyralid.

Commodity	Proposed/Existing Tolerance (ppm)	Recommended Tolerance (ppm)
Comments; Correct Commodity Definition

40 CFR §180.431(a)

Swiss Chard	5.0	3.0	Adequate field trial data are available.

Bushberry subgroup 13-07B	6.0	0.50	Adequate field trial data are
available*.

Cranberry 	4.0	4.0	The tolerance for cranberries should remain due to
differences in use pattern and residue level versus the currently
proposed use on bushberry.

Strawberry	4.0	4.0	Adequate field trial data are available to support a
7-day PHI for strawberries grown under an annual-type production system
in FL and NC only.  This tolerance will supersede the existing 1.0-ppm
tolerance already established for strawberry (grown under a perennial
production system).

* The Summary of Analytical Chemistry and Residue Data (D361787, M.
Doherty, 27 October 2009) recommends that the tolerance be for Subgroup
13-07B, except for low-growing varieties.  After further review, HED is
recommending that the tolerance be for residues in/on all of Subgroup
13-07B and has determined that label language prohibiting application to
low-growing varieties will be sufficient.

10.3	Occupational and Residential Exposure  TC \l2 "10.3	Occupational
and Residential Exposure

None.

References:  TC \l1 "References:

D270885, D. Dotson, 26 September 2002.  PP No. 4F4379: Human Health Risk
Assessment for Clopyralid Uses on garden beets, crambe, mustard seed,
rapeseed, cranberry, flax, canola, mustard greens, head and stem
brassica, hops, spinach, strawberries, turnips, stone fruit crop group,
sweet corn, and popcorn.

D361787, M. Doherty, 27 October 2009.  Clopyralid – Petition for
Tolerances on Swiss chard, Bushberry Subgroup 13-07B, and Strawberry
(Regional Restriction).  Summary of Analytical Chemistry and Residue
Data.  PP No. 8E7481.

D368855, M. Doherty, 27 October 2009.  Clopyralid – Acute and Chronic
Combined Dietary (Food + Drinking Water) Exposure and Risk Assessments.

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

A.1	Toxicology Data Requirements TC \l2 "A.1	Toxicology Data
Requirements

The requirements (40 CFR 158.340) for non-food use for clopyralid are
shown in Table A.1 and are based on the revised 40 CFR, Part 158
guidelines (March, 2009). Use of the new guideline numbers does not
imply that the new (1998) guideline protocols were used.

Test

	Technical

	Required	Satisfied

870.1100    Acute Oral Toxicity

870.1200    Acute Dermal Toxicity

870.1300    Acute Inhalation Toxicity

870.2400    Primary Eye Irritation

870.2500    Primary Dermal Irritation

870.2600    Dermal Sensitization		yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

yes

870.3100    Oral Subchronic (rodent)

870.3150    Oral Subchronic (nonrodent)

870.3200    21-Day Dermal

870.3250    90-Day Dermal

870.3465    28-Day Inhalation		yes

yes

yes

no

yes	yes

 yes1

yes

-

no

870.3700a  Developmental Toxicity (rodent)

870.3700b  Developmental Toxicity (nonrodent)

870.3800    Reproduction		yes

yes

yes	yes

yes

yes

870.4100a  Chronic Toxicity (rodent)

870.4100b  Chronic Toxicity (nonrodent)

870.4200a  Oncogenicity (rat)

870.4200b  Oncogenicity (mouse)

870.4300    Chronic/Oncogenicity		yes

yes

yes

yes

yes	 yes2

yes

 yes2

yes

yes

870.5100    Mutagenicity—Gene Mutation - bacterial

870.5300    Mutagenicity—Gene Mutation - mammalian

870.5300    Mutagenicity—Structural Chromosomal Aberrations

870.5550    Mutagenicity—Other Genotoxic Effects		yes

yes

yes

yes	 yes3

yes

yes

yes

870.6100a  Acute Delayed Neurotoxicity (hen)

870.6100b  90-Day Neurotoxicity (hen)

870.6200a  Acute Neurotoxicity Screening Battery (rat)

870.6200b  90-Day Neurotoxicity Screening Battery (rat)

870.6300    Develop. Neurotoxicity		no

no

yes

yes

no	-

-

no

no

-

870.7485    General Metabolism

870.7600    Dermal Penetration		yes

no	yes

-

870.7800     Immunotoxicity
………………………………………	yes	no

Special Studies for Ocular Effects

Acute Oral (rat)

Subchronic Oral (rat)

Six-month Oral (dog)

 no

 no

 no

   -

   -

   -

1  Satisfied by 870.4100 b, chronic dog

2  Satisfied by 870.4300, rat combined chronic toxicity/carcinogenicity

3  Satisfied by overall negative genotoxicity database including
host-mediated assay of S. typhimurium

A.2	Toxicity Profiles TC \l2 "A.2	Toxicity Profiles

Table A.2.a.  Acute Toxicity Profile for Clopyralid

Guideline Number	Study Type

Classification	MRID

Number	Results 	Toxicity Category

870.1100	Acute-oral-rat	41641301	  SEQ CHAPTER \h \r 1 LD50  SEQ CHAPTER
\h \r 1  (M/F) >5,000 mg/kg 	IV

870.1200	Acute-dermal-rat	41641302	LD50 (M/F) > 5000 mg/kg	IV

870.1300	Acute-inhalation-rat	41848300	LC50 (M/F) > 5mg/L	IV

870.2400	Acute-eye irritation-rabbit	41641304	Severe irritation at 7
days (corrosive)	I

870.2500	Acute-dermal irritation-rabbit	41641305	Not an irritant	IV

870.2600	  SEQ CHAPTER \h \r 1 Skin sensitization - guinea pig	41641306
Not a sensitizer	-

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

  SEQ CHAPTER \h \r 1 GDLN 	Study Type/ Classification	Dose Levels	MRID
Results

870.3100	13 Week Feeding-Mouse (1983)

Acceptable/Guideline	0, 200, 750, 2000, 5000 mg/kg/day

	00127276	NOAEL = 2000 mg/kg/day (M/F)

LOAEL = 5000 mg/kg/day (M/F), based on decreased body weight gain

870.3100	13 Week Feeding - Rat	No study available.  Requirement
satisfied by subchronic study in mouse (870.3100) and
chronic/carcinogenicity study in rat (870.4300)

870.3150	13 Week Capsule- Dog	No study available.  Requirement satisfied
by chronic dog study (870.3200b).

870.3200	21-day Dermal Toxicity – Rabbit (1990)

NOAEL ≥ 1000 mg/kg/day (limit dose)

LOAEL = not attained (>1000 mg/kg/day)

No local dermal irritation was observed

870.3465	28-Day Inhalation Toxicity - Rat	No study available.  Study
required under revised 40 CFR Part 158 Guidelines.

870.3700	Developmental Toxicity-Rat (gavage)

(1981)

Acceptable/guideline	0, 15, 75, 250 mg/kg/day	00127279

	Maternal NOAEL = 75 mg/kg/day

LOAEL = 250 mg/kg/day, based on mortality, reduced body weight gains and
reduced food consumption

Developmental NOAEL ≥ 250 mg/kg/day

LOAEL = not attained (>250 mg/kg/day).

870.3700	Developmental Toxicity-Rabbit (gavage) (1990)

Acceptable/Guideline	0, 15, 110, 250 mg/kg/day

	41649801, -02	Maternal NOAEL = 110 mg/kg/day

LOAEL = 250 mg/kg/day, based on mortality, decreased body weight gains
and food consumption and lesions in the gastric mucosa

Developmental NOAEL = 110 mg/kg/day

LOAEL = 250 mg/kg/day, based on decreased fetal body weight and
hydrocephalus

870.3800	2-Generation Reproduction-Rat (feeding) (1983)

Acceptable/Guideline

	0, 150, 500, 1500

mg/kg/day

	00138155

	Parental  NOAEL = 500 mg/kg/day

(M/F)

LOAEL = 1500 mg/kg/day(M/F), based on decreased body weights and body
weight gain in F0 and  F1 males; body weights in F1 and F2 females

Reproductive NOAEL ≥1500 mg/kg/day

LOAEL = not attained based on lack of effects on reproductive parameters
(>1500 mg/kg/day)

Offspring  NOAEL = 500 mg/kg/day (M/F)

LOAEL = 1500 mg/kg/day (M/F), based on decreased Day 28 body weights in
F1 male pups and increased relative liver weights of  F1a male and
female pups and F1b male pups.

870.4100 and 870.4200	104 Week Chronic Toxicity and 104 Week
Carcinogenicity in Rat, respectively	Requirement satisfied by 870.4300

870.4100	52 Week Capsule-Dog (1984)

Acceptable/Guideline 	0, 100, 320, 1000 mg/kg/day	00158256	NOAEL = 100
mg/kg/day (M/F):

LOAEL = 320 mg/kg/day (M/F), based on decreases in RBC parameters,
increased liver weight (males) and vacuolated adrenal cortical cells
(females).  Clinical chemistry changes (decreased serum albumin,
globulin, protein) and skin lesions observed at high dose.

870.4200	24-month Carcinogenicity – Mice (feeding) (1984)

Acceptable/Guideline	0, 100, 500, 2000 mg/kg/day

	00157783	NOAEL = 500 mg/kg/day (males); 2000 mg/kg/day (females)

LOAEL = 2000 mg/kg/day (males),

based on decreased body weight/weight gain and decreased food
efficiency.

No evidence of carcinogenicity

870.4300	104 Week Combined Chronic Toxicity/ Carcinogenicity-Rat
(feeding)

(1986)

Acceptable/Guideline	0, 15, 150 or 1500 mg/kg/day	00162393, 00162434
NOAEL = 15 mg/kg/day (M/F)

LOAEL = 150 mg/kg/day (M/F), based on gastric lesions (epithelial
hyperplasia and thickening of the limiting ridge).  At 1500 mg/kg/day,
decreased body weight gains and food consumption was observed.

No evidence of carcinogenicity

870.5100	Bacterial Reverse Mutation Assay	Study not submitted.  Not
required due to lack of tumorigenicity in rat/mouse bioassays and
negative findings in all other genotoxicity assays.

870.5300	In Vitro and In Vivo  Host Mediated Assay  (Salmonella  strains
TA 1530, G-46 and Saccharomyces strain D-3) (1973)

In vivo assays were conducted using mice

Acceptable/Guideline	In vitro testing:  without S9 activation at 5% w/v
solution

In vivo testing:  0, 4, 40 or 400 mg/kg by gavage to 10 mice	00057086

	Negative – no evidence of induced mutant colonies over background
levels in Salmonella or Saccharomyces strains tested in either the in
vitro or the in vivo assays.

870.5385	In Vivo Micronucleus assay, Rat (1973)

Acceptable/Guideline	0, 4, 40 or 400 mg/kg for one day or for 5 days to
male rats; sacrifice at 6, 24 or 48 hrs postdosing for all groups.
00073638

	Negative – no evidence of an increase in the formation of chromosomal
aberrations in bone marrow at any dose tested.

870.5450	Dominant Lethal Assay in Rats (1973)

Acceptable/Guideline	4, 40 or 400 mg/kg/day for 5 days to male rats
prior to mating	00059053, 00099100

	Negative – no evidence of treatment-related resorptions.

870.5550	Unscheduled DNA Synthesis, Rat Hepatocytes (1985, 1990)

Acceptable/Guideline	5 X 10-5, 1.56 X 10-4, 5 X 10-4, 1.56 X 10-3, 5 X
10-3, 1.56 X 10-2, 5 X 10-2 M, incubated for 18-20 hrs	00156387

41790702	Negative – no evidence of increased unscheduled DNA synthesis
in the initial or supplementary assays testing up to insoluble/toxic
concentrations.

870.6200	Acute Gavage Neurotoxicity- Rat	Study not submitted.  Required
under revised 40 CFR Part 158.

870.6200	Subchronic Dietary Neurotoxicity –Rat 	Study not submitted.
Required under revised 40 CFR Part 158.

870.7485	Metabolism – Rat

(1991)

Acceptable/Guideline	5.0 and 50 mg/kg, single oral doses; 5.0 mg/kg,
single IV dose and 5.0 mg/kg/day, repeated daily dose for 14 days
41790703	Clopyralid was rapidly and completely absorbed and eliminated,
with 95-115% of the total administered dose recovered by 72 hr, and most
of that within 6-12 hrs postdosing.  Almost all radioactivity was
eliminated via urine regardless of dose or route of administration
(91-113% of dose), with <4% excreted in the feces.  Tissue retention was
negligible (<0.01% of dose).  There was essentially no metabolism of
clopyralid; only parent compound was identified.  No significant gender,
dose or exposure route differences were identified.

870.7800	Immunotoxicity	Study not submitted.  Required under revised 40
CFR Part 158.

A.3	Rationale for Toxicology Data Requirements  TC \l2 "A.3	Rationale
for Toxicology Data Requirements

Table A.3.a Guideline Number: 870.3465

Study Title:   28- or 90-Day Inhalation Toxicity

Rationale for Requiring the Data

This study is required if there is the likelihood of significant
repeated inhalation exposure to the pesticide as a gas, vapor or
aerosol. The Agency has determined that there are potential inhalation
exposures to mixers, loaders and applicators, as well as potential
postapplication exposures, associated with clopyralid applications. The
inhalation study may potentially be shortened (i.e., 28-day exposure) as
appropriate to exposures from current use patterns.

Because toxicity via the inhalation route may differ from that observed
following oral dosing, the study is required to better assess potential
effects resulting from inhalation exposure and provide a refined
assessment of risk from inhalation exposure.

Practical Utility of the Data

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

In the absence of  inhalation toxicity studies on a pesticide, The
Agency estimates occupational risk from inhalation exposure by using the
most sensitive oral endpoint appropriate for a given exposure scenario.
To account for route-to-route extrapolation, 100% absorption is assumed.

How will the data be used?

An inhalation study may result in changes to the endpoints and how the
risks are quantified.  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.

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

The Agency does not have a full picture of the potential effects which
could occur as a result of exposure via the inhalation route.  In some
cases, toxicity observed via the inhalation route is higher than
toxicity observed via oral exposure, which means that route-to-route
extrapolation could result in an underestimation of risks from
inhalation.  The study may be used to confirm that no further mitigation
is needed for uses where inhalation exposure occurs.

Table A.3.b    Guideline Number:  870.6200

Study Title:  Acute & Subchronic Neurotoxicity

Rationale for Requiring the Data

The acute and subchronic neurotoxicity studies are 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 Neurotoxicity Test Guideline (OPPTS 870.6200) prescribes functional
and structural neurotoxicity testing and is designed to evaluate the
potential of a repeated chemical exposure to produce adverse effects on
the nervous system.  Although some information on neurotoxicity may be
obtained from standard guideline toxicity study data, studies not
specifically conducted to assess neurotoxic endpoints may be inadequate
to characterize a pesticide’s potential neurotoxicity.  While data on
clinical signs of toxicity or histopathology in routine chronic or
subchronic toxicity studies may offer useful information on potential
neurotoxic effects, these endpoints alone may be insufficient to detect
more subtle neurological effects.

Practical Utility of the Data

How will the data be used?

Neurotoxicity studies provide critical scientific information needed to
characterize potential hazard to the human population on the nervous
system from pesticide exposure.  Since epidemiologic data on the effects
of chemical exposures on neurologic parameters are limited and may be
inadequate to characterize a pesticide’s potential neurotoxicity 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.

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

If the neurotoxicity studies show 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 these data, a 10X database uncertainty
factor may be applied for conducting a risk assessment from the
available studies.

Table A.3.b Guideline Number:  870.7800

Study Title:  Immunotoxicity

Rationale for Requiring the Data

The immunotoxicity study 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?

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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 these data, a 10X database uncertainty
factor may be applied for conducting a risk assessment from the
available studies.

Page   PAGE  24  of   NUMPAGES  33


[Federal Register Volume 84, Number 136 (Tuesday, July 16, 2019)]
[Notices]
[Page 34044]
[FR Doc No: 2019-15041]

=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF TRANSPORTATION

NextGen Advisory Committee (NAC); Notice of Public Meeting

AGENCY: Federal Aviation Administration (FAA), Department of
Transportation.

ACTION: Notice of public meeting.

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

SUMMARY: This notice announces a meeting of the NextGen Advisory
Committee (NAC).

DATES: The meeting will be held on July 30, 2019, from 9 to 12:30 p.m.
EDT.
    Requests for accommodations to a disability must be received by
July 16, 2019.
    Requests to speak during the meeting must submit a written copy of
their remarks to FAA by 4:00 p.m. on July 16, 2019.
    Requests to submit written materials to be reviewed during the
meeting must be received no later than 4:00 p.m. on July 16, 2019.

ADDRESSES: The meeting will be held at The MITRE Corporation, MITRE 1
Building Conference Center: 7525 Colshire Drive, McLean, VA 22102.
Copies of the meeting minutes will be available on the NAC internet
website at https://www.faa.gov/about/office_org/headquarters_offices/ang/nac/. Any committee related request should be sent to the person
listed in the following section.

FOR FURTHER INFORMATION CONTACT: Greg Schwab, NAC Coordinator, U.S.
Department of Transportation, at<EMAIL_ADDRESS>or 202-267-
1201. Also, visit the NAC website at https://www.faa.gov/about/office_org/headquarters_offices/ang/nac/.

SUPPLEMENTARY INFORMATION:

I. Background

    The NAC was created under the Federal Advisory Committee Act
(FACA), in accordance with the provisions of the FACA as amended,
Public Law 92-463, 5 U.S.C. App to provide independent advice and
recommendations to the FAA and to respond to specific taskings received
directly from the FAA. The NAC recommends consensus-driven standards
for FAA consideration relating to Air Traffic Management System
modernization.

II. Agenda

    At the July 30, 2019, meeting, the agenda will cover the following
topics:

 Official Statement of Designated Federal Official
 NAC Chairman's Report
 FAA Report
[cir] FAA Reauthorization
 NAC Subcommittee Chairman's Report
[cir] NAC NextGen Priority Focus Area Updates
 Domestic ADS-B Out Equipage Status Update
 Recommendations
 NAC Chairman Closing Comments

    A final agenda will be posted on the NAC website at https://www.faa.gov/about/office_org/headquarters_offices/ang/nac/ at least one
week in advance of the meeting.

III. Public Participation

    The meeting will be open to the public on a first come, first
served basis, as space is limited. Members of the public who wish to
attend in-person are asked to register via email by submitting your
full legal name, country of citizenship, and name of your industry
exception occurred on : 2019-15041.htm
exception occurred on : 2019-15041.htm
association, or applicable affiliation, to solutions.com">[email protected]solutions.com by July 10, 2019. For Foreign National attendees, please
also provide your company/organization country.
    Individuals requesting accessibility accommodations, such as sign
language, interpretation, or other ancillary aids, may do so by
contacting the person listed under the heading FOR FURTHER INFORMATION
CONTACT by July 10, 2019.
    Five (5) minutes total time will be allotted during the meeting for
all oral comments from members of the public in attendance. To
accommodate as many speakers as possible, the time for each commenter
may be limited. Individuals wishing to reserve speaking time during the
meeting must submit a request at the time of registration. If the
number of registrants requesting to make statements is greater than can
be reasonably accommodated during the meeting, the FAA may conduct a
lottery to determine the speakers. Speakers are requested to submit a
written copy of their prepared remarks for inclusion in the meeting
records and for circulation to NAC members. All prepared remarks
submitted on time will be considered as part of the record.
    Persons who wish to only submit written comments to the NAC may do
so. All written comments submitted on time will be reviewed and
considered for inclusion as part of the record. Comments received after
the due date and time will be distributed to the members but may not be
reviewed prior to the meeting.
    Copies of the meeting minutes will be available on the NAC website
at https://www.faa.gov/about/office_org/headquarters_offices/ang/nac/.

    Dated: July 11, 2019.
Tiffany Ottilia McCoy,
General Engineer, NextGen Office of Collaboration and Messaging, ANG-M,
Office of the Assistant Administrator for NextGen, Federal Aviation
Administration.
[FR Doc. 2019-15041 Filed 7-15-19; 8:45 am]
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