 

<EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  >

<EPA Registration Division contact: Laura Nollen (703) 305-7390>

 

<Interregional Research Project Number 4 (IR-4) >

<Petition Number 8E7481>

<	EPA has received a pesticide petition (PP# 8E7481) from Interregional
Research Project Number 4 (IR-4), Rutgers, The State University of NJ,
500 College Road East, Suite 201 W, Princeton, NJ 08540 proposing,
pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act
(FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.431 (a) by
establishing a tolerance for residues of clopyralid,
(3,6-dichloro-2-pyridinecarboxylic acid), in or on the raw agricultural
commodity swiss chard at 5.0 parts per million (ppm), bushberry subgroup
13-07B at 6.0 ppm and to amend 40 CFR part 180.431(c) by establishing a
tolerance with regional restrictions for residues of clopyralid in or on
the raw agricultural commodity strawberry at 4.0 ppm.  EPA has
determined that the petition contains data or information regarding the
elements set forth in section 408 (d)(2) of  FFDCA; however, EPA has not
fully evaluated the sufficiency of the submitted data at this time or
whether the data supports granting of the petition. Additional data may
be needed before EPA rules on the petition.>

<A. Residue Chemistry>

<	1. Plant metabolism. The Agency has previously concluded that the
nature of the residue in plants and animals is adequately understood. 
Additionally the Agency has determined that tolerances should be
comprised of the parent compound only as no metabolites of toxicological
significance were detected in metabolism studies.>

<	2. Analytical method. An adequate residue analytical method is
available for enforcement of the tolerances listed below.  This method
determines clopyralid as the methyl ester by gas chromatography using
electron capture detection. This method has been successfully validated
by EPA and has been published in FDA’s Pesticide Analytical Manual,
Volume II (PAM II).>

<	3. Magnitude of residues. Swiss chard: IR-4 has received requests from
the states of Georgia, Michigan, New Jersey, New York, Oklahoma, Texas,
and Washington for the use of clopyralid on Swiss chard.  To support
these requests, a total of eight crop field trials on Swiss chard were
conducted encompassing NAFTA Region 1 (NY, two trials at one site),
Region 2 (NJ, two trials at one site), and Region 11 (WA, four trials at
two sites) during the 2002 growing season.

At each test location, side-by-side plots established in Swiss chard
received one broadcast foliar application of clopyralid (3 lb/gal SL) at
rates of 0.093-0.103 lb ae/A (Treatment 02, low rate, 0.10-0.12 kg
ae/ha) or 0.188-0.199 lb ae/A (Treatment 03, high rate, 0.21-0.22 kg
ae/ha).  The applications were made in a spray volume of 16-34 gal/A
(150-318 L/ha of water), and did not include an adjuvant in the spray
mixture.  Swiss chard RAC samples (petioles) were harvested at
commercial maturity, 28 or 29 days after treatment (DAT).

The lowest level of method validation (LLMV) for residues of clopyralid
in/on Swiss chard petioles was 0.05 ppm.  For clopyralid in/on Swiss
chard, the calculated limits of detection (LOD) and quantitation (LOQ)
were 0.024 and 0.073 ppm, respectively.

The maximum storage interval of Swiss chard samples from harvest to
analysis was 91 days (3 months).  Adequate storage stability data for
clopyralid are available to support the storage conditions and intervals
of samples from the field trials on Swiss chard.

The results from these trials show that residues of clopyralid were
0.05-0.70 ppm and <0.05-1.9 ppm, respectively, in/on Swiss chard RAC
samples (petioles) harvested 28-29 days after one broadcast foliar
application of clopyralid (3 lb/gal SL) at rates of 0.093-0.103 lb ae/A
(low rate, n=8) or 0.188-0.199 lb ae/A (high rate, n=8).

Blueberry: IR-4 has received requests from Michigan, Minnesota, North
Carolina, and Washington for the use of clopyralid on blueberry.  To
support this requested use, magnitude of residue data were collected
from nine field trials.  Each field trial site consisted of one
untreated control plot and one treated plot.  Common cultural practices
were followed to maintain the crop.  At each trial, two applications of
the test substance 12-15 days apart were made to the treated plots.  (In
the Oregon and North Carolina trials, the retreatment intervals were 18
and 21 days, respectively.)  The protocol required that the applications
be directed to the soil extending from the plants to the row middle,
without allowing the spray solution to contact the foliage or woody
portions of the blueberry bushes.  In the North Carolina trial, the
spray solution did contact the base of the bushes; the application
method in this trial simulated the actual grower technique in the
region.  The Maine trial was conducted on lowbush blueberry, which is
the dominant type of blueberry grown in Maine and which is grown in
solid plantings, without rows and row spacing.  The application rates
ranged from 0.240 to 0.264 lb ai/A per application for a total rate
range of 0.483 to 0.525 lb ai/A per season.  All applications were made
using appropriate spray equipment, and the spray volume was sufficient
to provide adequate dispersal of the test substance. 

The LOD for the method was calculated to be 0.017427793 ppm and the LOQ
was calculated to be 0.05228338 ppm, using the method described in
Roy-Keith Smith’s Handbook of Environmental Analysis, 4th Edition. 
The lowest level of method validation (LLMV) for blueberry was 0.050 ppm
for clopyralid.  

The total residues of clopyralid ranged from <0.050 ppm to 5.8 ppm in
samples taken at 27-33 days PHI.  The samples with the highest residues
were lowbush blueberries from Maine.  Among highbush blueberry samples,
the highest residue was 0.42 ppm.  The untreated samples from trial MI16
were found to have apparent residues of clopyralid at levels similar to
the treated samples from that trial; an additional trial was conducted
in Michigan the following year.  The storage interval for field-treated
samples in this study ranged from 41 days to 132 days.  No storage
stability fortifications were conducted in this study.

Strawberry: IR-4 has received a request from the state Florida for the
use of clopyralid on strawberries.  To support this request, a total of 
3 crop field trials on strawberries were conducted encompassing NAFTA
Region 2 (NC, one trial), Region 3 (FL, two  trials) during the 2002
growing season.

At each test location, side-by-side plots established in strawberries
received one broadcast foliar application of clopyralid (3 lb/gal SL) at
rates of 0.119-0.125 lb ae/A (Treatment 02, low rate, 0.133-0.140 kg
ae/ha) or 0.246-0.255 lb ae/A (Treatment 03, high rate, 0.276-0.286 kg
ae/ha).  The applications were made in a spray volume of 29-35 gal/A
(271-327 L/ha of water), and did not include an adjuvant in the spray
mixture.  Strawberry RAC samples (berries) were harvested at commercial
maturity, 7 or 8 days after treatment (DAT).

The lowest level of method validation (LLMV) for residues of clopyralid
in/on strawberries was 0.05 ppm.  For clopyralid in/on strawberries, the
analytical laboratory reported the limits of detection (LOD) and
quantitation (LOQ) as 0.0032 and 0.0095 ppm, respectively.  No example
calculation was provided.  Using the calculation method described in
Roy-Keith Smith's Handbook of Environmental Analysis, Fourth Edition,
Genium Publishing Corporation, the LOD and LOQ were calculated by the
final study report author as 0.0224 and 0.0673 ppm, respectively.  

The maximum storage interval of strawberries samples from harvest to
analysis was 99 days (3 months).  Adequate storage stability data for
clopyralid are available to support the storage conditions and intervals
of samples from the field trials on strawberries.

The results from these trials show that residues of clopyralid were
0.79-1.8 ppm and 1.6-3.0 ppm, respectively, in/on strawberries RAC
samples harvested 7 or 8 days after one broadcast foliar application of
clopyralid (3 lb/gal SL) at rates of 0.119-0.125 lb ae/A (low rate, n=6)
or 0.246-0.255 lb ae/A (high rate, n=6).>

<B. Toxicological Profile>

<	1. Acute toxicity.  For acute risk assessments, EPA has established an
acute reference dose (aRfD) of 0.75 mg/kg/day for all population
sub-groups including infants and children.  The aRfD is based on the
developmental toxicity study on rats with a NOAEL of 75 mg/kg/day and
uncertainty factor of 100 accounting for both interspecies extrapolation
(10x) and intraspecies variability (10x).  A decrease in weight gain was
observed during gestation of 6-9 days at a maternal LOAEL of 250
mg/kg/day.  EPA determined that an additional factor to protect infants
and children was not appropriate.>  

Clopyralid has low acute toxicity.  The rat oral LD50 is 5,000 mg/kg or
greater for males and females.  The rabbit dermal LD50 is >2,000 mg/kg
and the rat inhalation LC50 is >1.0 mg/L air (the highest attainable
concentration).  In addition, clopyralid is not a skin sensitizer in
guinea pigs and is not a dermal irritant in rabbits.  Technical
clopyralid is an ocular irritant, but ocular exposure to the technical
material would not normally be expected to occur to infants or children
or the general public. End use formulations of clopyralid have similar
low acute toxicity profiles and most have low ocular toxicity as well.

<2. Genotoxicty. Clopyralid is not genotoxic. The following in vitro and
in vivo studies have been conducted and all were negative for genotoxic
responses:  Ames bacterial mutagenicity assay (with and without
exogenous metabolic activation); Host-Mediated assay In vivo cytogenetic
test, rat; In vivo cytogenetic test, mouse; In vivo dominant lethal
test, rat; In vitro unscheduled DNA synthesis assay in primary rat
hepatocyte cultures; In vitro mammalian cell gene mutations assay in
Chinese hamster ovary cell cultures (with and without exogenous
metabolic activation).>

<	3. Reproductive and developmental toxicity. Developmental toxicity was
studied using rats and rabbits.  The developmental study in rats
resulted in a developmental NOEL of >250 mg/kg/day (a maternally toxic
dose) and a maternal toxicity NOEL of 75 mg/kg/day.  A 1974 study in
rabbits revealed no evidence of developmental or maternal toxicity at
250 mg/kg/day; thus, the developmental and maternal NOEL was >250
mg/kg/day.  A more recent study in rabbits (1990) resulted in
developmental and maternal NOELs of 110 mg/kg/day based on maternal
toxicity at 250 mg/kg/day.  Based on all of the data for clopyralid,
there is no evidence of developmental toxicity at dose levels that do
not result in maternal toxicity.  In a 2-generation reproduction study
in rats, pups from the high dose group which were fed diets containing
clopyralid had a slight reduction in body weight during lactation and an
increase in liver weights in F1a and F1b weanlings.  The NOEL for
parental systemic toxicity was 500 mg/kg/day.  There was no effect on
reproductive parameters at >1,500 mg/kg/day nor was there an adverse
effect on the morphology, growth or viability of the offspring; thus,
the reproductive NOEL is >1,500 mg/kg/day.>

<	4. Subchronic toxicity. The following studies have been conducted
using clopyralid.  In a rat 90-day feeding study, Fischer 344 rats were
fed diets containing clopyralid at doses of 5, 15, 50 or 150 mg/kg/day
with no adverse effects attributed to treatment.  In a second study,
Fischer 344 rats were fed diets containing clopyralid at doses of 300,
1,500 and 2,500 mg/kg/day.  Effects at the highest doses were decreased
food consumption accompanied by decreased body weights and weight gains
in both males and females.  Slightly increased mean relative liver and
kidney weights were noted in males of all doses and in females at the
top 2 doses.  Because there were no other effects, the kidney and liver
weight effects were judged as being adaptive rather than directly toxic.
 The no-observed-adverse-effect level (NOAEL) was 1,500 mg/kg/day for
males and females.  The no-observed-effect level (NOEL) was 300
mg/kg/day for females.  In a mouse 90-day feeding study, B6C3F1 mice
were fed diets containing clopyralid at doses of 200, 750, 2,000 or
5,000 mg/kg/day.  A slight decrease in body weight occurred at the top
dose in both sexes.  The liver was identified as the target organ based
on slight increases in liver weights and minimal microscopic alterations
at the higher dose levels.  The liver changes were considered to be
reversible and adaptive.  The NOEL for males was 2,000 mg/kg/day and for
females was 750 mg/kg/day.  In a 180-day feeding study, beagle dogs were
fed diets containing clopyralid at doses of 15, 50 or 150 mg/kg/day;
there were no adverse effects.  In a second dietary study, dogs also
were fed diets containing clopyralid at doses of 15, 50 or 150
mg/kg/day; the only effect was an increase in the mean relative liver
weight in females at the 150 mg/kg/day.  In a 21-day dermal study,
clopyralid was applied by repeated dermal application to New Zealand
White rabbits at dose levels up to 1,000 mg/kg/day.  Treatment produced
no systemic effects.]>

<5. Chronic toxicity. For chronic dietary risk assessments, EPA has
established a chronic reference dose (cRfD) of 0.15 mg/kg/day for all
population sub-groups.  The cRfD is based on the 2-year combined chronic
feeding-carcinogencity study in rats with a NOAEL of 15 mg/kg/day  and
uncertainty factor of 100 accounting for both interspecies extrapolation
(10x) and intraspecies variability (10x).  An increase in epithelial
hyperplasia and thickening of the limiting ridge of the stomach was
observed in both sexes with a LOAEL of 150 mg/kg/day.  No tumorigenic
response was present.  EPA determined that an additional factor to
protect infants and children was not appropriate. 

Clopyralid has been classified as “not likely” to be a human
carcinogen based on no evidence of carcinogencity in rats and mice and
no evidence of genotoxicity in an acceptable mutagenicity studies. 
Thus, an exposure assessment to address cancer risk is not required.>

<	6. Animal metabolism. Disposition and metabolism of clopyralid were
tested in male and female rats at a dose of 5 mg/kg (oral).  The
majority of a radioactive dose was excreted in 24 hours of all dose
groups through urine.  Fecal elimination was minor.  Detectable levels
of residual radioactivity were observed in the carcass and stomach at 72
hours post-dose.  HPLC and TLC analysis of urine and fecal extracts
showed no apparent metabolism of clopyralid. 

Following oral administration, clopyralid was rapidly and completely
eliminated from goats, chickens and sheep.  In goats and sheep, the
majority of the administered dose was excreted in the urine.  This
residue was found to be mostly unchanged clopyralid, and in goats, the
remainder was found to be a glycine conjugate of clopyralid.  Residues
in milk were low, reaching a plateau of 0.03-0.05 mg/kg after 3-4 days. 
Radioactivity levels in milk fat were below the limit of detection,
indicating that there is no tendency for clopyralid to accumulate in
milk fat.   Tissue residue levels were also low and comprised unchanged
clopyralid only.  The residues in the eggs and chicken tissues were
unchanged clopyralid.  Based on the ruminant and poultry nature of
residue (NOR) studies, the residue definition for animal tissue is
clopyralid, the parent compound. 

In animal feeding studies, calves fed clopyralid at levels as high as
1,000 ppm showed no ill, effects due to ingestion of the chemical. 
Additionally, no difference is observed between the control and treated
groups in weight gain and feed consumption. After withdrawal from
treated feed, residues in all tissues diminished rapidly from the levels
found after feeding clopyralid at 1,000 ppm for 28 days. At the levels
of herbicide that would be expected in grains used at cattle feed, no
residues would occur above the 0.05 ppm level.>

<7. Metabolite toxicology. Following oral administration in the rat,
clopyralid was rapidly and completely (>80%) absorbed and excreted
quantitatively unchanged in the urine.  There were no differences in
distribution of radioactivity between dose rates, sex, route (oral vs.
iv) or frequency of administration.  Clopyralid was not metabolized in
the rat. The Residue of Concern (ROC) in plant and animal products is
the parent compound, clopyralid.>

<8. Endocrine disruption. There is no evidence to suggest that
clopyralid has an effect on the endocrine system.>

<C. Aggregate Exposure>

<	1. Dietary exposure. Dietary exposure to US-general population and
sensitive population subgroups was assessed from all clopyralid
currently listed uses, plus the newly proposed use on Swiss chard,
Bushberry Subgroup 13-07B and Strawberry.  Water from direct and
indirect exposure was also included in the dietary exposure and risk
assessment.>

<i. Food. Tolerances are established for residues of the herbicide,
clopyralid (3,6-dichloro-2-pyridinecarboxylic acid) in or on the raw
agricultural commodities and are published in 40 CFR Section 180.431.
Parent clopyralid, only, is the residue definition in animal and plant
commodities.  Tolerances have been proposed for the residues of
clopyralid in or on Swiss chard at 5 parts per million (ppm), Bushberry
Subgroup 13-07B at 6 parts per million (ppm), Strawberry at 4 parts per
million (ppm).  These proposed tolerances are adequate to cover the
highest expected field residues from the labeled use of clopyralid.  

In conducting the acute and chronic dietary assessments, Dow
AgroSciences used the Dietary Exposure Evaluation Model software with
the Food Commodity Intake Database (DEEM-FCID, Version 2.14) which
incorporates food consumption data as reported in the CSFII Survey
1994-1996 and 1998.  A conservative analysis (Tier 1) was performed with
the assumptions that 100% of crops with approved and proposed uses of
clopyralid would be treated with the pesticide and that the residues
would be present at the tolerance levels.

Based on these conservative assumptions and using an aRfD of 0.75
mg/kg/day, for the U.S. general population, the Tier I acute dietary
exposure at the 95th percentile from food to clopyralid was estimated to
be 0.033 mg/kg/day, or 4.5% of the aRfD for the U.S. population; and
0.069 mg/kg/day, which represents 9.2% of the aRfD for children (1-2
years), the population sub-group predicted to be potentially most
exposed. Adverse effects are not expected for exposures utilizing <100%
of the aRfD, therefore, acute dietary exposure and risk for the general
U.S. population and children are well within the acceptable levels. 

Based on these conservative assumptions and using an cRfD of 0.15
mg/kg/day, for the U.S. general population, the Tier I chronic dietary
exposure from food to clopyralid was estimated to be 0.013 mg/kg/day, or
8.5% of the cRfD for the U.S. population; and 0.035 mg/kg/day , or 23.2%
of the cRfD for children (1-2 years), the population sub-group predicted
to be potentially most exposed. Adverse effects are not expected for
exposures utilizing <100% of the aRfD, therefore, chronic dietary
exposure and risk for the general U.S. population and children are well
within the acceptable levels.>

<	ii. Drinking water. Since the Agency lacks sufficient monitoring data
to complete a comprehensive exposure and risk assessment for florasulam
in drinking water, drinking water concentration estimates are made on
simulation taking into account data on the physical characteristics of
clopyralid.  

Guidance from EPA has indicated that Tier 1 screening level models, such
as FIRST (FQPA Index Reservoir Screening Tool), and SCI-GROW, maybe used
to estimate upper-bound pesticide residues in surface water and ground
water when assessing potential exposure through drinking water. 

FIRST is an extremely conservative estimate for predicting surface water
concentrations, and considers adsorption of the pesticide to soil or
sediment, incorporation of the pesticide at application, direct
deposition of spray drift into the water body, and degradation of the
pesticide in soil before runoff and within the water body.  

In an assessment published in Federal Register, Vol. 67, No. 186,
September 25, 2002, FRL-7198-4), EPA used FIRST and SCI-GROW models to
estimate the environmental concentration (EEC) for surface water and
ground water, respectively. The EECs of clopyralid estimated by EPA for
ground water is 9.7 parts per billion (ppb) for both acute and chronic
exposures.  The EECs for surface water were estimated to be 46 ppb for
acute exposure and 18 ppb for chronic exposure.

Estimated environmental concentrations (EEC) of pesticide in surface
water were then inputted into DEEM model for estimation of dietary
exposure from water both direct and indirect sources. The input of water
residues along with food into the DEEM model provides a conservative
estimate of the total exposure from food and water sources.

When water exposure was aggregated with food, acute dietary exposure was
9.5% of the aRfD for children 1-2 years, the most highly exposed
population sub-group. Additionally, chronic dietary exposure was 23.6%
of the cRfD for children 1-2 years, the most highly exposed population
sub-group. Therefore, aggregate exposure to clopyralid in drinking water
would not result in unacceptable levels of human health risk.>

<	2. Non-dietary exposure. Clopyralid is no longer registered for
residential turf uses that would result in residential exposure.  Thus,
the risk from non-dietary exposure is considered negligible.>

<D. Cumulative Effects>

<Currently, no methodologies are available to resolve the complex
scientific issues concerning common mechanism of toxicity and cumulative
exposure and risk. The U.S. EPA has begun a pilot process to study this
issue further through the examination of particular classes of
pesticides. Unlike other pesticides for which EPA has followed a
cumulative risk approach based on a common mechanism of toxicity,
clopyralid does not appear to produce a toxic metabolite produced by
other substances. For the purposes of this notice, therefore, EPA has
not assumed that clopyralid has a common mechanism of toxicity with
other substances. As such, Dow AgroSciences believes it is appropriate
to consider only the potential risks of clopyralid in this exposure
assessment.>

<E. Safety Determination>

<1. U.S. population. Using the conservative exposure assumptions
described above, and based on  the completeness and reliability of the
toxicity data, the aggregate exposure (food and water only) to
clopyralid, as determined under the guidance of the FQPA, will utilize <
5 % of the aRfD and < 9% of the cRfD from the dietary exposure for the
U.S. population.  The calculated exposure was greatest from water as
estimated by FIRST surface water modeling. Generally, and under the
FQPA, the U.S. EPA has no concern for exposures below 100% of the aRfD. 
Therefore, there is a reasonable certainty that no harm will result to
the general U.S. population from aggregate exposure to clopyralid
residues from the approved and proposed uses.>

<	2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of clopyralid, data from
developmental toxicity studies in rats and rabbits and a
multi-generation reproduction study in the rat are considered.  The
developmental toxicity studies are designed to evaluate adverse effects
on the developing organism resulting from pesticide exposure during
prenatal development.  Reproduction studies provide information relating
to effects from exposure of both parents to the pesticide on the
reproductive capability and potential systemic toxicity of mating
animals and on various parameters associated with the well being of
offspring.   There was no effect on reproductive parameters at >1,500
mg/kg/day nor was there an adverse effect on the morphology, growth or
viability of the offspring.  

FFDCA section 408 provides that the U.S. EPA may apply an additional
safety factor for infants and children in the case of threshold effects
to account for pre- and post-natal toxicity and the completeness of the
database.  Based on the current toxicological data requirements, the
database for clopyralid relative to pre- and post-natal effects for
children is complete.

The EPA determined that an additional FQPA factor to protect infants and
children is not required for clopyralid as there is no indication of
increased sensitivity of infants and children relative to adults.

Thus, based on the completeness and reliability of the toxicity data and
the conservative exposure assessment, the aggregate exposure (food and
water only) to clopyralid, as determined under the guidance of the FQPA,
will utilize <10% of the aRfD and <24% of the cRfD from the dietary
exposure for the most sensitive population sub-group, children 1-2 years
old. It is concluded then that there is a reasonable certainty that no
harm will result to infants and children from acute- and chronic-term
aggregate exposures to clopyralid residues from the approved and
proposed uses.>

<F. International Tolerances>

<	There are no Codex or Mexican maximum residue limits (MRLs).

Canada has set maximum residue limits of 2.0 ppm for barley, oats, and
wheat, 7.0 ppm for the milled fractions of barley, oats, and wheat
(excluding flour), 1.0 ppm for strawberries and 0.2 ppm for flax.>

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