Document ID: EPA-HQ-OPP-2007-0350-0170
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-07-16T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

	

B OFFICE OF PREVENTION,

 PESTICIDES AND

TOXIC SUBSTANCES

				June 18, 2008

MEMORANDUM

SUBJECT:	RESPONSE TO PUBLIC COMMENTS.  The Health Effects Division’s
Response to Comments on the Agency’s April 12, 2007 document,
Chloropicrin: Revised HED Human Health Risk Assessment for Phase 5
(Docket EPA-HQ-OPP-2007-0350).  

PC Code:  081501	DP Barcode: 348676

MRID No.:  NA	Registration No.: NA

Petition No.: NA	Regulatory Action: Reregistration

Eligibility Decisions (Phase VI)

Assessment Type: Single Chemical/ Non-food	Reregistration Case No.: 0040

TXR No.:  NA	CAS No.:  76-06-2

FROM:	Elissa Reaves, Ph.D., Toxicologist/Risk Assessor

		Charles Smith, Environmental Scientist/Risk Assessor

Reregistration Branch II

Health Effects Division (7509P)

THRU:	Felecia Fort, Branch Chief

Reregistration Branch II

Health Effects Division (7509P)

TO:		Andrea Carone, Chemical Review Manager

		Special Review Branch

		Special Review & Reregistration Division (7508P)

The attached document was generated in Phase 6 of the Public
Participation Process to address comments submitted by a variety of
stakeholders including: the Chloropicrin Manufacturers’ Task Force
(CMTF) and the Pesticide Action Network North America (PANNA).  The
comments were submitted following the publication of the Agency’s
Phase 5 Revised Human Health Risk Assessment document for chloropicrin
in the Federal Register May 2, 2007.  The attached document is the
Agency’s response to those comments.TABLE OF CONTENTS

 TOC \f 

I.  Introduction	Page 4 of  10

II.  Toxicology	Page 4 of  10

III.  Occupational and Residential Exposures	Page 8 of  10

 

EPA’S RESPONSE TO COMMENTS FOR CHLOROPICRIN

I.  Introduction tc \l1 "I.  Introduction 

The following is EPA’s response to comments on the Phase 5 Revised
Human Health Risk Assessment document for chloropicrin.  This document
was generated in response to the comments submitted to the public docket
by the registrant and environmental advocacy groups.  Issues related to
the availability/efficacy of substitute pesticides, the environmental
fate and persistence of chloropicrin, and possible mitigation of
chloropicrin raised in the comments will be addressed in separate
documents by the appropriate divisions; the Biological and Economics
Assessment Division (BEAD), the Ecological Fate and Effects Division
(EFED), and the Special Review and Reregistration Division (SRRD),
respectively. 

II.  Toxicology tc \l1 "II.  Toxicology 

Toxicology Comments from PANNA

The HED appreciates the comments submitted by PANNA and they have been
considered.  The response to each question is addressed below.

PANNA Comment 1: PANNA believes that EPA inappropriately removed the
intraspecies uncertainty factor in the revised chloropicrin risk
assessment because variability among healthy human test subjects in the
chloropicrin human eye irritation study is high.

EPA Response:  

The Agency has relied on three key guidance/framework documents for
consideration of mode of action and refinement of the intraspecies
factor for chloropicrin.  These guidance and framework documents which
focus on mode of action and kinetic and mechanistic data to refine
inter-species and intra-species extrapolation factors have been outlined
in a chloropicrin memo (D293356, 06/18/08).  This memorandum considered
toxicokinetics, dynamics and mode of action as well as the level at
which individuals in the population detect and become irritated to
chloropicrin.  All of this information was considered in the refinement
of the intraspecies factor.  The BMCL10 or NOAEL of 73 ppb is protective
of all individuals without an inclusion of intraspecies factor since it
is 2-fold below a level that the most sensitive subpopulation was
beginning to detect chloropicrin without direct irritation (150 ppb). 
The point of departure (0.073 ppm) is 145-fold lower than the acute
rodent inhalation study (10.6 ppm), 14-fold lower than irritation
produced in repeat inhalation rodent studies (1.0 ppm) and 14-fold lower
than acute eye and respiratory effects observed in incident reports (1.0
ppm).

PANNA Comment 2: PANNA believes that EPA inappropriately removed the
intraspecies uncertainty factor in the revised chloropicrin risk
assessment based on a number of scientific weaknesses that the EPA Human
Subjects Review Board (HSRB) identified with the chloropicrin human
study during their review.  The most problematic weaknesses included the
following:

In Phase III, no lower doses were tested—in spite of the low-dose
responses in Phase II—and no NOAEL could be determined.  Additionally,
there was no correspondence between the doses used in Phase II and Phase
III.

The concentrations and durations explored in each of the three Phases of
this study failed to identify a level at which none of the subjects
responded to either irritation or odor of chloropicrin.

Lack of confidence intervals for the data.

The study did not include the most-sensitive individuals who are part of
the potential bystander population. Only subjects who reported, inter
alia, no smoking within a year, no use of recreational drugs within a
year, no recent illness, and no history of chronic illness qualified to
go on to screening in the laboratory.

EPA Response:  

Again the refinement of the intraspecies factor is outlined in a mode of
action chloropicrin memorandum (D293356, 06/18/08).  This memo outlines
the three key guidance/framework documents for consideration of
uncertainty factors.  The Health Effects Division also considered the
dose-response, time-course, and comments from the HSRB when considering
the intraspecies factor.  Although similar concentrations were not
assessed in Phase II and III, a NOAEL or BMCL10 was established.  The
study examined a concentration as low as 50 ppb which some individuals
assigned a confidence score.  Furthermore, the BMCL10 is based on scores
from the most sensitive subpopulation for detecting sensory irritants. 
The BMCL10 of 73 ppb is 2-fold below a level at which the most sensitive
individuals began to detect chloropicrin in the eyes and without
irritation.  This information took into consideration the differences in
responses among all of the participating subjects.  

PANNA Comment 3: PANNA has stated that one of EPA’s justifications for
removing the intraspecies uncertainty factor is that “incident reports
suggest that children are as responsive to chloropicrin as adults.” 
PANNA does not believe this statement is true.

EPA Response:  

HED considered the mode of action and IPCS guidance documents for
refinement of the intraspecies factor which is outlined in the
chloropicrin memo (D293356, 06/18/08).  These guidance documents
consider mode of action in the refinement of the intraspecies factor. 
Toxicokinetics and toxicodynamics are components of the intraspecies
factors.  Both the toxicokinetics and dynamics may be reduced to 1X
based on the mode of action, temporal concordance, key events, targets,
and incident reports for chloropicrin.  The symptoms reported in the
2003 Kern County chloropicrin incident are concordant with the sequence
and onset of symptoms observed in the human study and animal database
for chloropicrin. Nearly all individuals in the Kern County incident,
both young and old, reported eye irritation.  Furthermore, the animal
database demonstrates that as concentrations increase the potential for
upper respiratory irritation increases.  Individuals of the 2003 Kern
County incident were exposed to concentrations greater than 20-fold
higher (1 ppm or 1,000 ppb) than the Cain 2005 human study (50-150 ppb
or 0.05 – 0.15 ppm).  As would be expected at these higher
chloropicrin concentrations, upper respiratory irritation was reported
in approximately 50% of individuals.  Asthma exacerbation was only
reported for approximately 6 of 165 persons (4%).  This exacerbation was
likely due to the high chloropicrin concentrations causing upper
respiratory irritation.  According to the American Lung Association (May
2006), Kern County reported approximately 2.6% pediatric asthma (19,004
children /724,846 total population), 5.3% adult asthma (39,061 adults/
724,846 total population), and 2.8% chronic bronchitis (20,617
individuals/ 724,846 total population).  Therefore, the 4% of
individuals reporting asthma exacerbation in Kern County is not above
the County average, suggesting that chloropicrin did not induce asthma
at a higher rate.  Overall, the 2003 Kern County reports symptoms
consistent with those for chloropicrin, namely eye irritation being the
most sensitive followed by upper respiratory irritation at higher
concentrations.  The similar number and type of symptoms among children
and the older population suggest that individuals are capable of
detecting chloropicrin and respond similarly to chloropicrin.  Based on
the known mode of action for chloropicrin and the consistency and
specificity of the symptoms in both young and old individuals in the
Kern County incident with those of the chloropicrin database, the
toxicodynamics compartment may be reduced to 1x.

  

PANNA Comment 4: PANNA states that a one-hour test exposure period does
not accurately model effects for exposures over a 24-hour period.  PANNA
believes the Agency has no scientific basis to justify using a 1-hour
acute HC to determine buffer zones that are stated to be protective for
a 24-hour period.

EPA Response:  

The toxicity profile of both rodent and human data and mode of action
for chloropicrin support the importance of concentration and duration on
the onset of effects from exposure to chloropicrin.  The lower the
concentration the longer it takes for subjects to first identify the
feeling (eye) of chloropicrin.  As the concentration of chloropicrin
increases the time required for an individual to detect chloropicrin
decreases.  This was demonstrated in the human study.  Concentrations of
chloropicrin of 50-75 ppb took longer for the sensitive subpopulation to
correctly identify compared to 20-30 minutes for recognition to 100-150
ppb in phase 3.  Detection of chloropicrin occurred without irritation
to the eyes and upper respiratory tract. Furthermore, the toxicity
profile and database for chloropicrin demonstrate that exposure to a low
concentration that does not elicit a detection response would not be
expected to produce an adverse respiratory outcome. The longer-term
studies in which exposure is for 6 hours/day, 5 days/week does not
produce a respiratory or port-of-entry effect until 1200 ppb in the
rabbit developmental and 1,000 ppb in the subchronic mouse study (NOAEL
400 ppb rabbit developmental, NOAEL 300 ppb 13-week mouse study). 
Therefore, the profile of chloropicrin does not suggest that 24 hours at
a significantly lower concentration would be a concentration of concern.
 The acute inhalation risk assessment is based on a NOAEL of 73 ppb
which is protective of longer-term exposures.  

PANNA Comment 5: PANNA stated that an aggregate exposure and risk
assessment is still missing from the fumigant documents and should be
part of a finalized risk assessment.

EPA Response:  

HED’s policy concerning the aggregation of exposure scenarios is
defined in the chloropicrin risk assessment.  HED includes food, water
(dietary), and residential uses if applicable.  For chloropicrin there
are no food uses, no water concerns, and no residential uses. 
Therefore, there are no scenarios with which to aggregate in the
chloropicrin risk assessment. 

PANNA Comment 6: PANNA urged EPA to broaden their definition of
“cumulative risk” to include exposures to all chemicals, not just
chemicals with common mechanisms of action.  The fact that these
pesticides are marketed to be used as mixtures means that people will be
exposed to mixtures of chemicals.  The effects of mixtures will not be
the same as the effects of a single chemical, and the Agency needs to be
taking these exposures into account when conducting risk assessments.

EPA Response:  

HED has performed risk assessments of all the fumigants in order to be
consistent across fumigants and for consideration of mitigation of
possible mixtures if necessary.  The fumigants likely have different
modes of action such that each toxicity profile would need to be
considered for each fumigant.  Therefore, the hazard of those fumigants
used in a mixture would be driven by the most sensitive effect such that
other effects at higher concentration would also be protected in the
risk assessment.

B.  Toxicology Comments from the CMTF

CMTF Comment 1: Short-term and intermediate-term exposure limits for
chloropicrin should be based on the human response data and not the
animal study data.  The HSRB did not preclude use of the UCSD for short
term and intermediate term exposures.

EPA Response:  The Agency notes the rationale provided by the CMTF for
the short- and intermediate- inhalation durations for chloropicrin. 
However, the Human Studies Review Board concluded the human study was
appropriate for use in the acute inhalation assessment.  Furthermore,
the human study does not provide physiological parameters of the nasal
and upper respiratory tract beyond an acute exposure.  The animal
database, therefore, provides the most appropriate inhalation
information for the short- and intermediate-term durations.  As
indicated by the HED policy for fumigants, the short- and
intermediate-term inhalation assessments for chloropicrin will rely on
the RfC methodology as with the other fumigants being assessed.

CMTF Comment 2: If EPA continues to use animal toxicity data for
assessing short- and intermediate-term exposures, the uncertainty
factors should be lower than those currently used in the Phase 5
chloropicrin risk assessment.

EPA Response:

HED has relied on animal data to inform the HECs calculated for short-
and intermediate-term exposures.  The uncertainty factors used are
appropriate factors based on HED policy for use of animal data in
calculating HECs.  Therefore, the uncertainty factors will not be
revised at this time.  

CMTF Comment 3: EPA has incorrectly characterized the 2-generation
reproductive toxicity study on chloropicrin as unreliable.  In the Phase
5 chloropicrin risk assessment, EPA compared results from studies of
extremely different design and purpose to support a conclusion that the
reproductive toxicity study was unreliable.  The studies cited by EPA
actually produced consistent results when examined in the context of the
study designs.  Moreover, in November, 1996 EPA concluded in its Data
Evaluation Report (DER) for the Two Generation Reproduction Toxicity
Study with chloropicrin that the study was acceptable.

EPA Response:

HED has reviewed Table 7 provided by the CMTF in which the 3 different
studies are outlined and compared.  In consideration of port-of-entry
type effects, there were no nasal (rhinitis), ET (goblet cell
hyperplasia, epithelial hyperplasia), or PU (peribronchiolar fibrosis)
type effects observed in the 2-generation reproductive study (0.5, 1.0,
1.5 ppm) that were observed in the mid- (1.0 ppm) and high- dose (3.0
ppm) of the 90-day inhalation study.  Again, the lack of port-of-entry
effects in a study with a similar duration and concentration as another
inhalation study suggests the port-of-entry data from the 2-generation
study is inconsistent.   

III. Occupational and Residential Exposures

A.  Occupational Comments from PANNA

PANNA Comment 1: PANNA stated that the accurate flux rates are essential
inputs if accurate results are to be obtained from modeling.  Yet the
model does not account for changes in soil temperature, a major factor
influencing the rate of off-gassing of fumigants from soils.  The flux
rates used in the model are based on studies that may not be
representative of worst-case conditions, and in many cases are certainly
not representative.

EPA Response: In the chloropicrin risk assessment, the Agency has
characterized the field volatility studies by discussing the factors
(such as soil temperature) that occurred during the study.  The Agency
believes that many of the field volatility studies used in the
chloropicrin risk assessment are representative of high-end conditions. 
It should also be acknowledged that the Agency has produced an extensive
separate analysis which evaluated the possible impacts of changing
conditions upon emissions based on a variety of factors (D306857
Authors: Dawson and Smith).

PANNA Comment 2: The Pesticide Action Network commented that calm
conditions and other factors leading to high atmospheric stability
classes are critical for EPA to model in order to be assured of
realistic fumigant exposure estimates.

EPA Response: The Agency agrees that calm conditions and other factors
leading to high atmospheric stability classes are critical in modeling
fumigant emissions.

The treatment of calm periods (wind speeds below 1 m/s) in PERFUM/ISCST3
is an uncertainty in the Agency’s fumigant assessments.  PERFUM runs
the ISCST3 model in the “regulatory default option” (the default
setting for ISCST3), which includes the use of the calms processing
routine as is described in Agency guidance.  The calms processing
routine for wind speeds below 1 m/s essentially ignores any hourly
sequence in the calculations that meets this criteria.  The Agency
agrees that this approach can possibly skew results, particularly for
shorter averaging times (like metam sodium) because an analysis period
that contained several calm hours would be dominated by any period where
there was a windspeed above 1m/s.  This is a common approach in Gaussian
plume modeling.  See the U.S. Environmental Protection Agency’s
Guideline on Air Quality Models, which is published as Appendix W to 40
CFR Part 51 1-4
(http://www.epa.gov/scram001/guidance/guide/appw_05.pdf).   

AERMOD is also a Gaussian plume model and it too has issues in dealing
with wind speeds below 1 m/s.  The new and improved algorithms included
in AERMOD have little to no effect on the Agency’s approach to
modeling fumigant applications as area sources.  In fact, preliminary
work has shown that AERMOD produces neligible differences when compared
to ISCST3 for modeling fumigant applications as area sources.

The Agency is still examining PUFF-based models such as CALPUFF that
have meander algorithms that can account for calm conditions by
accounting for static or near static plume conditions and representing
such events in the results.  Whether or not buffer estimates are
enhanced or under-reported as a result of this phenomenon depends upon
the nature of the weather data used for the calculations.  Preliminary
analysis in a general sense related to this issue does not indicate
significant differences when hourly calculation steps are used.  If less
than hourly steps (e.g., minute by minute calculations such as in
CALPUFF v6) are used, the effect is attenuated because the relative
percentage of calm periods in the available weather data seems to be
diminished.

	B.  Occupational Comments from the CMTF

 tc \l1 "IV.  Occupational and Residential Exposures 

CMTF Comment 1: The CMTF has presented application data, soil conditions
and ambient conditions from agricultural fields where chloropicrin
emissions have been studied.  Using the relationship between
pre-application moisture and mass loss, the CMTF has proposed
“realistic” alternative emission factors incorporating this
mitigation measure.  To determine the emission profiles for fields under
moist soil conditions, the CMTF proposes that EPA attenuate the emission
profiles from the field studies listed in the “Low Soil Moisture”
column to correct for moist pre-application soil conditions.  These data
demonstrate a 50% reduction in emissions when these mitigation measures
are incorporated into chloropicrin field shank applications.

EPA Response: The Agency acknowledges that soil moisture is important in
controlling chloropicrin emissions.  However, there are other
environmental factors (e.g., soil temperature, soil type, compaction,
etc.) that could have an effect on chloropicrin emissions coming off of
treated fields.  The Agency believes that the chloropicrin assessment
represents a range of possible real world application conditions and
does not believe that the mass loss values for all flux studies in the
Agency’s risk assessment should be adjusted to reflect fields that
have good soil moisture.

CMTF Comment 2: The CMTF stated that although there is currently no
field volatility data to represent buried (> 5”) non-tarped drip
irrigation applications, field moisture conditions are >100% field
capacity.  Chloropicrin mass loss is therefore expected to be less than
or equal to the surface tarped method.  A mass loss factor of 15% of
applied chloropicrin is a conservative mass loss value, using the
Salinas poly drip flux emission profile.

EPA Response: The Agency agrees that field moisture conditions would be
near 100% field capacity for non-tarped drip irrigation applications. 
However, the Agency believes that this would be the case for most drip
irrigation applications.  In fact, the Agency has three drip irrigation
field volatility studies and the mass losses range from 10.8% to 15% of
the chloropicrin applied.  The field moisture conditions in all three of
these studies are very close to 100% of field capacity and thus the
Agency does not believe that the CMTF’s comment is necessarily
accurate.  As a result, the Agency does not feel that it would be
appropriate to use a mass loss factor of 15% of applied chloropicrin
from the Salinas poly drip flux emission profile.  The Agency believes
that field volatility data is required to support the chloropicrin
buried drip irrigation application method.

CMTF Comment 3: The CMTF stated that mass loss for the replant wand
application method is expected to be significantly less than for the
shank methods, as injections are made one per tree site and the
injection point is compacted following withdrawal of the application
wand.  It is also important to note that tree site applications involve
small treated areas (10’ x 10’) of existing orchards.  The CMTF
believes that no emission modeling is necessary as the application rate
per gross acre is low.

EPA Response: The Agency acknowledges and agrees with the CMTF’s
comments regarding the chloropicrin orchard replant wand application
method.

CMTF Comment 4: The CMTF stated that for the greenhouse drip irrigation
method, the appropriate “released amount” should be 15% of the
applied chloropicrin.

EPA Response: The Agency has used a range of mass loss values in its
assessment of greenhouse drip irrigation applications.  This assessment
shows that generally, if less than 25% mass loss occurs then risks are
below the Agency’s level of concern at minimal distances from the
greenhouse.

CMTF Comment 5: The CMTF stated that shank, deep broadcast applications
(> 18” deep) are expected to have lower emissions than shallow
applications. A field flux study is planned for spring of 2008 to
measure chloropicrin emissions from deep shank applications.  Until
those data are available, the CMTF believes that a 20% mass loss is
appropriate for deep shank applications, using the Phoenix Site #1 as a
surrogate flux profile.

EPA Response: The Agency agrees that it is likely that shank, deep
broadcast untarped applications (> 18” deep) would have lower
emissions than shallower broadcast untarped applications.  However,
until field volatility data are submitted to support deep broadcast
untarped applications, the Agency plans on using the flux profile from
the Phoenix Site #1 (62% mass loss using a 12” injection depth) as a
conservative estimate to represent this type of application.

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