 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES AND

TOXIC SUBSTANCES

MEMORANDUM

Date:  January 12, 2010 

SUBJECT:	Chlorpyrifos Methyl. Human Health Assessment Scoping Document
in Support of Registration Review.

PC Code:  059102	DP Barcode: D370119

Decision No.: 421187	Registration No.: NA

Petition No.: NA	Regulatory Action: Registration Review Scoping Document

Risk Assessment Type: NA	Case No.: 8011

TXR No.: NA	CAS No.: 5598-13-0

MRID No.: NA	40 CFR: 40 CFR §180.419



FROM:	Danette Drew, Chemist

		Seyed Tadayon, Chemist

		John Doherty, Toxicologist

		Risk Assessment Branch V

		Health Effects Division (7509P)

		Office of Pesticide Programs

THROUGH: Jack Arthur, Acting Branch Chief		

		Risk Assessment Branch V

		Health Effects Division (7509P)

		Office of Pesticide Programs

TO:	Katie Weyrauch

		Tom Myers

		Pesticide Re-evaluation Division (7508P)

	   Office of Pesticide Programs

Executive Summary 

Chlorpyrifos methyl (CPM) is an organophosphate insecticide limited to
post-harvest treatment of stored grains or grain storage facilities.
Tolerances are established for the combined residues of chlorpyrifos
methyl and its metabolite 3,5,6-thrichloro-2-pyridinol (TCP) on grains
(wheat, barley, oats, rice, and sorghum) and livestock commodities. Food
and feed additive tolerances for grain milled fractions are also
established. Currently there are no registered uses of CPM that could
result in residential exposure or exposure from drinking water. Exposure
to CPM may occur via food. Occupational activities may result in dermal
and inhalation exposures.

EPA’s Health Effects Division (HED) has evaluated the available data
and the most recent human health risk assessments for CPM to determine
the scope of work necessary to support the registration review process. 
HED considered the current use patterns as well as the available
toxicity and exposure information for CPM.  The primary source for the
status update was the most recent HED Human Health Risk Assessment
conducted April 19, 2000 and the Tolerance Reassessment and Risk
Management Decision (TRED) for CPM issued 12/30/2000 and made final in
2006 as part of the organophosphate (OP) cumulative risk assessment.  

The purpose of this scoping process is to determine whether sufficient
data are available to assess the safety of this pesticide, as well as to
determine whether any new data have been submitted since the last
assessment that would necessitate conducting a new human health risk
assessment to support registration review.

CPM, like other organophosphate pesticides, affects the nervous system
by inhibiting the activity of cholinesterase (ChE), an enzyme necessary
for the proper functioning of the nervous system. Inhibition of ChE was
the most sensitive effect in all animal species evaluated. For all
exposure routes and durations, the most recent risk assessments for CPM
were based on ChE inhibition. In the 2000 assessment, a 10x FQPA factor
was retained for the protection of infants and children to CPM exposures
(HED was unable to rule out or establish the potential for
susceptibility to young based on existing data). In 2003 HED determined
that because CPM is likely to be less toxic than chlorpyrifos (CPY),
many of the CPY toxicology studies may be bridged to CPM, including the
results of a CPY DNT study. However, it was determined that the 10x FQPA
factor was still applicable  to CPM  in the absence of chemical specific
DNT data because it was not possible to either establish or rule out the
potential for susceptibility from CPM exposure based on the weight of
the evidence findings for CPY. The requirement for a DNT study for CPM
has since been waived. Comparative cholinesterase assays (CCAs) with
post-natal exposures have been shown to provide more sensitive results
than DNT studies or from studies using in utero only exposures. In lieu
of a DNT study, a CCA is required for CPM.

The scoping team has concluded that the only new toxicology data needed
at this time to support the registration review of CPM are acute
toxicity studies [acute oral, acute dermal, acute inhalation, primary
eye irritation, primary skin irritation; the dermal sensitization study
may be waived. The technical has been classified as a skin sensitizer
(TB/HED 1/20/82)], a subchronic inhalation study, an immunotoxicity
study, and a non-guideline acute and repeated dose comparative
cholinesterase assay (CCA) (see Appendix 1, DCI rationale tables). The
toxicological points of departure (PoDs) may be revised after receipt
and review of additional toxicity data. A 10x FQPA factor is still
appropriate at this time and will cover uncertainties remaining because
of the lack of a CPM CCA study. If the registrant desires to submit the
results of a pending CCA study for CPY (and any other relevant
toxicology data for CPY) for bridging to CPM, EPA will examine those
data for suitability for bridging and for possible toxicological PoD
selection for CPM.

In the 2000 TRED, additional magnitude of the residue data (aspirated
grain fractions) were identified as outstanding. Those data remain
outstanding. The results of these studies would not be expected to have
a significant impact on the dietary (food) risk assessment. However, if
the tolerances for livestock commodities increase because of higher
residues on feedstuffs, the dietary assessment may be revised to reflect
those residues. 

Refined acute and chronic dietary exposure and risk estimates associated
with the supported uses of CPM did not exceed HED's level of concern for
any population subgroup. Because of the use pattern for CPM (on stored
grains and inside grain storage facilities), residues in water are not
anticipated. Therefore, a drinking water exposure analysis was not
conducted and will not be required under registration review. If acute
and chronic PoDs are revised, a food only dietary assessment will be
performed under registration review.

To date, there are no residential uses of CPM; therefore, aggregate risk
estimates are equivalent to the dietary risk estimates.

The 2000 CPM occupational assessment was based on Reldan 2% and 3% dust
products and the liquid product Reldan 4E (43% EC) and. Handler exposure
estimates were of concern for all but one scenario- mixing and loading
liquids for direct grain treatment using an automated system. In
response to those concerns, the registrant requested voluntary
cancellation of all dust products and agreed to mitigation measures to
address risks to liquid handlers. Post-application exposures from liquid
applications were expected to be minimal. A 22% EC replaced the 43%EC
and is the only currently registered product. The 22% EC has a lower
maximum application rate than the 43%EC and it was determined that
occupational risks would be lower than those for the 43% EC (MOEs were
not calculated for the 22% EC). The number of bushels treated per day
was assumed to be 80,000 for the 43% formulation and was assumed to be
26,000 for the 22%. Under registration review, an occupational
assessment should be performed for the 22% EC (Storcide II) assuming the
default 80,000 bushels treated a day along with the maximum application
rate currently supported. Any changes to the toxicity PoDs will also be
incorporated.

Hazard Identification/Toxicology

At the time of the 2000 HED risk assessment, the toxicity and exposure
databases, while incomplete, were considered adequate to perform CPM
human health risk assessments. CPM, like other organophosphate
pesticides, affects the nervous system by inhibiting the activity of
cholinesterase (ChE), an enzyme necessary for the proper functioning of
the nervous system. Inhibition of ChE was the most sensitive effect in
all animal species evaluated. All exposure routes and durations in the
2000 HED risk assessment were based on ChE inhibition.

The 2000 TRED identified a number of gaps in the CPM database. The Data
Call-In toxicology requirements included acute, subchronic, and
developmental neurotoxicity studies. In lieu of developing data to
address the neurotoxicity and other data gaps, the registrant decided at
that time to voluntarily cancel registered uses (but maintain tolerances
for import purposes). To address some of the data gaps and allow EPA to
better characterize the risks associated with CPM during a proposed
product phase out period, the registrant agreed to provide EPA with an
acute delayed neurotoxicity study and a two-generation rat reproduction
study. A two-generation rat study was subsequently submitted and
reviewed (MRID 45048301; TXR 0051811; 6/04).The study LOAEL is not
expected to have an impact on the current CPM risk assessment. An acute
delayed neurotoxicity study was not submitted.

In 2003, HED examined the existing toxicity database for the closely
related structural analog, chlorpyrifos (CPY), and determined that CPM
was likely to be less toxic than CPY and that toxicity data generated
using CPY could be used to address data gaps for CPM (memos dated
7/8/2003: D291405 and D289974, TXR 0051734). At that time it was
determined that the only remaining data gaps for CPM were those gaps for
CPY with the exception of the acute toxicity test requirements which
were required to be performed for CPM (acute studies review is under the
purview of OPPs Registration Division). The current outstanding data for
CPY are a comparative ChE assay (CCA) study on both CPY and its oxygen
analog and an immunotoxicity study (new data requirement under 40 CFR
Part 158) (memo dated 2/9/09, D361144). An acute delayed neurotoxicity
study with CPM is no longer a requirement.  Additionally, the inhalation
studies for CPY did not demonstrate a NOAEL and cannot be bridged to
CPM. Therefore, a subchronic inhalation study should be performed for
CPM. HED also concluded in the 2003 memos that CPM continue to be
regulated using CPM specific endpoints and that the 10x FQPA factor be
retained in the absence of chemical specific DNT data because it was not
possible to either establish or rule out the potential for
susceptibility from CPM exposure based on the weight of the evidence
findings for CPY. The endpoint selection table for previous risk
assessments can be seen in Appendix 2.

For the 2006 cumulative risk assessment, registrants of the
organophosphates had the option of retaining the 10x FQPA safety factor
or provide a comparative cholinesterase study. Comparative
cholinesterase data were not available for CPM at that time, therefore,
the 10x FQPA safety factor was retained. This study has not yet been
submitted for CPM and is now being requested (see Appendix 1, DCI
rationale tables). The CCA study would provide information on whether
juvenile animals are more susceptible to the toxicity of CPM than adult
animals.  Because there is no expected exposure to chlorpyrifos methyl
oxon in drinking water, on food or to workers, a CCA study with
chlorpyrifos methyl oxon is not being required at this time. If the
registrant desires to submit the results of a pending CCA study for CPY
for bridging to CPM, EPA will examine those data for suitability for
bridging and for possible point of departure selection for CPM. A
developmental neurotoxicity (DNT, OPPTS 870.3700) study is waived for
CPM.  

An immunotoxicity study is required as a part of new data requirements
in the 40 CFR Part 158 (870.7800) for conventional pesticide
registration. Because the immune system is highly complex, studies not
specifically conducted to assess immunotoxic endpoints are considered
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.   In the absence of the required
immunotoxicity studies, EPA may use a database uncertainty factor of up
to10x.  An immunotoxicity study on CPM should be conducted (see Appendix
1). Once all data have been received and reviewed, the HED Registration
Review Team recommends that the points of departure and safety factors
used for CPM risk assessment purposes be reexamined and a new risk
assessment performed, if necessary. In support of the need for an
immunotoxicity study for CPM, although no reports of immunotoxicity with
this chemical itself were found, there are reports in the open
literature associating the closely related organophosphate chlorpyrifos
(CPY) with alterations in the immune system.  For example, immunologic
abnormalities due to CPY exposure have been reported in workers
(Thrasher, 1993 and Gotoh et al, 2001). In laboratory rats, when dosed
orally for 28 days, CPY induced immune alterations associated with
lymphocyte subpopulations (Blakely et al, 1999).  Dosing rat pups on
post-natal days 1-4 or on post-natal days 11-14 subcutaneously in DMSO
and testing the pups when they became 60 day old adults demonstrated
that T-cell responses were significantly impaired in a manner
implicating an effect on mitogenic activation (Navarro et al, 2001). 
According to one review of the issue of immunotoxicity associated with
the chemical class of organophosphates, immunotoxicity is a concern for
this class of chemicals in general (Galloway and Handy, 2002).  A more
recent paper Oostingh, et al. 2009) determined that in vitro the
immunomodulatory effects of CPY (and diazinon) were similar for most
cytokine promoters and that induction of cellular stress enhanced the
effect of CPY.  Yet another recent paper (Li et al, 2009) demonstrated
that CPY induces apoptosis in human T cells in vitro. 

Developmental and reproductive toxicity. Prenatal developmental toxicity
in rats and rabbits and the rat reproduction studies provided no
evidence of increased susceptibility of the fetuses or offspring.  There
is no developmental neurotoxicity study with CPM. The developmental
neurotoxicity study with the closely related CPY did not provide clear
indications of increased quantitative susceptibility in the offspring,
although there were concerns for qualitative susceptibility in
offspring.  However, the DNT study together with a growing body of
studies in the open literature suggest that gestational and early
postnatal exposure to CPY to pups may result in persistent alterations
as indicated by various assessments of the laboratory animals when they
reach adulthood.  A summary of these studies with CPY from the open
literature was prepared for consideration by the September 16-18, 2008
Science Advisory Panel (SAP).  The SAP (final report dated December 17,
2008) did not conclude that there was a non-cholinergic effect
responsible for any adverse effects and that regulating CPY based on
NOAELs for ChE inhibition would be protective against developmental
effects.  Since CPM is so closely related to CPY and because HED already
recognizes the similarity between CPY and CPM (memos dated 7/8/2003:
D291405 and D289974, TXR 0051734), HED considers that the conclusions of
the SAP regarding possible adverse developmental effects for CPY may
also apply to CPM. 

Subchronic Toxicity.  The subchronic feeding study in rats demonstrated
a NOAEL and LOAEL of 0.1 and 1 mg/kg/day, respectively, based on ChE
inhibition.  There was slight plasma ChE inhibition at 0.1 mg/kg in
males.  At higher doses, the rats demonstrated decreased body weight and
gain and urine staining, decreased hair coat condition and lacrimation. 
Adrenal weights were increased along with histological changes
(hypertrophy, vacuolation and necrosis).  Liver weight was also
increased with indications of hypertrophy.  A NOAEL of > 0.1 mg/kg/day
(highest dose tested) was demonstrated in dogs.  There are no acceptable
subchronic dermal or inhalation studies with CPM although a subchronic
dermal study with CPY may be bridged to CPM. 

Chronic Toxicity.  CPM was evaluated for chronic toxicity in rats and
dogs. In all animal species, the most sensitive effect is inhibition of
plasma, RBC and brain ChE. In the rat, the NOAEL and LOAEL for
inhibition were established at 0.1 and 1 mg/kg/day, respectively, but
there were no indications of clinical signs.   At higher doses in the
rat, body weight deceases, alterations in the adrenals (increased
weight, slight to moderate vacuolation with lipid accumulation in the
zona fasciculata).  The dog chronic feeding study demonstrated a NOAEL
and LOAEL of 0.1 and 1 mg/kg/day for ChE inhibition. At higher doses,
there was increased liver weight and indications of increased SGPT and
SAP).    

Carcinogenicity/Genotoxicity. CPM was evaluated for carcinogenic
potential in both rats and mice. There was no evidence of
carcinogenicity following oral exposure. CPM is not mutagenic in in
vitro in bacteria (Ames test) or in a CHO/HGPRT mammalian cells tests. 
No evidence of a clastogenic effect was found in either an in vitro
cytogenetics test or in an in vivo mouse micronucleus test.  There was
also no evidence of unscheduled DNS synthesis.  

Metabolism/Pharmacokinetic Studies.  Available studies indicate that CPM
is metabolized to produce 3,5,6-trichloro-2-pyridinol (TCP) which is
conjugated and excreted in the urine.  Seventy two hours following oral
administration in corn oil, 83-85% radiolabeled originating from CPM was
recovered in the urine, only 7-9% in the feces with < 0.5% in the
respiratory air.   The carcass retained 0.65 to 1.3% with label found in
the fat, muscle, bone and liver).  In another study, three hours after
administration in olive oil, labeled material was found in fat, liver,
kidney with a “moderate” amount in the adrenal cortex, brain and
nerve tissue with low levels in the spleen.  

FQPA Considerations. HED recommended that the FQPA factor should be
retained at 10x for the protection of infants and children to exposure
resulting from CPM.  The Hazard Identification Assessment Review
Committee (HIARC) could not make a determination on the increased
susceptibility to infants and children (as required by FQPA) to CPM due
to the inadequate toxicology database (HIARC Document 013377, 5/17/99).
Based on the hazard and exposure data, the HED FQPA Safety Factor
Assessment Review Committee determined that the additional 10x factor
should be retained for acute and chronic dietary risk assessments (FQPA
Safety Factor Recommendations for the organophosphates, 8/6/98).  HED
also concluded in 2003 that although CPY toxicology data could be
bridged to CPM, the 10x FQPA factor be retained in the absence of
chemical specific (DNT) data for CPM. A DNT study requirement is waived.
A 10x FQPA will cover the uncertainties remaining because of the lack of
a CPM CCA study. The default 10x interspecies factor and 10x
intraspecies factor are also appropriate for CPM (total UF=1000).

The scoping team has concluded that the only new toxicology data needed
at this time to support the registration review of CPM are the acute
toxicity studies [oral, dermal, inhalation, ocular and dermal
irritation; the dermal sensitization study may be waived according to M.
Lewis, email communication 12/4/09.The technical has been classified as
a skin sensitizer (TB/HED 1/20/82)], a subchronic inhalation study, an
immunotoxicity study, and a non-guideline acute and repeated dose
comparative cholinesterase assay (CCA) (see Appendix 1, DCI rationale
tables). The toxicological points of departure (PoDs) may be revised
after receipt and review of additional toxicity data.

Residue Chemistry and Dietary Assessment

Tolerances are currently established (40 CFR §180.419) for residues of
CPM and its metabolite TCP in/on barley, oats, rice, sorghum, wheat
grain at 6.0 ppm, and in milk, eggs, meat and meat-by-products (mbyp)
and fat of cattle, goats, hogs, horses, poultry and sheep at levels
ranging from 0.1 ppm to 1.25 ppm; tolerances for milled grain fractions
(excluding flour) are established at levels ranging from 30 ppm to 130
ppm. During the reregistration of CPY, the Agency determined that the
metabolite TCP, common to both CPY and CPM, is no longer considered to
be of toxicological concern; HED recommended the removal of TCP from the
tolerance expression for CPM (M. Flood, 4/29/91 and S.Levy, 11/1/99;
D259808).  Therefore, tolerances for residues in/on plant and animal
commodities should be changed to be expressed in terms of parent CPM
only. Additional previously recommended changes to the tolerances as
listed in 40 CFR §180.419 are summarized in the Tolerance Assessment
and International Harmonization

section of this document and in Appendix 3B.

In the 2000 TRED, additional magnitude of the residue data were required
for aspirated grain fractions. Those data do not appear to have been
submitted to date. The results of these studies would not be expected to
have a significant impact on the dietary (food) risk assessment.
However, if the tolerances for livestock commodities increase because of
higher residues on feedstuffs, the dietary assessment may be revised to
reflect those residues.

Refined acute and chronic dietary (food only) exposure and risk
estimates associated with the supported uses of CPM did not exceed HED's
level of concern (100% aPAD or cPAD) for any population subgroup.
Dietary assessments included USDA Pesticide Data Program (PDP;
1995-1997) monitoring data for wheat (translated to other grains) and
milk, as well as processing factors and cooking factors. More recent PDP
data (2005-2006) for CPM on wheat are available and indicate similar
average residue levels on wheat grain, but a much lower percentage of
samples with detectable residues, compared to the values used in the
2000 assessment. For the years 1995 to 1997, average detectable residues
in wheat were 0.09 ppm to 0.11 ppm and percentage of samples with
detects were 54% to 73%.  For the 2005-2006 data, average detectable
residues were 0.11 ppm to 0.12 ppm and the percentage of samples with
detects were 23% and 17%. More recent milk and cream data (PDP;
2004-2005, 2007), like the older data, show no detectable residues of
CPM. If acute and chronic toxicological PoDs are revised, a food only
dietary assessment will be performed under registration review.

Because of the use pattern for CPM (on stored grains and inside grain
storage facilities), residues in water are not anticipated. Therefore, a
drinking water exposure analysis was not conducted and will not be
required under registration review.

Residential/Aggregate Assessment

To date, there are no residential uses of chlorpyrifos methyl;
therefore, aggregate risk estimates are equivalent to the dietary
estimates and are not of concern.

Occupational Assessment

Chlorpyrifos methyl is an organophosphate insecticide used to protect
stored grain, including wheat, barley, oats, rice, and sorghum.  The
current end-use product formulation (Storcide II) is a liquid containing
22% CPM.  Deltamethrin is also an active ingredient in Storcide II.
Workers may be exposed to CPM during mixing, loading, and applying
activities associated with stored grains, bins and warehouses.  Based on
the proposed use patterns, short- and intermediate-term dermal and
inhalation exposure are expected to occur.  The following exposure
scenarios were identified for CPM: (1) mixing/loading liquid formulation
for automated equipment (admixture); (2) mixing/loading liquid
formulation for hand-held equipment; (3) applying liquid formulation by
hand wand to grain bins in warehouses.  Grain elevator workers are known
to apply this product in liquid form to a moving stream of grain (i.e.,
conveyor or auger) using automated equipment.  Only mixing and loading
are expected to contribute significantly to worker exposure when using
an automated process.  Grain storage workers and farm workers also apply
liquid CPM to the walls of empty grain storage containers using hand
sprayers such as high or low pressure hand wands.  

The 2000 occupational assessment was based on the CPM product Reldan 4E
(43% EC) and Reldan 2% and 3% dust products. Handler exposure estimates
were of concern for all but one scenario- mixing and loading liquids for
direct grain treatment using an automated system. In response to those
concerns, the registrant requested voluntary cancellation of all dust
products and agreed to mitigation measures to address risks to liquid
handlers. Post-application exposures from liquid applications were
expected to be minimal. The only liquid uses to remain were empty bin
treatment with downward spray from outside bins and direct grain
treatment with automated systems. 

Reldan dust formulations were cancelled in 2002. Reldan 4E (43% EC) was
cancelled in 2007. A 22% EC formulation (Storcide) was registered in
2002 and cancelled in 2005. The only currently registered formulation is
a 22% EC (Storcide II) formulation. The 22% EC may be applied to stored
grains at 0.18 lb a.i/1000 bushels to provide a concentration of 3 ppm
of CPM on stored grains whereas the 43% EC could be applied at 0.42 lb
ai/1000 bushels to provide 6 ppm CPM on grain. 

Wheat is the highest treated commodity, so the rate at which Reldan 4E
is applied to wheat was used for the 2000 assessment (0.42 lb ai/1000
bushels).  The default assumption was made that 80,000 bushels are
treated in an 8 hour work day. In 2001 for the purposes of a Section 18
exemption to use Storcide 22% EC on stored grains, a memo (D268142;
1/2/2001) compared the handler assumptions between the 43% EC and the
22% EC. For the 22%EC it was assumed the product is mixed and loaded and
automatically applied as a spray on grain (0.18 lb ai/1000 bushels) as
it travels along a conveyer belt. Empty bin wall and floor applications
with hand wands assumed 0.0254 lbs ai/1000ft2 and 20 gallons (0.51 lb
ai) handled per day. That memo, while it did not provide exposure
estimates or MOEs, concluded that occupational exposures from Storcide
22% would be no higher than exposures from Reldan 43% EC.  That memo
also concluded that the established tolerances for CPM are adequate to
support the Storcide 22% use.

Under registration review, an occupational handler assessment should be
performed for the 22%EC (Storcide II) assuming the default 80,000
bushels treated a day along with the maximum application rate currently
supported. Any changes to the toxicity PoDs will also be incorporated.

Post-application exposures may include bystander exposure to dusts
generated by treated grain being conveyed into, out of or within storage
containers, and dermal exposure when sampling treated grain.  Personnel
rarely have direct contact with the stored grain and therefore skin
exposure is only likely during short exposures for testing of grain,
maintenance, or other intermittent activities.  Bystander dust exposure
may be significant for either the employee of a grain elevator or
farmer/operator who operates a portable auger to load treated grain into
a bin but there are no data available to quantify these exposures.

Public Health and Pesticide Epidemiology Data 

A summary report for incidents of CPM has been provided in the
memorandum, “Updated Review of Chlorpyrifos Methyl Incident Reports”
(D370451, M. Hawkins, 11/24/09).  According to the review, no incidents
occurred (were reported) in the United States from 2002 to the present
for the single chemical CPM. 

Tolerance Assessment and International Harmonization

Tolerances for CPM residues are currently expressed as the combined
residues of CPM and TCP (3,5,6-trichloro-2-pyridinol) in or on plant and
animal commodities [40 CFR §180.419; Appendix 3A].  HED has previously
concluded that the U.S. tolerance expression should be amended to
include only CPM (M. Flood, 4/29/91 and D259808, Chlorpyrifos Methyl
Residue Chemistry Chapter of the RED, 11/1/99).   Accordingly, the
tolerance definition for CPM should be amended to include only parent
CPM.  

Several commodity tolerances were reassessed in the 11/1/99 chemistry
chapter of the RED and a full discussion of those recommendations can be
found in that document. In summary, tolerances for aspirated grain
fractions should be established based on the results of the outstanding
residue data for aspirated grain fractions. Once those data are
received, the tolerances for livestock commodities (meat, meat
byproducts and milk) should also be reassessed. In addition, available
data support lowering the tolerances for poultry commodities.  The
tolerances for grain milled fractions (exc. flour) listed separately
under 40 CFR §185.419 (b) should be revoked concomitant to establishing
the appropriate tolerances for residues of CPM in processed commodities
under 40 CFR §180.419. A summary of the CPM tolerance reassessment for
the above commodities as well as recommended modifications in commodity
definitions are presented in Appendix 3B. 

Summary tables of U.S. tolerances (40§CFR180.419) and Codex Maximum
Residue Limits (MRLs) are provided in Appendix 3C. U.S. tolerances are
not harmonized with Codex MRLs.  [Note: that there have been recent
(2009) changes to the Codex MRLs that have not yet been finalized and
some older Codex recommendations remain pending. These items are marked
as ‘proposed’ in the Appendix 3C table. Where there have been
multiple proposals for the same commodity only the most recent proposal
has been included]. There are no Canadian or Mexican MRLs. Any CPM
tolerances reassessed during registration review will be considered for
possible harmonization with international MRLs. 

Environmental Justice

Potential areas of environmental justice concerns, to the extent
possible, will be considered in the chlorpyrifos methyl human health
risk assessment, in accordance with U.S. Executive Order 12898, "Federal
Actions to Address Environmental Justice in Minority Populations and
Low-Income Populations,"   HYPERLINK
"http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pd
f" 
http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf
.  The Office of Pesticide Programs (OPP) typically considers the
highest potential exposures from the legal use of a pesticide when
conducting human health risk assessments, including, but not limited to,
people who obtain drinking water from sources near agricultural areas,
the variability of diets within the U.S., and people who may be exposed
when harvesting crops.  Should these highest exposures indicate
potential risks of concern, OPP further refines the risk assessments to
ensure that the risk estimates are based on the best available
information.

Cumulative  

The Food Quality Protection Act (FQPA) requires the Agency to consider
the cumulative risks of chemicals sharing a common mechanism of
toxicity. Chlorpyrifos methyl is a member of the organophosphate common
mechanism group. The most recent cumulative risk assessment for the
organophosphates was published on in 2006 and is available at
http://www.epa.gov/pesticides/cumulative/2006-op/op_cra_main.pdf. No
cumulative risks of concern for chlorpyrifos methyl were identified in
that assessment.

Prior to a final registration review decision for chlorpyrifos methyl,
the Agency will determine if there is any new information, such as new
hazard or exposure data or information on changes to the use pattern,
which would affect the cumulative risk assessment. Should the Agency
determine that new information on chlorpyrifos methyl is available that
could potentially impact the cumulative risk assessment and result in a
risk of concern, the Agency will revisit the cumulative risk assessment.

Human Studies

The occupational assessments were completed based on the use of the
Pesticide Handlers Exposure Database (PHED).  The PHED has been reviewed
from an ethics perspective and no issues were found that would preclude
its use in the risk assessment process. Two toxicity human studies with
CPM were considered by the HED (MRID 00030754, 00043238 and MRID
00030755, 00043239) but were classified as unacceptable for technical
reasons and were not relied on in the risk assessment.

A human study using CPY was used as part of a weight of the evidence
approach for determining a dermal absorption factor for CPM (MRID
00124144 and 47918801). This study was reviewed by the Human Study
Review Board (HSRB June 2009 meeting; final report dated 10/26/09) and
it was concluded that the data were reliable. The HSRB did not find the
study to be unethical. If OPP determines any other human studies have
potential use for future risk assessments, they will need to undergo
HSRB review.

Endocrine Disruptor Screening Program

As required under FFDCA section 408(p), EPA has developed the Endocrine
Disruptor Screening Program (EDSP) to determine whether certain
substances (including pesticide active and other ingredients) may have
an effect in humans or wildlife similar to an effect produced by a
“naturally occurring estrogen, or other such endocrine effects as the
Administrator may designate.”  The EDSP employs a two-tiered approach
to making the statutorily required determinations. Tier 1 consists of a
battery of 11 screening assays to identify the potential of a chemical
substance to interact with the estrogen, androgen, or thyroid (E, A, or
T) hormonal systems.  Chemicals that go through Tier 1 screening and are
found to have the potential to interact with E, A, or T hormonal systems
will proceed to the next stage of the EDSP where EPA will determine
which, if any, of the Tier 2 tests are necessary based on the available
data. Tier 2 testing is designed to identify any adverse endocrine
related effects caused by the substance, and establish a dose-response
relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA is issuing test orders/data
call-ins for the first group of 67 chemicals, which contains 58
pesticide active ingredients and 9 inert ingredients.  This list of
chemicals was selected based on the potential for human exposure through
pathways such as food and water, residential activity, and certain
post-application agricultural scenarios.  This list should not be
construed as a list of known or likely endocrine disruptors.

Chlorpyrifos methyl is not among the group of 58 pesticide active
ingredients on the initial list to be screened under the EDSP.  Under
FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. 
Accordingly, EPA anticipates issuing future EDSP test orders/data
call-ins for all pesticide active ingredients. 

For further information on the status of the EDSP, the policies and
procedures, the list of 67 chemicals, the test guidelines and the Tier 1
screening battery, please visit the website:  http://www.epa.gov/endo/.

Data Requirements

Toxicology    

• 870 Series acute toxicity studies (acute oral, acute dermal, acute
inhalation, primary eye irritation, primary skin irritation). The dermal
sensitization study may be waived according to M. Lewis, 12/4/09 email
communication to J. Doherty.

• 870.3250 Subchronic inhalation study.

• 870.7800 Immunotoxicity (This is a new data requirement under 40 CFR
Part 158; see Appendix 1)

• Comparative cholinesterase assay (CCA):  required for
organophosphates including chlorpyrifos methyl. This study has not been
submitted for chlorpyrifos methyl (see Appendix 1).

Residue Chemistry

• 860.1500 Magnitude of the residue data were identified as
outstanding in the 2000 TRED for aspirated grain fractions. Those data
remain outstanding. 

Occupational – no data gaps currently identified

Appendix 1

Data Call In Tables

Guideline Number: 870.7800

Study Title:  Immunotoxicity

Rationale for Requiring the Data

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

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



Practical Utility of the Data

How will the data be used?

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

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

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

 

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



Guideline Number:  Special Study

Study Title: Comparative Cholinesterase Assay (CCA)

Rationale for Requiring the Data

Chlorpyrifos methyl is an organophosphate pesticide (OP) whose mode of
toxic action is inhibition of the enzyme, acetylcholinesterase (AChE)
via phosphorylation of the active site leading to accumulation of
acetylcholine and to clinical signs of neurotoxicity.  The detoxifying
systems for destroying both the parent and active forms of OPs are less
developed in the neonatal animals and humans.  

The Agency does not have comparative AChE inhibition studies conducted
using chlorpyrifos methyl to compare the relative sensitivity of
juvenile to adult animals.  Thus, EPA is seeking a comparative
cholinesterase assay for chlorpyrifos methyl.  Specifically, this study
should include both acute (1 day) and repeated (11 days) exposures to
pups and young adult rats.  The acute exposures should be administered
to post-natal day 11 (PND 11) rats and young adults.  The repeated
exposures should be given for 11 consecutive days beginning at PND 11.
The chlorpyrifos methyl should be administered directly (e.g., gavage). 


Practical Utility of the Data



How will the data be used?  

The new data generated in the CCA study with chlorpyrifos methyl will be
used in the dietary assessment for chlorpyrifos methyl to account for
any additional risks arising from exposure to neonatal subjects to
chlorpyrifos methyl. 

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

The newly generated CCA data could potentially impact the FQPA safety
factor in both the single chemical and cumulative risk assessments.  If
the FQPA safety factor changes, then this impacts the calculation of the
acute and chronic Population Adjusted Doses, and therefore may either
reduce or increase risk estimates in the dietary assessments for the
chlorpyrifos methyl and cumulative risk assessments.  If the dietary
risk is increased based on information in the new CCA study, then
additional mitigation may be needed to address potential risks of
concern.  If the dietary risk is decreased, then the registrants may be
able to expand uses.



Appendix 2  

Toxicology Endpoint and Dose Selection 

Appendix 3A

Chlorpyrifos Methyl: U.S. Tolerances (currently)

[Code of Federal Regulations]

[Title 40, Volume 23]

[Revised as of July 1, 2008]

From the U.S. Government Printing Office via GPO Access

[CITE: 40CFR180.419]

                   TITLE 40--PROTECTION OF ENVIRONMENT

 

         CHAPTER I--ENVIRONMENTAL PROTECTION AGENCY (CONTINUED)

 

PART 180_TOLERANCES AND EXEMPTIONS FROM TOLERANCES FOR PESTICIDE
CHEMICALS IN 

 

                      Subpart C_Specific Tolerances

 

Sec. 180.419  Chlorpyrifos-methyl; tolerances for residues.

    (a) General. (1) Tolerances are established for the combined 

residues of the insecticide chlorpyrifos-methyl [O,-O,-dimethyl O-

(3,5,6-trichloro-2-pyridyl)] phosphorothioate and its metabolite (3,5,6-

trichloro-2-pyridinol) in or on the following food commodities:

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

                                                               Parts per

                          Commodity                             million

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

Barley, grain...............................................        6.0

Cattle, fat.................................................        0.5

Cattle, meat................................................        0.5

Cattle, meat byproducts.....................................        0.5

Egg.........................................................        0.1

Goat, fat...................................................        0.5

Goat, meat..................................................        0.5

Goat, meat byproducts.......................................        0.5

Hog, fat....................................................        0.5

Hog, meat...................................................        0.5

Hog, meat byproducts........................................        0.5

Horse, fat..................................................        0.5

Horse, meat.................................................        0.5

Horse, meat byproducts......................................        0.5

Milk, fat (0.05 ppm (N) in whole milk.......................        1.25

Oat, grain..................................................        6.0

Poultry, fat................................................        0.5

Poultry, meat...............................................         .5

Poultry, meat byproducts....................................         .5

Rice, grain.................................................        6.0

Sheep, fat..................................................        0.5

Sheep, meat.................................................        0.5

Sheep, meat byproducts......................................        0.5

Sorghum, grain..............................................        6.0

Wheat, grain................................................        6.0

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

    (2) Tolerances are established for the combined residues of the 

insecticide chlorpyrifos-methyl (O,-O- dimethyl-O-(3,5,6-trichloro-2-

pyridyl) phosphorothioate and its metabolite (3,5,6-trichloro-2-

pyridinol) in or on the following food commodities when present therein 

as a result of application to stored grains:

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

                                                               Parts per

                             Food                               million

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

Barley milling fractions (except flour)......................         90

Oat milling fractions (except flour).........................        130

Rice milling fractions (except flour)........................         30

Sorghum, grain, bran.........................................         90

Wheat milling fractions (except flour).......................         30

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

    (b) Section 18 emergency exemptions. [Reserved]

    (c) Tolerances with regional registrations. [Reserved]

    (d) Indirect or inadvertent residues. [Reserved]

[65 FR 33715, May 24, 2000]

Appendix 3B

Chlorpyrifos Methyl: Reassessed U.S. Tolerances 

(11/1/99 HED memo:Chlorpyrifos Methyl Residue Chemistry Chapter of the
RED; D259808)

Commodity	

Current Tolerance

(ppm)	

Tolerance Reassessment (ppm)	

Comment/Correct Commodity Definition



Tolerances listed under 40 CFR §180.419:



Barley, grain	

6.0	

6.0	





Oats, grain	

6.0	

6.0	





Rice, grain	

6.0	

6.0	





Sorghum, grain	

6.0	

6.0	

Sorghum, grain, grain



Wheat, grain	

6.0	

6.0	





Fat of cattle, goats, hogs, horses, & sheep	

0.5	

TBD1	

Residue data on aspirated grain fractions derived from treated wheat and
sorghum are required.  Aspirated grain fractions contribute
significantly to the dietary burden for cattle and swine.  If
significantly higher residues are found in wheat or sorghum aspirated
grain fractions, then a new ruminant feeding study may be required. 



Meat and meat byproducts of cattle, goats, horses, & sheep	

0.5





Hogs, muscle	

0.5





Hogs, meat byproducts	

0.5





Milk	

0.05





Milk, fat	

1.25





Poultry, fat	

0.5	

0.05	

Residue data support lowering the tolerances established on poultry
commodities.



Poultry, meat byproducts	

0.5	

0.01

	

Poultry, meat	

0.5	

0.01

	

Eggs	

0.1	

0.01

	

Tolerances listed under 40 CFR §185 and §186.1050:



Barley, milled fractions

(excluding flour)	

90.0	

Revoke

	

Tolerance should be revoked concomitant with establishing a 20 ppm
tolerance on barley bran.



Oats, milled fractions

	

130.0



Tolerance should be revoked concomitant with establishing a ppm
tolerance for oat bran.



Rice, milled fractions

(excluding flour)	

30.0



Tolerance should be revoked concomitant with establishing tolerances on
rice bran (12.5 ppm).



Sorghum, milled fractions

(excluding flour)	

90.0



Tolerance should be revoked.  There are no longer any processed
commodities of grain sorghum considered as food for humans or feed for
livestock.  



Wheat, milled fractions

(excluding flour)	

30.0



Tolerance should be revoked concomitant with establishing a tolerance on
wheat bran, wheat germ and germ oil at 20 ppm.



Tolerances needed under 40 CFR §180.419



Aspirated Grain Fractions	

None	

TBD1	

The available data on corn support a tolerance of at least 400 ppm. 
Additional data are required for sorghum and wheat



Barley, bran	

90.0	

20.0	

Concomitant with revoking the tolerance for barley milled fractions, a
tolerance on barley bran should be established



Rice, bran	

30.0	

12.5	

Concomitant with revoking the tolerance for rice milled fractions, a
tolerance on rice bran should be established.



Rice, hulls	

None	

25.0	

Concomitant with revoking the tolerance for rice milled fractions, a
tolerance on rice bran should be established.



Oat, bran	

None	

17.0	

Concomitant with revoking the tolerance for oat milled fractions, a
tolerance on oat,bran should be established.



Wheat, bran	

30.0	

20.0	

Concomitant with revoking the food/feed additive tolerance for wheat
milled fractions, a tolerance on wheat,bran should be established.



Wheat, germ	

30.0	

20.0	

Concomitant with revoking the food/feed additive tolerance for wheat
milled fractions, a tolerance on wheat,germ should be established.

1 TBD = To be determined; i.e., the Agency considers the existing
tolerance to be reassessed at the current level; however, adequate
confirmatory data are warranted and if found lacking, the Agency intends
to modify or revoke the tolerance.

Appendix 3C

Chlorpyrifos Methyl: Codex Maximum Residue Limits (MRLs) 

Summary of US and International Tolerances and Maximum Residue Limits 

US	Canada	Mexico	Codex

Residue Definition:

40CFR180.419.

combined residues of the insecticide chlorpyrifos-methyl [ O,-O,-
dimethyl O -(3,5,6-trichloro-2-pyridyl)] phosphorothioate and its
metabolite (3,5,6-trichloro-2-pyridinol)	None	None	Chlorpyrifos-methyl
(fat-soluble). 

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

Commodity	US	Canada	Mexico	Codex2, 3

Barley, grain	6.0	None	None	3 Po proposed

Cattle, fat	0.5

	0.05

(withdrawal proposed)

Cattle, meat	0.5

	0.05

(0.1 proposed)

Cattle, meat byproducts	0.5

	0.05

(0.01 proposed)

Egg	0.1

	0.05

(0.01 (*) proposed)

Goat, fat	0.5



	Goat, meat	0.5



	Goat, meat byproducts	0.5



	Hog, fat	0.5



	Hog, meat	0.5



	Hog, meat byproducts	0.5



	Horse, fat	0.5



	Horse, meat	0.5



	Horse, meat byproducts	0.5



	Milk, fat (0.05 ppm (N) in whole milk	1.25

	0.01 (*)

Oat, grain	6.0

	10 Po proposed

Poultry, fat	0.5

	0.05

Poultry, meat	0.5

	0.05

(0.01 proposed)

Poultry, meat byproducts	0.5

	0.05

(0.01 (*) proposed)

Rice, grain	6.0

	0.1

(withdrawal proposed)

Sheep, fat	0.5



	Sheep, meat	0.5



	Sheep, meat byproducts	0.5



	Sorghum, grain	6.0

	10 Po

Wheat, grain	6.0

	10 Po

(3 proposed)

Barley, bran1	90



	Barley, pearled barley1	90



	Rice, bran1	30



	Rice, hulls1	30



	Rice, polished rice1	30



	Sorghum, grain, bran1	90



	Wheat, bran1	30

	20 PoP

(6 proposed)

Wheat, germ1	30

	5 PoP proposed

Wheat, middlings1	30



	Wheat, shorts1	30



	1As a result of application to stored grains.

2 * = absent at the limit of quantitation; Po = postharvest treatment,
such as treatment of stored grains.  PoP = processed postharvest treated
commodity, such as processing of treated stored wheat.

3Commodities with Codex MRLs but without corresponding US tolerances
have been excluded. For example, there is a Codex MRL of 0.5 mg/kg for
apple.

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