Document ID: EPA-HQ-OPP-2008-0023-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-06-26T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

February 28, 2007

				

MEMORANDUM

	SUBJECT:	Coumaphos:  Human Health Risk Assessment for Proposed Use on
Honey and Honeycomb.  PC Code:  036501; Petition Number: 2E6504; DP
Number: D315769.

Regulatory Actions:		Section 3

		Risk Assessment Type:	Single Chemical/Aggregate

	FROM:	Kelly M. Schumacher, Biologist

		Margarita Collantes, Biologist

		William T. Drew, Chemist

		Registration Action Branch 2

		Health Effects Division (7509P)

		and

		Sheila Piper, Chemist		

		Chemistry and Exposure Branch

		Health Effects Division (7509P)

THROUGH: 	Richard A. Loranger, Ph.D., Branch Senior Scientist

		Christina Swartz, Branch Chief

		Registration Action Branch 2

		Health Effects Division (7509P)

	

TO:	Shaja Brothers, RM 05

Daniel Rosenblatt, RM 05

	Insecticide Branch

	Registration Division (7505P)	

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc154473701"  1.0	Executive
Summary	  PAGEREF _Toc154473701 \h  4  

  HYPERLINK \l "_Toc154473702"  2.0	Ingredient Profile	  PAGEREF
_Toc154473702 \h  9  

  HYPERLINK \l "_Toc154473703"  3.0	Hazard Characterization/Assessment	 
PAGEREF _Toc154473703 \h  10  

  HYPERLINK \l "_Toc154473704"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc154473704 \h  10  

  HYPERLINK \l "_Toc154473705"  3.2	FQPA Considerations	  PAGEREF
_Toc154473705 \h  12  

  HYPERLINK \l "_Toc154473706"  3.3	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc154473706 \h  12  

  HYPERLINK \l "_Toc154473707"  3.3.1	Acute Reference Dose (aRfD) -
Females age 13-49	  PAGEREF _Toc154473707 \h  12  

  HYPERLINK \l "_Toc154473708"  3.3.2	Acute Reference Dose (aRfD) -
General Population	  PAGEREF _Toc154473708 \h  13  

  HYPERLINK \l "_Toc154473709"  3.3.3	Chronic Reference Dose (cRfD)	 
PAGEREF _Toc154473709 \h  13  

  HYPERLINK \l "_Toc154473710"  3.3.4	Incidental Oral Exposure (Short-
and Intermediate-Term)	  PAGEREF _Toc154473710 \h  13  

  HYPERLINK \l "_Toc154473711"  3.3.5	Dermal Absorption	  PAGEREF
_Toc154473711 \h  14  

  HYPERLINK \l "_Toc154473712"  3.3.6	Dermal Exposure (Short-,
Intermediate- and Long-Term)	  PAGEREF _Toc154473712 \h  14  

  HYPERLINK \l "_Toc154473713"  3.3.7	Inhalation Exposure (Short-,
Intermediate- and Long-Term)	  PAGEREF _Toc154473713 \h  14  

  HYPERLINK \l "_Toc154473714"  3.3.8	Level of Concern for Margin of
Exposure	  PAGEREF _Toc154473714 \h  14  

  HYPERLINK \l "_Toc154473715"  3.3.9	Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc154473715 \h  15  

  HYPERLINK \l "_Toc154473716"  3.3.10	Classification of Carcinogenic
Potential	  PAGEREF _Toc154473716 \h  15  

  HYPERLINK \l "_Toc154473717"  3.3.11	Summary of Toxicological Doses
and Endpoints for Coumaphos for Use in Human Risk Assessments	  PAGEREF
_Toc154473717 \h  15  

  HYPERLINK \l "_Toc154473718"  3.4	Endocrine Disruption	  PAGEREF
_Toc154473718 \h  16  

  HYPERLINK \l "_Toc154473719"  4.0	Public Health and Pesticide
Epidemiology Data	  PAGEREF _Toc154473719 \h  16  

  HYPERLINK \l "_Toc154473720"  5.0	Dietary Exposure/Risk
Characterization	  PAGEREF _Toc154473720 \h  16  

  HYPERLINK \l "_Toc154473721"  5.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc154473721 \h  16  

  HYPERLINK \l "_Toc154473722"  5.1.1	Metabolism in Primary Crops	 
PAGEREF _Toc154473722 \h  17  

  HYPERLINK \l "_Toc154473723"  5.1.2	Metabolism in Rotational Crops	 
PAGEREF _Toc154473723 \h  17  

  HYPERLINK \l "_Toc154473724"  5.1.3	Metabolism in Livestock	  PAGEREF
_Toc154473724 \h  17  

  HYPERLINK \l "_Toc154473725"  5.1.4	Analytical Methodology	  PAGEREF
_Toc154473725 \h  17  

  HYPERLINK \l "_Toc154473726"  5.1.5	Environmental Degradation	 
PAGEREF _Toc154473726 \h  18  

  HYPERLINK \l "_Toc154473727"  5.1.6	Pesticide Metabolites and
Degradates of Concern	  PAGEREF _Toc154473727 \h  18  

  HYPERLINK \l "_Toc154473728"  5.1.7	Drinking Water Residue Profile	 
PAGEREF _Toc154473728 \h  18  

  HYPERLINK \l "_Toc154473729"  5.1.8	Food Residue Profile	  PAGEREF
_Toc154473729 \h  19  

  HYPERLINK \l "_Toc154473730"  5.1.9	International Residue Limits	 
PAGEREF _Toc154473730 \h  20  

  HYPERLINK \l "_Toc154473731"  5.2	Dietary Exposure and Risk	  PAGEREF
_Toc154473731 \h  20  

  HYPERLINK \l "_Toc154473732"  5.2.1	Acute Dietary Exposure/Risk	 
PAGEREF _Toc154473732 \h  20  

  HYPERLINK \l "_Toc154473733"  5.2.2	Chronic Dietary Exposure/Risk	 
PAGEREF _Toc154473733 \h  21  

  HYPERLINK \l "_Toc154473734"  5.3	Anticipated Residue and Percent Crop
Treated (%CT) Information	  PAGEREF _Toc154473734 \h  21  

  HYPERLINK \l "_Toc154473735"  6.0	Residential (Non-Occupational)
Exposure/Risk Characterization	  PAGEREF _Toc154473735 \h  22  

  HYPERLINK \l "_Toc154473736"  7.0	Aggregate Risk Assessments and Risk
Characterization	  PAGEREF _Toc154473736 \h  22  

  HYPERLINK \l "_Toc154473737"  7.1	Acute Aggregate Risk	  PAGEREF
_Toc154473737 \h  22  

  HYPERLINK \l "_Toc154473738"  7.2	Short- and Intermediate-Term
Aggregate Risk	  PAGEREF _Toc154473738 \h  22  

  HYPERLINK \l "_Toc154473739"  7.3	Long-Term Aggregate Risk	  PAGEREF
_Toc154473739 \h  22  

  HYPERLINK \l "_Toc154473740"  7.4	Cancer Risk	  PAGEREF _Toc154473740
\h  22  

  HYPERLINK \l "_Toc154473741"  8.0	Cumulative Risk
Characterization/Assessment	  PAGEREF _Toc154473741 \h  23  

  HYPERLINK \l "_Toc154473742"  9.0	Occupational Exposure/Risk Pathway	 
PAGEREF _Toc154473742 \h  25  

  HYPERLINK \l "_Toc154473743"  10.0	Data Needs and Label
Recommendations	  PAGEREF _Toc154473743 \h  25  

  HYPERLINK \l "_Toc154473744"  10.1	Toxicology	  PAGEREF _Toc154473744
\h  25  

  HYPERLINK \l "_Toc154473745"  10.2	Residue Chemistry	  PAGEREF
_Toc154473745 \h  25  

  HYPERLINK \l "_Toc154473746"  10.3	Occupational and Residential
Exposure	  PAGEREF _Toc154473746 \h  25  

  HYPERLINK \l "_Toc154473747"  References:	  PAGEREF _Toc154473747 \h 
26  

  HYPERLINK \l "_Toc154473748"  A.1	Toxicity Profile	  PAGEREF
_Toc154473748 \h  27  

 1.0	Executive Summary  TC \l1 "1.0	Ex

ecutive Summary 

Background

Coumaphos (O-[3-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl] O,O-diethyl
phosphorothioate) is an organophosphate insecticide/acaricide currently
used for the control of mites and insects on livestock.  Permanent
tolerances are established for the residues of coumaphos and its oxygen
analog (coumaphos-PO) at 1.0 ppm in fat, meat, and meat byproducts of
cattle, goats, hogs, horses, and sheep, along with a tolerance at 0.5
ppm in milk fat.  The Agency has granted Section 18 emergency exemptions
for the use of coumaphos on beehives to control varroa mites and/or
small hive beetles in 40-46 states, starting in 1999 as a non-food use. 
In 2000, these Section 18s were reclassified as a food use, and
time-limited tolerances were first established for residues of coumaphos
and its oxygen analog at 0.1 and 100 ppm, respectively, in honey and
honeycomb; these tolerances expire on 12/31/2007. 

This assessment addresses the risks associated with making the use of
coumaphos on beehives permanent.  Interregional Research Project #4
(IR-4) has submitted a petition proposing a Section 3 registration for
the use of coumaphos-impregnated strips in beehives for the control of
varroa mites and small hive beetles.  The strips (CheckMite+ Bee Hive
Pest Control Strips) contain 10% coumaphos, the active ingredient (ai),
by weight.  The proposed label would allow for use of up to two 10%
strips hung in the hive’s brood chamber for control of varroa mites,
and the concurrent use of another 10% strip attached to the bottom board
for control of small hive beetles.  The strips could remain in the hive
for up to 45 days, and the application could be made at anytime during
the year, including during honey flow (honey accumulation).  In
conjunction with this use, the petitioner is proposing permanent
tolerances for the combined residues of coumaphos and coumaphos-PO at
0.1 ppm in honey and at 100 ppm in honeycomb (beeswax).

Hazard Characterization

The mammalian toxicology database for coumaphos is complete.  Acute
toxicity studies in rats and rabbits; an acute delayed neurotoxicity
study in hens; subchronic oral and dermal studies in rats;
chronic/carcinogenicity studies in rats, mice, and dogs; developmental
toxicity studies in rats and rabbits; a two-generation study in rats;
mutagenicity studies; and a metabolism study were discussed and
considered in the Reregistration Eligibility Decision (RED) for
coumaphos (  HYPERLINK "http://www.epa.gov/oppsrrd1/REDs/0018.pdf" 
http://www.epa.gov/oppsrrd1/REDs/0018.pdf ).  Acute and subchronic
neurotoxicity studies in rats were received subsequent to the RED and
were considered in the Reregistration Eligibility Decision Addendum and
FQPA Tolerance Reassessment Progress Report (TRED) for coumaphos ( 
HYPERLINK "http://www.epa.gov/oppsrrd1/REDs/0018tred.pdf" 
http://www.epa.gov/oppsrrd1/REDs/0018tred.pdf ).  Subsequent to the
TRED, a developmental neurotoxicity study and a comparative
cholinesterase study in rats were received; these studies are discussed
and considered in the current risk assessment.

The acute toxicity of coumaphos is high via the oral route of exposure
(Category I), moderate via the inhalation route (Category II), and
slight via the dermal route (Category III).  Coumaphos is not a dermal
sensitizer or a dermal irritant, and it does not cause delayed
neuropathy.  As an organophosphate insecticide, coumaphos primarily
affects the nervous system through cholinesterase (ChE) inhibition,
although systemic toxicity in the form of decreased body weight gains
was observed in chronic studies.  Females are consistently more
sensitive to the cholinergic effects than males.  In developmental
toxicity studies in rats and rabbits, no developmental toxicity was
observed, while clinical signs of ChE toxicity were seen in the maternal
animals.  In a two-generation reproduction study, ChE inhibition was
noted in both parents and offspring, with parents more susceptible;
reproductive toxicity was not observed.  A comparative ChE study
demonstrated increased quantitative susceptibility of the offspring in
that ChE inhibition was seen at a lower dose in neonatal pups, compared
to young adults.  Coumaphos is not carcinogenic and is classified as a
Group E chemical, indicating that it is “Not Likely” to be
carcinogenic in humans via relevant routes of exposure.  No evidence of
mutagenicity was seen in any study. 

Food Quality Protection Act (FQPA) Considerations

There was no evidence of increased qualitative or quantitative
susceptibility of the offspring in the developmental, reproduction, or
developmental neurotoxicity studies.  Although increased quantitative
susceptibility of the offspring was observed in the comparative ChE
study, the degree of concern is low because the effects are well
characterized and there are clear NOAELs and LOAELs for both neonatal
and adult animals.  There are no residual uncertainties for pre- and/or
postnatal toxicity for the comparative ChE study because the endpoint of
concern is the one used for the acute dietary exposure risk assessment,
and a more protective endpoint (based on long-term exposure) is used for
chronic dietary exposure risk assessment.  

In addition to the hazard data, the coumaphos risk assessment team
evaluated the quality of the exposure data and found no residual
uncertainties.  The acute dietary exposure assessment is based on 2002
PDP monitoring data for beef, 2004 PDP monitoring data for milk, and
field trial data for honey and assumes 100% crop treated.  The chronic
assessment is based on the latest PDP monitoring data for beef and milk,
as well as average field trial data for honey; this analysis also
assumes 100% crop treated.  For water, estimates from conservative Tier
1 screening models were used.  By using these conservative assessments,
acute and chronic exposures/risks to infants and children will not be
underestimated.  There are currently no registered or proposed
residential uses of coumaphos.  Based on the exposure and hazard data,
the coumaphos risk assessment team concluded that the FQPA safety factor
can be removed (i.e., reduced to 1X).

Residue Chemistry

Since there are currently no registered or proposed uses of coumaphos on
plants, no plant metabolism data are required.  The nature of the
residue in livestock has been established, based on an adequate cow
metabolism study reflecting dermal dosing.  In livestock, the residues
of concern (ROC) for risk assessment and for tolerance expression are
coumaphos and its oxygen analog (coumaphoxon, also referred to as
coumaphos-PO).  The existing animal data are adequate for purposes of
the proposed use on beehives.  In honeybee products (honey and
honeycomb), the ROC are coumaphos and its oxygen analog.

The available honeybee field trials are adequate, and support the
proposed use of coumaphos-impregnated strips (containing 10% ai) in
beehives for up to 45 days during honey flow.  The number and
distribution of the field trials are adequate, and a sufficient number
of samples were collected at the appropriate intervals.  The field
trials are supported by the available storage stability data, and
residues of coumaphos and coumaphos-PO in honey and beeswax were
determined using adequate LC/MS/MS methods.

The honey processing data are adequate, and indicate that the processing
of raw honey by heating and filtration will reduce coumaphos residues in
honey by 0.5x.  Coumaphos residues were shown to partition largely into
beeswax, which had an average processing factor of approximately 25x.

Adequate LC/MS/MS methods are available for enforcing tolerances and
collecting data on residues of coumaphos and coumaphos-PO in honey and
beeswax (Bayer Methods #75043 and #75044 for honey and beeswax,
respectively).

Dietary Exposure Assessment

ure and risk assessments were conducted using the Dietary Exposure
Evaluation Model (DEEM-FCID™, Version 2.03), which uses food
consumption data from the U.S. Department of Agriculture’s Continuing
Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998. 
The tier 1 GENEEC and SCI-GROW screening models were used to estimate
surface water and groundwater concentrations of coumaphos and its oxygen
analog, coumaphoxon.  The acute assessment incorporated 2002 PDP
monitoring data for beef, 2004 PDP monitoring data for milk, and field
trial data for honey; this analysis assumes 100% crop treated.  Total
coumaphos (coumaphos + coumaphoxon) acute estimated environmental
concentrations in drinking water derived from surface water sources are
not likely to exceed 1.86 ppb.  The chronic assessment incorporated the
latest PDP monitoring data for beef and milk, as well as average field
trial data for honey; this analysis also assumes 100% crop treated. 
Total coumaphos (coumaphos + coumaphoxon) chronic estimated
environmental concentrations in drinking water derived from surface
water sources are not likely to exceed 0.41 ppb.

Based on these assumptions, acute dietary risk estimates at the 99.9th
percentile of exposure are less than or equal to 38% of the acute
population-adjusted dose (aPAD) for all population subgroups.  Chronic
dietary risk estimates are less than or equal to 13% of the chronic
population-adjusted dose (cPAD) for all population subgroups. 
Generally, HED is concerned when risk estimates exceed 100% of the PAD;
therefore, all acute and chronic dietary risk estimates are below
HED’s level of concern.

 TC \l2 "5.2  Dietary Exposure and Risk 

Residential Risk

There are currently no registered or proposed uses of coumaphos in or
around residences; therefore, risk assessments for residential
(non-occupational) exposure are not warranted at this time.

Aggregate Risk

The acute and long-term aggregate assessment for coumaphos exposure
includes only food and water exposures.  Short- and intermediate-term
aggregate assessments are not required since none of the currently
registered or proposed uses result in residential exposure. Because
coumaphos has been classified as a “not likely human carcinogen”, a
cancer aggregate risk assessment is not required.  Estimates of acute
and long-term aggregate risks associated with the registered and
proposed uses of coumaphos do not exceed HED’s level of concern for
the general U.S. population or any population subgroup.

Occupational Risk

The proposed new use pattern does not indicate significant potential for
applicator or post-application dermal or inhalation exposure.  The
CheckMite+ Bee Hive Pest Control Strips come prepackaged and do not
involve any mixing or loading of active ingredient.  Occupational
exposure resulting from use of these strips is highly improbable, as the
only potential times for worker contact are during application, when the
beehive keeper removes the strips from the containers and places them in
the hives, and during removal and disposal of the strips six weeks
later.  As indicated previously, coumaphos is not a dermal irritant or a
sensitizer.  However, in an effort to mitigate any potential for dermal
exposure, the proposed label requires the use of chemical resistant
gloves by applicators.  After six weeks, at the time of disposal,
residues have significantly decreased, so post-application exposure is
minimal.  Since most beehives are located outdoors, there is negligible
potential for inhalation exposure, at any time, to the applicator or
during post-application activities.  Therefore, while short- and
intermediate dermal and inhalation endpoints for coumaphos have
previously been identified, risk assessments for occupational exposure
are not required for this proposed new use.

Environmental Justice Considerations

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

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures. 
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Surveys of Food Intake by Individuals (CSFII) and are used in pesticide
risk assessments for all registered food uses of a pesticide.  These
data are analyzed and categorized by subgroups based on age, season of
the year, ethnic group, and region of the country.  Whenever
appropriate, nondietary exposures based on home use of pesticide
products and associated risks for adult applicators and for toddlers,
youths, and adults entering or playing on treated areas post-application
are evaluated.  Further considerations are currently in development as
OPP has committed resources and expertise to the development of
specialized software and models that consider exposure to bystanders and
farm workers as well as lifestyle and traditional dietary patterns among
specific subgroups.

Review of Human Research

This risk assessment does not rely on any data from studies in which
human subjects were intentionally exposed to a pesticide or other
chemical.

Recommendations

Based on the results of our assessment, HED recommends the establishment
of the following permanent tolerances for combined residues of coumaphos
and coumaphos-PO:

	Honey	0.15 ppm

	Honeycomb	45 ppm

	

Additional Data Needs

None

2.0	Ingredient Profile

Coumaphos is an organophosphate insecticide/acaricide currently used for
the control of mites and insects in or on livestock.  The chemical
structure and nomenclature of coumaphos are presented in Table 2.1, and
the physicochemical properties of the technical grade coumaphos are
presented in Table 2.2.  The proposed directions for the new use of
coumaphos in beehives are summarized in Table 2.3.  The proposed use is
similar to currently allowed Section 18 emergency uses, except that the
proposed use would allow treatment during honey flow (the period of
honey accumulation before harvest).  The current Section 18 uses require
a 14-day withdrawal period between treatment and the beginning of honey
collection.  

Common Name	Coumaphos

Molecular Formula	C14H16ClO5PS

Molecular Weight	362.78

IUPAC Name	O-3-chloro-4-methyl-2-oxo-2H-chromen-7-yl O,O-diethyl
phosphorothioate

CAS Name	O-(3-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl) O,O-diethyl
phosphorothioate

CAS Registry Number	56-72-4

End-use Product (EP)	CheckMite+ Beehive Pest Control Strips (10% ai),
EPA Registration #11556-???*

Chemical Class	Organophosphate

* Not yet registered.  

Table 2.2.	Physicochemical Properties of Technical Grade Coumaphos.

Parameter	Value	Reference

Melting Point/Range	90-95ºC	DP #207352, Chris Olinger, 12/12/1994

pH	Not available

	Specific Gravity	1.47	Occupational Health Services MSDS for Coumaphos,
2/12/1991

Water Solubility (20ºC)	2.0 mg/100 mL	DP #207352, Chris Olinger,
12/12/1994

Solvent Solubility (g/100 mL at 20ºC)	Acetone	23.82

Diethyl phthalate	21.50

Ethanol	0.9

Xylene 	0.9

Octanol	0.13

Mineral spirits	0.09

Hexane	0.07

	Vapor Pressure (20ºC)	1 x 10-7 mm Hg 

	Dissociation Constant (pKa)	Not required

	Octanol/Water Partition Coefficient (Log[KOW])	Not available

	UV/Visible Absorption Spectrum	Not available

	 

 Table 2.3.	Summary of Proposed Directions for the Use of Coumaphos in
Beehives.

Application Timing, Type, and Equipment 1	Formulation

[EPA Reg. #]	Application Rate	Max. # of Applications per Season	Max.
Seasonal Application Rate	PHI

(Days)

For Control of Varroa Mites

At anytime during the year, hang strips between combs near center of the
brood chamber for 6 weeks.	10% strips

[11556-???]	1 strip per 5 combs in brood chamber 2	2	4 strips per hive.
0

For Control of Small Hive Beetles

At anytime during the year, attach strip to 4x4 inch corrugated plastic
or cardboard and place, strip-side down, in center of bottom board. 
Leave strip in place for 6 weeks.	10% strips

[11556-???]	1 strip/hive	4	4 strips per hive.	0

1. Do not leave strips in hive for more than 45 days.

2. As a brood chamber typically has 9-10 combs, this would be a rate of
2 strips per hive.

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

3.1	Hazard and Dose-Response Characterization

The mammalian toxicology database for coumaphos is complete.  Acute
toxicity studies in rats and rabbits; an acute delayed neurotoxicity
study in hens; subchronic oral and dermal studies in rats;
chronic/carcinogenicity studies in rats, mice, and dogs; developmental
toxicity studies in rats and rabbits; a two-generation study in rats;
mutagenicity studies; and a metabolism study were discussed and
considered in the Reregistration Eligibility Decision (RED) for
coumaphos (  HYPERLINK "http://www.epa.gov/oppsrrd1/REDs/0018.pdf" 
http://www.epa.gov/oppsrrd1/REDs/0018.pdf ).  Acute and subchronic
neurotoxicity studies in rats were received subsequent to the RED and
were considered in the Reregistration Eligibility Decision Addendum and
FQPA Tolerance Reassessment Progress Report (TRED) for coumaphos ( 
HYPERLINK "http://www.epa.gov/oppsrrd1/REDs/0018tred.pdf" 
http://www.epa.gov/oppsrrd1/REDs/0018tred.pdf ).  Subsequent to the
TRED, a developmental neurotoxicity study and a comparative
cholinesterase study in rats were received; these studies are discussed
below and were considered in the current risk assessment.

The acute toxicity of coumaphos is high via the oral route of exposure
(Category I), moderate via the inhalation route (Category II), and
slight via the dermal route (Category III).  Coumaphos is not a dermal
sensitizer or a dermal irritant.

Coumaphos, an organophosphate insecticide, primarily affects the nervous
system through cholinesterase (ChE) inhibition.  Females are
consistently more sensitive to the cholinergic effects than males.  In
the acute oral toxicity studies, female rats are approximately 17 times
more sensitive to the toxic and lethal effects of coumaphos compared to
male rats.  In a single dose oral study, female rats had ChE inhibition
and cholinergic symptoms at much lower doses than male rats.  In a
short-term (5 days) dermal toxicity study, brain ChE inhibition was the
most sensitive indication of the toxic effects of coumaphos dermal
treatment.  In subchronic and chronic studies in rats, the magnitude of
ChE inhibition in red blood cell and plasma and brain was also more
pronounced in females, compared to males.  Coumaphos does not cause
delayed neuropathy.  In chronic studies, systemic effects other than
cholinergic toxicity include decreases in body weight gain.

There was no evidence of malformations or decreases in the number of
pups and/or litter or surviving offspring in any of the developmental
toxicity or reproduction studies.  In developmental toxicity studies in
rats and rabbits, no developmental toxicity was observed, while clinical
signs of ChE toxicity were seen in the maternal animals.  In a
two-generation reproduction study, ChE inhibition was noted in both
parents and offspring, with parents more susceptible.  Reproductive
toxicity was not observed in this study.  

In a developmental neurotoxicity study (MRID 45912101), coumaphos was
administered to 30 parent female Wistar rats/dose in the diet at
concentrations of 0, 1, 5, or 30 ppm from gestation day 0 through
postnatal day 21.  The average daily intake of coumaphos was 0, 0.09,
0.47, and 2.77 mg/kg/day during gestation and 0, 0.22, 1.06, and 7.40
mg/kg/day during lactation, for the 0, 1, 5, and 30 ppm groups,
respectively.  In the dams, the maternal LOAEL was based on 21% and 78%
inhibition of plasma and erythrocyte ChE activities, respectively, at
the mid dose (0.47 mg/kg/day).  Higher inhibition of plasma and
erythrocyte ChE activities (68% and 85%, respectively), as well as brain
ChE inhibition (36%), was observed at the high dose.  In offspring,
changes in brain morphometry in PND 21 males, as well as inhibition of
plasma, erythrocyte, and brain ChE activities, were noted only at the
high dose.  Since no effects, including ChE inhibition, were seen in the
offspring at the mid dose, where ChE activities were depressed in dams
at this same dose, the developmental neurotoxicity study shows that
there is no increased susceptibility of the young.  Consistent with the
other mammalian toxicity studies, female pups were more sensitive to
cholinergic effects than males; at the high dose, female plasma,
erythrocyte, and brain ChE activities were inhibited 27%, 33%, and 8%,
respectively, but only plasma ChE activity was significantly inhibited
(30%) at this dose in males.

The relative sensitivities to ChE inhibition at peak inhibition by
coumaphos were measured in neonatal and young adult Wistar rats (MRID
46258301).  In these studies, coumaphos was administered in a single
gavage dose of 0, 0.25, 0.50, or 1.0 mg/kg/day to neonatal (postnatal
day 11) rats and of 0, 1.0, 2.0 or 4.0 mg/kg/day to young adult
(postnatal day 58-63) rats.  Peak ChE inhibition was measured 8 or 4
hours following dosing to young adult or neonatal rats, respectively. 
In young adults, the NOAEL/LOAEL was 1.0/2.0 mg/kg, based on plasma
(male/females=33%/38%) and erythrocyte (males/females=34%30%) ChE
inhibition.  Brain ChE activities were not inhibited at any dose level
in males or females.  In neonates, the NOAEL/LOAEL was 0.25/0.5 mg/kg
based on plasma (males/females 19%/22%), erythrocyte (males /females
20%/19%), and brain (8%/7%) ChE inhibition.  The study shows that
coumaphos treatment of PND 11 male and female pups by a single gavage
dose results in ChE inhibition at a lower dose than similar treatment of
PND 58-63 male and female young adults.  In addition, brain ChE was
inhibited at the same LOAEL as plasma and erythrocyte ChE in male and
female neonatal pups, whereas young adults showed no brain ChE
inhibition at any dose level in males or females.  Therefore, this
comparative ChE study does demonstrate increased quantitative
susceptibility of the offspring.

Coumaphos is not carcinogenic and is classified as a Group E chemical,
indicating that it is “Not Likely” to be carcinogenic in humans via
relevant routes of exposure.  This classification is based on adequate
studies in two animal species.  No evidence of mutagenicity was seen in
any study. 

	

Following oral administration, coumaphos is rapidly broken down into
nontoxic metabolites and eliminated in urine and feces with no evidence
of bioaccumulation. The plasma half-life ranges from approximately 3 to
5 hours.  Tissue residues of coumaphos are highest in fat, kidney, liver
and muscle.  Approximately 63 - 83% of administered dose is excreted in
the urine within 24 hours and 76-96% is excreted within 7 days.   Dermal
absorption is estimated to be 100%.  This estimate is based on the
observation that erythrocyte ChE inhibition is observed in both oral and
dermal rat studies at similar dose levels.  Inhalation absorption is
also assumed to be 100%.

3.2	FQPA Considerations

As of December 2006, the mammalian toxicology database for coumaphos is
complete for FQPA considerations, including an acceptable two-generation
reproduction study in rats; acceptable prenatal developmental toxicity
studies in rats and rabbits; acceptable acute, subchronic, and
developmental neurotoxicity studies in rats, and an acceptable
comparative ChE assay in rats.  There was no evidence of increased
qualitative or quantitative susceptibility of the offspring in the
developmental, reproduction, or developmental neurotoxicity studies. 
Increased quantitative susceptibility of the offspring was observed in
the comparative ChE study in that ChE inhibition was seen at a lower
dose in neonatal rats, compared to young adult rats.  The degree of
concern for this comparative ChE study is low because the effects are
well characterized and there are clear NOAELs and LOAELs for both
neonatal and adult animals.  Furthermore, there are no residual
uncertainties for pre- and/or postnatal toxicity for the comparative ChE
study because the endpoint of concern is the one used for the acute
dietary exposure risk assessment and a more protective endpoint (based
on long-term exposure) is used for chronic dietary exposure risk
assessment.

In addition to the hazard data, the coumaphos risk assessment team
evaluated the quality of the exposure data and found no residual
uncertainties.  The acute dietary exposure assessment is based on 2002
PDP monitoring data for beef, 2004 PDP monitoring data for milk, and
field trial data for honey and assumes 100% crop treated.  The chronic
assessment is based on the latest PDP monitoring data for beef and milk,
as well as average field trial data for honey; this analysis also
assumes 100% crop treated.  For water, estimates from conservative Tier
1 screening models were used.  By using these conservative assessments,
acute and chronic exposures/risks to infants and children will not be
underestimated.  There are currently no registered or proposed
residential uses of coumaphos.  Based on the exposure and hazard data,
the coumaphos risk assessment team concluded that the FQPA safety factor
can be reduced to 1X.

3.3	Hazard Identification and Toxicity Endpoint Selection

3.3.1	Acute Reference Dose (aRfD) - Females age 13-49

A separate acute dietary endpoint for females age 13-49 years was not
selected because coumaphos does not induce any effects attributable to a
single dose, including developmental effects, that would affect this
population subgroup. 

3.3.2	Acute Reference Dose (aRfD) - General Population

Study Selected:  Comparative cholinesterase (ChE) study in rats

MRID Number:  46258301

Dose and Endpoint for Establishing aRfD:  0.25 mg/kg (NOAEL), based on
plasma (19%/22%; M/F), RBC (20%/19%; M/F), and brain (8%/7%; M/F) ChE
inhibition in PND 11 males and females observed at 0.5 mg/kg (LOAEL)

Uncertainty Factor(s):  100X (10X for interspecies variability, 10X for
intraspecies variability)

Comments about Study/Endpoint/Uncertainty Factor:  

The acute dietary endpoint for the general population is based on
plasma, erythrocyte and brain ChE inhibition (measured at time of peak
inhibition) in PND 11 rats following a single oral dose in the
comparative ChE study.  This endpoint is considered appropriate for the
general population because the effects were observed following a single
dose, and the route of administration (oral) is appropriate for dietary
considerations.  Previously, the acute dietary endpoint was based on
plasma and erythrocyte ChE inhibition observed in rats at a LOAEL of 2
mg/kg (no NOAEL was observed) in an acute neurotoxicity study.  The
newly selected endpoint is protective of this effect, as well as all
others seen in the mammalian toxicology database attributable to a
single dose.

3.3.3	Chronic Reference Dose (cRfD) 

Study Selected:  Chronic toxicity study in dogs

MRID Number:  43055301

Dose and Endpoint for Establishing cRfD:  0.025 mg/kg (NOAEL), based on
plasma and RBC ChE inhibition in males and females observed at
0.775/0.705 mg/kg/day (LOAEL; M/F) 

Uncertainty Factor(s):  100X (10X for interspecies variability, 10X for
intraspecies variability)

Comments about Study/Endpoint/Uncertainty Factor:  

The chronic dietary endpoint is based on plasma and RBC ChE inhibition
in males and females in the chronic toxicity study in dogs.  This
endpoint is considered appropriate for chronic dietary exposure due to
the oral route of administration and the chronic duration of exposure. 
The study and endpoint were selected because they are protective of
effects observed in all the other available studies, including offspring
effects seen in the recently submitted developmental neurotoxicity
study.

3.3.4	Incidental Oral Exposure (Short- and Intermediate-Term) 

There are currently no registered or proposed uses of coumaphos in or
around residences; therefore, incidental oral exposure is not expected
and an incidental oral exposure assessment is not warranted at this
time.

3.3.5	Dermal Absorption

Previously, the HED HIARC determined that in the absence of dermal
absorption data and considering the observation that erythrocyte ChE
inhibition is observed in both oral gavage and dermal rat studies at
similar dose levels, the default of 100% absorption should be used. 
However, note that the proposed use on beehives is not residential and
is unlikely to result in occupational dermal exposure; therefore, a
dermal exposure assessment is not required for this risk assessment.

3.3.6	Dermal Exposure (Short-, Intermediate- and Long-Term) 

To assess short-term dermal exposure, the HED HIARC previously
determined that a dermal NOAEL of 5.0 mg/kg/day should be used, based on
brain ChE inhibition in female rats at 10 mg/kg/day from a 5-day dermal
toxicity study (MRID 44749401).  To assess intermediate-term dermal
exposure, the HED HIARC previously determined that a dermal NOAEL of 0.5
mg/kg/day should be used, based on RBC ChE inhibition in female rats at
1.1 mg/kg/day from a 21-day dermal toxicity study (MRID 42084901).  A
dose and endpoint have not been selected to assess long-term dermal
exposure because the use pattern and exposure scenarios for the
registered and proposed uses do not indicate a need for long-term dermal
risk assessment.  

Note that because the proposed use is not residential and is unlikely to
result in occupational dermal exposure, a dermal exposure assessment is
not required for this risk assessment.

3.3.7	Inhalation Exposure (Short-, Intermediate- and Long-Term) 

To assess short-term inhalation exposure, the HED HIARC previously
determined that an oral LOAEL of 2.0 mg/kg should be used (a NOAEL was
not determined), based on plasma and RBC ChE inhibition in male and
female rats from an acute neurotoxicity study (MRID 44544801).  To
assess intermediate-term inhalation exposure, the HED HIARC previously
determined that an oral LOAEL of 0.2 mg/kg/day should be used (a NOAEL
was not determined), based on RBC ChE inhibition in rats from a
subchronic feeding study in rats (MRID 00126527).  A dose and endpoint
have not been selected to assess long-term inhalation exposure because
the use pattern and exposure scenarios for the registered and proposed
uses do not indicate a need for long-term inhalation risk assessment.  

Note that because the proposed use is not residential and is unlikely to
result in occupational inhalation exposure, an inhalation exposure
assessment is not required for this risk assessment.

3.3.8	Level of Concern for Margin of Exposure  TC \l3 "3.5.8	Level of
Concern for Margin of Exposure 

Residential and occupational exposure assessments are not required for
the risk assessment of the proposed use of coumaphos on beehives.  See
sections 6.0 and 9.0 for more details.

3.3.9	Recommendation for Aggregate Exposure Risk Assessments

As per FQPA, 1996, when there are potential residential exposures to a
pesticide, aggregate risk assessment must consider exposures from three
major sources: oral, dermal and inhalation exposures.  At this time, an
aggregated exposure risk assessment across these routes of exposure is
not required since there are no registered or proposed residential uses
for coumaphos.  The aggregate assessment, in this case, consists of just
the dietary sources of exposure (i.e., food and water).

3.3.10	Classification of Carcinogenic Potential

Coumaphos is classified as a Group E chemical, indicating that it is
“Not Likely” to be carcinogenic in humans via relevant routes of
exposure.  This classification is based on adequate studies in two
animal species.  No evidence of mutagenicity was seen in any study. 

3.3.11	Summary of Toxicological Doses and Endpoints for Coumaphos for
Use in Human Risk Assessments

Table 3.3.11a.  Toxicological Doses and Endpoints for Coumaphos for Use
in Dietary and Non-Occupational Human Health Risk Assessments.

Exposure/

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

Acute Dietary (General Population, including Infants and Children)	NOAEL
= 0.25 mg/kg	UFA= 10x

UFH = 10x

FQPA SF = 1x

	Acute RfD = 0.0025 mg/kg

aPAD = 0.0025 mg/kg/day	Comparative cholinesterase study in rats

LOAEL = 0.5 mg/kg based on plasma (19%/22%; M/F), RBC (20%/19%; M/F),
and brain (8%/7%; M/F) ChE inhibition in PND 11 males and females

Chronic Dietary (All Populations)	NOAEL = 0.025 mg/kg/day	UFA= 10x

UFH = 10x

FQPA SF = 1x

	Chronic RfD = 0.00025

mg/kg/day

cPAD = 0.0003 mg/kg/day	Chronic toxicity study in dogs LOAEL =
0.775/0.705 mg/kg/day (M/F) based on plasma and RBC ChE inhibition in
males and females

Incidental Oral (All Durations)	The proposed use is not residential, so
incidental oral exposure is not expected.

Dermal 

(All Durations)	The proposed use is not residential, so dermal exposure
due to residential use is not expected.

Inhalation

(All Durations)	The proposed use is not residential, so inhalation
exposure due to residential use is not expected.

Cancer	Classification:  “Not likely to be Carcinogenic to Humans” 

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  UFDB = to account for the absence of key data (i.e.,
lack of a developmental immunotoxicity study).  FQPA SF = FQPA Safety
Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD =
reference dose.  MOE = margin of exposure.  LOC = level of concern.

Table 3.3.11b.  Summary of Toxicological Doses and Endpoints for
Coumaphos for Use in Occupational Human Health Risk Assessments.

Exposure/

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

Dermal 

(All Durations)	The proposed use is unlikely to result in occupational
dermal exposure, so a dermal exposure assessment is not required for
this risk assessment.

Inhalation

(All Durations)	The proposed use is unlikely to result in occupational
inhalation exposure, so an inhalation exposure assessment is not
required for this risk assessment.

Cancer 	Classification:  “Not likely to be Carcinogenic to Humans” 

3.4	Endocrine Disruption

EPA is required under the Federal Food Drug and Cosmetic Act (FFDCA), as
amended by FQPA, to develop a screening program to determine whether
certain substances (including all pesticide active and other
ingredients) "may have an effect in humans that is similar to an effect
produced by a naturally occurring estrogen, or other such endocrine
effects as the Administrator may designate."  Following the
recommendations of its Endocrine Disruptor Screening and Testing
Advisory Committee (EDSTAC), EPA determined that there was scientific
basis for including, as part of the program, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system.  EPA also
adopted EDSTAC’s recommendation that the Program include evaluations
of potential effects in wildlife.  For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA has authority to
require the wildlife evaluations.  As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).

In the available toxicity studies on coumaphos, there was no estrogen-,
androgen-, and/or thyroid-mediated toxicity.

When the appropriate screening and/or testing protocols being considered
under the Agency’s EDSP have been developed, coumaphos may be
subjected to additional screening and/or testing to better characterize
effects related to endocrine disruption.

4.0	Public Health and Pesticide Epidemiology Data

No public health or epidemiology data were used in the development of
this risk assessment.

5.0	Dietary Exposure/Risk Characterization

HED Residue Chemistry Summary Document (D334589, W. Drew, 2/29/2007)

HED Dietary Exposure Memo (D335163, S. Piper, 1/9/2007)

Reregistration Eligibility Decision
(http://www.epa.gov/oppsrrd1/REDs/0018.pdf)

Reregistration Eligibility Decision Addendum and FQPA Tolerance
Reassessment Progress Report (TRED) for coumaphos
(http://www.epa.gov/oppsrrd1/REDs/0018tred.pdf)

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

5.1.1	Metabolism in Primary Crops

No primary crop metabolism data are required, as coumaphos is not
registered for use on plants.

5.1.2	Metabolism in Rotational Crops

No rotational crop metabolism data are required, as coumaphos is not
registered for use on plants.

5.1.3	Metabolism in Livestock

The nature of the residue in livestock has been established, based on an
adequate cow metabolism study reflecting dermal dosing.  In livestock,
the residues of concern (ROC) for risk assessment and for tolerance
expression are coumaphos and its oxygen analog (coumaphoxon, also
referred to as coumaphos-PO).

The existing animal data are adequate for purposes of the proposed use
on beehives.  In honeybee products (honey and honeycomb), the ROC are
coumaphos and its oxygen analog.

5.1.4	Analytical Methodology

Adequate LC/MS/MS methods are available to collect residue data and
enforce tolerances for coumaphos and its oxygen analog (coumaphos-PO) in
honey (Bayer Method 75043) and honeycomb (Bayer Method 75044).  The
limits of quantitation (LOQs) for both coumaphos and coumaphos-PO are
0.010 ppm in honey and 0.50 ppm in honeycomb (beeswax).  The limits of
detection (LODs) were not reported.  

For Bayer Method 75043, residues in honey are extracted by dissolving
the sample in 10% methanol in water.  Residues are then cleaned up using
a C 2 solid phase extraction (SPE) cartridge eluted with 70% ACN in
water, and the residues in the resulting eluate were analyzed by
LC/MS/MS.  For Bayer Method 75044, residues in beeswax are extracted by
dissolving the sample in isopropanol at 65ºC for 15-20 minutes, and
then diluting the extract with 0.1N NaOH at 65ºC.  Residues in the
extract are then purified using a ChemElut column.  After loading, the
column is rinsed with 5N formic acid, residues are eluted with ethyl
ether, and then concentrated. Residues are then re-dissolved in 70% ACN
in water, filtered, and analyzed via LC/MS/MS.  

Both methods used the same parameters for the LC/MS/MS analysis. 
Residues are separated using a reverse-phase ODS-2 column at 30ºC, with
an isocratic solvent gradient of ACN/water (4:1), each containing 0.1%
acetic acid.  The retention times for coumaphos and coumaphos-PO are
approximately 4.6 and 2.9 minutes, respectively.  Residues are
quantified by MS/MS using the m/z 363 to 227 transition for coumaphos
and the m/z 347 to 291 transition for coumaphos-PO.  The validated LOQs
for both compounds are 0.010 ppm in honey and 0.50 ppm in beeswax;
method LODs were not reported.  

The methods were subjected to independent laboratory validation (ILV)
studies.  For Method 75043, the overall average recovery of coumaphos
from honey was 94% (with standard deviation of 2%), and the overall
average recovery of coumaphos-PO was 93% (std. dev. 6%).  The
calibration curve correlation coefficients for coumaphos ranged from
0.9973 to 0.9999, while those for coumaphos-PO ranged from 0.9979 to
0.9999.  For Method 75044, the overall average recovery of coumaphos
from honeycomb was 77% (std. dev. 3%), and the overall average recovery
of coumaphos-PO was 80% (std. dev. 7%).  The calibration curve
correlation coefficient for coumaphos was 0.9971, while that for
coumaphos-PO was 0.9984.  

These methods were also validated in conjunction with the analysis of
beehive field trial samples, using control samples of honey fortified
with each analyte at 0.010 and 0.100 ppm and control samples of beeswax
fortified with each analyte at 0.50-5.00 ppm.  

Based on communications with FDA laboratories, the existing FDA
multiresidue methods can be used to enforce coumaphos and coumaphos oxon
tolerances in honey using the Luke or 'modified' Luke procedures. 
However, it is uncertain whether residues of the parent or oxon in
beeswax can be determined by the multiresidue Luke method since  the
'wax' would probably present interference problems.

5.1.5	Environmental Degradation

Coumaphos is persistent in the environment, with the exception that
aqueous photolysis is rapid (half-life 33 hours).  The half-life is much
greater than 30 days for hydrolysis; much greater than a year for
aerobic soil metabolism; and ca. 118 to 185 days for field dissipation. 
Coumaphos also appears to be immobile, with Kd values ranging from 61 to
298 for parent and from 91 to 161 for the degradate chlorferon. 
Coumaphos accounted for 0.4% of leachate from a sandy loam column and
less than 2% of leachate from columns of sand, silt loam, and silty clay
loam.

5.1.6	Pesticide Metabolites and Degradates of Concern TC \l3 "5.1.8
Pesticide Metabolites and Degradates of Concern 

Table 5.1.6.  Summary of Metabolites and Degradates to be included in
the Risk Assessment and Tolerance Expression.

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants

	Primary Crop	Not Applicable 1	Not Applicable1

	Rotational Crop	Not Applicable1	Not Applicable1

Livestock

	Ruminant	Parent and Coumaphoxon	Parent and Coumaphoxon

	Poultry	Not Applicable 2	Not Applicable 2

Drinking Water	Parent and Coumaphoxon	Parent and Coumaphoxon

1 There are currently no registered or proposed uses of coumaphos on
plants.

2 There are currently no registered or proposed uses of coumaphos on
poultry.

5.1.7	Drinking Water Residue Profile

The GENEEC and SCI-GROW screening models were used to estimate surface
water and groundwater concentrations of coumaphos and its oxygen analog,
coumaphoxon.  This degradate is considered in the drinking water
assessment, as it was in the assessment for consumption of food (honey
and livestock commodities).  The acute and chronic surface values were
incorporated directly into these dietary assessments under the DEEM-FCID
food categories “water, all sources” and “water, indirect, all
sources.”  The model and its description are available at the EPA
internet site:   HYPERLINK "http://www.epa.gov/oppefed1/models/water/" 
http://www.epa.gov/oppefed1/models/water/ .  

Tier I GENEEC screening model, representing a worst-case runoff scenario
for pesticides in

surface water, was used to estimate the upper-bound concentrations in
surface water. Total

coumaphos (coumaphos + coumaphoxon) acute and chronic estimated
environmental concentrations in drinking water derived from surface
water sources are not likely to exceed 1.86 ppb and 0.41 ppb,
respectively.

A Tier I screening model, SCI-GROW, was used to estimate total coumaphos
concentrations in ground water. This is an empirical model based on
field data from prospective ground water studies.  Estimated
environmental concentration of total coumaphos, representing acute and
chronic exposures to ground water, is 0.17 ppb.

The recommended application rate for coumaphos spent solution from dip
vat operations on non-agricultural land is 10,000 liters (L) of
coumaphos spent solution containing 10 ppb spread over a one-acre field.
 A conversion efficiency of coumaphos to coumaphoxon of 10.2% was
derived from available (supplemental) data on photodegradation in water.
 This conversion efficiency was used to estimate a coumaphoxon
application rate of 0.02 lbs ai/A.

Total coumaphos (coumaphos + coumaphoxon) acute and chronic estimated
environmental concentrations in drinking water were derived from surface
water sources.  HED believes the environmental concentrations (EECs) are
still conservative estimates because most of the coumaphos spent
solution resulting from the dip use on livestock is collected and
transported to concrete-lined evaporation pits, thereby negating any
potential for groundwater contamination.

Table 5.1.7.  Summary of Estimated Surface Water and Groundwater
Concentrations for Coumaphos and Coumaphoxon.

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

Acute	1.86	0.17

Chronic (non-cancer)	0.41	0.17

Chronic (cancer)	N/A	N/A

a From the Tier 1 GENEEC model.

b From the Tier 1 SCI-GROW model. 

5.1.8	Food Residue Profile

The available honeybee field trials are adequate, and support the
proposed use of coumaphos-impregnated strips (containing 10% ai) in
beehives for up to 45 days during honey flow.  The number and
distribution of the field trials are adequate, and a sufficient number
of samples were collected at the appropriate intervals.  The field
trials are supported by the available storage stability data, and
residues of coumaphos and coumaphos-PO in honey and beeswax were
determined using adequate LC/MS/MS methods.

The honey processing data are adequate, and indicate that the processing
of raw honey by heating and filtration will reduce coumaphos residues in
honey by 0.5x.  Coumaphos residues were shown to partition largely into
beeswax, which had an average processing factor of approximately 25x.

International Residue Limits

There are Canadian MRLs set at 0.5 mg/kg, calculated on the fat content,
for coumaphos (defined as coumaphos, per se) in meat, meat byproducts,
and fat of cattle, goats, horses, hogs, poultry, and sheep.  As of
December 2006, there are currently no Mexican or Codex MRLs for
coumaphos.

5.2	Dietary Exposure and Risk

HED Dietary Exposure Memo (D335163, S. Piper, 1/9/2007)

Acute and chronic dietary exposure and risk assessments were conducted
using the Dietary Exposure Evaluation Model (DEEM-FCID™, Version
2.03), which uses food consumption data from the U.S. Department of
Agriculture’s Continuing Surveys of Food Intakes by Individuals
(CSFII) from 1994-1996 and 1998.  Cancer dietary exposure and risk
assessments are not required since coumaphos is classified as “Not
likely to be Carcinogenic to Humans”.  The dietary exposure and risk
assessments for coumaphos include the following:  (1) Section 3 requests
for coumaphos in honey; (2) a new acute toxicological endpoint; (3) and
the latest monitoring data for beef and milk.  Table 5.2 presents a
summary of the acute and chronic dietary exposure and risk estimates for
coumaphos.

5.2.1	Acute Dietary Exposure/Risk

A partially refined acute dietary exposure assessment was conducted to
estimate the dietary exposure and risk associated with the registration
of coumaphos.  The acute dietary exposure assessment incorporated 2002
PDP monitoring data for beef and 2004 PDP monitoring data for milk. 
Field trial data were used for honey and support the proposed use
pattern.  The dietary exposure assessment assumes 100% crop treated for
the acute analysis.  

The GENEEC and SCI-GROW screening models were used to estimate surface
water and groundwater concentrations of coumaphos and its oxygen analog,
coumaphoxon.  Tier 1 GENEEC screening model, representing a worst-case
runoff scenario for pesticides in surface water, was used to estimate
the upper-bound concentrations in surface water.  Total coumaphos
(coumaphos + coumaphoxon) acute estimated environmental concentrations
in drinking water derived from surface water sources are not likely to
exceed 1.86 ppb.

The acute dietary risk estimates are below HED’s level of concern
(<100 % aPAD) for the U.S. population and all population subgroups. 
Combined dietary exposure from food and drinking water at the 99.9th
percentile of exposure is 15% of the aPAD for the U.S. population and
38% of the aPAD for all infants (<1 yr), the most highly exposed
population subgroup.

  TC \l3 "5.2.1  Acute Dietary Exposure/Risk 

Chronic Dietary Exposure/Risk

A partially refined chronic dietary exposure assessment was conducted to
estimate the dietary risks associated with the registration of
coumaphos.  The chronic dietary exposure assessment incorporated the
latest PDP monitoring data, average field trial data for honey, and
assumed 100% crop treated.  Total coumaphos (coumaphos + coumaphoxon)
chronic estimated environmental concentrations in drinking water derived
from surface water sources are not likely to exceed 0.41 ppb.

The chronic dietary risk estimates are below HED’s level of concern (<
100% of the cPAD) for the U.S. population and all population subgroups. 
Combined dietary exposure from food and drinking water is 6% of cPAD for
the U.S. population and 13% of the cPAD for all infants (<1 yr), the
most highly exposed population subgroup.

Table 5.2.  Summary of the Dietary Exposure and Risk Estimates for
Coumaphos.

Population Subgroup	Acute Dietary

(99.9 Percentile)	Chronic Dietary	Cancer

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

(mg/kg/day)	% cPAD	Dietary Exposure

(mg/kg/day)	Risk

General U.S. Population	0.000370	15	0.000015	5.9	N/A	N/A

All Infants (< 1 year)	0.000945	38	0.000032	13

Children 1-2 years 	0.000399	16	0.000027	11

Children 3-5 years 	0.000383	15	0.000025	10

Children 6-12 years	0.000239	9.6	0.000018	7.1

Youth 13-19 years	0.000252	10	0.000012	5.0

Adults 20-49 years	0.000276	11	0.000013	5.3

Adults 50+ years	0.000199	8.0	0.000013	5.1

Females 13-49 years	0.000263	11	0.000012	5.0

5.3	Anticipated Residue and Percent Crop Treated (%CT) Information

The acute dietary assessment is based on PDP monitoring data for beef
and milk and on field trial data for honey; the acute analysis assumes
100% crop treated.  The chronic dietary exposure is based on PDP
monitoring data for beef and milk and on average residues from field
trials on honey; the chronic analysis assumes 100% crop treated.

6.0	Residential (Non-Occupational) Exposure/Risk Characterization

There are currently no registered or proposed uses of coumaphos in or
around residences; therefore, risk assessments for residential
(non-occupational) exposure are not warranted at this time.

7.0	Aggregate Risk Assessments and Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide
exposures and risks from three major sources:  food, drinking water, and
residential exposures.  In an aggregate assessment, exposures from
dietary and residential sources are added together and compared to
quantitative estimates of hazard (e.g., a NOAEL), or the risks
themselves can be aggregated.  When aggregating exposures and risks from
various sources, HED considers both the route and duration of exposure. 
Because there are no residential uses for coumaphos at this time, the
aggregate assessments include dietary exposures only.

7.1	Acute Aggregate Risk

Rather than using back-calculated drinking water levels of comparison
(DWLOCs), estimates of pesticide residues in drinking water were
incorporated directly into the dietary exposure analysis to assess
aggregate acute risk.  Therefore, the acute aggregate risk estimates are
equivalent to the acute dietary risk estimates provided in Table 5.2. 
The acute aggregate risks associated with the registered and proposed
uses of coumaphos do not exceed HED’s level of concern for the general
U.S. population or any population subgroup.

7.2	 TC \l2 "7.1	Acute Aggregate Risk  TC \l2 "7.1	Acute Aggregate Risk
Short- and Intermediate-Term Aggregate Risk

Short- and intermediate-term aggregate assessments are not required
since none of the currently registered or proposed uses result in
residential exposure.  

7.3	Long-Term Aggregate Risk

None of the currently registered or proposed uses result in residential
exposure.  Estimates of pesticide residues in drinking water were
incorporated directly into the dietary exposure analysis to assess
aggregate chronic risk.  Therefore, the long-term aggregate risk
estimates are equivalent to the chronic dietary risk estimates provided
in Table 5.2.  The long-term aggregate risks associated with the
registered and proposed uses of coumaphos do not exceed HED’s level of
concern for the general U.S. population or any population subgroup.

7.4	Cancer Risk

Coumaphos has been classified by HED HIARC as “Not likely to be
Carcinogenic to Humans”; a cancer aggregate risk assessment is not
required.

8.0	Cumulative Risk Characterization/Assessment

  SEQ CHAPTER \h \r 1 FQPA (1996) stipulates that when determining the
safety of a pesticide chemical, the EPA shall consider, among other
things, available information concerning the cumulative effects on human
health that may result from dietary, residential, or other
non-occupational exposure to the pesticide chemical and other substances
that have a common mechanism of toxicity.  The reason for consideration
of other substances is due to the possibility that low-level exposures
to multiple chemical substances that cause a common toxic effect by a
common mechanism could lead to the same adverse health effect as would a
higher level of exposure to any of the substances individually.  A
person exposed to a pesticide at a level that is considered safe may, in
fact, experience harm if that person is also exposed to other substances
that cause a common toxic effect by a mechanism common with that of the
subject pesticide, even if the individual exposure levels to the other
substances are also considered safe.

The organophosphate pesticides (OPs) were established as the first
common mechanism group by EPA in 1999, based on their shared ability to
bind to and phosphorylate the enzyme acetylcholinesterase in both the
central (brain) and peripheral nervous systems.  Coumaphos is an OP
pesticide.   In December 2001, the Agency issued the "Preliminary OP
Cumulative Risk Assessment", available at   HYPERLINK
"http://www.epa.gov/pesticides/cumulative/pra_op_methods.htm__" 
http://www.epa.gov/pesticides/cumulative/pra_op_methods.htm .  In June
2002, the Agency released its Revised OP CRA, available at   HYPERLINK
"http://www.epa.gov/pesticides/cumulative/rra-op/__" 
http://www.epa.gov/pesticides/cumulative/rra-op/  , which included the
cumulative risk due to the OPs from exposures in food, drinking water,
and residential uses.  In August 2006, the Agency issued an update to
the 2002 Revised OP CRA document, which emphasized changes,
modifications, and amendments.  With the 2006 update, available at  
HYPERLINK "http://www.epa.gov/pesticides/cumulative/2006-op/index.htm__"
 http://www.epa.gov/pesticides/cumulative/2006-op/index.htm  , the
Agency has developed a highly refined and complex cumulative risk
assessment for the OPs that represents the state of the science
regarding existing hazard and exposure data and the models and
approaches used.  In accordance with the August 2006 deadline under the
FQPA, the Agency concluded that the results of the OP cumulative risk
assessment support a reasonable certainty of no harm finding.

ation and subpopulations using the Dietary Exposure Evaluation Model
(DEEM-FCID™, Version 2.03), which uses food consumption data from the
U.S. Department of Agriculture’s Continuing Surveys of Food Intakes by
Individuals (CSFII) from 1994-1996 and 1998 (personal correspondence, D.
Hrdy, 2/1/2007).  Consumption estimates at the 99.9th percentile of
exposure range from 21 grams of honey/day in all infants (<1 yr) to 96
grams/day in adults 50+ years, the population subgroup who reported the
greatest amount of honey consumed.  Estimates of honey consumption for
all other subpopulations, including children 1-2, 3-5, and 6-12 years;
youth 13-19 years; females 13-49 years; and adults 20-49 years are
within this range.

Although PDP data on coumaphos data in honey is not available,
monitoring for coumaphos in honey is conducted under the Food and Drug
Administration’s (FDA’s) Center for Food Safety and Applied
Nutrition (CFSAN) Surveillance Monitoring Program.  This monitoring
program is designed primarily for enforcement of EPA pesticide
tolerances on imported foods and domestic foods shipped in interstate
commerce.  In this monitoring program, domestic samples are generally
collected close to the point of production in the distribution system. 
Import samples are collected at the point of entry into US commerce. 
The emphasis in sample collection is on the agricultural commodity,
which is analyzed as the unwashed, whole (unpeeled), raw commodity. 
Processed foods are also included in the program.  A description of the
program and residue data for recent years can be found online ( 
HYPERLINK "http://vm.cfsan.fda.gov/~lrd/pestadd.html" 
http://vm.cfsan.fda.gov/~lrd/pestadd.html  ).  Because the emphasis of
this program is not on dietary exposure, it was used in the 2006
cumulative assessment mostly as a semi-quantitative check on the
potential for residues and as support for data from other sources.  Data
are available from 1996-2003.  Although the Agency has granted emergency
exemptions, starting in 1999, such that the coumaphos strips assessed in
this document have been and continue to be used on beehives in 40-46
states (  HYPERLINK "http://www.epa.gov/opprd001/section18" 
http://www.epa.gov/opprd001/section18  ), the FDA has detected coumaphos
in honey only once, in 2003, at levels lower than the level of
quantification.  Thus, FDA data indicates that there is a low
expectation of meaningful coumaphos residues in honey.

EPA does not believe that inclusion of anticipated coumaphos residues in
honey in the OP CRA will significantly modify the calculated risk.  This
conclusion is based on three factors.  First, honey is a low consumption
food, and, thus, even if honey contained quantifiable levels of OPs, it
would be unlikely to significantly alter the OP CRA.  Second, available
monitoring data indicates that, despite widespread use of coumaphos,
residues of coumaphos in honey as consumed are exceedingly low, if
present at all.  Finally, a prior risk assessment for coumaphos
indicated that aggregate risk from coumaphos was essentially unchanged
when honey containing levels of coumaphos residues found in field trials
was added to the coumaphos risk assessment.  (65 FR 49927, 49934-49935,
August 16, 2000).  In the current assessment, no discernible difference
in exposure was observed when coumaphos residues in honey and beeswax
were or were not included in an aggregate assessment (personal
correspondence, S. Piper, 1/25/2007).  If coumaphos exposure from honey
is insignificant in comparison to exposure to coumaphos from other uses
of the chemical, it necessarily is insignificant in comparison to
exposure to the more than 30 other OPs.  For these reasons, EPA
concludes that the establishment of a coumaphos honey tolerance will not
raise a concern regarding cumulative OP exposure.

9.0	Occupational Exposure/Risk Pathway

HED Occupational/Residential Exposure Memo, (D263035, M. Collantes,
2/11/2000)

This risk assessment addresses the proposed permanent new use of
coumaphos on beehives.  The end use product, CheckMite+ Bee Hive Pest
Control Strips, consists of plastic strips that are impregnated with 10%
liquid solution of the active ingredient, coumaphos.  These strips come
prepackaged and do not involve any mixing or loading of active
ingredient.  As previously mentioned, the proposed label would allow for
use of up to two strips hung in the hive’s brood chamber for control
of varroa mites, and the concurrent use of another 10% strip attached to
the bottom board for control of small hive beetles.  The strips could
remain in the hive for up to 45 days.  

This specific use pattern does not indicate significant potential for
applicator or post-application dermal or inhalation exposure. 
Occupational exposure resulting from use of these strips is highly
improbable, as the only potential times for worker contact are during
application, when the beehive keeper removes the strips from the
containers and places them in the hives, and during removal and disposal
of the strips six weeks later.  As indicated previously, coumaphos is
not a dermal irritant or a sensitizer.  However, in an effort to
mitigate any potential for dermal exposure, the proposed label requires
the use of chemical resistant gloves by applicators.  

After six weeks, at the time of disposal, residues have significantly
decreased, so post-application exposure is minimal.  Since most beehives
are located outdoors, there is negligible potential for inhalation
exposure, at any time, to the applicator or during post-application
activities.  Therefore, while short- and intermediate dermal and
inhalation endpoints for coumaphos have previously been identified, risk
assessments for occupational exposure are not required for this proposed
new use.

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

10.1	Toxicology  TC \l2 "10.1	Toxicology 

None

10.2	Residue Chemistry

None

  TC \l2 "10.2	Residue Chemistry 

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

None

References:

  TC \l1 "References: 

HED Residue Chemistry Summary Document (D334589, W. Drew, 2/28/2007)

HED Dietary Exposure Memo (D335163, S. Piper, 1/9/2007)

HED Occupational/Residential Exposure Memo, (D263035, M. Collantes,
2/11/2000)

Reregistration Eligibility Decision (RED) (  HYPERLINK
"http://www.epa.gov/oppsrrd1/REDs/0018.pdf" 
http://www.epa.gov/oppsrrd1/REDs/0018.pdf )

Reregistration Eligibility Decision Addendum and FQPA Tolerance
Reassessment Progress Report (TRED) (  HYPERLINK
"http://www.epa.gov/oppsrrd1/REDs/0018tred.pdf" 
http://www.epa.gov/oppsrrd1/REDs/0018tred.pdf )

Personal correspondence from D. Hrdy to K. Schumacher (2/1/2007, 04:09
PM)

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 TC \l1 "Appendix A:  Toxicology Assessment 

A.1	Toxicity Profile

Table A.1 is identical to the acute toxicity profile table included in
“The HED Chapter of the Reregistration Eligibility Decision Document
(RED) for Coumaphos” (J. Redden, 4/21/1995).  

 (♂)

LD50 = 17 mg/kg (♀)	I

81-2	Acute dermal - rat	00110598	LD50 > 2400 mg/kg (♂+♀)	III

81-3	Acute inhalation - rat	00110601	LC50 = 1.081 mg/L (♂)

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	81-5	Acute dermal irritation - rabbit	00110600	Not irritating	IV

81-6	Skin sensitization - rabbit	00110602	Not a sensitizer	N/A

 TC \l1 " Appendix D:  Review of Human Research 

	Page   PAGE  27  of   NUMPAGES  27