UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

	OFFICE OF PREVENTION, PESTICIDES

                   AND TOXIC SUBSTANCES

  SEQ CHAPTER \h \r 1 MEMORANDUM

Date:		5/19/09

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

PC Code:  059201	DP Barcode:  D364685

Decision No.:  406941	Registration No.:  Multiple Registrations

Petition No.:  N/A	Regulatory Action: Registration Review
Scoping Document

Risk Assessment Type:  N/A	Case No.:  0242

TXR No.:  N/A	CAS No.:  732-11-6

MRID No.:  N/A	40 CFR:  180.261

FROM:		Donna S. Davis, Chemist

		Matthew Lloyd, Industrial Hygienist

		Linda Taylor, Toxicologist

		Risk Assessment Branch VII

		Health Effects Division (7509P)

		Office of Pesticide Programs

THROUGH:	Jeff Dawson, Senior Chemist

		Michael S. Metzger, Chief

		Risk Assessment Branch VII

		Health Effects Division (7509P)

		Office of Pesticide Programs

TO:		Katie Weyrauch, CRM

		Special Review and Reregistration Division (7508P)

		Office of Pesticide Programs

Attached is the Health Effects Division’s (HED) human health risk
assessment scoping document for phosmet to support registration review.

Executive Summary

Phosmet, N-(mercaptomethyl) phthalimide S-(O,O-dimethyl
phosphorodithioate) is an organophosphate insecticide registered for use
on a variety of fruits, vegetables, and field crops, and for direct
application to cattle and swine.  All residential uses of phosmet have
been voluntarily cancelled.

Phosmet is acutely toxic via the oral and inhalation routes (Toxicity
Category II and I, respectively) of exposure, but is not acutely toxic
via the dermal route, is non-irritating to the skin, and is not an eye
irritant in the rabbit.  As with other organophosphates, the predominant
toxicological effects seen in various toxicity studies on phosmet are
those associated with cholinesterase inhibition (plasma, red blood cell,
and brain) that occur following all routes and durations of exposure.
Phosmet produces the associated clinical signs, including tremors,
shaking, unsteady gait, subdued mood, decreased activity, salivation,
muscle weakness, and convulsions in rats and rabbits (2-generation
reproduction study in rats and developmental toxicity studies in rats
and rabbits), and decreased cholinesterase activity in rats, mice, and
dogs following acute, subchronic, and chronic exposures.  In the acute
and subchronic neurotoxicity studies, cholinesterase activity is
significantly inhibited in the absence of clinical signs of
cholinesterase inhibition.

An acceptable dermal absorption study conducted in rats indicates a
dermal absorption factor of 10%.  Phosmet does not cause neurological
changes indicative of delayed neurotoxicity in the hen, and there is no
evidence of neuropathology in the acute, subchronic, and chronic studies
in rats, in the chronic dog study, or in the mouse long-term study.  No
treatment-related effects are observed in the functional observational
battery (FOB) parameters or on motor activity in the acute and
subchronic neurotoxicity studies in rats, and neuropathology is not
observed in either study.  Phosmet does not produce developmental or
reproductive toxicity, and there is no indication of an increased
sensitivity of offspring in rats or rabbits following prenatal and/or
postnatal exposure to phosmet.  In all of these studies, maternal or
parental NOAELs are lower or equivalent to the offspring NOAELs.  In
both the acute oral dose and repeat oral dose comparative cholinesterase
studies, submitted to the Agency since the 2000 risk assessment, a
4-fold sensitivity (based on NOAELs) was observed in the postnatal day
11 (PND 11) rat pups compared to the young adult rats.  Based on a
weight-of evidence evaluation of the mutagenicity and carcinogenicity
data for phosmet, there is suggestive evidence of carcinogenicity but
not sufficient for quantification of cancer risk.

Current dietary and non-dietary/non-occupational points of departure
(PoD) have been established separately for three populations (females
13+, infants and children and the general population, excluding females
13+ and infants and children).  A database uncertainty factor/FQPA
safety factor of 10X has been retained for females 13+ due to residual
concerns resulting from the lack of the gestational component of the
comparative cholinesterase assay (CCA).  Retention of the FQPA safety
factor for sensitivity of the young is not required for infants and
children since the PoD selected for risk assessment of this
subpopulation is for pups from a study in which young animals were
assessed.  The FQPA safety factor need not be retained for the third
subpopulation considered, “general population, excluding females 13+
and infants and children”, since the requested in-utero toxicity data
are not likely to impact the risk assessment PoDs for this
subpopulation.

All submitted toxicity data on phosmet have been reviewed by the Agency
and incorporated into the most recent decisions regarding regulatory
endpoints.  However, the toxicology database for phosmet is not
complete.  The gestational component of the CCA study, as well as an
immunotoxicity study, are outstanding.  Once these data have been
received and reviewed by the Agency, their impact on the regulatory
endpoints and safety factors for phosmet should be assessed.

Residue data required in the RED for cotton gin byproducts and residue
data previously required to support the Section 24(c) use on citrus
remain outstanding.

Revised acute and chronic dietary (food and water) risk assessments that
incorporate updated PoDs, consumption information, recent monitoring
data, updated percent crop treated information and revised drinking
water estimates are required to support the Registration Review of
phosmet.

Currently there are no uses that would result in residential handler
exposure.  The only residential post-application uses for phosmet are
associated exposure that can occur through the general public entering
commercial orchards or blueberry fields to pick their own fruits.  A
revised residential postapplication “pick your own” exposure and
risk assessment should be conducted that reflects current PoDs, levels
of concern (LOCs), is consistent with HED’s current exposure duration
definitions, and reflects current SOP parameters.

Revised aggregate risk assessments for phosmet which incorporate dietary
(food and water) exposures and updated residential “pick your own”
exposures are required for phosmet.

The phosmet handler exposure and risk assessments will need to be
revised to support Registration Review.  The revised assessment should
consider HED’s current definition of exposure duration, incorporate
new PoDs and current phosmet application rates and reflect current
standard operating procedures and policies for exposure assessment.

The postapplication risk assessment for all phosmet exposure scenarios
will need to be revised to reflect the April 2009 short- and
intermediate-term dermal PoDs as well as all current exposure assessment
policies and practices.

Phosmet residue definition and tolerance level differences currently
exist between the U.S. and Codex, Canada and Mexico.  At this time,
harmonization is not possible due to the difference in residue
definition.

Introduction

HED has evaluated the most recent human health risk assessment for
phosmet entitled Phosmet.  HED Revised Human Health Risk Assessment for
the Reregistration Eligibility Decision Document dated 2/09/2000
(D262365, C. Swartz) as well the most recent occupational risk
assessment entitled Phosmet: Revision To The Occupational
Postapplication Exposure and Risk Calculations for Phosmet dated
2/17/2009 (D296595, M. Lloyd) to determine if sufficient data are
available and if updates are needed to support registration review.
Additionally, HED has considered updates to its toxicity, exposure and
usage databases, and the latest Agency science policy and risk
assessment methodologies for phosmet.

Phosmet, N-(mercaptomethyl) phthalimide S-(O,O-dimethyl
phosphorodithioate) is an organophosphate insecticide registered for use
on a variety of fruits, vegetables, and field crops, and for direct
application to cattle and swine.  There are no residential uses of
phosmet.

Hazard Identification/Toxicology

The primary source for the toxicology status update was the 2000 Phosmet
Reregistration Eligibility Decision Document (RED).  An OPPIN
bibliography search for any newly submitted data was performed, and new
toxicity data submitted to the Agency since the 2000 assessment were
identified.  Additionally, to support registration review, a limited
search of the open literature was conducted for toxicity studies
involving phosmet.  A few articles were found on the generic issue of
organophosphate exposure and deficits in neurobehavioral performance.
No additional studies relevant to HED’s human health risk assessments
were found.

Phosmet is acutely toxic via the oral and inhalation routes of exposure
(Toxicity Category II and I, respectively), but is not acutely toxic via
the dermal route, is non-irritating to the skin, and is not an eye
irritant in the rabbit.  An acceptable dermal absorption study conducted
in rats indicates a dermal absorption factor of 10% is appropriate for
phosmet risk assessment.

Phosmet is an organophosphate insecticide. The predominant effects seen
in various toxicity studies on phosmet are those associated with
cholinesterase inhibition [plasma, red blood cell (RBC), and brain] that
occurs following all routes and durations of exposure.  Phosmet produces
the associated clinical signs, including tremors, shaking, unsteady
gait, subdued mood, decreased activity, salivation, muscle weakness,
convulsions in rats and rabbits (2-generation reproduction study in rats
and developmental toxicity studies in rats and rabbits), and decreased
cholinesterase activity in rats, mice, and dogs following acute,
subchronic, and chronic exposures.  In the acute and subchronic
neurotoxicity studies, cholinesterase activity is significantly
inhibited in the absence of clinical signs of cholinesterase inhibition.

Phosmet does not cause neurological changes indicative of delayed
neurotoxicity in the hen, and there is no evidence of neuropathology in
the acute, subchronic, and chronic studies in rats, in the chronic dog
study, or in the mouse long-term study.  No treatment-related effects
are observed in the functional observational battery (FOB) parameters or
on motor activity in the acute and subchronic neurotoxicity studies in
rats, and neuropathology is not observed in either study.  Phosmet does
not produce developmental or reproductive toxicity, and there is no
indication of an increased sensitivity of offspring in rats or rabbits
following prenatal and/or postnatal exposure to phosmet.  In all of
these studies, maternal or parental NOAELs are lower or equivalent to
the offspring NOAELs.  In both the acute oral dose and repeat oral dose
comparative cholinesterase studies, submitted to the Agency since the
2000 RA, a 4-fold sensitivity (based on NOAELs) was observed in the
postnatal day 11 (PND 11) rat pups compared to the young adult rats.  In
the mouse carcinogenicity study, phosmet causes increases in liver
carcinomas/adenomas in males and increased mammary gland tumors in
females.  Phosmet is not carcinogenic in rats.  Phosmet is considered to
cause direct effects on DNA in vitro, inducing mutations in bacteria and
mammalian cells in the absence of exogenous metabolic activation.  In
the in vivo systems, there is no evidence of a mutagenic effect.
Overall, the data indicate that phosmet has intrinsic mutagenic
potential that is not expressed in whole animals.  Based on a weight-of
evidence evaluation of the mutagenicity and carcinogenicity data for
phosmet, there is suggestive evidence of carcinogenicity but not
sufficient to assess human carcinogenic potential.

The decision to remove the 10X factor relative to hazard considerations
in the 2000 assessment was made based on having a complete toxicity data
base, which was thought to allow reasonable understanding in predicting
possible effects on infants and children, and the lack of increased
susceptibility in the fetuses and/or pups in the developmental and
reproduction studies.  This decision has since been changed as discussed
below.

A summary of the toxicological endpoints and doses selected for risk
assessment from the HED RED Chapter/Revised Risk Assessment may be found
in Attachment 1, Table 1.

Subsequent to completion of the 2000 risk assessment, a requirement for
comparative cholinesterase assays (CCA) to evaluate comparative
sensitivity in juvenile and adult rats [2006 Data-Call-In (DCI) notice
for a comparative cholinesterase study in adults and offspring] was
issued for all organophosphate pesticides under the Cumulative
Organophosphate (OP) Assessment.  Typically for the OPs, the CCA
includes the following components:  (1) Gestational exposures to
pregnant dams followed by sacrifice at gestational day 20.  Brain and
blood cholinesterase activity is measured in dams and fetuses; (2)
Acute, direct dosing to post-natal day 11 and young adult rats.  The
acute study is typically accompanied by a range-finding and time to peak
effect study; (3) Repeated, direct, dosing to juvenile rats (PND11-21)
and young adult rats.  Each study includes a control group and at least
3 treatment groups.  The repeated study is typically accompanied by a
range-finding and time to peak effect study.

Additionally, as specified in the revised 40 CFR Part 158 data
requirements, an immunotoxicity study on phosmet is a data requirement.

Since the 2000 Human Health Risk Assessment, an acute time of peak
cholinesterase depression study for phosmet in neonatal rats (MRID
47083001), an acute dose relative sensitivity study for phosmet in
neonatal and adult rats (MRID 47087401), an oral repeat dose relative
sensitivity study in neonatal and adult rats (MRID 47695401), a new
21-day dermal toxicity study (MRID 47262502) in rats, and an in vitro
comparative dermal penetration study (MRID 47262501) in rat and human
skin have been submitted on phosmet.  To data, there is no gestational
exposure component of the CCA available for phosmet.

Prior to submission of the repeat dose comparative cholinesterase study,
HED made revisions to the occupational postapplication exposure and risk
calculations for phosmet (2/17/09).  At that time, new dermal endpoints
and points of departure were selected for the short- and
intermediate-term dermal exposure scenarios using the subchronic oral
neurotoxicity (SCN) study in rats (MRID 44811801) as the primary study,
supported by the MPI 21-day dermal study in rats (MRID 44795801) as
co-critical.

Following the submission of the repeat dose CCA, new oral, dermal, and
inhalation endpoints and new points of departure (PoD) were again
recommended for the acute oral, chronic oral, and
non-occupational/non-dietary and occupational dermal and inhalation
exposure scenarios.  Each of these assessments (except occupational)
addresses three separate population subgroups (females 13+; infants and
children; and general population, excluding females 13+ and infants and
children).

For the acute dietary assessment (females 13+), the acute comparative
cholinesterase assay (MRID 47087401) was selected.  The point of
departure (PoD) BMDL10 of 3.56 mg/kg/day was selected, based on RBC
cholinesterase inhibition with an estimated BMD10 of 7.092 mg/kg/day.
The acute RfD (aRfD) and the acute population adjusted dose (aPAD) for
females 13+ is 0.00356 mg/kg/day.  The 10X FQPA safety factor was
retained for the lack of the gestational component of the comparative
cholinesterase assay.  Exposure to women who are pregnant or could
become pregnant and their fetuses are key life stages that OPP considers
in its risk assessments.  The results of recent epidemiology studies in
mothers and children highlights the importance of considering
gestational exposure for OPs (Whyatt et al. 2003, Berkowitz et al. 2004
; Eskenazi et al. 2004; Whyatt et al. 2004 ; Rauh et al. 2006 ; Eskenazi
et al. 2007).   Given that such data are available for many OPs and
sensitivity to juvenile pups has been shown in post-natal studies with
phosmet, in the absence of such a gestational exposure study to evaluate
the comparative sensitivity of dams and fetuses for cholinesterase
inhibition, OPP will retain the FQPA 10X safety factor to women of child
bearing age.

For the acute dietary assessment (infants and children), the acute
comparative cholinesterase assay (MRID 47087401) was selected. The PoD
BMDL10 of 1.2 mg/kg/day was selected, based on female PND 11 pup brain
cholinesterase inhibition with an estimated BMD10 of 1.9 mg/kg/day.  The
aRfD for infants and children is 0.012 mg/kg/day, and the aPAD is 0.012
mg/kg/day.  The FQPA Safety factor for sensitivity of the young was
removed for this assessment because sensitivity is already accounted for
based on the fact that young animals (PND 11) were assessed in this
study, and the response in the young animal is the basis of the dose and
endpoint.

For the acute dietary assessment (general population, excluding females
13+ and infants and children), the acute comparative cholinesterase
assay (MRID 47087401) was selected.  The PoD BMDL10 of 3.56 mg/kg/day
was selected, based on adult RBC cholinesterase inhibition with an
estimated BMD10 of 7.092 mg/kg/day.  The acute RfD and aPAD for the
general population, excluding females 13+ and infants and children are
both 0.0356 mg/kg/day.  The FQPA safety factor was removed because the
outstanding study which is the basis for retaining the factor for other
subpopulations is not pertinent for this subpopulation; i.e., the
database for this subpopulation is complete.

For the chronic dietary assessment (females 13+), the 7-day repeat dose
comparative cholinesterase assay (MRID 47695401) was selected.  The PoD
BMDL10 of 0.6 mg/kg/day was selected, based on adult RBC cholinesterase
inhibition at the BMD10 of 1.19 mg/kg/day.  The chronic RfD (cRfD) and
the chronic population adjusted dose (cPAD) for females 13+ is 0.0006
mg/kg/day.  The FQPA safety factor of 10X was retained for the lack of
the gestational component of the comparative cholinesterase assay (see
discussion under acute dietary assessment).

For the chronic dietary assessment (infants and children), the 7-day
repeat dose comparative cholinesterase assay (MRID 47695401) was
selected. The PoD BMDL10 of 0.16 mg/kg/day was selected, based on pup
RBC cholinesterase inhibition with an estimated BMD10 of 0.36 mg/kg/day.
 The cRfD and the cPAD for infants and children are both 0.0016
mg/kg/day.  The FQPA safety factor was removed for this assessment
because sensitivity is already accounted for based on the fact that
young animals were assessed in this study, and the response in the young
animal is the basis of the dose and endpoint.

For the chronic dietary assessment (general population, excluding
females 13+ and infants and children), the 7-day repeat dose comparative
cholinesterase assay (MRID 47695401) was selected.  The PoD BMDL10 of
0.6 mg/kg/day was selected, based on adult RBC cholinesterase inhibition
with an estimated BMD10 of 1.19 mg/kg/day.  The cRfD and the cPAD for
the general population, excluding females 13+ and infants and children
are both 0.006 mg/kg/day.  The FQPA safety factor was removed because
the outstanding study which is the basis for retaining the factor for
other subpopulations is not pertinent for this subpopulation; i.e., the
database for this subpopulation is complete.

For non-occupational, short- and intermediate-term dermal and inhalation
exposure scenarios, the acute oral comparative cholinesterase assay
(MRID 47087401) was selected for each population subgroup.  For females
13+ and the general population (excluding infants and children), the PoD
BMDL10 of 3.56 mg/kg/day was selected, based on adult RBC cholinesterase
inhibition with an esimtated BMD10 of 7.092 mg/kg/day.  The FQPA safety
factor of 10X is retained for females 13+ for the lack of the
gestational component of the comparative cholinesterase assay. For
infants and children, the PoD BMDL10 of 1.2 mg/kg/day was selected,
based on female PND 11 pup brain cholinesterase inhibition with an
estimated BMD10 of 1.9 mg/kg/day.  The FQPA safety factor was removed
because the outstanding study which is the basis for retaining the
factor for other subpopulations is not pertinent for this subpopulation;
i.e., the database for this subpopulation is complete.  Since the dermal
and inhalation exposure scenarios are based on an oral study, for the
dermal assessments, both a 10% dermal absorption factor and a 4.5X in
vitro dermal correction factor are applicable.  For the inhalation
assessments, inhalation toxicity is assumed to be equivalent to oral
toxicity.

For the occupational dermal and inhalation exposure assessments (short-
and intermediate-term, the 7-day repeat dose comparative cholinesterase
assay (MRID 47695401) was selected.  The PoD BMDL10 of 0.6 mg/kg/day was
selected, based on adult RBC cholinesterase inhibition with an estimated
BMD10 of 1.19 mg/kg/day.  Since the dermal and inhalation exposure
scenarios are based on an oral study, for the dermal assessments, both a
10% dermal absorption factor and a 4.5X in vitro dermal correction
factor are applicable.  For the inhalation assessments, inhalation
toxicity is assumed to be equivalent to oral toxicity.

A summary of the most recent toxicological endpoints and doses selected
for phosmet risk assessment may be found in Attachment 1, Table 2.

Conclusions

All submitted toxicity data on phosmet have been reviewed by the Agency
and incorporated into the most recent decisions regarding regulatory
endpoints.  However, the toxicology database for phosmet is not
complete.  The gestational component of the CCA study required under the
2006 organophosphate DCI remain outstanding.  Additionally an
immunotoxicity study is outstanding based on revised part 158 data
requirements (see Attachment 2 for DCI justification).  Once these data
have been received and reviewed by the Agency, their impact on the
regulatory endpoints and safety factors for phosmet should be assessed.

Dietary Exposure

Phosmet is a broad spectrum organophosphate insecticide that is marketed
in formulations including dusts, soluble concentrates, emulsifiable
concentrates, and wettable powders.  In an agricultural setting, phosmet
is used to control a variety of pests including maggots, moths, beetles,
weevils and aphids in terrestrial crops including fruit and nut trees,
grapes, blueberries, and field and vegetable crops.  Direct dermal
application to livestock to control fleas, lice, horn flies, sarcoptic
mange and ticks is permitted via sprays and a backrubber.

Phosmet can be applied using a wide array of application equipment.  In
agriculture, groundboom, airblast, chemigation and aerial applications
can be made.  Label application rates range from approximately 1 to 6 lb
ai/A depending on the crop.  Multiple foliar applications can be made to
some crops in a growing season.  Applications can generally be made up
to within seven to 14 days of harvest.  Post-harvest application of a
dust formulation to sweet potatoes is permitted using commercial dusting
equipment.

Residue chemistry data requirements articulated in the 2000 RED which
have not been resolved include the need for geographically
representative field trial residue data for blueberry and residue data
for cotton gin byproducts.  IR-4 has submitted blueberry field trial
data (MRID 44480201) to the Agency.  These data will need to be reviewed
as part of Registration Review.  Cotton gin byproduct data required in
the RED remain outstanding.

Additionally, in connection with a review of a request for a 24(c) use
of phosmet on citrus, HED recommended that additional field trial data
be required (6 orange and 2 grapefruit field trials).  At the time of
the recommendation, it was suggested that the total number of field
trials may be able to be reduced due to the regional limitation of the
citrus use.  However, subsequent to the approval of the use in Florida,
additional citrus growing states have requested expansion of the
regional registration; therefore, the full number of field trials
required to support a national registration should be provided.  These
data, once available, will be reviewed as part of the Registration
Review of phosmet.

used the Dietary Exposure Evaluation Model (DEEM™) which incorporated
consumption data generated in USDA’s Continuing Survey of Food Intakes
by Individuals 1989 – 1991.  The assessments include highly refined
exposure inputs using anticipated residues generated from field trials,
USDA Pesticide Data Program (PDP) data and FDA monitoring data with
adjustments for percent crop treated information and washing and cooking
factors.  The acute dietary assessment was conducted using a
probabilistic/Monte Carlo method.  Acute and chronic dietary risks were
not of concern.  The acute dietary exposure (food only) from phosmet
resulted in an estimated risk equivalent to 3.3% of the aPAD (acute
population adjusted dose) for the general population and 7.5% of the
aPAD for children 1 – 6 year of age, the most highly exposed
subpopulation.  The chronic dietary exposure (food only) from phosmet
resulted in an estimated risk equivalent to <1% of the cPAD (chronic
population adjusted dose) for the general population and all
subpopulations.

The most recent dietary risk assessments did not directly incorporate
drinking water values into the assessments, but relied on comparison of
modeled surface and ground water estimated environmental concentrations
(EECs) to back calculate DWLOCs (drinking water levels of concern) to
assess dietary risk from drinking water sources.  Both acute and chronic
EECs were below the calculated DWLOCs; therefore the Agency concluded
that acute and chronic aggregate dietary (food and water) risks were not
of concern.

Subsequent to the completion of the human health risk assessment to
support the RED noted above, additional toxicological information has
been submitted and reviewed which impacts the PoDs used to assess
dietary risk.  Additionally, the Agency notes that the dietary
assessment reflects outdated consumption and exposure information.
Finally, EFED has indicated that a revised drinking water assessment is
required for phosmet.  Therefore, to support the Registration Review of
phosmet, the Agency will need to conduct a revised dietary risk
assessment which incorporates updated PoDs, consumption information,
recent monitoring data, updated percent crop treated information and
revised drinking water estimates.  The Agency notes that based on
revisions to the dietary risk assessment, most notably the revised PoDs,
the acute and chronic dietary risks estimated are likely to increase.

Conclusions

Residue data required in the RED for cotton gin byproducts and residue
data previously required to support the Section 24(c) use on citrus
remain outstanding.

Revised acute and chronic dietary (food and water) risk assessments that
incorporate updated PoDs, consumption information, recent monitoring
data, updated percent crop treated information and revised drinking
water estimates are required to support the Registration Review of
phosmet.

Residential Exposure

Residential Handlers

Phosmet currently has no uses which would result in exposure to
residential handlers.  Therefore, a residential handler exposure and
risk assessment is not required for phosmet.

Residential (Non-dietary/Non-occupational) Postapplication

A residential postapplication risk assessment was performed in the
February 9, 2000 HED Human Health Risk Assessment.  In the 2000 risk
assessment, risks of concern were identified for residential exposures
that could have occurred through applications in and around the home or
contact with treated ornamental plants and/or pets.  Risk concerns
identified at the time led to the voluntary cancellation of phosmet uses
in and around homes and in residential settings.

Based on the current uses of phosmet in agricultural settings, phosmet
non-dietary/non-occupational postapplication exposure can occur through
the general public entering commercial orchards or blueberry fields to
pick their own fruits.  HED completed a “pick-your-own” exposure
assessment in November 2006 (D333957).  The endpoint selected for the
“pick-your-own” exposure scenarios at the time of the assessment was
cholinesterase inhibition (plasma, red blood cell, brain) and decreased
motor activity from a rat acute neurotoxicity study.  The PoDs for the
“pick-your-own” exposure scenario have been revised based on
toxicological data submitted since November 2006 (see Attachment 1,
Table 2).

The HED Phosmet Registration Review Team recommends that the residential
postapplication “pick your own” exposure and risk assessment be
revised to reflect the current toxicological endpoint selection, HED’s
current exposure duration definitions and all current exposure policies
and practices.  The Agency notes that the revised risk assessment using
these current points of departure and levels of concern will likely
result in risk estimates significantly higher than those reported in the
November 2006 risk assessment.

Aggregate Risk Assessment

Revised aggregate risk assessments for phosmet which incorporate dietary
(food and water) exposures and updated residential “pick your own”
exposures are required for phosmet.

Occupational Exposure

Occupational Handlers

Occupational handlers are likely to be exposed to phosmet during mixing
and loading of liquid concentrate/wettable powder formulations to
support aerial and groundboom equipment, applying sprays with aerial and
groundboom equipment, application of wettable powders as dusts, and
flagging to support aerial spray applications and during commercial
livestock applications.  In the 2000 RED, the Pesticide Handlers
Exposure Database was used as a source of surrogate data to assess the
occupational handler scenarios.  HED believes that potential
occupational handler exposure routes for phosmet are dermal and
inhalation.  Exposures may be of short-term (1 to 30 days) and
intermediate-term (30 days to 6 months).  Phosmet is not expected to be
used on a continuous long-term basis (greater than 6-months a year)
resulting in chronic exposure.

In the RED for phosmet, handler risk assessments were performed using
the short- and intermediate-term dermal endpoint from a 21-day dermal
rabbit toxicity study and using the short- and intermediate-term
inhalation endpoint from an oral acute neurotoxicity study in rats and
an oral subchronic neurotoxicity study in rats, respectively.  Since the
IRED was issued, HED has revised the definition of short-,
intermediate-, and long-term exposure and has received and evaluated new
toxicological data relevant to the phosmet occupational exposure
assessment. Additionally, subsequent to the RED, there have been
revisions to the phosmet product labels changing the maximum application
rate for a number of crops.  No new occupational handler assessments
have been conducted since the issuance of the RED.

Given the redefinition of exposure intervals, the selection of new PoDs
for occupational handler risk assessments and the phosmet label
revisions, the HED Phosmet Registration Review Team recommends that the
occupational handler risk assessment be revised to reflect this new
information as well as to incorporate the most recent exposure
assessment policies and practices.

Occupational Postapplication

As previously noted, subsequent to issuance of the RED, additional
toxicity data have been received and PoDs for occupational risk
assessment have been redefined.  In updates to the RED occupational
postapplication exposure and risk assessment, HED has focused on the
nine crops specified in the OPP’s Special Review and Reregistration
Division’s Reregistration Decisions on Nine Phosmet “Time Limited”
Uses, dated January 18, 2007.  Calculations for postapplication risk
consider dermal exposures alone because inhalation exposures are a
negligible contribution to postapplication exposure for the specific
crop groups assessed.

The most recent HED revision to the occupational postapplication
assessment was completed in February of 2009.   The key occupational
postapplication scenarios identified in that assessment that yielded
risks of concern were thinning and harvesting for tree fruit crops and
cane turning/girdling and thinning for vine/trellis crops (grapes and
high bush blueberries).

Since the most recent occupational postapplication risk assessment was
completed, the registrant has submitted new toxicological information
which resulted in additional modifications to the PoDs pertinent to this
risk assessment.  PoDs for short- and intermediate-term dermal risk
assessments in April 2009 are significantly lower than PoDs used in the
February 2009 risk assessment; therefore, HED expects that occupational
postapplication risks will increase when current exposure estimates are
compared to the most recent dermal PoDs.

The HED Phosmet Registration Review Team recommends that the
postapplication exposure assessment for all scenarios, including, but
not limited to the nine most recently assessed crops, be revised to
reflect the most recent PoDs as well as current exposure assessment
policies and practices.

Conclusions

The phosmet handler exposure and risk assessments will need to be
revised to support Registration Review.  The revised assessment should
consider HED’s current definition of exposure duration, and
incorporate new PoDs and current phosmet application rates.

The postapplication exposure assessment for all applicable phosmet
scenarios will need to be revised to reflect the April 2009 short- and
intermediate-term dermal PoDs.

Public Health and Pesticide Epidemiology Data

A preliminary evaluation of phosmet incident data (M. Hawkins, 2/3/09)
from 2002 – 2007 showed only 37 incidents reported.  Of the 37
incidents, HED notes that 26 were for pet products which have now been
cancelled.  In all incidents, symptoms reported appear generic in nature
and were not confirmed to be related to exposure.  There was no clear
evidence of a trend or exposure pattern seen in the incident data.

Tolerance Assessment and International Harmonization

Currently issues of international harmonization exist for phosmet.  The
tolerance definition for the U.S., which includes the phosmet oxon
metabolite, is inconsistent with the Codex, Canadian and Mexican residue
definitions, which include parent compound only.  Further specific
residue level discrepancies exists between the U.S. and one or more of
the other MRL setting authorities for apples, blueberry, cherry, cotton,
citrus fruits, kiwi, nectarines, nuts, and pears as shown in Attachment
3.

Conclusions

Residue definition as well as tolerance level differences currently
exist between the U.S. and Codex, Canada and Mexico.  At this time,
harmonization is not possible due to the difference in residue
definition.

Environmental Justice

Potential areas of environmental justice concerns, to the extent
possible, were considered in the 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/nepa/tools/guidance/Volume1/2-6-EO_12898envjustic
e.pdf"
http://www.eh.doe.gov/nepa/tools/guidance/Volume1/2-6-EO_12898envjustice
.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.  Phosmet is a member of the organophosphate common mechanism
group.  The most recent cumulative risk assessment for the
organophosphates was published on July 31, 2006 and is available at
HYPERLINK
"http://www.epa.gov/pesticides/cumulative/2006-op/op_cra_main.pdf"
http://www.epa.gov/pesticides/cumulative/2006-op/op_cra_main.pdf .  No
cumulative risks of concern were identified in that assessment.

Prior to a final registration review decision for phosmet, 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 phosmet 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

Phosmet risk assessments rely in part on data from studies monitoring
exposure of adult workers who handle pesticides as part of their jobs.
These studies, which comprise the Pesticide Handlers Exposure Database
(PHED), have been reviewed by the Agency and found on the basis of
available evidence to have been neither fundamentally unethical nor
significantly deficient relative to standards of ethical research
conduct prevailing when they were conducted.  There is no barrier in
EPA's "Protection of Human Subjects" regulation to reliance on these
studies.

HED notes that Gowan has submitted a biomonitoring study (MRID #
44682301) of workers hand thinning peaches treated with phosmet
insecticide.  HED conducted a science review in March of 2006.
Subsequently, the Office of Pesticide Program’s ethics panel concluded
that the research did involve intentional exposure of a person who had
not attained the age of 18 years from the documentation available.
Reliance on the biomonitoring study by EPA in any action under FIFRA or
FFDCA is therefore prohibited by §26.1703.

Data Requirements

Toxicology

Data previously requested under the 2006 OP DCI.

Gestational component of the comparative cholinesterase assay

New data requirement under revised 40 CFR Part 158.

Immunotoxicity study

Residue Chemistry

Data were previously required in connection with the phosmet RED.

Residue data for cotton gin byproducts.

Data previously requested in conjunction with Section 24(c) uses on
citrus.

Residue data to support use on citrus crops.

Occupational/Residential Exposure

There are currently no uses of phosmet permitted in residential
settings; therefore, no new data with respect to residential exposure is
required.  Further, no outstanding data with respect to occupational
handler or postapplication exposure have been identified.

References

Author	Barcode	Date	Title

Christina Swartz	D262365

	2/9/2000	Phosmet (Chemical ID No. 059201/List A Reregistration Case No.
0242).  HED Revised Human Health Risk Assessment for the Reregistration
Eligibility Decision Document (RED).

Christina Swartz	D279663	7/12/2002	Phosmet (List A Reregistration Case
No. 0242/chemical ID No. 059201).  SLN FL010006.  Proposed Special Local
Need Use to Control Apopka Weevil on Citrus Crops Growing in FL.

Matthew Lloyd	D296595	2/17/2009	Phosmet: Revision To The Occupational
Postapplication Exposure and Risk Calculations for Phosmet; D296595;
Case #838564.

Matthew Lloyd	D296574	3/28/2006	Secondary Review of "Biomonitoring of
Workers Hand Thinning Peaches Treated with Phosmet Insecticide"

Matthew Lloyd	 D333957	11/20/2006	Phosmet:  Revisions to the
Occupational and Residential Post-Application Exposures and Risk
Calculations and Determination of buffer Zones for Phosmet Applications,
Case #838564

Steve Nako, John Carley	None	8/13/2006	Initial Ethics Review of a Human
Study to Support Reregistration Activities.

Monica Hawkins	None	2/03/2009	Updated Review of Phosmet Incident Report

CCA Study Literature References:

Berkowitz GS, Obel J, Deych D, Lapinski R, Godbold J, Liu Z, Landrigan
PJ, and Wolff MS. (2003). Exposure to indoor pesticides during pregnancy
in a multiethnic urban cohort. Environ. Health Perspect. 111, 1: 79-84.

Eskenazi B, Harley K, Bradman A, Weltzien E, Jewell NP, Barr DB, Furlong
CE, Holland NT.  (2004).  Association of in utero organophosphate
pesticide exposure and fetal growth and length of gestation in an
agricultural population.  Env. Health Perspectives.  112(10): 1116-1124.

Eskenazi B, Marks AR, Bradman A, Harley K, Barr DB, Johnson C, Morga N,
Jewell NP. (2007). Organophosphate pesticide exposure and
neurodevelopment in young Mexican-American children. Environ. Health
Perspect. 115:792–798.

Furlong CE, Holland N, Richter RJ, Bradman A, Ho A, Eskenazi B. (2006).
PON1 status of farmworker mothers and children as a predictor of
organophosphate sensitivity. Pharmacogenetics and Genomics Vol. 16, No
3, 183-190.

Rauh VA, Garfinkel R, Perera FP, Andrews HF, Hoepner L, Barr DB,
Whitehead R, Tang D, and Whyatt RM. (2006). Impact of prenatal
chlorpyrifos exposure on neurodevelopment in the first 3 years of life
among inner-city children. Pediatrics 118;e1845-e1859; originally
published online Nov 20, 2006;DOI: 10.1542/peds.2006-0338.

Whyatt RM, Barr DB, Camann D, Kinney PL, Barr JR, Andrews HF, Hoepner
LA, Garfinkel R, Hazi Y, Reyes A, Ramirez J, Cosme Y, Perera FP.
(2003).Contemporary-use pesticides in personal air samples during
pregnancy and blood samples at delivery among urban minority mothers and
newborns. Environ. Health Perspect. 111,5  749-756.

Whyatt RM, Rauh V, Barr DB, Camann DE, Andrews HF, Garfinkel R, Hoepner
LA, Dazi D, Dietrich J, Reyes A, Tang D, Kinney P, Perera FP. (2004).
Prenatal insecticide exposures and birth weight and length among an
urban minority cohort. Environ. Health Perspect. 112,10 1125-1132.

Attachments

Attachment 1.  Phosmet Endpoint Selection Tables

Attachment 2.  DCI Justification for Immunotoxicity Study

Attachment 3.  International Residue Limit Status

Attachment 1.  Phosmet Endpoint Selection Tables

Table 1. Phosmet 2000 Toxicology Endpoint Selection

EXPOSURE SCENARIO	DOSE

(mg/kg/day)	ENDPOINT	STUDY

DIETARY AND NON-DIETARY INGESTION EXPOSURES

Acute Dietary	NOAEL = 4.5

(UF = 100)	Cholinesterase inhibition [plasma, RBC, brain] and decreased
motor activity at LOAEL of 22.5 mg/kg/day	Oral Acute Neurotoxicity/rat

Acute RfD = 0.045 mg/kg/day

Chronic Dietary	NOAEL = 1.1

(UF = 100)	Cholinesterase inhibition [RBC and serum] at LOAEL of 1.8
mg/kg/day	Oral Chronic Toxicity/Carcinogenicity/Rat

Chronic RfD = 0.011 mg/kg/day

DERMAL EXPOSURES

Short-Term

(Dermal*)	NOAEL = 15

(UF = 100)	Cholinesterase inhibition

[brain (females)/plasma (males)] at LOAEL  of 22.5 mg/kg/day	21-day
Dermal Toxicity/Rat

Intermediate-Term (Dermal* <30 days)	NOAEL = 15

(UF = 100)	Cholinesterase inhibition

[brain (females)/plasma (males)] at LOAEL  of 22.5 mg/kg/day	21-day
Dermal Toxicity/Rat

Intermediate-Term (Dermal* >30 days)	NOAEL = 1.1

(UF = 100)	Cholinesterase inhibition [RBC and serum] at LOAEL of 1.8
mg/kg/day	Oral Chronic Toxicity/Carcinogenicity/Rat

INHALATION EXPOSURES

Short-Term

(Inhalation*)	NOAEL = 15

(UF = 100)	Cholinesterase inhibition

[brain (females)/plasma (males)] at LOAEL  of 22.5 mg/kg/day	21-day
Dermal Toxicity/Rat

Intermediate-Term (Inhalation* <30 days)	NOAEL = 15

(UF = 100)	Cholinesterase inhibition

[brain (females)/plasma (males)] at LOAEL  of 22.5 mg/kg/day	21-day
Dermal Toxicity/Rat

Intermediate-Term (Inhalation* >30 days)	NOAEL = 1.1

(UF = 100)	Cholinesterase inhibition [RBC and serum] at LOAEL of 1.8
mg/kg/day	Oral Chronic Toxicity/Carcinogenicity/Rat

*Appropriate route-to-route extrapolation should be performed for these
risk assessments. For dermal risks, a 10% dermal absorption factor
should be used to convert relevant exposure estimates to equivalent oral
doses and compared to the oral NOAEL. For inhalation risks, a 100%
absorption factor should be used to convert exposure estimates to
equivalent oral doses and compared to the oral NOAEL.

Table 2. Current (2009) Phosmet Endpoint Selection

Endpoint Scenario	POD  (mg/kg/day)	UF	LOC (mg/kg/day)	Study and Endpoint

Oral

Acute Dietary (females 13+)	BMDL10 = 3.56	UFA 10x

UFH 10x

UFDB 10x*	aRfD = aPAD = 0.00356	Acute oral CCA – rat

MRID 47087401

BMD10 = 7.092 mg/kg (RBC ChEI)

Acute Dietary (infants and children)	BMDL10 = 1.2	UFA 10x

UFH 10x	aRfD = aPAD = 0.012	Acute oral CCA – rat

MRID 47087401

BMD10 = 1.9 mg/kg (female PND 11 brain ChEI)

Acute Dietary (general pop, excluding infants and children and females
13+)	BMDL10 = 3.56	UFA 10x

UFH 10x	aRfD = aPAD = 0.0356	Acute oral CCA – rat

MRID 47087401

BMD10 = 7.092 mg/kg (RBC ChEI)

Chronic Dietary (females 13+)	BMDL10 = 0.6	UFA 10x

UFH 10x

UFDB/FQPA SF = 10x	cRfD = cPAD = 0.0006	7-day repeat CCA – rat

MRID 47695401

BMD10 = 1.19 mg/kg/day  (adult RBC ChEI; grouped)

Chronic Dietary (infants and children)	BMDL10 = 0.16	UFA 10x

UFH 10x	cRfD = cPAD = 0.0016	7-day repeat CCA – rat

MRID 47695401

BMD10 = 0.36 mg/kg/day (pup RBC ChEI; grouped)

Chronic Dietary (general pop, excluding infants and children and females
13+)	BMDL10 = 0.6	UFA 10x

UFH 10x

	cRfD = cPAD = 0.006	7-day repeat CCA – rat

MRID 47695401

BMD10 = 1.19 mg/kg/day  (adult RBC ChEI; grouped)

Incidental oral

(Short- and Intermediate-Term)	BMDL10 = 1.2	UFA 10x

UFH 10x	LOC for MOE ≤ 100	Acute oral CCA – rat

MRID 47087401

BMD10 = 1.9 mg/kg (female PND 11 brain ChEI)

Non-Occupational, Non-Dietary

Dermal & Inhalation (females 13+)

(Acute)	BMDL10 = 3.56

10% dermal absorption

4.5X in vitro dermal correction factor

- inhalation hazard assumed to be equivalent to oral hazard 	UFA 10x

UFH 10x

UFDB/FQPA SF = 10x	Non-occupational LOC for MOE ≤ 1000	Acute oral CCA
– rat

MRID 47087401

BMD10 = 7.092 mg/kg (RBC ChEI)

Dermal & Inhalation (infants and children)

(Acute)	BMDL10 = 1.2

10% dermal absorption

4.5X in vitro dermal correction factor

- inhalation hazard assumed to be equivalent to oral hazard	UFA 10x

UFH 10x	Non-occupational LOC for MOE ≤ 100	Acute oral CCA – rat

MRID 47087401

BMD10 = 1.9 mg/kg (female PND 11 brain ChEI)

Dermal & Inhalation (general pop, excluding infants and children and
females 13+)

(Acute)	BMDL10 = 3.56

10% dermal absorption

4.5X in vitro dermal correction factor

LOC for MOE ≤ 100	Acute oral CCA – rat

MRID 47087401

BMD10 = 7.092 mg/kg (RBC ChEI)

Occupational

Dermal & Inhalation

(Short- and Intermediate-Term)	Oral BMDL10 = 0.6

10% dermal absorption

4.5X in vitro dermal correction factor

- inhalation hazard assumed to be equivalent to oral hazard	UFA 10x

UFH 10x	Occupational LOC for MOE ≤ 100	7-day repeat CCA – rat

MRID 47695401

BMD10 = 1.19 mg/kg/day  (adult RBC ChEI; grouped)

CCA is Comparative Cholinesterase Assay.

BMD is Bench Mark Dose Analysis.Attachment 2.  DCI Justification for
Immunotoxicity Study

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?

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

Attachment 3.  International Residue Limit Status

Phosmet Summary of US and International Tolerances and Maximum Residue
Limits

US	Canada	Mexico1	Codex2

Residue Definition:

180.261

sum of the residues for the insecticide N -(mercaptomethyl) phthalimide
S- ( O,O -dimethyl phosphorodithioate) and its oxygen analog N
-(mercaptomethyl) phthalimide S -( O,O -dimethyl phosphorothioate	O,O
-dimethyl phthalimidomethyl phosphorodithioate

	phosmet	phosmet

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

Commodity	US	Canada	Mexico	Codex

Alfalfa	40

40

	Almond, hulls	10

	Apple	10	10	10	3 (pome fruits)

Apricot	5

	10

Blueberry	10	5.0

10

Cattle, fat	0.2

	Cattle, meat	0.2

	Cattle, meat byproducts	0.2

	Cherry	10	7.0

Cotton, undelinted seed	0.1

0.1	0.05

Cranberry	10

	Fruit, citrus	5

	3

Goat, fat	0.2

	Goat, meat byproducts	0.2

	Goat, meat	0.2

	Grape	10	10

10

Hog, fat	0.2

	Hog, meat byproducts	0.2

	Hog, meat	0.2

	Horse, fat	0.2

	Horse, meat byproducts	0.2

	Horse, meat	0.2

	Kiwifruit	25	1.0 (edible portion)

Nectarine	5	10

10

Nut	0.1(N)

	0.2

Peach	10	10

10

Pear	10	10

3 (pome fruits)

Pea	0.5

	Pea, field, hay	10

	Pea, field, vines	10

	Plum, prune, fresh	5	5.0

Potato	0.1

	0.05 *

Sheep, fat	0.2

	Sheep, meat byproducts	0.2

	Sheep, meat	0.2

	Sweet potato, roots	10

	Crabapple (regional)	20

	Pistachio (regional)	0.1

	1 As of 2004, latest date for available information.  General practice
is for Mexico to defer to US or Codex tolerances for its export
purposes.

2  * = Absent at the limit of quantitation (LOQ).

Phosmet Registration Review Human Health Assessment Scoping Document

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