SEQ CHAPTER \h \r 1

                    UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

                                                   WASHINGTON, D.C.
20460

                  OFFICE OF

PREVENTION, PESTICIDES AND

         TOXIC SUBSTANCES

November 1, 2006

MEMORANDUM

SUBJECT:	Aldicarb (List A Case 0140, Chemical ID No. 098301).  HED
Revised Human Health Risk Assessment for the Reregistration Eligibility
Decision Document (RED).  DP Barcode No. D331540.

FROM:	Felecia Fort, Chemist

		Linda Taylor, Ph.D, Toxicologist

		Jeff Dawson, Chemist

Reregistration Branch 1

Health Effects Division (7509P)

THRU:	Michael Metzger, Branch Chief

Reregistration Branch 1

Health Effects Division (7509P)

TO:		Tracy Perry, Chemical Review Manager

		Sherrie Kinard, Chemical Review Manager

Special Review Branch

Special Review and Reregistration Division (7508P)

Attached is a revised human health risk assessment for aldicarb prepared
by Reregistration Branch 1 RRB1) of the Health Effects Division.  This
document has been revised to incorporate comments received during the
public comment period.  A response to comments document was also
prepared which summarizes and illustrates specifically how the comments
were addressed for the risk assessment. This document is entitled
“Aldicarb (List A Case 0140, Chemical ID No. 098301).  HED Response to
Comments Received During the Public Comment Period.  DP Barcode No.
D331538.”

The aldicarb risk assessment team is comprised of Felecia Fort (risk
assessment, and dietary exposure assessment); Christina Swartz (residue
chemistry chapter,); Linda Taylor (hazard assessment), Jeff Dawson
(occupational risk assessment), all of HED and Jonathan Angier and
Nelson Thurman of EFED (drinking water estimates).

An intentional dosing human oral study [Inveresk] was relied upon in
this risk assessment.  This study has been reviewed by EPA’s Human
Studies Review Board (HSRB), as required by EPA’s Human Subjects
Protections Rule (40 CFR part 26 (effective April 7, 2006)).   The HSRB
discussed the study extensively during a meeting held on April 2-4, 2006
and concluded that the cholinesterase data from the aldicarb human study
were reliable for use in the aldicarb single chemical, aggregate risk
assessment.  Additionally,  it was concluded that there was no clear and
convincing evidence of significant deficiencies in the ethical
procedures that could have resulted in serious harm (based on the
knowledge available at the time the study was conducted), nor that
information provided to participants seriously impaired their informed
consent. The final report of the HSRB is available at   HYPERLINK
"http://www.epa.gov/osa/hsrb/files/"  http://www.epa.gov/osa/hsrb/files/
april2006mtgfinalreport62606.pdf

Note to Risk Manager: Updated pesticide residue monitoring data from the
USDA Pesticide Data Program (PDP) have not been incorporated into the
dietary exposure assessment.  However, the monitoring data support the
results of the current assessment, and these data are not expected to
result in any significant changes in estimated dietary exposure.   It
should also be noted that this assessment supercedes the previous
occupational and residential exposure (ORE) assessment (D311821; January
11, 2005; Author: Jeff Dawson) and Toxicology RED chapter (D266321;
August 20, 2002; Author: Linda Taylor, Ph.D).  These chapters were not
revised and reissued; instead, certain relevant modifications were
included in this document.

HUMAN HEALTH

RISK ASSESSMENT

Aldicarb

U.S. Environmental Protection Agency

Office of Pesticide Programs

Health Effects Division (7509C)

Felecia Fort, Chemist/Risk Assessor

Date: October 31, 2006

HUMAN HEALTH RISK ASSESSMENT

Aldicarb

Risk Assessment Team:

Risk Assessor:						Felecia Fort

Residue Chemistry/Dietary Assessment		Felecia Fort

								Christina Swartz

Occupational and Residential Exposure:		Jeffrey Dawson

Toxicology:  						Linda Taylor, Ph.D

Drinking Water Estimates:				Nelson Thurman

								Jonathan Angier, Ph.D

TABLE OF CONTENTS

  TOC \o "1-4" \u  1.0	EXECUTIVE SUMMARY	  PAGEREF _Toc149965483 \h  7

2.0	PHYSICAL/CHEMICAL PROPERTIES	  PAGEREF _Toc149965484 \h  16

3.0	HAZARD ASSESSMENT	  PAGEREF _Toc149965485 \h  16

               3.1   Hazard Profile	  PAGEREF _Toc149965486 \h  16

               3.2   Dose Response Assessment	  PAGEREF _Toc149965487 \h
 21

                  3.2.1   Benchmark Dose (BMD) Analysis	  PAGEREF
_Toc149965488 \h  21

                  3.2.2   Endpoint Selection	  PAGEREF _Toc149965489 \h
22

               3.3   Reversibility	  PAGEREF _Toc149965490 \h  25

               3.4   FQPA Considerations	  PAGEREF _Toc149965491 \h  26

               3.5   Endocrine Disruption	  PAGEREF _Toc149965492 \h  27

4.0	EXPOSURE ASSESSMENT AND CHARACTERIZATION	  PAGEREF _Toc149965493 \h
27

               4.1   Summary of Registered Uses	  PAGEREF _Toc149965494
\h  27

               4.2   Dietary Exposure/Risk Pathway	  PAGEREF
_Toc149965495 \h  28

                  4.2.1   Residue Profile	  PAGEREF _Toc149965496 \h  28

                  4.2.2   Dietary Exposure	  PAGEREF _Toc149965497 \h
30

                        <IP_ADDRESS>   Acute Dietary Exposure	  PAGEREF
_Toc149965498 \h  32

                        <IP_ADDRESS>   Chronic Dietary	  PAGEREF
_Toc149965499 \h  33

               4.3   Water Exposure/Risk Pathway	  PAGEREF _Toc149965500
\h  35

                  4.3.1   Environmental Fate Properties	  PAGEREF
_Toc149965501 \h  35

                  4.3.2   Estimated Environmental Concentrations (EECs)
 PAGEREF _Toc149965502 \h  36

               4.4   Residential Exposure/Risk Pathway	  PAGEREF
_Toc149965503 \h  38

5.0	AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATIONS	  PAGEREF
_Toc149965504 \h  39

               5.1 Acute Aggregate Risk Assessment [Food plus Drinking
Water from Surface Water Sources]	  PAGEREF _Toc149965505 \h  40

               5.2 Acute Aggregate Risk Assessment [Food plus Drinking
Water from Ground Water  Sources]	  PAGEREF _Toc149965506 \h  41

               5.3 Chronic Aggregate Risk Assessment	  PAGEREF
_Toc149965507 \h  44

6.0	CUMULATIVE RISK	  PAGEREF _Toc149965508 \h  44

7.0	OCCUPATIONAL EXPOSURE	  PAGEREF _Toc149965509 \h  45

               7.1   Handler	  PAGEREF _Toc149965510 \h  46

              7.2.    Incident Data	  PAGEREF _Toc149965511 \h  51

8.0	DATA NEEDS/LABEL REQUIREMENTS	  PAGEREF _Toc149965512 \h  52

               8.1   Toxicology	  PAGEREF _Toc149965513 \h  52

               8.2    Residue Chemistry	  PAGEREF _Toc149965514 \h  53

9.0	SUPPORTING DOCUMENTATION	  PAGEREF _Toc149965515 \h  53

1.0	EXECUTIVE SUMMARY  TC \l1 "1.0	EXECUTIVE SUMMARY

The Health Effects Division (HED) of EPA's Office of Pesticide Programs
has evaluated the toxicity and exposure databases for the pesticide
active ingredient aldicarb, and has conducted a human health risk
assessment to support the reregistration of products containing
aldicarb.  This risk assessment addresses risks to aldicarb alone, and
does not consider cumulative effects of other carbamate pesticides.

Use and Usage Information

Aldicarb is registered for use as a systemic insecticide, acaricide and
nematicide on agricultural crops including citrus, cotton, dry beans,
peanuts, pecans, potatoes, sorghum, soybeans, sugar  beets, sugarcane,
sweet potatoes, and seed alfalfa (CA).  In addition, aldicarb may be
applied to field grown ornamentals (CA) and tobacco, and on coffee grown
in Puerto Rico.  Pests controlled by aldicarb include leaf phylloxera;
bud moth; citrus nematode (suppression); aphids; mites; white flies;
thrips; fleahoppers, leafminers; leafhoppers; overwintering boll weevil;
lygus; nematodes (suppression); cotton leaf perforator; seedcorn maggot;
Mexican bean beetle; flea beetles; Colorado potato beetle; greenbug;
chinch bug; three cornered alfalfa hopper (suppression); and sugar beet
root maggot.

Aldicarb is a restricted use pesticide, and may only be applied in
occupational settings by certified applicators.  There are no aldicarb
products intended for sale to homeowners or for use in residential
settings.  Aldicarb is formulated and marketed solely as a granular
pesticide under the trade name Temik®.  The granulars (5, 10 and 15%)
consist of aldicarb adhered to a corn cob grit or gypsum substrate,
which are formulated to produce less dust than typical clay substrates
used for granular pesticides.  The gypsum granular only is available in
closed loading systems.  Aldicarb is applied early in the growing
season, either pre-plant, at-planting, or early post-emergent, using
ground application equipment.  Positive displacement application
equipment and immediate soil incorporation are required.

Regulatory Background

Aldicarb is currently under Special Review because of concerns regarding
ground water contamination.  Position Documents (PD’s) 1 and 2/3 were
published on 7/11/84 (49 FR 28320) and 6/29/88 (53 FR 24630),
respectively.  A Special Review Data Call-In-Notice (DCI) was issued
6/3/89 requiring the registrant to submit additional ground water data.
In addition, because a National Food Survey identified discrepancies
between anticipated residues in foods and actual residues from food
survey samples, the Special Review required a variety of studies related
to use on potatoes and citrus crops.  In 1990, the sale and use of
aldicarb on potatoes were voluntarily suspended due to detection of
tolerance-exceeding aldicarb residues on individual potatoes.
Additional studies were conducted to alleviate concerns for dietary risk
due to high residues in potatoes, and the use was reinstated in the
states of FL, ID, WA and OR (EPA Desk Statement, 9/22/95).  Aldicarb
remains in EPA's Special Review process because of continued concerns
about ground water contamination.  A PD4 is to be issued in conjunction
with a reregistration eligibility decision.  Registrations of aldicarb
currently reside with Bayer CropScience LP.

Hazard Profile and Food Quality Protection Act (FQPA) Decision

Aldicarb is an N-methyl carbamate pesticide that exerts its pesticidal
activity and elicits adverse toxic effects by inhibition of
cholinesterase activity [ChEI].    SEQ CHAPTER \h \r 1 Overall, the
studies supporting the toxicity database for aldicarb are considered
adequate, and there is confidence in the hazard and dose response
assessments.  Acutely, aldicarb is highly toxic via the oral, dermal,
and inhalation routes of exposure (Toxicity Category 1).  It is not a
dermal sensitizer; dermal and eye irritation studies were waived due to
severe effects (death) following corneal and dermal dosing.

  SEQ CHAPTER \h \r 1 The toxicity database for aldicarb is adequate,
including acceptable studies submitted to determine toxic effects
associated with acute, subchronic and chronic exposure durations by the
oral route; acceptable acute and subchronic neurotoxicity studies; a
developmental neurotoxicity study in rats; developmental studies (rat
and rabbit); and a reproduction study (rat).  Acceptable dermal and
inhalation toxicity and dermal penetration studies are not available.

Aldicarb toxicity studies have demonstrated inhibition of cholinesterase
activity in whole blood, plasma, red blood cells (RBC) and brain of
rats, mice, and dogs following acute, subchronic, and chronic exposures
and in plasma and RBC in humans following acute exposure.  It should be
noted that aldicarb-induced ChEI has been shown to be reversible in less
than 24 hours.  Both the acute and subchronic rat neurotoxicity studies
show a variety of typical clinical signs of ChEI after oral exposures to
aldicarb, including decreased motor activity, lacrimation, tremors,
salivation, pinpoint pupils, and decreased grip strength.

In guideline developmental or reproduction studies including a rat
developmental neurotoxicity study submitted by the registrant, there was
no indication of qualitative or quantitative susceptibility of
offspring.  Maternal toxicity occurred at doses where no offspring
toxicity was observed; i.e., the no observed adverse effects level
(NOAEL) for maternal toxicity was lower than the offspring NOAEL. A
published non-guideline oral acute neurotoxicity study conducted by
EPA/ORD (Moser) reported evidence for increased sensitivity of young
rats based on brain ChEI measurements. Decreased motor activity was
observed only in the adult animals, and clinical signs of ChEI occurred
more frequently in,  and recovery was more prolonged in the adult
relative to the young animal. The magnitude of the brain ChEI was
approximately 2-fold greater in the young rat compared to the adult rat
at comparable acute doses. Therefore, a FQPA safety factor of 2X is
retained.

In an acute oral study conducted in human volunteers, aldicarb treatment
of both males and females resulted in statistically-significant
inhibition of both red blood cell and plasma cholinesterase at two
common dose levels. The results of the acute oral human study suggest a
two-fold difference between animals and humans with respect to toxic
responses following acute exposure to aldicarb, with humans being the
more sensitive species.

  SEQ CHAPTER \h \r 1 The metabolism of aldicarb is well understood in
animals (livestock and rats), plants, and in the environment (soil and
water).  In rats, with oral administration, aldicarb is rapidly
absorbed, widely distributed, and rapidly eliminated.  In rats,
livestock, plants, and in the environment, aldicarb is rapidly
metabolized to aldicarb sulfoxide, then slowly converted to aldicarb
sulfone.  These three moieties (aldicarb, sulfoxide, and sulfone) may
then be further metabolized to oximes and nitriles.  Both the sulfoxide
and sulfone are also potent cholinesterase inhibitors.  The sulfone is
less toxic following an acute oral exposure than either the parent
compound or the sulfoxide, which show comparable acute oral toxicity.
Aldicarb and its two cholinesterase-inhibiting metabolites are the
residues of concern for risk assessment for all routes of exposure and
for tolerance reassessment.

There are acceptable genotoxicity studies for all three required
categories of mutagenic effects:  gene mutations, chromosomal
aberrations, and other genotoxic effects.  The results of these studies
are all negative.  Aldicarb is not considered a mutagen, and it is
classified as Category E, Evidence of Non-Carcinogenicity for Humans,
based on the lack of evidence of carcinogenicity in studies in rats and
mice.

Consideration of all available toxicity data was used to determine the
toxicity endpoints and reference doses appropriate for the aldicarb risk
assessment. There is a complete toxicology database of oral studies
including a human oral study. HED's previous risk assessment reported
risks using multiple endpoints, including those from the human study, to
fully characterize risks, but focused on results using the rat RBC
cholinesterase inhibition endpoint.  This decision reflected the
Agency's interpretation of the conclusions drawn by the HSRB prior to
issuance of the final report.  Based on the final report, which clearly
concluded that use of the human study endpoint was appropriate for human
health risk assessment, the current risk assessment continues to provide
results using all three endpoints considered, but focuses on the results
of the human study since these data best reflect human response to the
chemical. Because these human data are considered reliable, and the
study is considered scientifically valid, at this time the Agency
considers the human study to be the most suitable for risk assessment
purposes for this single-chemical risk assessment.

Dose Response Assessment

Acute RfD

In order to evaluate the appropriate point of departure (PoD) for ChEI,
the Agency considered benchmark dose (BMD) estimates developed from the
human acute oral study. In an acute oral study conducted in human
volunteers of both sexes, aldicarb treatment resulted in
statistically-significant inhibition of both red blood cell and plasma
cholinesterase at the two common dose levels of 0.025 and 0.050 mg/kg.
Although use of data from multiple studies provides a more robust
analysis than a single study, for aldicarb there are data on the species
of interest [human], there is a similarity in response between rats and
humans at a common dose level [0.05 mg/kg], and there are data in the
human at dose levels lower than those tested in the rat.  At this time
the Agency considers the human RBC ChE inhibition data to be
sufficiently reliable for developing a point of departure (i.e., BMD and
BMDL values were calculated) for risk assessment purposes for this
single chemical risk assessment. Note that EPA's use of a human oral
study in the aldicarb risk assessment is in accordance with the Agency's
Final Rule promulgated on January 26, 2006, related to Protections for
Subjects in Human Research, which is codified in 40 CFR Part 26.

Also considered were the benchmark dose (BMD) estimates developed from
the rat acute and subchronic neurotoxicity studies and the non-guideline
acute neurotoxicity study (Moser) along with BMD estimates provided in
the preliminary cumulative risk assessment for N-methyl carbamates (NMC;
presented to the FIFRA SAP in February and August, 2005; USEPA, 2005).
 SEQ CHAPTER \h \r 1 In the previous analysis, the Agency used data from
both the registrant’s dose-response studies and from the Agency’s
comparative study (adult rat data only).  The RBC ChE data from the
aldicarb human study were utilized in the model in the same manner as
the acute rat data (brain and RBC) that are available for the NMCs of
the cumulative hazard assessment.

As previously stated, there was no evidence of increased sensitivity in
developing animals in any of the guideline studies reviewed.
Developmental toxicity was not seen in rats or rabbits nor were
reproductive effects seen in the rat multi-generation reproduction
study. Additionally, there was no developmental toxicity in the
developmental neurotoxicity study in rats. However, the comparative ChE
inhibition study [Moser] demonstrated that pups were more sensitive than
the adults with respect to brain ChEI.  Based on benchmark dose (BMD)
estimates calculated from these data, the pups are 2X more sensitive
than the adults  [brain BMD10s ranged from 0.014 to 0.020 in juvenile
animals and 0.024 to 0.031 in adult animals]. Therefore, a FQPA safety
factor of 2X is retained.

The acute reference dose (aRfD) for dietary exposure assessment was
derived from the human RBC BMDL10 as the point of departure [0.013
mg/kg] divided by an intraspecies factor of 10X and an interspecies
factor of 1X, resulting in an acute RfD of 0.0013 mg/kg. Using the FQPA
SF of 2X, the population adjusted dose (aPAD) is 0.00065 mg/kg.   For
additional risk characterization,  aPADs using the rat brain and rat RBC
BMDL10  were determined.  The aPAD based on rat brain ChEI  is 0.00075
mg/kg and the aPAD based on rat RBC BMDL10  is 0.0005 mg/kg/day.  More
detailed information about the derivation of these aPADs can be found in
the Dose Response chapter in this document.

Chronic RfD

Aldicarb-induced inhibition of ChE activity is rapidly reversible (less
than 24 hours). Therefore, chronic exposure to aldicarb is considered to
be a series of acute exposures, and a separate chronic assessment is not
necessary.

There are no residential uses of aldicarb; therefore, a residential
exposure assessment was not conducted.

Dermal and Inhalation

There are no suitable dermal or inhalation toxicity studies for aldicarb
risk assessment purposes. Therefore, the Agency selected the same dose
and endpoint (0.013 mg/kg/day, based on RBC ChEI) for short-term dermal
and inhalation risk assessments.  The BMDL10 value of 0.013 mg/kg/day in
the human calculated from the RBC ChEI data is appropriate for assessing
risks from dermal and inhalation exposure (all durations) for
occupational workers (the most sensitive effect in the population of
concern, adults).  Only short- and intermediate term (i.e., no long term
exposures) dermal and inhalation exposures are expected to occur based
on the use patterns for aldicarb.  The target margin of exposure (MOE)
is 10 (i.e., 10X for intraspecies variability and 1x for interspecies
extrapolation).

The submitted dermal toxicity studies are considered unacceptable, and
there is no dermal penetration study; therefore, dermal exposure
assessments have been conducted assuming a default dermal absorption
factor of 100% relative to oral dosing.  A comparison of cholinesterase
data from unacceptable dermal toxicity studies to cholinesterase data
from oral studies suggests 100% dermal absorption is conservative, and
therefore protective, for dermal exposures.  An inhalation absorption
factor of 100% relative to oral exposures was applied in assessing
inhalation exposure and risk for aldicarb.  In accordance with Agency
policy, the FQPA SF does not apply to occupational assessments.

Exposure Assessment

The use pattern for aldicarb is expected to result in exposure to the
general population through food and drinking water.  There is a
potential for inhalation exposure from aldicarb-treated tobacco, but
there are no residential uses or agricultural uses that would result in
residential  exposure to the general population.  Exposures can occur
for occupational handlers loading or applying aldicarb granulars, but no
postapplication exposure is expected because aldicarb is
soil-incorporated at planting.

Aldicarb Exposure from Food

The residue chemistry database is essentially complete, including
acceptable plant and animal metabolism studies, analytical methods,
field residue trials, processing studies and rotational crop studies.
The data are adequate for both tolerance reassessment and dietary
exposure assessment.  Aldicarb residues are not expected in livestock
commodities such as meat, milk and eggs, and residues in most field
crops are low or nondetectable.  Higher residues (primarily of aldicarb
metabolites and not aldicarb per se) have historically been found in
monitoring of citrus and potato commodities, including individual
oranges and potatoes.

tion Model (DEEM-FCID™) and consumption data from the US Department of
Agriculture (USDA) Continuing Surveys of Food Intake by Individuals
(CSFII, 1994-1996 and 1998.).  The acute dietary exposure assessment
incorporated monitoring and market basket survey data from the USDA
Pesticide Data Program (PDP, potatoes and sweet potatoes) and the
Carbamate Task Force (CTF, oranges).  These three data sets were used to
assess exposure from all potato and sweet potato food forms, as well as
all citrus (orange, grapefruit, lemon and lime) food forms.

The PDP and CTF data were considered the best available data (for
potatoes, sweet potatoes and citrus) for use in the dietary exposure
assessments, since they reflect exposures closer to the point of
consumption and would therefore be a more accurate representation of
actual (i.e., “dinner plate") dietary exposure.  For all other
commodities, field trial data were used in the assessment, but residues
were either very low or nondetectable (soybeans, cottonseed, peanuts,
dry beans and coffee).  Sugarbeet and sugarcane were excluded from the
assessments, since aldicarb residues are not expected in the processed
commodities as consumed; the tolerance for sorghum was used in the
assessment, but did not contribute significantly to estimated dietary
exposure due to the low percent crop treated (%CT), the low tolerance,
and low consumption.

Use information for aldicarb has been summarized in two Quantitative
Usage Analyses (QUAs) generated by the Biological and Economic Analysis
Division (BEAD), dated 12/99 and 5/00.  The use information, including
distinctions in %CT estimates for fresh vs. processed potatoes, oranges
and grapefruit, was included in the dietary exposure analyses along with
extensive processing/cooking data, generally indicating reduction of
residues through boiling and juicing.  Since aldicarb is systemic,
typical food preparation practices such as washing and peeling are not
expected to significantly reduce residues.

Estimated acute dietary (food only) exposure and risk do not exceed
HED's level of concern [i.e., >100 % aPAD] for all population subgroups
when compared to the human endpoint.  The estimated dietary exposure and
risk for the general U.S. population at the 99.9th percentile exposure
using the human RBC ChEI endpoint was 0.000280 mg/kg/day, or 37% aPAD.
For children 1 – 2 years old, the most highly exposed population
subgroup, dietary exposure was 0.000592 mg/kg/day, or 78% aPAD.  If the
PAD is based on the rat RBC or brain ChEI endpoint, risk estimates for
children 1-2 years old were 102% and 68%, respectively.  For all
population subgroups, residues in potatoes were the most significant
source of dietary exposure.  Sensitivity analyses showed that actual
detected residues from monitoring are the source of the estimated
exposure and risk, and not assumed residues for nondetects in the
monitoring data sets.  For example, in a sensitivity analysis which
assumed aldicarb per se residues of 0 ppm in all potato and citrus
commodities, and zero residues for citrus nondetects, the risk for the
general US population was reduced from 37% to 36 %aPAD; for children 1-2
years old the estimated risk was reduced from 78% to 76 %aPAD at the
99.9%ile of exposure when compared to the human RBC ChEI endpoint.

Aldicarb Exposure from Drinking Water

The OPP Environmental Fate and Effects Division (EFED) prepared the
drinking water assessment for aldicarb reregistration.  Aldicarb has the
potential to reach surface and ground water sources of drinking water
following applications in agricultural settings.  The environmental fate
database for aldicarb and its degradates (sulfoxide and sulfone) is
incomplete but adequate for characterizing the potential for aldicarb
residues to reach and to persist in ground and surface water sources of
drinking water.

Total aldicarb residues (i.e., aldicarb plus the sulfoxide and sulfone
degradates) are persistent and mobile in most soil types.  The
environmental profile is similar to that observed in plants, which
consists of rapid oxidation of the parent aldicarb to aldicarb sulfoxide
and sulfone, followed by breakdown to the relatively non-toxic
non-carbamate residues.  The degradates are more soluble in water than
the parent.

EFED used Tier-II modeling to generate estimated environmental
concentrations (EECs) for both surface water and groundwater sources of
drinking water. Specifically, the Pesticide Root Zone Model and Exposure
Analysis Model System (PRZM/EXAMS) Index Reservoir was used to generate
surface water EECs and the PRZM model system was used to generate
groundwater EECs for drinking water.  For the purpose of the drinking
water assessment, both surface and groundwater concentrations were
reported for three vulnerable regions selected based on broad similarity
in aldicarb usage, crop type or soil conditions and which have the
greatest potential for exposure to aldicarb.  Additionally, for
groundwater sources of drinking water, EECs were calculated based on
proposed or established well setbacks ranging from 300 to 1000 ft.
Total aldicarb residues are not expected to occur at levels that will
contribute to dietary exposures for most of the country.

Aggregate Exposure

Since there is no potential for exposure to aldicarb and metabolites in
residential settings, aggregate exposure and risk assessments include
only dietary food and water sources of exposure.

The acute aggregate risk estimates when food and drinking water from
surface water sources are assessed show HED’s level of concern is not
exceeded (<100% aPAD).   The most highly exposed population subgroup was
infants at 89% aPAD at the 99.9th percentile when compared to the human
RBC endpoint.

Using the DEEM dietary model, the data indicate that aggregate exposure
from food and ground water sources of drinking water is of concern for
some regions including Florida which has a well setback of 1000 feet.
Risk estimates ranged from 80 to 145% of the aPAD for children 1-2 years
old and 53 to 285% of the aPAD for infants (<1 years old).  These risk
estimates are considered conservative since the food diaries used by
Dietary Exposure Evaluation Model-Food Consumption Intake Database
(DEEM-FCID Version 2.03) are based on total daily intake.  The estimated
risks are overestimates to the extent that food and drinking water are
consumed throughout the day, rather than during only one event.
Consequently, HED further refined the acute aggregate risk from food and
groundwater by incorporating the time and amounts consumed for each
eating occasion from the USDA CSFII food diaries to estimate exposures
and risks on each eating occasion throughout the day and factoring in
the cholinesterase-inhibition half-life related to aldicarb exposure.
The eating occasion results are based on several major assumptions: (i)
2 hour half-life, (ii) allocation of direct drinking water consumption
based on 6 equal and fixed occasions, and (iii) no modifications to the
amount of indirect drinking water consumed as reported in the CSFII
diaries for infants.  Four drinking water (from groundwater sources)
concentration scenarios were modeled for aldicarb: 3 ground water
scenarios for aldicarb use on peanuts/cotton in Georgia with an
assumption of 300 ft, 500 ft and 1000 ft well set backs, and one ground
water scenario for aldicarb use on Florida citrus with a 1000 ft
setback.  The estimated risks at the per capita 99.9th percentile are
below the level of concern for all four scenarios, and for all
subpopulations except for infants under the Georgia 300 ft scenario(139%
- 147% of the aPAD).  For all other scenarios,  risks are not exceeded
for infants.

Aldicarb Exposure from Tobacco

Since aldicarb is registered for use on tobacco, HED conducted an
inhalation risk assessment for adult smokers.  The estimate of exposure
was generated using high-end residues in smoke from aldicarb-treated
tobacco, assumptions with respect to the frequency of smoking, and
assuming that all of the aldicarb residue in smoke is absorbed (i.e.,
none of the residue is exhaled along with the smoke).  Acute inhalation
MOEs for aldicarb from the use of tobacco are estimated to be 104 for
females and 121 for males; these MOEs are greater than the target MOE of
20, indicating that exposure and risk from aldicarb residues in tobacco
are not of concern.  These estimates are based on very conservative
assumptions, and may overestimate exposure through this route.

Aldicarb Occupational Exposure and Risk

The occupational risk assessment for aldicarb is based on potential
exposure to agricultural workers during loading and application of
granular products.  Aldicarb is applied early in the growing season, and
labels require immediate soil incorporation of granules; postapplication
exposures are not expected for workers, so a quantitative
postapplication risk assessment has not been conducted. Two basic
occupational handler scenarios, loading granules and applying granules,
were assessed using exposures derived from a formulation- and
chemical-specific study that monitored open loading and open-cab
application conducted by the registrant (MRID 438525-01), the PHED
(Pesticide Handlers Exposure Database), and a study which monitored
granular closed loading and closed cab application in conjunction with
high levels of personal protective equipment (i.e., MRID 447933-01 which
was conducted using terbufos, data compensation issues may apply, this
study was considered for comparative purposes based on comments from
Bayer Crop Sciences).

The formulation- and chemical-specific study (MRID 438525-01) used
aldicarb low-dust granules which are the only commercially marketed
products.  This study provides the most representative open loading and
open cab application exposure estimates for aldicarb because of the low
friability of aldicarb-containing products based on how it is
formulated.  PHED data are available for this scenario, and would be
used in lieu of MRID 438525-01 if not available, but it is not
recommended because exposure estimates would be based on the use of more
friable clay granules which create more dust and, hence, higher exposure
levels which would not be realistically expected.  Aldicarb is also
marketed in Lock-n-Load closed loading systems and it can be applied
using closed cab tractors.  As such, these exposures were also
considered in this assessment.  The aldicarb-specific study (MRID
438525-01) did not quantify the exposures associated with the use of
these types of engineering controls.  Instead, both PHED and the other
study (MRID 447933-01) were used to evaluate exposures associated with
closed loading systems and closed cab.  The PHED-based values reflect
the systems with normal work clothing and estimates from MRID 447933-01
reflect the use of aprons gloves for the loaders and coveralls with
gloves for the applicators inside of a closed cab.

In this assessment, risks were calculated using an endpoint derived from
a human administration toxicity study which was deemed appropriate based
on the recent Agency Human Study Review Board meeting.  The Agency
believes that these estimates are the most relevant for considering
risks for those occupationally exposed to aldicarb. In order to provide
further characterization, the Agency also calculated risks based on rat
endpoints (i.e., red blood cell and brain cholinesterase inhibition).

Aldicarb Incident Review

HED conducted a review of occupational and non-occupational incidents as
reported in the Incident Data System (IDS) from 1996 through 1999 and in
Poison Control Center (PCC) data generated from 1993 to 1998.  Several
incidents were reported from use in occupational settings.  During this
time, a total of 15 men were reported to be adversely exposed to
aldicarb in occupational settings.  Detailed information about these
incidents is discussed in the Incident Data section of this document.

Aldicarb Data Gaps and Labeling

Toxicology:

Comparative Cholinesterase Assay (PND 11 pups and adult rats)

1-day dermal toxicity study (including RBC/plasma/brain ChEI measures)

1-day inhalation toxicity study (including RBC/plasma/brain ChEI
measures)

For aldicarb, the Agency has relied primarily on the non-guideline
comparative cholinesterase study in juvenile and adult animals to
evaluate the potential sensitivity of young animals to cholinesterase
inhibition. However, RBC cholinesterase inhibition was not monitored in
that study (whole blood, plasma, and brain). Additionally, there are no
comparative cholinesterase activity recovery data available. Since RBC
cholinesterase inhibition has been selected as endpoint for derivation
for PODs in the aldicarb risk assessment, a comparative cholinesterase
assay (PND 11 pups and adult rats) measuring cholinesterase activity
(RBC and brain) is required. Time-course data for cholinesterase should
be generated prior to the dose-response study, to determine time to peak
effect and time to recover to control values (ChE activity). Protocols
should be submitted to OPP for comment prior to study initiation.

Additionally, the previous data gaps of 21-day repeat dermal and repeat
dose inhalation studies have been removed and replaced with the
requirement for one-day dermal and one-day inhalation studies in which
ChE activity (peak effect, time to recovery, dose response) is
monitored. These studies will provide more useful data for risk
assessment. Protocols should be submitted to OPP for comment prior to
study initiation.

Residue Chemistry:

860.1500	Field trials in sorghum forage and cotton gin by-products (gin
trash).  [HED recommends cotton field trials include residues in
cottonseed, since the available data for this commodity are limited and
of poor quality.]

Label Changes:

Registered labels must reflect maximum seasonal use rates (where
applicable).

The restriction against feeding grain sorghum forage must be removed.

A 10-month plantback interval (PBI) should be specified on EPA Reg. No.
264-331 for crops not listed on the label.

2.0	PHYSICAL/CHEMICAL PROPERTIES  TC \l1 "2.0	PHYSICAL/CHEMICAL
PROPERTIES

Technical aldicarb is a white crystalline solid with a melting point of
98-100 C and a slight sulfurous odor.  Crystalline aldicarb is
heat-sensitive and decomposes above 100 C.  Aldicarb is soluble in water
(0.6%) and increasingly more soluble in the following solvents: hexane
(<1%), carbon tetrachloride (4%), benzene (18%), methylethyl ketone
(20%), acetone (38%), and chloroform (42%).  The vapor pressure of
technical aldicarb is 2.9 x 10-5 mm Hg at 25 C.  Identifying codes and
characteristics are:

Empirical Formula:	C7H14N2O2S

Molecular Weight:	190.3

CAS Registry No.:	116-06-3

Chemical ID No.:	098301

Octanol/water partition coefficient (log Kow):	1.359

Density (at 25 C):	1.195

Structures of aldicarb and its two regulated metabolites, aldicarb
sulfoxide and aldicarb sulfone, are shown below:

Aldicarb sulfone:  2-Methyl-2-(methylsulfonyl)propionaldehyde O-(methyl
carbamoyl) oxime

3.0	HAZARD ASSESSMENT  TC \l1 "3.0	HAZARD ASSESSMENT

3.1	Hazard Profile  TC \l2 "3.1	Hazard Profile

Aldicarb is a N-methyl carbamate pesticide that exerts its pesticidal
activity and elicits adverse toxic effects by inhibition of
cholinesterase activity [ChEI], which has been demonstrated in whole
blood, plasma, red blood cells, and brain of rats, mice, and dogs
following acute, subchronic, and chronic exposure and in plasma and RBC
in humans following acute exposure.

The available data indicate a peak effect within an hour of dosing
followed by recovery within 24 hours. As a result, a comparable degree
of inhibition occurs whether delivered once or following subchronic or
chronic dosing.

There is an acute oral exposure study on aldicarb involving direct
dosing of humans in which plasma and RBC cholinesterase activity and
clinical signs were monitored.  There is also a full database of oral
animal toxicity studies.

  SEQ CHAPTER \h \r 1 Aldicarb is highly acutely toxic via the oral,
dermal, and inhalation routes of exposure in the acute studies required
for labeling (Toxicity Category I).  It is not considered to be a dermal
sensitizer; dermal and eye irritation studies were waived due to severe
effects (death) following corneal and dermal dosing.

Subchronic toxicity studies demonstrate that aldicarb inhibits
cholinesterase activity in plasma, red blood cells (RBC), and brain in
dogs, rats, and rabbits following exposure by the oral and dermal
routes.  Clinical signs associated with cholinesterase inhibition (ChEI)
observed in subchronic studies include tremors, salivation, lacrimation,
lethargy, and prostration.

The database for chronic toxicity is complete.  There were no
treatment-related effects on hematology, clinical chemistry [other than
ChE activity], organ weights, and histopathology.  Only scattered
effects on other measures at the high dose were noted, such as decreased
body weight and eye effects in rats.

The aldicarb database for neurotoxicity is complete, with acceptable
acute, subchronic, and developmental neurotoxicity studies.  In
addition, there is a published acute neurotoxicity study from an EPA
laboratory on the comparative sensitivity of young and adult rats
following acute oral exposures.  Both the acute and subchronic rat
neurotoxicity studies show a variety of typical clinical signs of ChEI
after oral exposures, including decreased motor activity, lacrimation,
tremors, salivation, pinpoint pupils, and decreased grip strength, as
well as significant decreases in plasma, RBC, and brain cholinesterase
activity.  In the developmental neurotoxicity study in rats, ChEI and
associated clinical signs, i.e., tremors, salivation, lacrimation,
ataxia, miosis, and hunched posture, were observed in the dams at the
same dose levels where decreased motor activity was observed in the
pups.  No neuropathological effects related to exposure were seen in any
of the acute, subchronic, chronic, or neurotoxicity studies.

There was no indication of increased susceptibility of offspring in rat
or rabbit developmental toxicity studies, in the rat reproduction study,
or in a rat developmental neurotoxicity study.  In the developmental
toxicity study in rabbits, no developmental effects were observed at any
dose level, but maternal toxicity was observed, as evidenced by
decreased body weight, pale kidneys, and hydroceles on the oviducts.  In
the developmental toxicity study in rats, the developmental effects,
ecchymosis (hemorrhagic spots) of the trunk, occurred at the same dose
level as the maternal effects, decreased body-weight gain and food
consumption.  Signs of ChEI including hypoactivity, ataxia, tremors,
lacrimation and cold extremities were observed in the maternal rats.  In
the reproduction study, the effects on the offspring, reduced survival
(day 4) and decreased body weight, were observed only at the highest
dose tested where parental toxicity occurred, as evidenced by decreased
body weight and blood cholinesterase inhibition. Maternal toxicity was
observed at a dose where no offspring toxicity was observed (i.e., the
NOAEL for maternal toxicity was lower than the offspring NOAEL).

A published acute oral exposure study (EPA/ORD; Moser) reported evidence
for increased sensitivity of young rats.  The only parameter that
demonstrated sensitivity was brain cholinesterase inhibition (i.e., the
magnitude of the brain ChEI was greater in the young rat compared to the
adult rat at comparable acute doses).  Decreased motor activity was
observed only in the adult animals, and clinical signs of ChEI occurred
more frequently in, and recovery was prolonged in, the adult compared to
the young animal. Sensitivity with respect to the whole blood
compartment could not be determined since whole blood ChEI was extremely
high in this compartment at all dose levels in both the young and adult
animal.

In an acute oral study conducted in human volunteers of both sexes, red
blood cell and plasma cholinesterase activities and clinical signs were
monitored.  Aldicarb treatment of both males and females resulted in
statistically significant inhibition of both red blood cell and plasma
cholinesterases at the two common dose levels. The inhibition observed
at the lowest dose, which was tested only in males, was not considered
toxicologically significant in males; i.e.  RBC ChEI <10%; plasma ChEI
<20%.  However, there is a lack of dose-response information in females
at the low dose level.  Ratios of the BMDL10s for RBC ChE  inhibition
suggest a two-fold difference in toxic responses between animals and
humans.  This study was evaluated by the HSRB, and they arrived at
similar conclusions.

Aldicarb is rapidly absorbed, widely distributed, and rapidly excreted,
with more than 90% excreted in the urine within 24 hours after either
acute or repeated oral doses.  It is metabolized primarily to aldicarb
sulfoxide, with a smaller amount then slowly converted to aldicarb
sulfone.  These three moieties (aldicarb, sulfoxide, and sulfone) may
then be further metabolized to oximes and nitriles.  Both the sulfoxide
and sulfone are also potent cholinesterase inhibitors.  The sulfone is
less toxic following an acute oral exposure than either the parent
compound or the sulfoxide which show comparable acute oral toxicity,
based on results of median lethal dose studies (i.e., LD50's).

There are acceptable negative studies for all three required categories
of mutagenic effects:  gene mutations, chromosomal aberrations, and
other genotoxic effects.  Aldicarb was negative in the in vitro forward
gene mutation assay, in the in vivo chromosomal aberration assay in
mouse bone marrow cells, in the dominant lethal assay, and in the
unscheduled DNA synthesis assay.  Based on these studies, aldicarb is
not considered mutagenic.

Aldicarb is classified as Category E, Evidence of Non-Carcinogenicity
for Humans, based on the lack of evidence of carcinogenicity in studies
in rats and mice and the absence of a mutagenicity concern.

There are no acceptable dermal toxicity or dermal penetration studies
that can be used, when considered with all available oral studies, to
estimate dermal absorption for occupational exposure and risk
assessments.  In this risk assessment, toxicity by the dermal route has
been considered to be equivalent to toxicity by the oral route of
exposure (100 %). Additionally, there is no inhalation toxicity study,
and toxicity by the inhalation route also has been considered to be
equivalent to toxicity by the oral route of exposure (100 %).  Table 1
summarizes the results of acute toxicity testing for aldicarb.

Table 1.  Aldicarb Acute Toxicity.

Guideline No./Study Type	MRID No.	Results	Tox Category

870.1100 Acute oral toxicity	00057333	LD50 = 0.8 mg/kg/day	I

870.1200 Acute dermal toxicity	00091241

00069916	LD50 = 20 mg/kg/day, water

LD50 = 5 mg/kg, propylene glycol	I

870.1300 Acute inhalation toxicity	00069916

00057333	LC50 < 0.007 mg/L	I

870.2400 Acute eye irritation	00069916	No corneal irritation at lethal
dose	N/A

870.2500 Acute dermal irritation	00069916	None at fatal levels	N/A

870.2600 Skin sensitization	N/A	N/A	N/A

The above studies satisfy the acute toxicity data requirements [OPPTS
870.1100, 870.1200, 870.1300]; dermal and eye irritation studies not
required due to severe effects [death] following eye and dermal
exposure; (N/A = not applicable).  Table 2 summarizes the toxicity
profile for technical aldicarb.

Table 2.  Toxicity Profile of Aldicarb Technical.

Study Type [GLN No.]	MRID No./Classification	Results1

Sub-chronic oral toxicity (dog)

[870.3150]	41919901 (1991)

Acceptable	NOAEL=0.02 mg/kg/day

LOAEL=0.06 mg/kg/day

Based on plasma and RBC ChEI in males and females

Developmental toxicity rodent (rat)

[870.3700a]	41004501 (1988)

Guideline	Maternal:	NOAEL=0.125 mg/kg/day

LOAEL=0.25 mg/kg/day

Based on decreased body weight gain and food consumption

Developmental:	NOAEL=0.125 mg/kg/day

LOAEL=0.25 mg/kg/day

Based on ecchymosis of the trunk

Developmental toxicity in non-rodent (rabbit)

[870.3700b]	0132668 (1983)

Guideline	Maternal:	NOAEL=0.1 mg/kg/day

LOAEL=0.25 mg/kg/day

Based on decreased body weight, pale kidneys, hydroceles on the oviducts

Developmental:	NOAEL=>0.5 mg/kg/day

Reproduction and fertility effects

[870.3800]	42148401 (1991)

Minimum	Parental/Systemic NOAEL=0.4 mg/kg/day

LOAEL=0.7-0.9 mg/kg/day

Based on decreased body weight gains and RBC and  plasma ChEI

Reproductive:	NOAEL=0.7-0.9 mg/kg/day

LOAEL=1.4-1.7 mg/kg/day

Based on decreased viability and body weights, and signs of debilitation

Chronic oral toxicity in rodents

[870.4100a]	43045401 (1993)

Minimum	NOAEL=0.047 mg/kg/day

LOAEL=0.47 mg/kg/day

Based on plasma and RBC ChEI

Chronic oral toxicity dogs

[870.4100b]	40695401, 42191501

(1988)

Supplementary	NOAEL<0.028 mg/kg/day

LOAEL=0.028 mg/kg/day

Based on plasma ChEI

Carcinogenicity in rats

[870.4200]	43045401 (1993)

Minimum	NOAEL=0.047 mg/kg/day

LOAEL=0.47 mg/kg/day

Based on plasma/RBC ChEI

No evidence of carcinogenicity

Carcinogenicity in mice

[870.4300]	00044732; 00044733; 00044734 (1972)

Minimum	NOAEL=0.2 mg/kg/day

LOAEL=0.4 mg/kg/day

Based on increased mortality.

No evidence of carcinogenicity.

Gene Mutation

[870.5300]	00148168 (1985)

Acceptable	1000-5000 ug/ml: Negative with and without activation at a
marginally cytotoxic dose.

Cytogenetics:

Mammalian bone marrow chromosome aberration test.

[870.5385]	41661301; 41663102

(1990)

Acceptable	0.1-0.4 mg/kg: No chromosomal aberrations in mouse bone
marrow cells.

Unscheduled DNA Synthesis

[870.5500]	00141673 (1984)

Acceptable	33-10,000 ug/well: No effects.

Rat Dominant Lethal Study	43575101 (1995)

Acceptable	Systemic LOAEL: 2.28 mg/kg

Based on body weight reductions, tremors, and plasma, RBC and brain
ChEI.

No evidence of a dominant lethal effect.

Acute neurotoxicity screening battery

[870.6200a]	43442301 (1994) Acceptable	NOAEL<0.05 mg/kg/day

LOAEL=0.05 mg/kg/day

Based on plasma ChEI.

Subchronic neurotoxicity screening battery

[870.6200b]	43829602 (1995) Acceptable	NOAEL<0.05 mg/kg/day

LOAEL=0.05 mg/kg/day

Based on pinpoint pupils and blood and brain ChEI.

Developmental neurotoxicity

[870.6300]	43829601 (1995)

Acceptable	Maternal:	NOAEL=0.05 mg/kg/day

LOAEL=0.1 mg/kg/day

Based on plasma ChEI

Offspring:	NOAEL=0.05 mg/kg/day

LOAEL=0.1 mg/kg/day

Based on reduced body weights and decreased motor activity

Metabolism and pharmacokinetics

[870.7485]	00102022 (1966)

00102023 (1967)	85% of an acute oral dose to rats was excreted in 24
hours.  The metabolism of aldicarb was primarily to the sulfoxide (40%),
with a smaller amount then slowly converted to the sulfone.

Special neurotoxicity studies:

Moser VC

	45068601 (1999)

TAP 157 94-106

	NOAEL<0.05 mg/kg.

LOAEL=0.05 mg/kg (pups)

Effects in pups: Blood (both sexes), brain ChEI (males).

Note: PND 17 day pups exhibited twice the level of brain ChEI as adults.

Acute oral study  (human)

Inveresk

	42373001 (1992)

46131001 (supplementary report) 	NOAEL = not determined for females

LOAEL = 0.01 mg/kg

1NOAEL = No observed adverse effects level; LOAEL = Lowest observed
adverse effects level; ChE = Cholinesterase; ChEI = Cholinesterase
inhibition; RBC = red blood cell.

	3.2    Dose Response Assessment

	3.2.1	Benchmark Dose (BMD) Analysis

In order to evaluate the appropriate point of departure (PoD) for ChEI,
the Agency considered benchmark dose (BMD) estimates developed from
several studies as mentioned above along with BMD estimates provided in
the preliminary cumulative risk assessment for the N-methyl carbamates
(USEPA, 2005).  Dose-response modeling is preferred over the use of
NOAEL/LOAELs (i.e., no or lowest observed adverse effect levels) since
NOAELs and LOAELs do not necessarily reflect the relationship between
dose and response for a given chemical, but instead reflect dose
selection (USEPA, 2000).  The estimated dose at which 10% ChEI is
observed (BMD10) and the lower 95% confidence intervals (BMDL10) were
estimated by fitting the ChE data to an exponential dose-response model
using generalized nonlinear least squares.  The BMD10 was selected
because it is generally at or near the limit of sensitivity for
discerning a statistically significant decrease in ChE activity across
the blood and brain compartments and is a response level close to the
background ChE activity.  Moreover, the Agency believes that 10% is
likely to be protective for other toxicities, such as clinical signs
and/or behavioral endpoints.

  SEQ CHAPTER \h \r 1 The Agency’s BMD analysis for the preliminary
cumulative risk assessment was presented to the FIFRA SAP in February
and August, 2005.  At those meetings, the panel supported the Agency’s
approach for developing BMD estimates for the N-methyl carbamates.  In
the current analysis, the Agency used ChE inhibition data for RBC from
the human study.  Ratios of the BMD10s for brain ChE inhibition between
juvenile and adult animals suggest that juvenile animals are 2X more
sensitive than adult animals.  Therefore, the Agency has retained a 2X
FQPA safety factor in the derivation of the aldicarb acute PAD and other
acute risk assessments.

The human toxicity study for aldicarb provides RBC and plasma ChE data
for both males and females. The blood ChE activity data (plasma and RBC)
provided in the human study are considered appropriate surrogate
measures of potential effects on peripheral nervous system (PNS)
acetylcholinesterase (AchE) activity, and of potential effects on the
central nervous system (CNS) when brain ChE data are lacking which is in
accordance with the 2000 Science Policy on Use of Cholinesterase
Inhibition in Risk Assessment of OPs and Carbamates  (USEPA, 2000).
AchE is the target enzyme for the cumulative risk assessment and is the
primary form of ChE found in RBCs. The RBC data from the human study are
being utilized by the Agency in this single chemical risk assessment.

The measured RBC ChE activity from the human study is adequate for
estimation of BMD and BMDLs.  The RBC ChE data from the aldicarb human
study was utilized in the model in the same manner as rat data (brain
and RBC) that are available for the NMCs of the cumulative hazard
assessment (USEPA 2005). The BMD10 and BMDL10 estimates for both rat
(RBC, brain) and human (RBC) are included in Table 3 below.

Table 3.   Oral BMD10s and BMDL10s Generated from Adult Rat ChE (RBC,
brain) and Human ChE (RBC)

                 Data for Aldicarb.

Chemical	Rat	Human

	Brain	RBC	RBC

	BMD10

(mg/kg)	BMDL10

(mg/kg)	BMD10

(mg/kg)	BMDL10

(mg/kg)	BMD10

(mg/kg)	BMDL10

(mg/kg)

Aldicarb	F=0.05

M=0.06	F=0.03

M=0.03	0.03	0.02	0.02

0.01

BMD estimates are presented as a single estimate when there are no
differences between sexes.

Human RBC data obtained from MRID 42373001

Rat brain and RBC data obtained from MRIDs 43442302, 43442305, 43829601,
43829602, 45068601.

3.2.2  Endpoint Selection

Based on the toxicity profile, the Agency has selected endpoints and
doses for assessment of risk. The Agency considered the human acute oral
study for assessment of the acute exposure scenarios.  Due to recovery
of ChEI within 24 hours following aldicarb exposure, the use of the
acute study in humans for endpoint selection is considered appropriate
and protective for all exposure durations (repeated dosing is considered
a series of acute exposures).   SEQ CHAPTER \h \r 1

For aldicarb, the similarity of response between humans and rats
following acute oral exposure allows for the use of both sets of data in
considering toxicity endpoint selection and uncertainty factors. As
mentioned previously in an acute oral study conducted in human
volunteers, aldicarb treatment of both males and females resulted in
statistically-significant inhibition of both red blood cell and plasma
cholinesterases at the two common dose levels.  Although brain ChEI is
not available from the human study, the RBC activity is considered
appropriate surrogate measures of potential effects on peripheral
nervous system (PNS) acetylcholinesterase (AChE) activity, and of
potential effects on the central nervous system (CNS) when brain ChE
data are lacking (USEPA 2000).  In addition, the human RBC ChEI observed
in both sexes at the two common dose levels suggest no differences
between sexes in humans.  Note that EPA's use of a human toxicity study
in the aldicarb risk assessment is in accordance with the Agency's Final
Rule promulgated on January 26, 2006, related to Protections for
Subjects in Human Research, which is codified in 40 CFR Part 26.  The
final report of the HSRB as it relates to aldicarb is available at
HYPERLINK "http://www.epa.gov/osa/hsrb/files/"
http://www.epa.gov/osa/hsrb/files/ april2006mtgfinalreport62606.pdf

There are several rat studies available where acute ChE inhibition was
measured at or near peak time of inhibition (45 minutes –1hour) and
these inform the derivation of the acute RfD and acute PAD.  These
include the acute and subchronic neurotoxicity studies performed by the
registrant and an acute comparative ChE activity study performed by
scientists from the National Health and Environmental Effects Research
Laboratory (NHEERL). Clinical signs were also reported in these studies,
but usually only at the higher dose levels; i.e., ChEI occurred at doses
lower than or equal to dose levels where clinical signs occurred  SEQ
CHAPTER \h \r 1 .  It is unknown whether changes in clinical signs
indicative of ChEI are related to brain or peripheral ChE inhibition;
the Agency cannot discount the potential that peripheral ChE inhibition
may be produced by aldicarb.  Given that numerous studies have shown RBC
ChE inhibition to be a sensitive measure and that dose-related changes
in behavioral endpoints and clinical signs have been observed at the
higher doses of aldicarb, at this time, the Agency considers the RBC ChE
inhibition data to be sufficiently reliable for developing a point of
departure for risk assessment purposes.

To repeat there are no suitable dermal or inhalation toxicity or dermal
penetration studies for aldicarb risk assessment. Therefore the same
study is considered appropriate for endpoint selection for short and
intermediate term occupational dermal and inhalation exposure.

Additionally, based on the recovery of effects within 24 hours seen in
both the human and animal studies and on the fact that repeat dosing is
considered a series of acute exposures,  the same toxicity study was
considered for establishing a chronic RfD and for assessing long-term
occupational risk. However, the Agency has determined that a chronic
risk assessment is not needed, since risks resulting from aldicarb
exposure are better described as a series of acute risks, and since
chronic risk estimates will necessarily be lower that acute risk
estimates since average rather than high-end exposure estimates are used
with the same POD.

Table 4 presents the toxicity endpoints for risk assessment.

The registrant submitted rat 21-day and 5-day dermal toxicity studies in
which the granular formulation containing 14.75 % ai was used as the
test substance, rather than the technical active ingredient.  These
studies had inconsistent findings with respect to body weight gains and
ChEI data, and were considered unacceptable for the purpose of risk
assessment.  HED had concerns about the extent of wetting of the skin,
as well as the percentage of body surface area treated, which may have
contributed to the lack of a dose-response.  The Hazard Identification
Assessment Review Committee (HIARC) discussed the data from these two
studies, along with ChEI data from oral studies of varying durations, in
order to determine if a weight-of-evidence-based dermal absorption
factor could be derived.  Although the HIARC agreed that most of the
data suggest a dermal absorption factor of less than 100%,
inconsistencies in the data and methodology concerns prevented a
possible departure from the use of 100% absorption for dermal exposure
assessments.  This value is thought to be conservative, and, therefore,
protective for dermal exposures.

Likewise, for inhalation exposures assessed using oral studies, the
HIARC selected an inhalation absorption factor of 100% relative to oral
exposures to be applied in assessing inhalation exposure and risk for
aldicarb.

Table 4.  Aldicarb Toxicology Endpoint Selection.

Exposure

Scenario	Dose Used in Risk Assessment,

UF1	FQPA SF and Reference Dose for Risk Assessment	Study and
Toxicological Effects

DIETARY EXPOSURES

Acute Dietary:

General US Population

[MRID No. 42373001]	BMDL10 = 0.013 mg/kg

UF = 10

Acute RfD = 0.0013 mg/kg/day

	FQPA SF = 2X

aPAD=acute RfD

             FQPA SF

          = 0.00065 mg/kg/day	human study

RBC ChEI

Chronic Dietary:

General US Population

[MRID No 42373001]	BMDL10 = 0.013 mg/kg

UF = 10

Chronic RfD = 0.0013 mg/kg/day

	FQPA SF = 2X

cPAD =chronic RfD

              FQPA SF

           =0.00065 mg/kg/day	human study

ChEI

DERMAL EXPOSURES

Short-Term (1-30 days);

Intermediate-Term (30 days to several months)

[MRID No. 42373001]	Oral study BMDL10 = 0.013 mg/kg

Absorption factor = 100%

		LOC for MOE = 10	human study

RBC ChEI

human study [reduction of interspecies factor to 2X]

INHALATION EXPOSURES

Any Duration

[MRID No 42373001]	Oral study BMDL10 = 0.013 mg/kg

Absorption factor = 100%	LOC for MOE = 10	human study

RBC ChEI

human study [reduction of interspecies factor to 2X]

 	The UF 10X is for intraspecies variability

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

For informational purposes, Table 5 shows aPADs using the rat brain and
rat RBC BMDL10  for comparison with the aPAD based on the human RBC
BMDL10.

Table 5. Comparison of Population Adjusted Dose

Parameter	Rat3	Human4

	Brain	RBC	RBC

	BMD10 (mg/kg)1	F=0.05

M=0.06	0.03

0.02

BMDL10 (mg/kg)2	0.03	0.02	0.013

UF (intraspecies)	10X	10X	10X

UF (interspecies)	2X	2X	1X

FQPA SF	2X	2X	2X

Acute RfD	0.0015	0.001 mg/kg	0.0013

Acute PAD	0.00075	0.0005 mg/kg	0.00065

1. BMD estimates are presented as a single estimate when there are no
differences between sexes.

2. BMDL10 used for risk assessment

3. Rat brain and RBC data obtained from MRIDs 43442302, 43442305,
43829601, 43829602, 45068601.

4. Human RBC data obtained from MRID 42373001

3.3  Reversibility

Aldicarb toxicity is characterized by maximal inhibition of
cholinesterase which occurs rapidly followed by recovery typically
occurring within hours.   A key consideration in risk assessment is
appropriate matching of the duration of exposure with the duration of
the toxic effect.  Typically, HED’s food and water exposure
assessments sum exposures over a 24 hour period.  This 24 hour total is
typically used in acute dietary risk assessment.  In the case of the
aldicarb, because of the rapid nature of aldicarb toxicity and recovery,
it may be appropriate to consider durations of exposure less than 24
hours.  Conceptually, a physiologically-based pharmacokinetic model
and/or biologically-based dose-response model would be available to
account for the dynamic nature of exposure, absorption, toxicity,
recovery, and elimination of aldicarb in animals and humans.  However,
such a model does not exist at this time.  In the interim, HED has
developed an analysis using information about external exposure, timing
of exposure within a day, and half-life of ChE inhibition from rats and
humans to estimate risk to aldicarb at durations less than 24 hours.
Specifically, HED has evaluated individual eating and drinking occasions
and used the ChE half-life information to estimate the residual effects
from aldicarb from previous exposures within the day.

Table 6 below provides information on the recovery of ChE inhibition in
rats and human subjects.  For both species, the recovery half-life for
RBC ChE inhibition is approximately two hours.  At high doses in rat,
the half-life is up to approximately 6 hours in females.  The estimates
of half-life at the lower doses are most relevant for risk assessment
and are thus the focus here.  As can be seen in the table, the estimated
recovery half life of aldicarb-inhibited AChE in the human is estimated
to be on the order of 2 hours using RBC AChE activity   This 2 hour
recovery half-life is what is used in this refined dietary exposure
assessment which incorporates information on eating/drinking occasions.
There is some uncertainty associated with the use of the two hour
recovery half-life.  As discussed in detail below, infants and children
are the focus of the current analysis.  Although there are dose-response
ChE data in juvenile animals exposed to aldicarb, there are no such data
to characterize ChE recovery in the young.  As such, the Agency has
assumed that the half-life to recovery in the young is similar to that
seen in adults.  The Agency is requiring such data in young animals to
confirm this assumption.

Table 6.  Recovery half-life information for ChE inhibition following
oral exposure to aldicarb in rats and human subjects

Chemical	Brain	RBC

	Recovery Half-Life Estimate (hrs)	Upper & Lower Confident Intervals
(hrs)	Recovery Half-Life Estimate in hrs

(dose; mg/kg)	Upper & Lower Confident Intervals (hrs)

Rat	1.52	1.16-1.99	F (< 0.1)  1.10

(0.1,0.3)  2.91

(0.3,0.5) 3.39

(>0.5) 5.90

M (<0.1) 1.91

(0.1,0.3) 1.20

(0.3,0.5) 1.62

(>0.5) 1.50	F  0.50-2.40

1.96-4.33

2.35-4.90

3.52-9.91

M  1.31-2.79

0.87-1.64

1.19-2.21

0.80-2.82

Human	N/A	2.07	1.74-2.46

  SEQ CHAPTER \h \r 1 3.4	FQPA Considerations

The FQPA (1996) instructs EPA, in making its “reasonable certainty of
no harm” finding, that in “the case of threshold effects, an
additional tenfold margin of safety for the pesticide chemical residue
and other sources of exposure shall be applied for infants and children
to take into account potential pre- and postnatal toxicity and
completeness of data with respect to exposure and toxicity to infants
and children.” Section 408 (b)(2)(C) further states that “the
Administrator may use a different margin of safety for the pesticide
chemical residue only if, on the basis of reliable data, such margin
will be safe for infants and children.”

There was no evidence of increased sensitivity in any of the guideline
studies reviewed. Aldicarb did not result in developmental toxicity in
either rats or rabbits or in reproductive effects in the rat
multi-generation reproduction study. Additionally, there was no
developmental toxicity in the developmental neurotoxicity study in rats.
However, the comparative cholinesterase inhibition study [Moser], in
which adult and juvenile rats were exposed to the same acute oral doses
of aldicarb, demonstrated that juvenile rats were more sensitive than
the adults with respect to brain cholinesterase inhibition. Based on
benchmark dose (BMD/BMDL) estimates calculated from these data, the
young animals are 2X more sensitive than the adults  [brain BMD10s
ranged from 0.014 to 0.020 in juvenile animals and 0.024 to 0.031 in
adult animals]. Therefore, a FQPA safety factor of 2X is retained.

3.5      Endocrine Disruption

  TC \l2 "3.4	Endocrine Disruption

EPA is required under the 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 recommendations of its Endocrine Disruptor and Testing
Advisory Committee (EDSTAC), EPA determined that there was a 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 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 aldicarb, there was no estrogen,
androgen, and/or thyroid mediated toxicity.

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

4.0	EXPOSURE ASSESSMENT AND CHARACTERIZATION  TC \l1 "4.0	EXPOSURE
ASSESSMENT AND CHARACTERIZATION

4.1	Summary of Registered Uses  TC \l2 "4.1	Summary of Registered Uses

Aldicarb is a carbamate pesticide which is registered for use as a
systemic insecticide, acaricide and nematicide on agricultural crops
including citrus, cotton, dry beans, peanuts, pecans, potatoes, sorghum,
soybeans, sugar beets, sugarcane, sweet potatoes, and seed alfalfa (CA).
 In addition, aldicarb may be applied to field grown ornamentals (CA)
and tobacco, and on coffee grown in Puerto Rico.  The types of plant
pests controlled by aldicarb include leaf phylloxera; bud moth; citrus
nematode; aphids; mites (citrus red, citrus rust, Texas citrus); white
flies; thrips; fleahoppers, leafminers; leafhoppers; overwintering boll
weevil (adults feeding on foliage); lygus; nematodes; cotton leaf
perforator; seedcorn maggot; Mexican bean beetle; flea beetles; Colorado
potato beetle; greenbug; chinch bug; three cornered alfalfa hopper
(suppression); and sugar beet root maggot.

Aldicarb is a restricted use pesticide (RUP), and may be applied only in
occupational settings by certified applicators.  There are no products
containing the active ingredient aldicarb which are intended for sale to
homeowners or in non-occupational settings (e.g., turf or golf course).

Aldicarb is formulated and marketed solely as a granular pesticide.
Aldicarb in a vinyl binder coating is adhered to either a corn cob grit
or gypsum substrate; these two substrates produce less dust than typical
clay substrates used for granular pesticides.   Only the gypsum granular
is available in closed loading systems.  The formulations consist of 5,
10 and 15% granulars, which are applied early in the growing season,
either pre-plant, at-planting, or early post-emergent, using ground
application equipment.  Labels specify use of positive displacement
application equipment and immediate soil incorporation.

For most crops, only one aldicarb application per season is allowed, but
2 or 3 split applications are permitted on sugar beets.  The pre-harvest
intervals (PHIs) are generally long due to the early application timing,
ranging from 80 to 150 days when specified.

Use information for aldicarb has been summarized in two Quantitative
Usage Analyses (QUAs) generated by BEAD/OPP, dated 12/99 and 5/00.
Estimates of the amount of active ingredient applied on a crop-specific
basis have been provided based on data from EPA, USDA, the National
Center for Food and Agricultural Policy, and the WEFA group.  In terms
of pounds of active ingredient (ai) applied, the most significant use
site for aldicarb is cotton, with 2 to 3 million lbs ai applied on an
annual basis.  Other significant use sites (in decreasing amounts of ai
applied) are peanuts, potatoes, sugar beets and oranges.  Based on acres
grown and pounds active ingredient applied, BEAD generates estimates of
the percent of crop treated (%CT) for use in HED’s dietary exposure
analyses.  For aldicarb, crops with %CT estimates of greater than 20%
are peanuts, sweet potatoes, cotton, potatoes and citrus.

4.2	Dietary Exposure/Risk Pathway  TC \l2 "4.2	Dietary Exposure/Risk
Pathway

Potential dietary (food only) exposure to aldicarb can occur following
application to food crops including pecans; potatoes; sweet potatoes;
cotton; dry beans; grain sorghum; soybeans; sugar beets; sugarcane;
peanuts; citrus (orange, grapefruit, lemon and lime); and coffee.

	4.2.1	Residue Profile  TC \l3 "4.2.1	Residue Profile

The aldicarb residue chemistry database is largely complete and is
considered adequate to reassess most tolerances listed in 40 CFR
§180.269.  The regulated residues are the combined residues of aldicarb
and its two cholinesterase-inhibiting metabolites aldicarb sulfoxide
[2-methyl-2-(methylsulfinyl)propionaldehyde O-(methyl carbamoyl) oxime]
and aldicarb sulfone [2-methyl-2-(methylsulfonyl)propionaldehyde
O-(methyl carbamoyl) oxime].  Aldicarb sulfoxide is considered to have
similar potency to the parent in terms of toxicity, while aldicarb
sulfone is less potent.  Aldicarb and the sulfoxide and sulfone
metabolites are the residues of concern for both tolerance reassessment
and risk assessment purposes.  Currently established tolerances for
aldicarb and its metabolites range from 0.002 ppm in milk to 1 ppm in
potatoes.

The metabolic breakdown and nature of aldicarb residues in plants and
livestock are adequately understood, based on metabolism studies
conducted in lemons, cotton, peanuts, potatoes, and sugar beets, and in
ruminants and poultry.  These studies have shown that following soil
application, aldicarb is readily taken up through root systems and
translocated throughout the plant.  Aldicarb is oxidized to form the
cholinesterase-inhibiting metabolites aldicarb sulfoxide and aldicarb
sulfone.  Further hydrolysis of the cholinesterase-inhibiting parent and
metabolites yields the (less toxic) oxime, acid, nitrile and alcohol
derivatives of the carbamate metabolites.  The metabolic pathway in
livestock is similar to that observed in plants; in addition, the
tentative identification of radiolabeled fatty acids and glycerol in
eggs, and the significant levels of dispersed radioactivity in the
chromatograms of tissue extracts, suggest incorporation of degraded
aldicarb into the biochemical pathway.

Adequate data collection and enforcement analytical methods are
available for aldicarb and its metabolites.  The enforcement method
involves oxidation of aldicarb and aldicarb sulfoxide to aldicarb
sulfone; total residues are quantified as the sulfone (Pesticide
Analytical Manual, Volume II, Method II) using gas-liquid chromatography
with flame photometric detection in the sulfur mode (GLC/FPD).  Data
collection methods that have been used to generate residue data in
certain commodities (e.g., potatoes and citrus) separately quantify
aldicarb and its metabolites using high performance liquid
chromatography (HPLC).

Aldicarb and aldicarb sulfone residues are completely recovered (>80%)
using multiresidue method PAM Volume I Section 302 (Luke method;
Protocol D) and Section 401 (method for N-methylcarbamates).  Aldicarb
sulfoxide residues are also completely recovered using multiresidue
method Section 302, but are only partially recovered (50-80%) using
Section 401.

In most raw agricultural commodities (RACs), aldicarb and metabolite
residues are expected to be low or nondetectable; however, in the past,
higher residues have been known to occur in individual citrus (orange
and grapefruit), potatoes and sweet potatoes.  In general, the parent,
aldicarb per se is not detected in plants; residues of aldicarb
sulfoxide tend to be detected more often and at higher levels than
aldicarb sulfone.

Residues of concern are not likely to be detected in livestock tissues,
milk and eggs, and HED has previously recommended against establishing
tolerances for residues in poultry commodities.  HED has recommended
revocation of existing tolerances for aldicarb residues in livestock
commodities.  Aldicarb and metabolite residues generally do not
concentrate during processing, with the exception of certain dried
commodities.  Since aldicarb is a systemic pesticide, food preparation
activities such as washing and peeling are not likely to reduce
residues; however, special studies in potatoes have shown a reduction in
residues during baking (oven) and boiling.  There is a potential for
uptake of residues in rotational crops; therefore, rotational crop
tolerances or adequate plantback intervals have been recommended.

Extensive monitoring data for aldicarb have been generated in composite
samples of numerous commodities and in multiple years by the USDA
Pesticide Data Program (PDP) and the FDA Surveillance Monitoring
Program.  Monitoring data reflect residues in commodities closer to the
point of consumption (i.e., “dinner plate”) rather than the maximum
residues generated in field trials, and can be used in dietary exposure
analyses to determine a more realistic estimate of dietary exposure and
risk.  In addition to the composite commodity samples routinely analyzed
by USDA, PDP conducted a special study on aldicarb in potatoes during
1997, which was designed to provide a comparison between a composite
residue value and the distribution of residues within that sample on a
single-serving basis.  The study included measurements of aldicarb
residues in composite samples and individual potatoes within those
composites.  Aldicarb per se was not detected in any of the composite or
single-serving samples.  In composite sample detects, the sulfoxide
constituted 79% of the total residue, while the sulfone constituted 21%
of the total residue; results for single tubers were similar, with
contributions of 78% and 22% for the sulfoxide and sulfone,
respectively.  The highest combined detected residue was in a single
serving sample (i.e, one tuber), at 0.402325 ppm (or 0.3994 ppm,
assuming an aldicarb per se residue of 0 ppm).  For samples with
detectable residues of the sulfoxide, the residue in the single serving
varied from 0.1 to 7.4 times the corresponding composite residue.  For
the sulfone, single serving residues were 0.2 to 6.1 times the composite
residue.  The results of the study demonstrated the wide range in
variability of individual tuber residues, relative to composite
residues; variability for the sulfoxide was 1.5-4.7, while the sulfone
variability was 2.1-4.9.

The Carbamate Task Force (CTF) also submitted a 1999 market basket
survey which included single oranges collected in grocery stores and
analyzed for aldicarb and metabolite residues.

In addition to the available monitoring data, extensive field trials
have been conducted in which total and individual residues have been
quantified in both composite and individual citrus fruits and potato
tubers, including sweet potatoes.  Many of these data are considered to
be "farm gate" monitoring data; they do not reflect the worst-case
conditions of field trials, but are not as close to the point of
consumption as warehouse or supermarket-level monitoring data.  In the
"farm gate" monitoring data generated by the registrant and various food
processors, most of the analyzed commodities were known to have been
treated.

4.2.2	Dietary Exposure  TC \l3 "4.2.2	Dietary Exposure

ry Exposure Evaluation Model (DEEM-FCID™) software Version 2.0, which
incorporates consumption data from USDA’s Continuing Surveys of Food
Intake by Individuals (CSFII), 1994-96, 98.  For risk assessment
purposes the risk estimates were based on the human red blood cell
cholinesterase depression endpoint.  Results based on rat RBC and brain
cholinesterase depression are provided for characterization purposes.

The aldicarb acute dietary exposure assessments were highly refined,
incorporating monitoring and market basket survey data from the USDA/PDP
(potatoes and sweet potatoes) and the CTF (oranges).  These data sets
were used to assess exposure from all potato and sweet potato food
forms, as well as all citrus commodities and food forms (orange,
grapefruit, lemon and lime).

In the 1997 PDP special survey, aldicarb and its metabolites were
analyzed in 342 composite potato samples collected from states where
aldicarb can be applied (FL, ID, OR and WA).  Residues were detected in
20 composite samples, and individual potato tubers (10 per composite)
from 16 of the composites with detects were analyzed.  The highest
combined residue in a composite sample was 0.17 ppm, which is below the
reassessed tolerance of 0.2 ppm.  The highest residue in an individual
tuber was approximately 0.4 ppm, or twice the tolerance.  Both the
special survey and the composite potato data were used in the
assessment. In the CTF market basket survey, aldicarb and metabolite
residues were measured in 399 peeled oranges collected from grocery
stores; residues were detected in 16 of the oranges sampled.  The
maximum orange residue of 0.03 ppm is 10 times lower than the reassessed
tolerance of 0.3 ppm.  In both the PDP and CTF studies, detected
residues were the sulfone and sulfoxide metabolites, but aldicarb per se
was not detected.

The PDP and CTF data were considered the best available data (for
potatoes and citrus) for use in the dietary exposure assessments, since
they reflect typical "dinner plate" exposures, and would not tend to
significantly overestimate dietary exposure.  For all other commodities,
field trial data were used in the assessment, but residues were either
very low or nondetectable (soybeans, cottonseed, peanuts, dry beans and
coffee).  Sugarbeet and sugarcane were excluded from the assessments,
since aldicarb residues would not be expected in the processed
commodities as consumed; the existing tolerance for sorghum was used in
the assessment, but did not contribute to estimated dietary exposure due
to the low %CT, the low tolerance, and the low consumption.

The most recent aldicarb use data and %CT estimates provided in the
12/99 and 5/00 Quantitative Usage Analyses (QUA) were incorporated into
the preliminary dietary exposure analyses.  Differences in %CT estimates
for fresh vs. processed potatoes, oranges and grapefruit were included
in the dietary exposure analyses.  In addition, extensive
processing/cooking data, generally indicating reduction of residues
through boiling and juicing, were incorporated into the assessment.  For
potatoes, processing factors of 0.3X, 0.6X and 0.5X were used for dried,
fried and boiled/cooked potatoes, respectively.  Since aldicarb is
systemic, typical home preparation practices such as washing and peeling
would not significantly reduce residues.

<IP_ADDRESS>	Acute Dietary Exposure  TC \l4 "<IP_ADDRESS>	Acute Dietary Exposure

Table 7 presents risk estimates calculated based on rat RBC ChEI, rat
brain ChEI and human RBC ChEI.  HED considers the human data to be the
most appropriate for risk assessment purposes since the data directly
measure the endpoint of concern in humans, rather than extrapolating
from animal data.  Risk estimates for all three endpoints are presented
only to provide a more broad characterization of risks.  The analysis
which included existing aldicarb registrations indicates estimated acute
dietary exposure and risk do not exceed HED's level of concern [i.e.,
>100 % of the acute population adjusted dose (aPAD)] for the general US
population and relevant population subgroups at the 99.9th %ile of
exposure.  The estimated dietary exposure and risk for the general U.S.
population at the 99.9th percentile exposure using the human RBC ChEI
endpoint was 0.000280 mg/kg/day, or 37% aPAD.  For children 1 – 2
years old, the most highly exposed  population subgroup, dietary
exposure was 0.000592 mg/kg/day, or 78% aPAD.  If the PAD is based on
the rat RBC or  brain ChEI endpoint, risk estimates for children 1-2
years old were 102% and 68%, respectively.

An analysis was conducted to determine the foods or food forms which
contribute the most to the exposure estimates.  For all population
subgroups, residues in potatoes were the most significant source of
dietary exposure.  For all infants, residues in sweet potato were also
significant contributors. Citrus was also a notable contributor to the
exposure estimates.

Sensitivity analyses were conducted to determine if assumptions for
nondetectable residues overestimated exposures.  These analyses
consisted of (1) assuming aldicarb per se residues were 0 ppm; and (2)
assuming nondetect residues in citrus monitoring samples were true
zeroes.  The sensitivity analyses indicated that these assumptions did
not significantly impact the estimated exposure and risk for any of the
population subgroups.  These analyses indicate that actual detected
residues from monitoring data were the source of the exposure and risk
at the higher percentiles of exposure, and not assumed residues for
nondetects (<LOD) (Table 8a).  For the general US population, assuming
aldicarb residues of 0 ppm and zero residues for nondetects in citrus,
the estimated exposure was reduced from 37 to 36 % of the aPAD; for
children 1-2 years old, the estimated exposure was reduced from 78 to 76
% of the aPAD.

Since residues in citrus and potatoes were identified as significant
contributors to estimated dietary exposure, analyses were conducted in
which citrus and potato commodities were separately omitted from the
exposure assessment (Table 8b).  When citrus commodities were excluded,
estimated exposure for children 1-2 years old was reduced from 78% to
73% of the aPAD; while exposures for the general US population and all
other population subgroups ranged from 29-59% of the aPAD.  When potato
commodities were excluded, the highest estimated exposure was for
children 1-2, at 0.000211 mg/kg/day, or 28% of the aPAD; estimated
exposures for all other population subgroups ranged from 4 to 22% of the
aPAD, all based on human RBC ChEI.  The comparative risk estimates based
on rat RBC and brain ChEI endpoints are also shown in the summary
tables.

More detailed information about these assessments can be found in the
document titled Aldicarb Revised Anticipated Residues and Dietary
Exposure Analyses for the HED Human Health Risk Assessment dated October
31, 2006.

		<IP_ADDRESS>	Chronic Dietary  TC \l4 "<IP_ADDRESS>	Chronic Dietary

A chronic assessment was not conducted because the toxicity database for
aldicarb indicates that the magnitude of ChEI does not increase with
continued exposure, due to the reversibility of ChEI (generally within
24 hours). The longer-term exposures could be considered as a series of
acute exposures.

Table 7.  Aldicarb Acute (Food Only) Dietary Exposure and Risk (99.9th %
ile) – Existing Registrations

Population	Exposure

(mg/kg/day)	Human (RBC ChEI)

%PAD	Rat (RBC ChEI)

%PAD	Rat (Brain ChEI)

%PAD

U.S. Pop	0.000280	37	48	32

All Infants	0.000312	41	54	36

Children 1-2 years 	0.000592	78	102	68

Children 3-5 years	0.000480	64	83	55

Children 6-12 years	0.000351	46	60	40

Youth 13-19	0.000237	31	41	27

Adults 20-49 yrs:	0.000231	31	40	26

Adults 50+	0.000256	34	44	29

Females13-49	0.000226	30	39	26

PAD =  	0.00065 mg/kg/day  Human (RBC CheI); 0.00075 mg/kg/day  Rat
(Brain CheI); 0.0005 mg/kg/day  Rat (RBC CheI)

Table 8a.  Sensitivity Analysis - Aldicarb Acute Dietary Exposure and
Risk (99.9th % ile) – (Aldicarb = 0; citrus nondetects = 0)

Population	Exposure

(mg/kg/day)	Human (RBC ChEI)

%PAD

	Rat (RBC ChEI)

%PAD	Rat (Brain ChEI)

%PAD

U.S. Pop	0.000272	36	47	31

All Infants	0.000250	33	43	29

Children 1-2 years 	0.000575	76	99	66

Children 3-5 years	0.000466	62	80	53

Children 6-12 years	0.000340	45	58	39

Youth 13-19	0.000230	30	40	26

Adults 20-49 yrs:	0.000224	29	39	26

Adults 50+	0.000251	34	43	29

Females13-49	0.000220	29	38	25

In citrus and potato commodities, aldicarb per se residues were assumed
to be 0 ppm; in citrus commodities,

2.	All nondetectable residues were assumed to be 0 ppm.

Table 8b.  Aldicarb Sensitivity Analysis

	No citrus	No potatoes

Population	Exposure	Human (RBC ChEI)	Rat (RBC ChEI)	Rat(Brain ChEI)
Exposure	Human (RBC ChEI)	Rat (RBC ChEI)	Rat(Brain ChEI)

U.S. Pop	0.000266	35	46	31	0.000067	9	12	8

All Infants	0.000310	41	53	36	0.000034	4	6	4

Children 1-2 years 	0.000555	73	95	64	0.000211	28	36	24

Children 3-5 years	0.000445	59	77	51	0.000169	22	29	19

Children 6-12 years	0.000343	46	59	39	0.000106	14	18	12

Youth 13-19	0.000232	31	40	27	0.000071	9	12	8

Adults 20-49 yrs:	0.000223	29	38	26	0.000051	7	9	6

Adults 50+	0.000250	34	43	29	0.000053	7	9	6

Females13-49	0.000220	29	38	25	0.000056	7	10	6

PAD =  	0.00065 mg/kg/day  Human (RBC CheI); 0.0005 mg/kg/day  Rat (RBC
CheI);  0.00075 mg/kg/day  Rat (Brain CheI)

	4.3	Water Exposure/Risk Pathway

In accordance with the requirements of FQPA, HED human health risk
assessments must consider the potential for exposure to pesticides in
drinking water.  The Environmental Fate and Effects Division (EFED/OPP)
has completed a drinking water assessment for the aldicarb RED [N.
Thurman, and J. Angier, 10/23/06, D333309].  The potential for aldicarb
to reach and contaminate ground water was discovered in 1979, when high
residues were detected in ground water on Long Island, NY.  Concerns for
aldicarb in ground water prompted the Agency to place aldicarb in
Special Review status.

4.3.1	Environmental Fate Properties  TC \l3 "4.3.1	Environmental Fate
Properties

The environmental fate database for aldicarb and its primary degradates,
aldicarb sulfoxide and aldicarb sulfone, is incomplete.  However,
sufficient information is available to characterize the potential for
aldicarb and its degradates to reach and persist in ground and surface
water sources of drinking water.

Total aldicarb residues (i.e., aldicarb plus the sulfoxide and sulfone
transformation products) are persistent and mobile in most soil types.
The environmental profile is similar to that observed in plants, which
consists of rapid oxidation of the parent aldicarb to aldicarb sulfoxide
and sulfone, followed by breakdown (largely through hydrolysis) to the
relatively non-toxic non-carbamate residues.  The sulfoxide and sulfone
are more soluble in water than the parent, aldicarb.

Aldicarb degradates readily leach to ground water when aldicarb is
applied in areas with permeable (sandy) soil, significant rainfall, and
shallow water tables.  The vast amount of ground water monitoring data
demonstrates that once aldicarb residues reach ground water, they
degrade very slowly.  Temperature is a significant factor in controlling
aldicarb degradation in ground water, and increased persistence is
observed in cooler northern climates.  However, most community ground
water supplies are from deeper, confined aquifers that would not likely
be contaminated with aldicarb residues.  Therefore, people most likely
to be exposed to aldicarb residues in drinking water are those who have
private (domestic) wells in vulnerable aldicarb use areas.

Surface water monitoring data for aldicarb and its metabolites are
limited, especially when compared with the quantity of ground water
monitoring data.  Aldicarb residues have not been detected frequently or
in high amounts in surface water in the USGS NAWQA monitoring . While
the NAWQA monitoring sites are not targeted to aldicarb use areas and
the frequency of sampling is not designed to capture peak concentrations
in surface water, the results suggest that actual concentrations of
aldicarb residues in surface water are likely to be closer to the single
or sub-parts per billion range than to 10-30 ppb.

Although previous drinking water (from groundwater sources) exposure
assessments for aldicarb relied on a summary of available monitoring
data, the vast majority of the monitoring represents unknown conditions
(in particular, no information on aldicarb rates, distances between
fields and wells, ground water depth, type of well, soil or
hydrogeologic conditions, or ground water pH) and represented monitoring
prior to label changes. Bayer CropScience has recently submitted a
compilation of recent monitoring of private wells in selected areas of
the US. Although EPA has not yet had time to fully evaluate the
monitoring (in particular, the correlation of aldicarb detects with high
leaching potential soils, distance between field and well, depth to
ground water, and nature of well), a brief review of study results
indicates that the estimated exposures reported below are on the same
order as reported detections.

EPA promulgated a final National Primary Drinking Water Regulation for
aldicarb, aldicarb sulfoxide, and aldicarb sulfone on July 1, 1991.  EPA
set the maximum contaminant level goal (MCLG, a non-enforceable health
goal that is used as the target for enforceable Maximum Contaminant
Levels, or MCLs) at 0.001 part per billion (ppb) and MCLs of 0.003 ppb
for aldicarb, 0.004 ppb for aldicarb sulfoxide, and 0.002 ppb for
aldicarb sulfone.  In response to an administrative petition from the
manufacturer and primary data-doer, the Agency issued an administrative
stay of the effective date of the MCLs; i.e., the MCLs never became
effective.

The Agency issued an updated drinking water health advisory in 1995.
Health advisories serve as informal technical guidance to assist
officials responsible for protecting public health (e.g., spills or
contamination) but are not enforceable federal standards.

4.3.2	Estimated Environmental Concentrations (EECs)   TC \l3 "4.3.2
Estimated Environmental Concentrations (EECs)/Monitoring Data

Surface Water

The revised surface water exposure assessment focused on three high
aldicarb use/ exposure scenarios: Florida citrus (central FL),
Louisiana/Mississippi cotton, and North Carolina peanuts/cotton.  While
these scenarios were selected based on combined N-methyl carbamate uses
in the vicinity of drinking water intakes in relatively high runoff
potential areas, they represent areas of relatively high aldicarb use.
Thus, the scenarios represent drinking water intakes with relatively
high potential for aldicarb exposure.

Region-specific typical application rates were used.  These rates, along
with the number of applications are less than the maximum label rates.
While typical rates, representing an “average” of high and low pest
pressures over time, might be reflective of ground water exposures, in
which the length of time for transport from the surface to groundwater
tends to lessen the variability in concentrations over time, they are
more likely to underestimate surface water concentrations in the case of
maximum use in response to high pest pressures. Likewise, they will
likely overestimate surface water concentrations in the case of low pest
pressures.  Table 9 summarizes the distributions of total aldicarb
residues for various scenarios, reflecting the relative contributions of
aldicarb from multiple crop uses in the watershed.

Table 9: Estimated concentrations of total aldicarb residues in surface
water sources of drinking water in high runoff potential areas based on
typical rates.

Scenario Location	Crops	Concentrations, ug/l

Max-imum	99th %ile	95th %ile	90th %ile	80th %ile	75th %ile

FL central ridge citrus	Oranges	9.6	1.5	0.24	0.08	0.014	0.007

	Grapefruit	0.6	0.1	0.02	0.005	0.001	0.0005

	Aggregate	10.2	1.6	0.26	0.85	0.015	0.007

NC Coastal Plain 	Cotton	4.5	1.0	0.14	0.04	0.004	0.001

	Peanuts	0.8	0.1	0.03	0.01	0.001	<0.001

	Aggregate	4.6	1.0	0.19	0.08	0.01	0.005

LA/MS Mid-south	Cotton	0.8	0.2	0.02	0.004	<0.001	<0.001

Ground Water

EPA used the Pesticide Root Zone Model (PRZM) to simulate transport
processes through high leaching potential soils to a shallow unconfined
aquifer with a water table at 30 feet (approximately 9 m) below the
surface.

Table 10 summarizes the distributions of total aldicarb residues for
various scenarios and varying well setback distances. These
distributions of total aldicarb residues (parent plus the sulfoxide and
sulfone transformation products)  represent 25 years of simulations in
ground water  and reflect shallow (30-ft) private wells; high leaching
potential soils,  aldicarb applications to fields at label setback
distances between the field of application and the well, as specified on
the current aldicarb label;  a high-end typical lateral flow velocity to
estimate the travel time from the field of application to the well based
on well setback distance; typical application rates for aldicarb,
provided by the Biological and Economic Analysis Division (BEAD); and
acidic soil and ground water, which favor the persistence of the
sulfoxide and sulfone transformation products (both degrade rapidly
under alkaline conditions; the parent aldicarb is less susceptible to
alkaline hydrolysis).   The distributions highlighted in bold in the
table represent estimated residues for the labeled setback distance
between the treated field and the well. The 0-foot “setback”
estimates in-field concentrations which were used to compare model
estimates with in-field ground water monitoring data.

The ground water exposure represents private drinking water wells. EFED
assumed in this assessment that, in general, public water supplies
supplied by ground water will typically draw from deeper aquifers and/or
aquifers that have a relatively impermeable layer between the surface
and the water supply. Such supplies are expected to be much less
vulnerable to pesticide contamination. Public water supplies have a
higher probability of being treated, although conventional treatments
processes are likely to result in little or no reduction of aldicarb
residues in water. However, where lime softening, which will accelerate
pH-dependent hydrolysis for aldicarb sulfoxide and sulfone, or activated
carbon filtration is used, some reduction in aldicarb residues between
untreated and treated water may occur.

Table 10: Estimated concentrations of total aldicarb residues in
private, shallow (30-ft) wells. Concentrations represent typical
application rates in high leaching potential soils.

Scenario	Well setback	Concentrations, ug/l

Max-imum	99th %ile	95th %ile	90th %ile	80th %ile	75th %ile	50th %ile

FL Central Ridge/ Citrus	0 ft	58.5	55.5	50.9	48.5	41.8	40.3	33.8

	300 ft	24.9	23.6	21.6	20.6	17.8	17.2	14.4

	1000 ft	3.0	2.8	2.6	2.4	2.1	2.0	1.7

FL Potatoes (alkaline GW)	0 ft	3.9e-05	3.0e-05	1.9e-05	1.3e-05	8.1e-06
6.2e-06	2.3e-06

	300 ft	1.7e-05	1.3e-05	8.0e-06	5.7e-06	3.5e-06	27.e-06	9.9e-07

GA Coastal Plain Peanuts/ cotton	0 ft	15.2	14.1	12.0	11.2	10.1	 9.6	 7.2

	300 ft	 6.5	 6.0	 5.1	 4.8	 4.3	 4.1	 3.1

	500 ft	3.7	3.4	2.9	2.7	2.5	2.4	1.8

	1000 ft	0.9	0.8	0.7	0.7	0.6	0.6	0.4

NC Coastal Plain Peanuts/ cotton	0 ft	 3.1	 2.9	 2.5	 2.3	 2.0	 2.0	 1.5

	300 ft	 1.3	 1.2	 1.1	 1.0	 0.9	 0.8	 0.6

	500 ft	0.8	0.7	0.6	0.6	0.5	0.5	0.4

	1000 ft	0.2	0.2	0.2	0.1	0.1	0.1	0.1

WA Potato (alkaline soil, GW)	300 ft, 15-ft depth	0.001	0.001	<0.001
<0.001	<0.001	<0.001	<0.001

	  TC \l2 "

		 4.4	Residential Exposure/Risk Pathway  TC \l2 "4.4	Residential
Exposure/Risk Pathway

No aldicarb products are intended for sale to homeowners or for use by
professional applicators in residential environments.  In addition, the
potential for off-target migration of aldicarb during agricultural
applications is minimal, due to the physical characteristics of the
products (all granular formulations) and the requirement for soil
incorporation at treatment.  Therefore, no residential exposure/risk
assessment has been completed in conjunction with the agricultural uses
for aldicarb.  However, an inhalation risk assessment for adult smokers
has been completed since aldicarb is registered for use on tobacco.

In assessing exposure through use of tobacco, HED has assumed that the
greatest exposure to aldicarb would come from cigarettes.  Further, HED
has assumed that the average U.S. smoker smokes 15 cigarettes per day
[Pierce, J. P., et al.  1989.  Tobacco Use in 1986 - Methods and Basic
Tabulations from Adult Use of Tobacco Survey.  U.S. Dept. of Health and
Human Services Publication Number OM90-2004.  Office on Smoking and
Health, Rockville, Maryland.].

Residue data submitted to support aldicarb use on tobacco were reviewed
in the Residue Chemistry Chapter of the Aldicarb Reg. Std. (11/18/83).
These data are considered adequate for the purpose of assessing human
exposure to aldicarb residues in cigarette smoke.

In a greenhouse study, [14C]aldicarb was applied close to the 1X rate,
and residues were measured in green leaves, flue-cured leaves, and in
smoke.  Residues in smoke were 0.5 ppm, consisting of aldicarb sulfone
(0.3 ppm) and aldicarb sulfoxide (0.2 ppm).  Total [14C]aldicarb
residues in leaves from the greenhouse study were higher than those
reported in a field study.  Smoke residues were not determined using
leaves from the field study.  Therefore, for the purpose of this
exposure assessment, aldicarb residues in tobacco smoke were assumed to
be 0.5 ppm; this is considered to be an overestimate of potential
residues in smoke, based on the higher residues in leaves from the
greenhouse study.

In assessing exposure to aldicarb from tobacco, HED has assumed that
100% of the aldicarb inhaled in the smoke is absorbed (i.e., that none
of the residue is exhaled along with the smoke).  This results in an
overestimate of actual likely exposure.  Assuming a smoke residue level
of 0.5 ppm, a smoking frequency of 15 cigarettes per day, and assuming
an average body weight of either 60 kg (females) or 70 kg (general adult
population), HED estimates that exposure to aldicarb will not exceed
0.000107 mg/kg/day for the general adult population [0.5 g/g
cigarette x 1 g/cigarette x 15 cigarettes/day x 1 mg/1000g 70 kg
body weight = 0.000107 mg/kg/day] and 0.000125 mg/kg/day for females (60
kg body weight).

The Margin of Exposure (MOE) is a measure of the estimated exposure with
respect to the Agency's level of concern, usually the NOAEL.  The MOE is
expressed as a ratio of the NOAEL (or LOAEL) to the estimated exposure;
the higher the MOE, the lower the risk.  The target MOE for aldicarb is
20 i.e., 10X (intraspecies) and 2X (interspecies); estimated MOEs less
than 20 represent a risk concern.  Using the inhalation BMDL10 of 0.013
mg/kg/day, the acute MOE for aldicarb exposure from the use of tobacco
is estimated to be 104 for females, and 121 for males.  These MOEs are
greater than the target MOE of 20, indicating that exposure and risk
from aldicarb residues in tobacco are not of concern.  These estimates
are considered to be very conservative assumptions with respect to
residues in tobacco, and may overestimate exposure through this route.

5.0	AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATIONS  TC \l1 "5.0
AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATIONS

In accordance with 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
relevant sources are added together and compared to quantitative
estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can
be aggregated.  When aggregating exposures and risks from various
sources, HED considers both the route and duration of exposure.

Since there is no potential for exposure to aldicarb and metabolites in
residential settings, aggregate exposure and risk assessments include
only dietary food and water sources of exposure, and are limited to
acute and chronic durations.  Chronic exposure to aldicarb is considered
to be a series of acute exposures, and a separate chronic assessment is
not necessary; therefore, the aggregate dietary exposure (food plus
water) can be compared to the acute PAD to determine the risk associated
with the estimated exposures (see Hazard Profile, Section 3.1 for
rationale concerning need for a chronic assessment.)  Per Agency policy,
tobacco use is not included in aggregate assessments.

Exposure and risk estimates from food alone were described in Section
4.2 of this document.  A distribution of estimates of possible
concentrations in drinking water was used in the dietary assessment.
Approximately 11,000 values were generated based on typical aldicarb use
patterns.  The values were not adjusted for percent crop area (PCA).
These values represent the complete daily 36 year PRZM-EXAMS (surface
water) and 25 year PRZM (groundwater) output distribution.  A RDF file
was created using these values for the two commodities “Water, direct,
all sources” and “Water, indirect, all sources” in the residue
file editor for DEEM-FCID.

5.1	Acute Aggregate Risk Assessment  TC \l2 "5.1	Acute Aggregate Risk
Assessment  [Food plus Drinking Water from Surface Water Sources]

The surface water concentrations used were provided by the Environmental
Fate and Effects Division (Nelson Thurmon and Jonathon Angier) and are
from a PRZM-EXAMS analysis.  The aldicarb distributions were generated
for 3 regions which represent high aldicarb use areas -  Florida citrus,
North Carolina peanuts/cotton, and Louisiana/Mississippi cotton.  The
results from this analysis have been characterized as somewhat
conservative, but it is possible that occasionally these levels of
residue concentrations may be found.  Results of these assessments are
shown in Table 11.

  SEQ CHAPTER \h \r 1 Table. 11.  Aldicarb Acute Aggregate Exposure and
Risk for Select Population Subgroups at the 99.9th %ile of Exposure
[Based on Surface Water Concentrations from Modeling]

Regions	U.S. Population	All infants	Children 1-2 years	Females 13-49

	Exposure	%PAD	Exposure	%PAD	Exposure	%PAD	Exposure	%PAD

Human  - RBC

Florida	0.000273	42	0.000579	89	0.000532	82	0.000231	36

North Carolina	0.000246	38	0.00036	55	0.000505	78	0.0002	31

Mississippi	0.000239	37	0.000267	41	0.000501	77	0.000194	30

Rat – RBC

Florida	0.000273	55	0.000579	116	0.000532	107	0.000231	46

North Carolina	0.000246	49	0.00036	72	0.000505	101	0.0002	40

Mississippi	0.000239	48	0.000267	53	0.000501	100	0.000194	67

Rat – Brain

Florida	0.000273	36	0.000579	77	0.000532	71	0.000231	31

North Carolina	0.000246	33	0.00036	48	0.000505	67	0.0002	27

Mississippi	0.000239	32	0.000267	36	0.000501	67	0.000194	55

  SEQ CHAPTER \h \r 1 1.    EDWCs were based on the following scenarios:
Mississippi/Loiusiana Cotton; North Carolina Peanut/Cotton; Florida
Citrus

2.    Generated using the DEEM-FCID model - Version 2.03

3.    Acute Aggregate Risk = % of the aPAD= [(Total Exposure/aPAD
mg/kg/day) x 100]

The acute aggregate risk estimates when food and drinking water from
surface water sources are assessed show HED’s level of concern is not
exceeded (<100% aPAD).   The most highly exposed population subgroup was
infants at 89% aPAD at the 99.9th percentile when compared to the human
RBC endpoint.

5.2	Acute Aggregate Risk Assessment  TC \l2 "5.1	Acute Aggregate Risk
Assessment  [Food plus Drinking Water from Ground Water 	Sources]

An aggregate assessment was also conducted combining food with ground
water sources of drinking water as described in the above Section 5.0.
The estimated drinking water concentrations were obtained from PRZM
Modeling.  The drinking water estimates were based on the three most
vulnerable regions of the United States and incorporates well setbacks
ranging from 300 to 1000 feet.  Using the DEEM dietary model alone, the
data indicate that aggregate exposure from food and ground water sources
of drinking water exceeds 100% aPAD for some regions including Florida
which has a well setback of 1000 feet.  Risk estimates ranged from 80 to
145% of the aPAD for children 1-2 years old and 53 to 285% of the aPAD
for infants (<1 years old).  Acute aggregate exposure and risk estimates
(food and drinking water from groundwater sources) for the general
population, all infants, children 1-2., and females 13-49 years are
shown in Table 12.   These are overestimates of actual risks since the
food diaries used by Dietary Exposure Evaluation Model-Food Consumption
Intake Database (DEEM-FCID Version 2.03) are based on total daily
intake.  The estimated risks are overestimates to the extent that food
and drinking water are consumed throughout the day, rather than during
only one event and there is regeneration of cholinesterase between
eating and drinking events.

HED further refined the acute aggregate risk from food and groundwater
by incorporating the time and amounts consumed for each eating occasion
from the USDA CSFII food diaries to estimate exposures and risks on each
eating occasion throughout the day.  This refined assessment also
incorporated the available toxicological data which indicates that the
estimated half-life for cholinesterase inhibition resulting from
aldicarb exposure is 2-hours or less.  Exposures and risks using this
approach were calculated using the DEEM model coupled to a SAS® program
which accounted for cholinesterase regeneration.  To verify these
DEEM-based eating occasion results, the Agency’s Office of Research
and Development’s Stochastic Human Exposure and Dose Simulation
(SHEDS) model was also used to conduct an eating occasion analyses for
aldicarb.  The SHEDS eating occasion results are similar to the
DEEM-based results, providing additional assurance regarding the
accuracy of these computations.  SHEDS was also used to conduct further
sensitivity analyses on the half-life parameter, as well as addressing
issues regarding both direct and indirect drinking water consumption.
Detailed information on the methods used to derive the aggregate
exposures are presented in the document titled “Aldicarb: Acute
Dietary Exposure Assessment to Support the Reregistration Eligibility
Decision” [S. Nako and J. Xue, 11/01/06].

Table 13 presents the respective DEEM-FCID® and SHEDS®’ estimated
risks at the per capita 99.9th percentile using a 2 hour half-life for
cholinesterase inhibition.  These eating occasion results are based on
several major assumptions: (i) 2 hour half-life, (ii) allocation of
direct drinking water consumption based on 6 equal and fixed occasions,
and (iii) no modifications to the amount of indirect drinking water
consumed as reported in the CSFII diaries for infants.  Direct water is
water that is consumed from the tap and indirect water is considered
water that is used in the preparation of food. For food only, these
levels are below the level of concern for all subpopulations (Table 7).
Four drinking water scenarios were modeled for aldicarb from groundwater
sources: 3 ground water scenarios for aldicarb use on peanuts/cotton in
Georgia with an assumption of 300 ft, 500 ft and 1000 ft well set backs,
and one ground water scenario for aldicarb use on Florida citrus with a
1000 ft setback.  The estimated risks at the per capita 99.9th
percentile are below the level of concern for all four scenarios, for
all subpopulations except for infants.  For infants, the estimated risks
at the per capita 99.9th percentile exceeds the level of concern under
the Georgia 300 ft scenario (139% - 147% of the aPAD).

It should be noted that incorporating eating occasion analysis and the 2
hr. recovery half life for aldicarb into the Food Only analysis  does
not significantly change the risk estimates when compared to baseline
levels (for which a total daily consumption basis – and not eating
occasion - was used)  From this, it is apparent that modifying the
analysis such that information on eating occasions and aldicarb half
life is incorporated results in only minor reductions in estimated risk:
generally  on the order of several percent, at most, for all age groups.
 However, risk estimates for which food and drinking water are jointly
considered and incorporated are reduced considerably (by a factor of 2
or more in some cases) compared to baseline and is not unexpected:
infants receive much of their exposures from indirect drinking water in
the form of water used to prepare infant formula.

Table. 12.  Aldicarb Acute Aggregate (Food plus Water) Exposure and Risk
for Select Population Subgroups at the 99.9th %ile of Exposure.

[Based on Ground Water Concentrations from Modeling]

Region1	Well Setback

(ft)	Gen Population	All  Infants (<1 Year)	Children (1 -2 Years)	Females
13-49 Years

Exp.

(mg/kg/day)2

%aPAD3	Exp.

(mg/kg/day)2

%aPAD3	Water Exp.

(mg/kg/day)2

%aPAD3	Water Exp.

(mg/kg/day)2

%aPAD3

Human RBC

Coastal Plain: southern GA peanuts/cotton	300 ft	0.000774	119	0.001853
285	0.000943	145	0.000595	92

Coastal Plain: southern GA peanuts/cotton	500 ft	0.000482	74	0.001089
168	0.000636	98	0.000370	57

Coastal Plain: southern GA peanuts/cotton	1000 ft	0.000255	39	0.000346
53	0.000519	80	0.000205	31

FL/Central Ridge Citrus	1000 ft	0.000444	68	0.001000	154	0.000598	92
0.000340	52

Coastal Plain: eastern NC peanuts/cotton	300 ft	0.000273	42	0.000460	71
0.000526	81	0.000217	33

Rat - RBC

Coastal Plain: southern GA peanuts/cotton	300 ft	0.000774	155	0.001853
371	0.000943	189	0.000595	175

Coastal Plain: southern GA peanuts/cotton	500 ft	0.000482	96	0.001089
218	0.000636	127	0.000370	74

Coastal Plain: southern GA peanuts/cotton	1000 ft	0.000255	51	0.000346
69	0.000519	104	0.000205	41

FL/Central Ridge Citrus	1000 ft	0.000444	89	0.001000	200	0.000598	120
0.000340	115

Coastal Plain: eastern NC peanuts/cotton	300 ft	0.000273	55	0.000460	92
0.000526	105	0.000217	43

Rat - Brain

Coastal Plain: southern GA peanuts/cotton	300 ft	0.000774	103	0.001853
247	0.000943	126	0.000595	117

Coastal Plain: southern GA peanuts/cotton	500 ft	0.000482	64	0.001089
145	0.000636	85	0.000370	49

Coastal Plain: southern GA peanuts/cotton	1000 ft	0.000255	34	0.000346
46	0.000519	69	0.000205	27

FL/Central Ridge Citrus	1000 ft	0.000444	59	0.001000	133	0.000598	80
0.000340	45

Coastal Plain: eastern NC peanuts/cotton	300 ft	0.000273	36	0.000460	61
0.000526	70	0.000217	29

Table 13.  Aldicarb Acute Aggregate (Food plus Drinking Water from
Groundwater Sources) Risks Assuming 2-hour Half Life for
Cholinesterase-Inhibition (per capita, 99.9th percentile exposure)

Subpopulation	DEEM-Based Eating Occasion

	Food Only	GA-GW 300 ft	GA-GW 500 ft	GA-GW 1000 ft	FL-SW 1000 ft

USPop	34%	58%	44%	36%	42%

All Infants	41%	147%	88%	43%	80%

Children 1-2 yrs	72%	95%	80%	76%	78%

Children 3-5 yrs	60%	77%	64%	59%	62%

Children 6-12 yrs	46%	48%	45%	42%	44%

Youth 13-19 yrs	28%	46%	33%	28%	30%

Adults 20-49 yrs	29%	54%	38%	30%	36%

Adults 50+ yrs	34%	47%	37%	34%	37%

Females 13-49 yrs	29%	50%	35%	28%	34%

Subpopulation	SHEDS-NMC Eating Occasion

	Food Only	GA-GW 300 ft	GA-GW 500 ft	GA-GW 1000 ft	FL-SW 1000 ft

USPop	35%	55%	42%	36%	41%

All Infants	41%	139%	85%	42%	77%

Children 1-2 yrs	77%	91%	80%	78%	79%

Children 3-5 yrs	57%	71%	61%	57%	60%

Children 6-12 yrs	43%	46%	44%	43%	44%

Youth 13-19 yrs	31%	44%	34%	31%	33%

Adults 20-49 yrs	30%	52%	37%	30%	36%

Adults 50+ yrs	32%	45%	36%	33%	35%

Females 13-49 yrs	30%	50%	37%	30%	36%

5.3	Chronic Aggregate Risk Assessment  TC \l2 "5.1	Chronic Aggregate
Risk Assessment

A chronic aggregate assessment was not conducted because the toxicity
database for aldicarb indicates that the magnitude of ChEI does not
increase with continued exposure, due to the reversibility of ChEI
(generally within 8 to 24 hours) exhibited by aldicarb and other
carbamate pesticides. The longer-term exposures could be considered as a
series of acute exposures.

6.0	CUMULATIVE RISK  TC \l1 "6.0	CUMULATIVE RISK

The Food Quality Protection Act (1996) stipulates that when determining
the safety of a pesticide chemical, EPA shall base its assessment of the
risk posed by the chemical on, among other things, available information
concerning the cumulative effects to human health that may result from
dietary, residential, or other non-occupational exposure to 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 other
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 Agency has determined that N-methyl carbamate pesticides should be
considered as a Common Mechanism Group due to their ability to inhibit
acetylcholinesterase.  A cumulative risk assessment for this Common
Mechanism Group, which includes aldicarb, will be available later this
year.  This human health risk assessment is for aldicarb does not
include cumulative exposures or risks from other N-methyl carbamate
pesticides.

7.0	OCCUPATIONAL EXPOSURE  TC \l1 "7.0	OCCUPATIONAL EXPOSURE

The HED occupational exposure and risk assessment for aldicarb is based
on a limited number of occupational exposure scenarios, or categories of
exposures, derived from the uses described on registered labels.  HED
risk assessments typically consider several types of  potentially
exposed populations including: handlers who are those involved in the
pesticide application process (e.g., mixer/loaders or applicators) and
post-application workers or those who can be exposed by working in
environments that have been previously treated.  The aldicarb use
pattern indicates that routine exposures are expected for occupational
handlers, including loaders and applicators.  Due to the application
timing and the requirement for soil incorporation of aldicarb granules,
postapplication exposures are not generally expected; hence, a
postapplication exposure assessment was not conducted.  Section 7.1
presents the results of the risk assessment for aldicarb handlers while
Section 7.2 describes the lack of potential for post-application
exposures.

Since the toxicological endpoints for aldicarb dermal and inhalation
risk assessments were the same (RBC cholinesterase inhibition), risks
were expressed in terms of combined dermal and inhalation MOEs.  In
addition, the same studies were used to assess risks for all pertinent
exposure durations; therefore, risk estimates do not vary with the
duration of exposure.

A summary of the use pattern and formulation information for
occupational risk assessment is provided in Table 14.

Table 14.  Aldicarb Use Pattern/Formulation Information Relevant to
Occupational Exposure Assessment.

Formulation

Type	Application

Equipment

(Loader/Applicator)	Use Sites	Appl. Rate

Range	Application Frequency	Average

Appl.

Rates

Terrestrial Crops

15G	Solid broadcast spreader	Tree fruit/

Nut crops	Pecans:2.6 to 10.1 lb ai/A/season

Citrus: 5 lb ai/A

Coffee: 0.11 oz/tree

[4.4 lb ai/A/season]

	Pecans: 1 or 2x/ season

Citrus: 1x/Season

Coffee: 2x/Season	1.4 - 3.8 lb ai/A/year

15G	Solid broadcast spreader	Field/forage

fiber/small fruit/veg.	Beans: 1.1 - 2.1 lb ai/A;

Cotton: 0.75 - 4.1 lb ai/A;

Peanuts/Potatoes/

Soybeans/Sugarcane/

Sweet potatoes: 3 lb ai/A;

Sorghum: 1.1 lb ai/A;

Sugar beets: 2.1-5 lb ai/A	3x/season (max.); typically 1 or 2x/season
0.6 - 2.7 lb ai/A/year

15G	Solid broadcast spreader	Non-Food/Feed	Tobacco: 3 lb ai/A	1x/season
1.6 lb ai/A/year

Ornamental Crops

10G	Solid broadcast spreader	Ornamentals	5 lb ai/A	no data	no data

7.1	Handler tc \l2 "7.1	Handler

The aldicarb use pattern results in a limited number of occupational
handler scenarios: (1) loading granules; and (2) applying granules using
a solid broadcast spreader.   Loading activities can involve both open
loading (i.e., with typical bags) or the use of closed Lock-n-Load
systems. Application activities can also involve open or closed cab
tractors.  These two scenarios were assessed using exposures derived
from a formulation- and chemical-specific study that monitored open
loading and open-cab application conducted by the registrant (MRID
438525-01), the PHED (Pesticide Handlers Exposure Database), and a study
which monitored granular closed loading and closed cab application in
conjunction with high levels of personal protective equipment (i.e.,
MRID 447933-01 which was conducted using terbufos, data compensation
issues may apply; this study was considered for comparative purposes
based on comments from Bayer Crop Sciences).  The two studies can be
identified by the following citations:

  SEQ CHAPTER \h \r 1

Worker Loader and Applicator Exposure to Temik 15G.  Study number 94388,
Unpublished study prepared by ABC Laboratories, Pan-Ag Division;
Rhone-Poulenc Ag Company, EPA MRID 43852501: Rosenheck, L., Schuster, L.
(1995).

Exposure of Farmworkers To Terbufos (CL 92100) While Loading COUNTER 15G
Systemic Insecticide-Nematicide With A Lock-N-Load Closed Handling
System And Applying COUNTER 15G To Corn At Planting Time; (3/26/99)
Authored by Joseph Higham; Completed by ABC Laboratories of Columbia MO,
Agrisearch of Frederick MD, and American Cyanamid of Princeton NJ.;
Project ID #s include: Exhibit 2 of EPA MRID 447933-01, Terbufos 99-02,
EXA 99-004, EXA 99-006, and RES 99-003, Sponsored by American Cyanamid.

The formulation- and chemical-specific study (MRID 438525-01) used
aldicarb low-dust granules which are the only commercially marketed
products.  This study provides the most representative open loading and
open cab application exposure estimates for aldicarb because of the low
friability of aldicarb-containing products based on how it is
formulated.  PHED data are available for this scenario, and would be
used in lieu of MRID 438525-01 if not available, but it is not
recommended because exposure estimates would be based on the use of more
friable clay granules which create more dust and, hence, higher exposure
levels which would not be realistically expected.  Aldicarb is also
marketed in Lock-n-Load closed loading systems and it can be applied
using closed cab tractors.  As such, these exposures were also
considered in this assessment.  The aldicarb-specific study (MRID
438525-01) did not quantify the exposures associated with the use of
these types of engineering controls.  Instead, both PHED and another
study (MRID 447933-01) were used to evaluate exposures associated with
closed loading systems and closed cab.  The PHED-based values reflect
normal work clothing and estimates from MRID 447933-01 reflect the use
of aprons gloves for the loaders and coveralls and gloves for the
applicators inside of a closed cab.

The following factors were also used to estimate handler exposure and
risk, and are considered typical for HED handler assessments:

Exposures were assessed for an 8-hour occupational workday.

Daily acres treated/day assumptions were 80 acres for orchard and field
crops; 50 acres for coffee plantations; and 10 acres for ornamentals.

Risk estimates were calculated based on an endpoint identified in a
human study which has been recently evaluated by the Agency’s Human
Studies Review Board and deemed appropriate for risk assessment.
Additionally risks have been calculated for comparative purposes in an
effort to provide additional characterization based on endpoints which
were identified in rat data (i.e., red blood cell and brain
cholinesterase inhibition).

Exposures were based on maximum application rates for representative
crops.

The average body weight for an adult handler is 70 kg.

Estimated short- and intermediate-term risks (MOEs) are presented in
Table 15 and were calculated based on each of the applicable endpoints
which have been identified.  Based on the human study endpoint and the
aldicarb specific worker exposure data (MRID 438525-01), risks were not
of concern for all open cab application and all but one open loading
exposure scenarios (i.e., only the highest rate on pecans at 6 lb
ai/acre for loaders was of concern with an MOE = 8.8 where no concern is
≥10).  The same general trend was also observed based on the risks
calculated using the rat-based endpoints.  PHED and the terbufos study
(MRID 447933-01 as identified in comments by Bayer Crop Science) were
both used to assess the risks for those who load and apply aldicarb
using closed systems or closed cab tractors.   The results for loaders
using closed systems also indicated that risks were of not concern for
most exposure scenarios regardless of which hazard endpoint was
considered (i.e., human- or rat-based) but results did vary based on the
source of the exposure data.  No risks of concern for closed loaders
were identified based on the use of the terbufos study which monitored
individuals using actual closed loading systems.  The PHED estimates
were based on the use of a protection factor which should be considered
in the interpretation of the results.  In only a few instances for
loaders using closed systems based on PHED were risks identified that
were of potential concern.  Loader risks based on the rat RBC endpoint
(i.e., target MOEs = 14.4 & 17.5 for 80 acres at ~5+ lb ai/acre) and the
human endpoint (i.e., MOE = 9.4 for 80 acres at 6 lb ai/acre) were just
slightly below the risk targets (i.e., MOEs = 20 & 10, respectively).
For applicators, no risks were identified based on the terbufos data
which monitored individuals in closed cabs with wearing coveralls and
gloves which represent more protective clothing than normally used in
cabs.  Based on PHED applicator data, the trend is very different in
that risks were of concern for all scenarios considered (i.e., MOEs
range from <1 to 8.2 where no concern is ≥10) based on the human study
endpoint.  The trend is similar based on the rat endpoints.

In the interpretation of the results of this assessment, several factors
should be considered including:

The aldicarb study (MRID 438525-01) which was used to address exposures
for open loading and open cabs is formulation- and chemical-specific
that mirrors how aldicarb is formulated, packaged, handled and used in
agriculture; the terbufos study (MRID 447933-01) monitored individuals
using engineering controls (i.e., closed loading and closed cab
tractors) and there were no risks associated with these exposure
estimates but risks were identified for closed cab applicators based on
PHED; the PHED-based risks are not believed to be a significant issue
for aldicarb because of the nature of the granular material as evidenced
by the lack of risk concerns for open-loaders based on the aldicarb
study and also the lack of risk concerns based on the terbufos study
exposure estimates.

The results of this assessment supersede those presented in the previous
risk assessment D327738 (May 12, 2006) and the previous occupational and
residential exposure chapter D311821 (January 11, 2005).  The scenarios
essentially remain the same but the major changes are that PHED
estimates for engineering controls are now included and the hazard
inputs have been modified so the key risk results are now based on the
human study endpoint since the recent HSRB meeting.

A dermal absorption factor of 100 percent has been used and if that
factor changed, risks would also change proportionately.

Current aldicarb labels require coveralls worn over shorts and
short-sleeved shirts, chemical-resistant gloves, respirator, footwear,
eyewear, and aprons for loaders.  In MRID 4385250, subjects wore
protective clothing similar to current label requirements including
loaders who wore aprons.  It should be noted that the PHED-based
exposure estimates do not reflect the use of aprons. It should also be
noted that in the terbufos study (MRID 447933-01), loader protective
clothing levels were similar to the label (except the subjects wore long
pants instead of shorts) but applicator levels of protective clothing
were higher than required for closed cab applicators since coveralls and
gloves were worn during application in closed cabs.  The use of
additional protective clothing does not impact the overall results,
however, because the margins of exposure are large compared to the
target levels which indicates that even if coveralls and gloves were not
worn it is anticipated that risks of concern would be unlikely because
the cab structure itself is protective as are the low-friability
granules themselves as evidenced by the low lack of risk concerns for
open loading.

Table 15: Summary of Short-/Intermediate-Term Occupational Handler
Noncancer Risks

Scenario

Rate

(lb ai/acre)

&

Crop

Area Treated

(acres/day)

	MOEs  Based On MRID 438525-01

[Aldicarb-specific study]

(Open bag/open cab tractor & label PPE)	MOEs  Based On PHED For

Engineering Controls

(Closed loading & Closed cab tractor)	MOEs  Based On MRID 447933-01

[Terbufos Engineering Control Study]

(Closed loading & cabs, apron or coverall, gloves)

Based On Rat RBC Endpoint

Based On Rat Brain Endpoint

Based On Human Endpoint

Based On Rat RBC Endpoint

Based On Rat Brain Endpoint

Based On Human Endpoint

Based On Rat RBC Endpoint

Based On Rat Brain Endpoint

Based On Human Endpoint

Loaders

1 Granular:

Solid broadcast spreader	6 (pecans)

4.95 (citrus)

4.4 (coffee)

3 (potato)

3.15 (cotton)

1.05 (sorghum)

5 (ornamentals)	80

80

50

80

80

80

10	13.6

16.4

29.6

27.1

25.8

77.5

130.2	20.3

24.7

44.4

40.7

38.8

116.3

195.3	8.8

10.7