Document ID: EPA-HQ-OPP-2006-0297-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-09-19T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES AND

TOXIC SUBSTANCES

				

MEMORANDUM						           February 1, 2007

							

SUBJECT:	Desmedipham.  Human Health Risk Assessment for Petition 6E7027

			Crops:		Spinach, Garden Beets

			DP Barcode:	327443

			CFR:		40 CFR 180.353

			PC Code:	104801 

						

FROM:	Yvonne Barnes, Chemist

Elissa Reaves, Toxicologist

Shanna Recore, Occupational Risk Assessor

Richard Griffin, Risk Assessor

		Reregistration Branch II

Health Effects Division (7509P)

THROUGH:	Alan Nielsen, Branch Senior Scientist, and

		William Hazel, Branch Chief

		Reregistration Branch II

Health Effects Division (7509P)

TO:		Barbara Madden, Minor Use Team 

Risk Integration, Minor Use, Emergency Response Branch

		Registration Division (7505P)

The Interregional Research Project No. 4 (IR-4) has submitted a petition
to the Agency (PP#6E7027) for the establishment of new tolerances for
desmedipham residue in/on garden beets and spinach.  The new tolerances
will replace the time-limited tolerances now in effect.  Also, based on
new field trial (residue) data for sugar beet, the Agency has revised
the recommended tolerances from 0.2 ppm on sugar beet roots to 0.1 ppm
and from 0.2 ppm on sugar beet tops to 5.0 ppm.  Accordingly, the
dietary and aggregate risk assessment for desmedipham has been revised
(from the 1/11/05 TRED assessment) to reflect the reassessed tolerances
for sugar beets, and the incremental exposure due to the addition of
garden beets and spinach. 

SUPPORTING DOCUMENTS

Desmedipham:  Revised HED Risk Assessment for the Tolerance Reassessment
Eligibility Decision (TRED) Document. [PC Code 104801, DP Barcode
301539] (E. Reaves memo, 1/11/2005).

DESMEDIPHAM – Report of the Hazard Identification Assessment Review
Committee.  (G. Dannan and J. Rowland memo, 11/30/98).

Desmedipham.  Registrants’s Response to Desmedipham Tolerance
Reassessment Eligibility Decision (TRED).  Submission of Additional
Sugar Beet Field Trials.  (Y. Barnes memo, 12/28/2006).

Desmedipham.  Request for Tolerances on Spinach and Garden Beet, Roots
and Tops.  Summary of Analytical Chemistry and Residue Data.  PP#6E7027.
 (Y. Barnes memo, 12/28/2006).

Desmedipham.  Acute and Chronic Aggregate Dietary Exposure Assessment
for the Tolerance Reassessment Eligibility Decision on Sugar Beets and
Garden Beets and Risk Assessment for New Uses on Spinach.  (Y. Barnes
memo, 1/10/2007).

Drinking Water Exposure Assessment for Use of Desmedipham on Spinach and
Garden Beets (IR-4 Petitions 00337 and 01922).  (W. Eckel memo,
9/5/2006).

Occupational and Residential Exposure/Risk Assessment for the New Uses
of Desmedipham on Sugar Beets, Table Beets and Spinach.  (Shanna Recore
memo, 1/25/2006)

SUMMARY

Desmedipham (ethyl m-hydroxycarbanilate carbanilate) is a member of the
phenylcarbamate family of herbicides.  Desmedipham is currently
registered by Bayer CropScience for use as a selective post-emergence
herbicide on sugar beets.  Formulations include emulsifiable
concentrates which are applied in spring by ground equipment as a band
treatment or by aircraft as a broadcast treatment.  

The toxicology database is adequate to characterize the “hazard”
associated with desmedipham use, and to establish the endpoints and dose
levels necessary for risk assessment.  Toxicological studies with
desmedipham technical have generally demonstrated a low to moderate
toxicity.  Acute oral toxicity is characterized as Category IV, dermal
toxicity as Category III, inhalation toxicity as Category IV, dermal
irritation as Category IV, eye irritation as Category II, and the
technical is characterized as a dermal sensitizer in the guinea pig.   

To assess acute dietary exposure, an endpoint and dose were selected
from a developmental study in the rat.  The maternal No Observed Adverse
Effect Level (NOAEL) was 10 mg/kg/day based on increased methemoglobin
at 100 mg/kg/day (LOAEL).  An Uncertainty Factor (UF) of 100 was applied
to the acute toxicity endpoint resulting in an aPAD of 0.1 mg/kg
bodyweight(bw)/day.  The FQPA safety factor was reduced from 10x to 1x.

To assess chronic dietary exposure, an endpoint and dose was selected
from a two-generation reproduction study in rats.  The NOAEL from this
study was 4 mg/kg bw/day and the LOAEL was 20 mg/kg/day based on
parental systemic toxicity of hemolytic anemia accompanied by
significant increases in splenic weights and compensatory functioning of
the thyroid.  An uncertainty factor of 100 (10x for interspecies
extrapolation and 10x for intraspecies variability) was applied to the
chronic toxicity endpoint resulting in a cPAD of 0.04 mg/kg bw/day.  The
FQPA safety factor was reduced from 10x to 1x.

Desmedipham is not considered a developmental toxicant or a mutagen.  It
has a cancer classification of Group E (evidence of non-carcinogenicity
for humans).

Desmedipham has been classified as separate from the N-methyl carbamate
pesticides and therefore is not (at this time) part of a cumulative risk
assessment that would consider cumulative risk from other pesticides, or
chemical compounds, having a common mechanism of toxicity.  

In the environment, at neutral to alkaline pH, desmedipham is rapidly
hydrolyzed to EHPC [ethyl-(3-hydroxyphenyl) carbamate].  The
Environmental Fate and Effects Division (EFED) calculated Tier 1
(upper-bound) Drinking Water Concentrations (EDWCs) for the combined
residues of parent desmedipham plus EHPC [ethyl-(3-hydroxyphenol)
carbamate].  EDWCs for desmedipham plus EHPC were calculated using FIRST
(surface water) and SCIGROW (ground water) drinking water models.  Both
models provide estimates suitable for screening purposes.  Modeled EDWCs
for peak and average concentrations of desmedipham plus EHPC in surface
water are 130 micro g/L (ppb) and 71 micro g/L respectively.  

Dietary exposure and risk estimates for desmedipham are based on residue
estimates for sugar beets, table beets, spinach, and drinking water
(note that there are no uses of desmedipham in or around residential
areas).  The residue estimates for sugar beet commodities, spinach, and
garden beets are based on the tolerance for those commodities, and each
crop is assessed as if 100% of the crop has been treated with
desmedipham.  The EEC inputs for drinking water are also described as
Tier 1, and are considered upper-bound estimates for finished drinking
water.

Aggregate acute and chronic dietary (food and water) exposure estimates
for desmedipham are significantly below HED’s level of concern for all
supported commodities.  The 95th percentile acute dietary exposure
estimate for the highest exposed population subgroup, “all infants”
is approximately 26% of the acute Population Adjusted Dose (aPAD).  The
chronic dietary exposure estimate for the highest exposed population
subgroup, all infants, is approximately 13% of the chronic PAD. 
Aggregate exposure estimates for desmedipham, based on the uses on
spinach, table beets, sugar beets, and drinking water, are also less
than the aPAD and the cPAD.  

Occupational risk is expressed as a Margin of Exposure, or MOE, which is
the ratio of the estimated exposure to the appropriate dose level for
that particular type of exposure.  The MOEs seen in the desmedipham
assessment are above the target MOE of 100, i.e. they do  not exceed the
Agency’s “level of concern” at the baseline level, or at the
baseline level with gloves for all exposure scenarios (except aerial
application which pass at the engineering control level of an enclosed
cockpit).  

In regard to postapplication exposure to pesticide workers, The
estimated MOEs associated with use on all crops (sugar beets, table
beets, and spinach) reach the target MOE of 100 on the day of
application.

Risk assessments for residential handlers (non-professional) and/or
residential postapplication exposures were not needed since there are no
proposed or registered residential uses for desmedipham.

In regard to the establishment of permanent tolerances for desmedipham
on spinach and garden beets, HED concludes that the supporting
toxicology, chemistry, and exposure data are adequate to support human
health risk assessment.   And, based on risk estimates for aggregate
exposure to the general U.S. population and risk estimates for pesticide
workers, the Agency can make a determination of safety for existing
desmedipham uses and the new uses of Petition 6E7027.   

USE / STRUCTURE / NOMENCLATURE / PROPERTIES

  

Use Profile

The area and distribution of desmedipham use is well defined.  About
150,000 to 200,000 U.S. acres are treated annually with desmedipham. 
Sugar beet use is concentrated in relatively small areas of the country,
mostly in the northern Great Plains, Great Lakes regions, Pacific
Northwest, and California.  Also, there is a Special Local Needs (SLN)
registration in Washington State for use on Swiss chard and garden beets
grown for seed, which comprises an area of approximately 100 acres. 

Table 1:  Structure / Nomenclature / Properties 

Chemical Structure	

IUPAC name	

Carbamic acid, N-phenyl-, 3-((ethoxycarbonyl)amino)phenyl ester

CAS name	

ethyl [3-[[(phenylamino)carbonyl]oxy]phenyl]carbamate

Trade names	

Betanex®, Betamix®, Progress®, Betanal®

CAS #	

13684-56-5

PC Code	

104801

Molecular Formula	

C16H16N2O4

Physical State	

colorless to off-white crystalline solid

Molecular Weight	

300.31

Melting Point	

120( C

Density	

570 g/l

Water solubility  (20(C)	

7 mg/l

Solvent solubility (20(C)	

0.5 g/l hexane

Dissociation constant (pKa)	

none

Vapor Pressure (Pa) 25(C	

4 x 10-8

Estimated Octanol/Water Partition Coefficient	

log Kow = 3.52

a  References: Crop Protection Handbook, 2004; Handbook of Pesticides,
1995

TOXICOLOGY / HAZARD

Toxicological Profile  

The toxicological (hazard) data base was reviewed by the HED Reference
Dose (RfD) Peer Review Committee (memoranda dated July 26, 1994 and
November 20, 1995) which recommended using the rat 2-generation
reproduction study to establish a chronic RfD (now termed a chronic
Population Adjusted Dose, or cPAD) of 0.04 mg/kg/day for desmedipham
based on the parental NOAEL of 4 mg/kg/day.  The conventional
Uncertainty Factor of 100, 10x for inter-species extrapolation and 10x
for intra-species variability (R. Whiting memo, 7/26/94) was applied.  

On October 27, 1998, the Health Effects Division’s Hazard
Identification Assessment Review Committee (HIARC) reassessed the RfD
(PAD) and also established toxicity endpoints for acute dietary
assessment as well as for occupational and residential assessment. The
Committee also evaluated the potential for “enhanced” sensitivity in
developing fetuses, infants, and children with regard to the Food
Quality Protection Act (FQPA) of 1996 (TXR 012996).  Desmedipham is not
considered a developmental toxicant or a mutagen.  On this basis the
FQPA safety factor was reduced from the default 10x to 1x.

The HIARC concurred with previous conclusions regarding the
chronic/carcinogenicity study in rats, and carcinogenicity in mice.  The
rat and mouse carcinogenicity studies are considered guideline
acceptable and the data evaluation records (DER) are considered
adequate.  The dose levels were also considered adequate for
carcinogenicity testing (memorandum dated November 20, 1995). 
Desmedipham was “tentatively” classified as a “Group E”
carcinogen (evidence of non-carcinogenicity for humans).

Table 2:  Summary of Acute Toxicity Data 

Test	

MRID	

Species	

Results	

Category

Oral LD50	

00155581	

rat	

LD50 (M/F) > 5,000 mg/kg	

IV

Dermal LD50	

00155582	

rabbit	

LD50 (M/F) > 4,000 mg/kg	

III

Inhalation LC50	

41957102	

rat	

LC50 (M/F) > 7.4 mg/L	

IV

Eye Irritation	

00155584	

rabbit	

Opacity and conjunctival irritation cleared by 72 hours	

II

Dermal Irritation	

00155583	

rabbit	

No irritation	

IV

Dermal sensitization	

40312901	

guinea pig	

A dermal sensitizer	

N/A

ENDPOINTS / DOSE SELECTION FOR RISK ASSESSMENT

Dietary Risk

Acute Population Adjusted Dose

For the assessment of acute dietary exposure, an endpoint and dose was
selected from a developmental study in the rat (MRID 00156725) with dose
levels of 0, 10, 100, or 500 mg/kg bw/day for gestation days 6 through
15.  The maternal No Observed Adverse Effect Level (NOAEL) was 10 mg/kg
bw/day based on increased methemoglobin at 100 mg/kg/day (LOAEL).  This
is considered an upper-end endpoint in that it assumes that the
hematological maternal effects are attributable to a single oral
exposure (dose).  This endpoint/dose is relevant to the general
population including females of child-bearing age and developing
fetuses.  

The HIARC’s decision to select the maternal NOAEL for risk assessment
was based on the following observations: 1) increased methemoglobin
(MtHb) is a common endpoint among the rat (this study) and other tested
species (in other studies);  2) this study did not measure MtHb, T3, or
T4 in dams or offspring (only mother’s MtHb was measured on day 16 of
pregnancy);  3) the NOAEL dose is applicable to all population
sub-groups; and 4) There is evidence that increased MtHb would occur
after a single dose.  An Uncertainty Factor (UF) of 100 (10x for
interspecies extrapolation and 10x for intraspecies variability) was
applied to the acute toxicity endpoint resulting in an aPAD of 0.1 mg/kg
bw/day.

Chronic Population Adjusted Dose

For the assessment of chronic dietary exposure, an endpoint and dose was
selected from a two-generation reproduction study (MRID 40387105) in
rats with dose levels of 0, 4, 20, or 110 mg/kg bw/day.  The NOAEL from
this study was 4 mg/kg/day and the LOAEL was 20 mg/kg/day based on
parental systemic toxicity of hemolytic anemia accompanied by
significant increases in splenic weights and compensatory functioning of
the thyroid that were observed at the higher dose of 20 mg/kg bw/day. 
An uncertainty factor of 100 (10x for interspecies extrapolation and 10x
for intraspecies variability) was applied to the chronic toxicity
endpoint resulting in a cPAD of 0.04 mg/kg bw/day.

FQPA Determination

In 1998, the HED HIARC committee recommended the additional FQPA 10x
factor should be reduced to 1x based on:  1)  developmental toxicity
studies show no increased sensitivity in fetuses as compared to maternal
animals following in utero exposures in rats and rabbits,  2)  a
two-generation reproduction toxicity study in rats showed no increased
susceptibility in pups when compared to adults,  3)  there was no
evidence of abnormalities in the development of the fetal nervous system
in the pre/post natal studies.  Neither brain weight nor histopathology
of the nervous system was affected in the subchronic and chronic
toxicity studies, and 4)  the toxicology data base is complete and there
are no data gaps.  There is no evidence to require a developmental
neurotoxicity study. 

Occupational Risk 

In 1998, the HED HIARC Committee established dermal and inhalation
endpoints for risk assessment (TXR 012991).  Since then, no additional
dermal or inhalation studies have been received by the Agency that would
alter the endpoints and dose levels previously identified.

Dermal Exposure / Short-Term and Intermediate-Term

A 21-day dermal toxicity study in rabbits is available, but not used for
risk assessment, because the endpoint of concern (methemoglobinemia, or
MtHb) was not measured.  Since increased MtHb is a common endpoint
observed across several species following oral exposure, the HIARC
selected the maternal toxicity characterized as increased MtHb in the
developmental toxicity study in rats (MRID 00156724) as the basis for
dermal risk assessment.  Furthermore, the 2-generation reproductive rat
study (MRID 40387105) was not chosen for risk assessment purposes due to
the dose spread in the study (i.e., NOAEL 4 mg/kg, LOAEL 20 mg/kg based
on anemia).  Therefore, the true NOAEL likely resides between the NOAEL
of 10 mg/kg in the developmental toxicity and the LOAEL of 20 mg/kg in
the reproduction rat study.  The dose/endpoint for risk assessment is
based on the NOAEL of 10 mg/kg, with hematological findings at 100 mg/kg
(LOAEL).

Dermal Exposure / Chronic 

Based on the use pattern, there is no potential for long-term (chronic)
dermal exposure, and is not assessed.

Dermal Absorption 

A dermal absorption study in rats (MRID 41957101) was available at the
time of the HIARC (1998) for evaluation.  In this study, following a
single 10 hour dermal exposure (at the lowest tested dose of 0.01
mg/rat) of 14C-labeled desmedipham in male rats, the 0-24 hour excretion
in feces and urine (representing the percentage of dose administered)
was 6.1 and 1%, respectively.  Of the administered dose (10 hour
exposure), the cumulative rate of systemic absorption was 7.6 and 11.3%
during the 24 and 120 hour follow-up, respectively.  The HIARC
recommended a dermal absorption of 10% based on the 10 hours exposure
and 120 hours follow-up findings in this study.  It should also be noted
that the HIARC agreed that it was not practical to estimate the dermal
absorption rate by comparing the LOAEL values of the existing oral and
dermal short-term studies (the endpoint in the 21-day dermal rabbit
study [T4] was not measured in the rabbit oral developmental study). 

Inhalation Exposure / Short-Term and Intermediate-Term 

For study review, see short-term dermal (Developmental Toxicity Study in
Rats) 

Dose/Endpoint for Risk Assessment:	 NOAEL = 10 mg/kg based on
hematological findings at 100 mg/kg (LOAEL). 

Inhalation Exposure / Chronic

Based on the use pattern, there is no potential for long-term (chronic)
inhalation exposure/risk.  A long-term inhalation assessment is not
warranted.

Table 3:  Endpoint / Dose Summary

 

 Summary of Toxicology Endpoint Selection

Exposure Scenario

	

Dose (mg/kg bw/day)	

Endpoint	

Study

Acute Dietary	

Maternal NOAEL = 10

FQPA = 1x	

Increased maternal methemoglobin

	

Developmental-Rat

	Total UF = 100	Acute PAD = 0.10 mg/kg bw/day

Chronic Dietary	

NOAEL = 4

FQPA = 1x	

Anemia and increased spleen weight

	

2-Generation Reproduction-Rat

	Total UF = 100	Chronic PAD = 0.04 mg/kg bw/day

Short-Term (Dermal)

	

Maternal NOAEL = 10a

MOE = 100	

Increased maternal methemoglobin	

Developmental-Rat

Intermediate-Term (Dermal)

	

Maternal NOAEL = 10a

MOE = 100	

Increased maternal methemoglobin	

Developmental-Rat

Long-Term (Dermal)	

None	

The use pattern does not indicate a potential Long-Term dermal exposure;
the risk assessment is not required

	

None

Short- & Intermediate-Term (Inhalation)

	

Maternal NOAEL = 10b

MOE = 100	

Increased maternal methemoglobin	

Developmental-Rat

Long-Term

(Inhalation)

 	

None	

The use pattern does not indicate a potential long-term inhalation
exposure; Desmedipham is applied by aerial and ground-boom operations

	

None

a   A dermal absorption factor of 10% should be used for route to route
extrapolation.

b   An inhalation absorption factor of 100% should be used for route to
route extrapolation.

METABOLISM / DEGRADATION

In Plants 

The metabolism of desmedipham in plants is adequately understood.  Based
on an acceptable phenmedipham sugar beet metabolism study, the Agency
has determined that  the residue of concern in plants is desmedipham per
se.  

In Livestock 

Based on acceptable poultry and ruminant metabolism studies with oral
dosing of 14C-desmedipham, the Agency also determined that desmedipham
per se should be the regulated residue in livestock commodities.  Using 
 SEQ CHAPTER \h \r 1 the reassessed tolerance of 5 ppm for sugar beet
tops, the maximum theoretical dietary exposure to desmedipham for beef
and dairy cattle are 4.3 ppm and 2.2 ppm, respectively.  Based on data
from the ruminant metabolism study, where goats were dosed at 10 ppm
(1.1x), the Agency has concluded that finite residues of desmedipham are
unlikely to occur in milk, meat and meat-byproducts of ruminants and a
feeding study and/or tolerances for livestock commodities has not been
required.  In addition, no tolerances are necessary for hog or poultry
commodities as sugar beet commodities are not utilized in swine or
poultry diets.  (Note that the Agency has drafted guidance that
concludes sugar beet tops are not a significant livestock feed item).

In the Environment

Desmedipham is rapidly hydrolyzed (half-life at pH 7 = 12 hours) at
neutral to alkaline pH with complete conversion to EHPC
[ethyl-(3-hydroxyphenyl) carbamate].  Soil and aqueous photolysis are
slower and were judged in the 1996 RED not to be major fate processes. 
The aerobic soil metabolism half-life was 8 days in a German standard
soil (this was the only aerobic soil study submitted).  EHPC reached a
maximum of 4.5% of the parent at 14 days, and declined to 0.9% at 100
days.  EHPC  is degraded to carbon dioxide in aerobic soil.  Desmedipham
is not volatile.  Parent desmedipham was too unstable in solutions above
pH 5 for its Koc to be measured in batch experiments.  Its estimated Koc
(EPI Suite estimated Koc = 310) indicates moderate mobility in soil. 
(The USDA ARS Pesticide Properties database reports values of 95 ml/g in
a sandy loam soil and 210 ml/g in a sand soil, based on NORAM company
data).  EHPC (EPI Suite estimated Koc = 134, variable with pH) should be
more mobile than the parent.  The parent and EHPC were relatively
immobile (remained in top 6 cm) in soil column experiments, however both
were detected as deep as 18 inches in an otherwise unacceptable North
Dakota field study.  The degradate EHPC is the major or only product in
all fate experiments.  It is stable to hydrolysis at pH 7 and 9, and
stable (212-day half-life) in anaerobic sediments, which therefore may
act as a reservoir of this degradate for slow release to surface water. 
The other product of the hydrolysis reaction that produces EHPC is
aniline (aminobenzene).  Aniline is expected to degrade rapidly in the
environment. 

DIETARY EXPOSURE ASSESSMENT

Food Uses  / Tolerances

Dietary exposure and risk estimates for desmedipham are based on residue
estimates for sugar beets, table beets, spinach, and drinking water. 
The following section provides a summary of the residue chemistry data
submitted to support use on foods.  Desmedipham is a phenyl-carbamate
herbicide currently used for the control of annual broadleaf weeds in
sugar beets.  Permanent tolerances are established for residues of
desmedipham [40 CFR §180.353] per se at 0.2 ppm in/on sugar beet roots
and at 0.2 ppm in/on sugar beet tops, and time-limited tolerances
(expiration 06/30/08) are in place for table beets and spinach.    SEQ
CHAPTER \h \r 1 Desmedipham is registered to Bayer CropScience under the
trade names of Betanex®, Betamix®, and Progress®. Betanex® is a 1.3
lb/gal EC, and Betamix® and Progress® are multiple active ingredient
(MAI) EC formulations containing 0.6 to 0.65 lb/gal of desmedipham.  The
current use on sugar beets allows for multiple foliar applications
totaling up to 1.95 lb ai/A/season, with a minimum retreatment interval
(RTI) of 5 days and a preharvest interval (PHI) of 75 days.

Enforcement

An LC/MS/MS method (Method AL/01/02) is available as a potential
tolerance enforcement method.  The method has a validated Limit of
Quantitation (LOQ) of 0.05 ppm for desmedipham in/on beet roots and tops
and has undergone a successful Independent Laboratory Validation (ILV)
trial (Agency validation is still required).  There is also the HPLC/UV
method (Method D23023) which was validated in conjunction with the
analysis of the sugar beet field trial samples.  The LOQ for the HPLC/UV
method is 0.05 ppm (roots/tops).

Storage Stability

In conjunction with the field trial data for table beets and spinach,
the petitioner provided adequate storage stability data indicating that
desmedipham is stable for up to 13 months in frozen spinach and for up
to 9-10 month in frozen beet roots and tops.  These data will support
the current field trails, in which spinach samples were stored frozen
for up to 11.6 months and beet root and tops samples were stored frozen
for up to 9.6 months

Field Trial Data

Sugar Beets:  The available field trial data are adequate and support
the proposed use pattern.  In the five field trials referenced in MRID
42516500 (1992) and the nine field trials conducted in 2004 (MRIDs
46773001 and 42516500), desmedipham (1.3 lb/gal EC) was applied to sugar
beets as two broadcast foliar applications at 0.95 to 1.09 lb
ai/A/application, at RTIs of 5 to 7 days, for a total of 1.93 to 2.09 lb
ai/A (1x rate).  All applications were made using ground equipment.  In
the trials referenced in MRID 42516500, residues of desmedipham in/on
sugar beet tops were <0.05 ppm to 6.54 ppm.  In the 2004 trials,
residues of desmedipham in/on sugar beets were <0.05 ppm for the 18 root
samples and <0.05 ppm to 0.135 ppm for the 18 tops samples, with only 5
of the 18 samples of tops having residues >LOQ.  Average residues were
0.025 ppm for roots and 0.045 ppm for tops from the 2004 trials.

Processed Sugar Beets:    SEQ CHAPTER \h \r 1 An adequate sugar beet
processing study is available.  Residues of desmedipham were
nondetectable (<0.05 ppm) in sugar beet processed commodities (processed
roots, cossettes, dried pulp, refined sugar, and molasses) generated
from sugar beet roots bearing nondetectable residues following treatment
at 2x the maximum seasonal rate (the highest tolerated rate). As
residues were <LOQ in the RAC and processed fractions following
applications at the highest tolerated rate, separate tolerances for
sugar cane molasses, dried pulp, and sugar are not required.

 

Garden Beets and Spinach (Petition 6E7027): Interregional Research
Project No.4 (IR-4) submitted a petition supporting the use of
desmedipham, formulated as a 1.3 lb/gal EC (BETANEX® Herbicide; EPA
Reg. No. 264-620), on garden beets and spinach. 

The submitted field trial data are adequate and support the proposed use
pattern for table beets.  The proposed use on garden (table) beets is
for up to three broadcast foliar applications using ground equipment at
0.24 to 0.49 lb ai/A/ per application from the cotyledon to 8-leaf
stage, with Retreatment Intervals (RTIs) of 5 to 7 days, for a total of
1.13 lb a.i./A/season.  No Preharvest Intervals (PHIs) are specified. 
Residues of desmedipham were <0.05 ppm -0.87 ppm in/on 10 samples of
tops harvested at 14-15 Days After Treatment (DAT) and <0.05 ppm in/on
12 samples of roots harvested at 49-52 DAT.  Average residues were 0.20
ppm for tops and 0.025 ppm (½LOQ) for roots.  

The submitted field trial data are adequate and support the proposed use
pattern for spinach.  The proposed use on spinach is for a single
broadcast foliar application at up to 1.0 lb a.i./A from the 2-leaf
stage up to 21 days before harvest.  In conjunction with these uses,
IR-4 is proposing permanent tolerances for residues of desmedipham at
6.0 ppm in/on spinach, and at 1.0 ppm and 0.05 ppm in/on garden beet
tops and roots, respectively.  In eight field trials conducted in
1997-1999, desmedipham (1.3 lb/gal EC) was applied to spinach as a
single broadcast foliar application during crop development at 0.96-1.02
lb a.i./A.  Residues in/on 12 samples of spinach leaves harvested at
20-24 DAT were <0.05 ppm to 5.0 ppm.

Drinking Water Exposure

The OPP Metabolism Assessment Review Committee (MARC) met on April 7,
2004 to consider which metabolites to include in the desmedipham
drinking water assessment.  Specific toxicity data for EHPC were not
available at the time of the meeting.  Given that EHPC has a
sub-structure that has been associated with methemoglobin effects, the
endpoint of concern for the parent desmedipham for acute and chronic
exposures, the committee recommended that EHPC be included in the
dietary risk assessment for drinking water.  EHPC is not expected to be
more toxic than the parent compound. 

The Environmental Fate and Effects Division (EFED) calculated
upper-bound, or Tier 1 Drinking Water Concentrations (EDWCs) for the
combined residues of parent desmedipham plus EHPC
[ethyl-(3-hydroxyphenol) carbamate] in accordance with the MARC
committee decision.  EDWCs for desmedipham plus EHPC were calculated
using the FIRST model (surface water) and the SCIGROW model (ground
water) drinking water models.  Both models provide estimates suitable
for screening purposes.  Modeled EDWCs for peak and average
concentrations of desmedipham plus EHPC in surface water are 130 micro
g/L (ppb) and 71 micro g/L respectively.  The modeled peak and average
EDWCs for ground water are 0.04 micro g/L.  

AGGREGATE EXPOSURE / RISK

The Agency is required by the Food quality Protection Act to ensure
“that there is reasonable certainty that no harm will result from
aggregate exposure to pesticide chemical residue, including all
anticipated dietary exposures and other exposures for which there is
reliable information.”  Aggregate risk estimates for desmedipham are
based on the combined exposure from food sources (sugar beets, garden
beets, and spinach) and from the contamination of drinking water. 
Desmedipham does not have any residential or other non-agricultural
uses.  Based on the hazard profile for desmedipham, both acute and
chronic aggregate exposure is assessed by comparing acute and chronic
dietary (food and water) exposure estimates to the respective aPAD and
cPAD, with risk expressed as percent aPAD and cPAD.  Exposure estimates
that are less than 100% of the aPAD and cPAD indicate a determination of
safety can be concluded for dietary exposure to desmedipham.

The acute and chronic aggregate exposure assessments were conducted
using the Dietary Exposure Evaluation Model – Food Commodity Intake
Database (DEEM-FCIDTM, Version 2.0) which incorporates food and water
consumption data from the USDA Continuing Surveys of Food Intakes by
Individuals (CSFII) 1994-1996, 1998.  Upper-bound (or “Tier 1”) risk
estimates for desmedipham were completed based on both acute and chronic
dietary exposure.  Residue estimates for sugar beet commodities,
spinach, and garden beets are based on the tolerances for those
commodities, and each commodity is assessed as if 100% of the crop has
been treated with desmedipham.  The EEC inputs for drinking water are
also described as Tier 1, and so are considered upper-bound estimates
for finished drinking water.  It should also be noted that, like the
tolerance level inputs for foods, the residue estimates for drinking
water are point estimates rather than a residue distribution (as seen in
probabilistic assessments).

Aggregate Exposure Estimates

 

Table 4.  Acute / Aggregate Food and Drinking Water Exposure and Risk
Estimates 

Population Subgroup

	

aPAD ( 0.1 mg/kg bw/day)

	

DEEM-FCID

	

Exposure, mg/kg bw/day / 95th  percentile	

% aPAD

U.S. Population	

0.007640

	

 8

All infants (< 1 yr)	

0.025626	

26

Children 1-2 yrs	

0.011649	

 12

Children 3-5 yrs	

0.010406	

 10

Children 6-12 yrs	

0.007231	

 7

Youth 13-19 yrs	

0.005902	

 6

Adults 20-49 yrs	

0.007016	

 7

Adults 50+ yrs	

0.006309	

 6

Females 13-49 yrs	

0.006424

	

 6

 

Table 5.  Chronic / Aggregate Food and Drinking Water Exposure and Risk
Estimates 

Population Subgroup

	

cPAD ( 0.04 mg/kg bw/day)

	

DEEM-FCID

	

Exposure, mg/kg bw/day	

% cPAD

U.S. Population	

0.001710

	

 4

All infants (< 1 yr)	

0.005037	

13

Children 1-2 yrs	

0.002585	

 7

Children 3-5 yrs	

0.002352	

6

Children 6-12 yrs	

0.001592	

 4

Youth 13-19 yrs	

0.001168	

 3

Adults 20-49 yrs	

0.001610	

 4

Adults 50+ yrs	

0.001735	

 4

Females 13-49 yrs	

0.001620

	

 4

Aggregate Exposure / Spray Drift

Spray drift is always a potential source of exposure to residents nearby
to spraying operations and can be a contributor to aggregate exposure
for some individuals.  This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from groundboom application methods.  The Agency has been
working with the Spray Drift Task Force, EPA Regional Offices and State
Lead Agencies for pesticide regulation and other parties to develop the
best spray drift management practices.  The Agency is now requiring
interim mitigation measures for aerial applications that must be placed
on product labels/labeling. 

The Agency has completed its evaluation of the new data base submitted
by the Spray Drift Task Force, a membership of U.S. pesticide
registrants, and is developing a policy on how to appropriately apply
the data and the AgDRIFT computer model to its risk assessments for
pesticides applied by air, orchard airblast and ground hydraulic
methods.  After the policy is in place, the Agency may impose further
refinements in spray drift management practices to reduce off-target
drift and risks associated with aerial as well as other application
types where appropriate.

CUMULATIVE EXPOSURE / RISK

Section 408(b)(2)(D)(v) of the FFDCA requires that, when considering
whether to establish, modify, or revoke a tolerance, the Agency consider
“available information” concerning the cumulative effects of a
particular pesticide’s residues and “other substances that have a
common mechanism of toxicity.” 

EPA has determined that desmedipham does not have a common mechanism of
toxicity with the other N-methyl carbamate pesticides.  Unlike other
pesticides for which EPA has followed a cumulative risk approach based
on a common mechanism of toxicity, EPA has not made a common mechanism
of toxicity finding as to desmedipham and any other substances, and
desmedipham does not appear to produce a toxic metabolite produced by
other substances.  For the purposes of this tolerance action, therefore,
EPA has not assumed that desmedipham has a common mechanism of toxicity
with other substances.  

For information regarding EPA’s efforts to determine which chemicals
have a common mechanism of toxicity and to evaluate the cumulative
effects of such chemicals, see the policy statements released by EPA’s
Office of Pesticide Programs concerning common mechanism determinations
and procedures for cumulating effects from substances found to have a
common mechanism on EPA’s website at   HYPERLINK
"http://www.epa.gov/pesticides/ cumulative/" 
http://www.epa.gov/pesticides/ cumulative/ .

OCCUPATIONAL EXPOSURE / RISK

Occupational risk is assessed for exposure at the time of application
(termed “handler” exposure) and assessed for exposure following
application, or “postapplication” exposure.  Application parameters
are generally defined by the physical nature of the formulation
(granular, EC, etc.) and packaging, by the equipment required to deliver
the chemical to the use site, and by the application rate required. 
Postapplication risk is assessed for various activities including
scouting, irrigating, pruning, and harvesting and is based primarily on
dermal exposure estimates.

Product Use Information tc \l1 "3.0  Product Use information 

Table 6.  Proposed Use Patterns

Crop 

 	Product, Formulation

	

Treatment Type

	

Applications Per Season 

	

Maximum Application Rate

(lb ai/acre)	

PHI

(days)

Per Application	

Per Season

	

Sugar Beets

	Liquid	ground

or aerial	Multiple at the low or micro-rates	1.2	1.95	75

Garden (Table) Beets

	Liquid	ground

or aerial	3	0.49	1.13	Not given

Spinach

	Liquid	ground

or aerial	1	0.98	1	21

Pesticide Handlers

Exposure Estimate Background tc \l2 "5.1 Handlers  

The following equations were used to calculate handler exposure and
risk:

     Dermal Dose (mg/kg/day) 	=	Rate (lb ai/A) x UE (mg/lb ai) x DA x
Acres Treated (A/day)

BW (kg)

     Inhalation Dose (mg/kg/day)	=	 Rate (lb ai/acre) x UE (mg/lb ai) x
Acres Treated (A/day)

BW (kg)

Where:

     Rate (Application Rate)	=	Maximum application rate on product label

			(lb ai/acre)

     UE (Unit Exposure)		=	Exposure value derived from August 1998 PHED 

					Surrogate Exposure Table (mg/lb ai handled)

     DA (dermal absorption factor)	=	Factor to account for dermal
absorption (100%) when   

		endpoint is selected from an oral study.

     Acres Treated			=	Maximum number of acres treated per day 

					(acres/day)

     BW				=	Body weight (kg)

    Combined Daily Dose		=	Dermal Dose (mg/kg/day)+Inhalation Dose 

		

    Short-term MOE	=           NOAEL (10 mg/kg/day)               

                                                                      
Combined Daily Dose (mg/kg/day)

    Intermediate-term MOE	=           NOAEL (10 mg/kg/day)              

                                                                      
Combined Daily Dose (mg/kg/day)

Exposure Scenarios

The five handler scenarios below are expected to demonstrate the
upper-end of estimated exposure for the proposed uses:

	Mixing/Loading Liquid for Aerial Applications (Scenario 1) 

 	Mixing/Loading Liquid for Ground Applications (Scenario 2) 

	Applying Sprays with Aerial Equipment (Scenario 3)

	Applying Sprays with Ground Equipment (Scenario 4)

	Flagging during Aerial Application (Scenario 5)

Application Rate

The maximum application rates listed on the proposed labels were used
for all exposure assessments. 

Area Treated

Based on HED’s Exposure Science Advisory Council Policy Number 9.1, 80
acres per day treated was assumed for applications using groundboom
equipment and 350 acres per day treated was assumed for applications
using fixed-wing aircraft on red (table) beets and spinach.  200 acres
per day treated was assumed for applications using groundboom and 1,200
acres per day treated was assumed for applications using fixed-wing
aircraft on sugar beets.

Body Weight

The average body weight for the general U.S population (70 kg) was used
for both short- and intermediate-term assessments.

Exposure Frequency

No data on the number of exposure days per year was provided   For this
risk assessment, it was assumed that handlers would be exposed for less
than 6 months per year (i.e. short-/intermediate-term duration). 
Chronic, or long-term exposure is not expected.  

Unit Exposures

The unit exposures used in this assessment are based on the Pesticide
Handlers Exposure Database (PHED), Version 1.10, as presented in the
August 1998 PHED Surrogate Exposure Guide.  PHED was designed by a task
force of representatives from the U.S. EPA, Health Canada, the
California Department of Pesticide Regulation, and member companies of
the American Crop Protection Association.  PHED is a software system
consisting of two parts–a database of measured exposure values for
workers involved in the handling of pesticides under actual field
conditions and a set of computer algorithms used to subset and
statistically summarize the selected data.  

Users select criteria to subset the PHED database to reflect the
exposure scenario being evaluated.  The subsetting algorithms in PHED
are based on the central assumption that the magnitude of handler
exposures to pesticides is primarily a function of activity (e.g.,
mixing/loading, applying), formulation type (e.g., wettable powders,
granulars), application method (e.g., aerial, groundboom), and clothing
scenarios (e.g., gloves, double layer clothing).

Risk Mitigation

There are three basic risk mitigation approaches considered appropriate
for controlling occupational exposures.  These include administrative
controls, the use of personal protective equipment or PPE, and the use
of engineering controls.  Occupational handler exposure assessments were
completed by HED using baseline, PPE, and engineering controls. [Note:
Administrative controls available generally involve lowering application
rates for handler exposure scenarios.  

This was not necessary for desmedipham.] The baseline clothing-level
scenario for occupational exposure scenarios is generally an individual
wearing long pants, a long-sleeved shirt, no chemical resistant gloves,
and no respirator.  The first level of mitigation generally applied (to
the assessment) is PPE.  As reflected in the calculations included
herein, PPE may involve the use of an additional layer of clothing,
chemical-resistant gloves, and a respirator.  The next level of
mitigation considered in the risk assessment process is the use of
appropriate engineering controls which, by design, attempt to reduce or
eliminate the possibility of human exposure.  Examples of commonly used
engineering controls include enclosed tractor cabs and enclosed aircraft
cockpits, closed mixing/loading/transfer systems, and water-soluble
packets.

Handler Exposure and Risk

The handler exposure estimates in this assessment are based on a central
tendency estimate of unit exposure and an upper-percentile assumption
for the application rate, and are assumed to be representative of
high-end exposures.  The uncertainties associated with this assessment
stem from the use of surrogate exposure data (e.g., differences in use
scenario and data confidence), and assumptions regarding that amount of
chemical handled.  The estimated exposures are believed to be high-end
estimates based on observations from field studies and professional
judgment.

In HED risk assessments, occupational risk is expressed as a Margin of
Exposure, or MOE, which is the ratio of the estimated exposure to the
appropriate dose level for that particular type of exposure.  The MOEs
seen in the desmedipham assessment are above the “level of concern”
at the baseline level, or at the baseline level with gloves for all
exposure scenarios (except aerial application which pass at the
engineering control level of an enclosed cockpit).  



Table 7. Summary Table for Desmedipham Short- & Intermediate-Term
Exposures

Exposure Scenario	Crop4	Application Rate	Acres Treated	Combined baseline
dermal1 and baseline inhalation2 MOE5	PPE-G Dermal3 + Baseline
Inhalation MOE5

Mixer/Loader

Mixing/Loading Liquids for Aerial application	  Sugar Beets	1.2	1200	1.7
140

Mixing/Loading Liquids for Aerial application	Table Beets	0.49	350	14
1100

Mixing/Loading Liquids for Aerial application	Spinach	0.98	350	6.9	570

Mixing/Loading Liquids for Groundboom application	Sugar Beets	1.2	200	10
830

Mixing/Loading Liquids for Groundboom application	Table Beets	0.49	80	60
5000

Mixing/Loading Liquids for Groundboom application

	Spinach	0.98	80	30	2500

Applicator

Applying Sprays via Aerial Equipment	Sugar Beets	1.2	1200	n/a	860
(enclosed cockpit)

Applying Sprays via Aerial Equipment	Table Beets	0.49	350	n/a	7000
(enclosed cockpit)

Applying Sprays via Aerial Equipment	Spinach	0.98	350	n/a	3500 (enclosed
cockpit)

Applying Sprays via Groundboom Equipment	Sugar Beets	1.2	200	1400	-

Applying Sprays via Groundboom Equipment	Table Beets	0.49	80	8200	-

Applying Sprays via Groundboom Equipment	Spinach	0.98	80	4100	-

Flagger

Flagging for Aerial Sprays Applications	Sugar Beets	1.2	350	1100	-

Flagging for Aerial Sprays Applications	Table Beets	0.49	350	2800	-

Flagging for Aerial Sprays Applications	Spinach	0.98	350	1400	-

Footnotes:

- scenario passed at previous PPE level.

1Baseline dermal represents long pants, long sleeved shirts, shoes, and
socks.  Values are reported in the PHED Surrogate Exposure Guide dated
August 1998. 

2Baseline inhalation represents no respirator.  Values are reported in
the PHED Surrogate Exposure Guide dated August 1998.

3PPE-G dermal represent long pants, long sleeved shirts, shoes, socks
and gloves.  Values are reported in the PHED Surrogate Exposure Guide
dated August 1998.

4Crops and use patterns are from product labeling.

5Total MOE = 1/ [1/MOE (dermal) +1/MOE (inhalation)] 

Target MOE is 100

Calculations used:

Dermal MOE =   Short & Intermediate-term oral NOAEL/Daily Dermal Dose;

Dermal dose (mg/kg/day) = [unit exposure (mg/lb ai) * Dermal absorption
* Application rate (lb ai/acre) * Daily area treated (acres or gallons)]
/ Body weight; 

Inhalation MOE = Short & Intermediate-term oral NOAEL/Daily Inhalation
Dose.

Postapplication Exposure / Risk

The Agency uses the term “postapplication” to describe exposures to
individuals that occur as a result of working in an environment that has
been previously treated with a pesticide (also referred to as reentry
exposure).  The Agency believes that there are distinct job functions or
tasks related to the kinds of activities that occur in previously
treated areas such as harvesting vegetables in a treated field.  Job
requirements (e.g., the kinds of jobs to cultivate a crop), the nature
of the crop or target that was treated, and the how chemical residues
degrade in the environment can cause exposure levels to differ over
time.  Each factor has been considered in this assessment.  	

HED has identified potential post-application occupational exposures
resulting from the various activities related to agricultural practices
associated with the uses being supported for the desmedipham
reregistration.  These activities range from low to high potential
exposure.  The activities associated with sugar beets, table beets,
spinach are: irrigation, scouting, thinning, weeding and pruning by
hand.  

The agency uses a concept known as the transfer coefficient to
numerically represent the post-application exposures one would receive
(i.e., generally presented as cm2/hour).  The transfer coefficient
concept has been established in the scientific literature and through
various exposure monitoring guidelines published by the U.S. EPA and
international organizations such as Health Canada and OECD (Organization
for Economic Cooperation and Development).  The establishment of
transfer coefficients also forms the basis of the work of the
Agricultural Reentry Task Force.

The formulas used to estimate daily dermal dose and the MOE for the
dermal post-application scenarios are similar to those described
previously in this document for the handler/applicator scenarios.  The
only major difference is that the daily dermal exposure is calculated by
multiplying the dislodgeable foliar residue (DFR) and/or a turf
transferable residue (TTR) level (ug/cm2 of leaf area) times a transfer
coefficient (amount of leaf area contacted per hour for a given
activity).  Inhalation exposures are not calculated for the
post-application scenarios because inhalation exposures have been shown
to account for a negligible percentage of the overall body burden.  

In calculating post-application dermal exposure to pesticides and its
consequent risk HED uses a formula which presumes the dermal dose will
be equal to the(DFR or TTR at day t) x  (conversion factor) x (transfer
coefficient) x (number of exposure hours/day).  

Where for agricultural crops:								

   DFR		=  	dislodgeable foliar residue (ug/cm2) at day (t) after
application

   day t 		= 	day or number of days after treatment

   CF1		=	conversion factor to convert DFR value in ug/cm2 to mg/cm2

   TC		=	transfer coefficient (cm2/hour)

   Hours/day 	= 	standard assumption is 8 hours exposure per day.

Short and intermediate-term risk is therefore calculated as follows: 

Absorbed Daily Dose is:

Absorbed daily dose (mg/kg/day) = (daily dermal exposure (mg/day) / BW
(kg)

Margin of Exposure is calculated:								

MOE (unitless) =  NOAEL (mg/kg/day)  / Absorbed  Daily Dose (mg/kg/day)

Risk Estimates 

All crops (sugar beets, table beets, and spinach) reach the target MOE
of 100 on the day of application.

Table 8.  Summary of “Days After Treatment” to Reach the Target MOE
for Short & intermediate-Term Exposure (Target MOE = 100)

Crop	Application Rate

(lbs ai/acre)	Exposure Activity Level	Activity	Transfer Coefficient
(cm2/hr)a	Days After Treatment Target MOEb is Achieved	MOE

Sugar beets	1.2	Low 	Irrigating, scouting (min foliage)

Thinning, hand weeding	100	0 (12 hours)	3300

Medium	Irrigating, scouting (full foliage)	1500	0 (12 hours)	220

Beets (table grown for seed)	0.5	Low	Irrigating, scouting, thinning,
hand weeding	300	0 (12 hours)	2600

High	Hand harvest	2500	0 (12 hours)	310

Spinach	1	Low	Irrigating, scouting, thinning (min foliage), hand weeding
500	0 (12 hours)	780

Medium	Irrigating, scouting (full foliage)	1500	0 (12 hours)`	260

High	Hand harvesting

	2500	0 (12 hours)	160

a Transfer coefficients from Policy #003.1 “Agricultural Transfer
Coefficients”

b  MOE = NOAEL (10 mg/kg/day; based on a developmental rat study) /
dermal dose.

HED notes that t  SEQ CHAPTER \h \r 1 he WPS establishes default
restricted-entry intervals based on the acute toxicity categories of the
active ingredient – considering acute dermal toxicity, skin irritation
potential, and eye irritation potential.  In determining the appropriate
REI for an active ingredient, the EPA compares the REI that would be
established by the postapplication exposure and risk assessment to the
default WPS REI established on the basis of the acute toxicity of the
active ingredient.  The longer of the two potential REIs is selected as
the REI for the active ingredient and is placed on the labeling.  Since
desmedipham is classified as toxicity category II for eye irritation
potential, the default WPS REI is 24 hours. 

		

Residential Exposure 		

Risk assessments for residential handlers (non-professional) and/or
residential postapplication exposures were not needed since there are no
proposed or registered residential uses for desmedipham. 

 PAGE   

 PAGE   23