Document ID: EPA-HQ-OPP-2004-0032-0026
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-06-28T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

December 23, 2005

MEMORANDUM

SUBJECT:	HED Revised Risk Assessment for Formetanate Hydrochloride
(097301)

 (Phase 4), D323945.

From:		Danette Drew, Chemist

 		John Doherty, Toxicologist

Seyed Tadayon, Chemist

Susan Stanton, Environmental Scientist

Reregistration Branch 3

Health Effects Division [7509C]

	

Through:	Catherine Eiden, Branch Chief

Reregistration Branch 3

Health Effects Division [7509C]

To:		Demson Fuller, Chemical Review Manager

Reregistration Branch

Special Review and Reregistration Division [7508C]

An HED Preliminary Risk Assessment for Formetanate Hydrochloride (HCl)
for the Reregistration Eligibility Decision was issued 4/6/99 (D233099).
Subsequently, a Memorandum of Agreement (MOA) between the registrant and
the EPA was issued (dated 10/14/99). This MOA was issued because the
Agency was concerned that formetanate HCl use presented dietary, worker,
and ecological risks that are not consistent with the FIFRA mandate that
pesticides must not pose unreasonable adverse effects.

A revised HED human health risk assessment was issued [HED Revised Risk
Assessment for Formetanate Hydrochloride (097301), D289007, 6/4/2003]
that included only those uses permitted under the MOA and takes into
consideration additional data that were submitted as a result of that
MOA. 

The previous assessment was revised herein to reflect, where
appropriate, HED response to comments submitted during Phase3 of the
reregistration process. Specifically addressed is the comparative
cholinesterase study in neonatal and adult rats that was recently
submitted by Gowan and the resulting selection of a benchmark dose for
use in this assessment. Additionally, the dietary risk assessment was
revised to include residue data from field trials and an additional
assessment was performed for mixer/loaders and applicators for aerial
application to alfalfa which assumed a reduction in the estimated acres
treated per day.				

The following documents and disciplinary chapters support the current
HED risk assessment:

Formetanate hydrochloride-4th Report of the Hazard Identification
Assessment Review Committee (TXR No. 0051909, 5/21/03, J. Doherty).

Benchmark Dose Analysis of Cholinesterase Levels from the Oral Gavage
Acute Relative Sensitivity Toxicity Study of Formetanate HCL in Neonatal
and Adult Rats. PC Code 097301 (TXR No. 0053699, D323943, 12/14/05,
P.Villanueva and A. Lowit).

Formetanate Hydrochloride- Toxicology Chapter for the Reregistration
Eligibility Document (TXR No. 0053982, D324302, 12/22/05, J.Doherty).

Formetanate Hydrochloride HED Product Chemistry Chapter of the RED
(D289011, 3/27/03, D. Drew).

Formetanate Hydrochloride HED Revised Chemistry Chapter of the RED:
Summary of Analytical Chemistry and Residue Data (Phase 4) (D3244543,
12/14/05, D. Drew)

Formetanate Hydrochloride: Revised Acute Probabilistic and Chronic
Dietary Exposure Assessments for the Reregistration Eligibility Decision
(D323946, 12/16/05, S. Stanton)

FORMETANATE HYDROCHLORIDE: The Occupational and Residential Exposure
Assessment and Recommendations for the Reregistration Eligibility
Document (RED) (D289008, 5/21/03, G. Bangs).

Revised Tier II Drinking Water Assessment for Formetanate HCL.(D289182,
3/27/03, I. Abdel-Saheb).	



1.0 Executive Summary	4

2.0 Physical/chemical Properties Characterization	10

3.0 Hazard Characterization	11

3.1 Hazard Profile	11

3.2 FQPA Considerations	16

3.3 Dose-Response Assessment	19

3.4 Endocrine Disruption	22

4.0 Exposure Assessment	22

4.1 Summary of Registered Uses	22

4.2 Dietary Exposure/Risk Pathway	23

4.2.1 Residue Profile	23

4.2.2 Acute and Chronic Dietary Exposure Assessment	25

4.2.3 Acute Dietary	28

4.2.4 Chronic Dietary	31

4.2.5 Cancer Dietary	33

4.3 Water Exposure/Risk Pathway	34

4.4 Residential Exposure/Risk Pathway	36

4.5 Spray Drift	36

5.0 Aggregate Risk Assessments And Risk Characterization	36

5.1 Acute Aggregate Risk	36

5.2 Short-Term Aggregate Risk	37

5.3 Intermediate-Term Aggregate Risk	37

5.4 Chronic Aggregate Risk	37

5.5 Cancer Risk	38

6.0 Cumulative Risk	38

7.0 Occupational Exposure and Risk	38

7.1 Occupational Handler	39

7.2 Occupational Postapplication	48

8.0  DATA NEEDS, LABEL REQUIREMENTS, TOLERANCE REASSESSMENT	50



1.0 Executive Summary

Formetanate hydrochloride {m-[[(dimethylamino)methylene]amino]phenyl
methylcarbamate hydrochloride} is a carbamate miticide/insecticide used
on a variety of orchard fruits and alfalfa grown for seed. The 92%
wettable powder formulation (Carzol® SP) contains formetanate
hydrochloride (HCl) as the sole active ingredient (a.i.) and is
registered for foliar or dormant applications using ground or aerial
equipment. The registrant is Gowan Company (transferred from Aventis
CropScience, formerly AgrEvo USA Company, on 4/30/01). This risk
assessment takes into consideration only those uses permitted under the
10/99 Memorandum of Agreement between the registrant and the EPA (apple,
pear, nectarine, peach, orange, grapefruit, lemon, lime, tangelo and
tangerine and alfalfa grown for seed). There are no residential uses.

Toxicology

Overall, the studies supporting the toxicity data base for formetanate
HCl are considered adequate and there is confidence in the hazard and
dose response assessments. Formetanate HCl has high acute toxicity via
the oral route, moderate acute toxicity via the inhalation route and has
low acute toxicity via the dermal route. It is not an eye irritant but
is a dermal sensitizer. Exposure to formetanate hydrochloride resulted
in decreased plasma, whole blood and/or brain cholinesterase. 
Cholinesterase inhibition (ChEI) appears to be the only manifestation of
exposure in the variety of studies run to support reregistration. The
clinical signs following acute and chronic exposure to formetanate HCl
in rats (decreased body weight) and dogs (excessive salivation, wheezing
labored breathing, trembling, vomiting, coughing, and abnormal
quietness) are consistent with cholinesterase inhibition.   

The toxicity database for formetanate HCl  indicates that the magnitude
of ChEI does not increase with continued exposure because of the rapid
reversibility of ChEI. Generally, recovery of red blood cell and brain
acetylcholinesterase inhibition occurred within 8 to 24 hours following
a single gavage dose of formetanate. Therefore, chronic exposures to
formetanate could be considered as a series of acute exposures. While
this indicates that neither a chronic dietary exposure assessment nor an
intermediate -term occupational assessment may be necessary, the risk
assessment team has provided these assessments for informational
purposes.

A comparative cholinesterase assay (CCA) study in neonates and adult
rats has been submitted, as required, in lieu of a developmental
neurotoxicity study. In order to evaluate the appropriate point of
departure (PoD) for ChEI, EPA performed a benchmark dose (BMD) analysis.
The BMD analysis indicates that for single oral gavage dosing of
formetante HCl based on the comparative ChE study in neonatal and adult
rats, brain ChE inhibition is the more sensitive endpoint compared to
red blood cell (RBC) ChE, female pups are more sensitive than male pups,
and  the 10% ChE is the appropriate benchmark response to consider. The
CCA study indicated that there was inhibition of brain AChE at all doses
and that the female pup brain AChE data resulted in the lowest BMDL10
(benchmark dose lower limit) of 0.065 mg/kg.   This dose and endpoint
was  selected for the oral exposure scenarios.

A dermal toxicity study demonstrating inhibition of whole blood and
plasma ChE is available and was used with route specific dermal exposure
assessments to estimate occupational risks. Although a dermal absorption
study for formetanate HCl is not available, a dermal absorption factor
is not necessary for the risk assessment because a route specific dermal
toxicity study is available. The risk assessment team determined that
the route-specific dermal toxicity study should be used for dermal
occupational risk assessments.

There are no inhalation toxicity studies available that assess for
cholinesterase inhibition. The risk assessment team determined that the
occupational inhalation risk endpoint should be retained from the acute
neurotoxicity study since there was no appropriate route-specific study
available. The LOAEL from the acute neurotoxicity study is 1 mg/kg base
on the appropriate endpoint of cholinesterase inhibition (whole blood,
plasma, and brain). The resulting NOAEL of 0.1 mg/kg is not much
different from the BMDL10 of 0.065 mg/kg and is appropriate for use in
occupational risk assessments as it is derived from a study using adult
animals.  Since an oral endpoint was selected, absorption via inhalation
is assumed to be equivalent to oral absorption.  Risk assessments for
dermal and inhalation occupational scenarios only are being presented as
there are no currently registered residential uses of formetanate HCl.  

There were no concerns for mutagenicity. There was no indication of a
carcinogenic effect in rats or mice. Formetanate HCl is classified as a
group “E” carcinogen (no evidence of carcinogenicity). There were
also no obvious effects on the immune or endocrine systems.  

FQPA Considerations

Formetanate HCl did not result in developmental toxicity in either rats
or rabbits or in reproductive effects in the multi-generation
reproduction study.  There was no indication of increased offspring
susceptibility in these studies. Therefore, the HIARC previously
determined that the hazard based special FQPA safety factor can be
reduced to1X because of a  lack of concern and no residual uncertainties
for pre-and/or post natal toxicity (5/21/03).  However, a comparative
ChE inhibition study was subsequently performed and benchmark dose (BMD)
estimates were calculated from the submitted data. The results
demonstrated that the pups were more sensitive than the adults to the
inhibitory effects of formetanate.  In particular, based on the BMD for
inhibition of brain AChE, the male pups are 2.7 times more sensitive
than the male adults and the female pups are 5 times more sensitive than
the female adults.  Using the BMDL10 values, the male pups are 2.4 times
more sensitive than the male adults and female pups are 4.77 times more
sensitive than the female adults. A special FQPA safety factor of 1X is
appropriate for use in formetanate risk assessment scenarios where the
endpoint and dose is based on female pup brain AChE inhibition data from
the special CCA study which used oral dosing. However, if in the future,
uses are registered which result in residential exposure scenarios,
where it is more appropriate to use a toxicity endpoint from a
route-specific study performed on adults (i.e. dermal toxicity study)
versus using the BMDL10 value based on the female pup brain inhibition
data, an additional special FQPA safety factor would need to be applied.
 Since the current acute and chronic dietary dose and endpoints are
based on the BMDL10 and there are no residential uses of formetanate
HCl, there are presently no risk assessment scenarios requiring a
special FQPA factor greater than 1X.

To derive both the acute and chronic reference doses, a total
uncertainty factor (UF) of 100 was applied to the dose selected for risk
assessment to account for both interspecies extrapolation (10x) and
intra-species variability (10x). 

  

Residue Chemistry

The nature of the residue of formetanate HCl in livestock and plants has
been adequately delineated. The residue of concern for tolerance
enforcement and risk assessment is parent formetanate. The tolerances
were reassessed based on limited residue data from field trials
performed at the MOA required  reduced rate and increased PHIs. In
general the field trial data did not satisfy the requirements for the
number of field trials (D324543, 12/14/05, D.Drew). At such time as the
additional field trials are received and deemed adequate, these
tolerances will be reevaluated.

 

Dietary Exposure and Risk Estimates

Acute probabilistic and chronic dietary risk assessments were conducted
using the Dietary Exposure Evaluation Model (DEEM-FCID, Version 2.03) to
support the reregistration eligibility decision.

USDA’s Pesticide Data Program (PDP), at HED’s request, collected and
analyzed oranges, apples and nectarines for residues of formetanate HCl
in 2000 and 2001; and HED used the 2001 data in its previous 2003
dietary exposure assessment.  Although these data were collected after
the 10/99 MOA which mandated lower application rates and longer PHIs,
the registrant argued that the PDP data did not reflect these label
changes, since most of the formetanate HCl product in the channels of
trade at the time still bore labeling with the previously approved rates
and PHIs.  Therefore, the registrant recommended that field trial data
reflecting current label rates and PHIs be used to assess dietary
exposure.  HED considered the registrant’s arguments and agreed to
reassess dietary exposure using the available field trial data, as
described below. 

Acute Dietary Risk Assessment:  A partially refined, Tier 3, acute
probabilistic dietary exposure assessment was conducted for all
supported formetanate food uses and drinking water.  Acute anticipated
residues for all foods were derived using field trial data reflecting
current maximum label rates and minimum PHIs.  Anticipated residues were
further refined using percent crop treated (%CT) data where appropriate,
and, where available, processing factors. 

Estimated residues in drinking water were provided by EFED (Revised
Tier II Drinking Water Assessment for Formetanate HCL; DP Barcode289182;
Ibrahim Abdel-Saheb; 03/27/03) and incorporated directly into the acute
assessment.  The assessment was conducted using the full distribution of
estimated residues in surface water generated by the PRZM-EXAMS model
for the North Carolina apple crop scenario, the crop scenario resulting
in the highest estimated peak surface water concentration.

The resulting acute dietary exposure risk estimates for food and water
exceed HED’s level of concern for the U.S. population and all reported
population subgroups.  Formetanate acute dietary (food + water) exposure
at the 99.9th percentile was estimated at 830% of the aPAD for the U.S.
population and  2600% of the aPAD for the most highly exposed population
subgroup (infants).  Most of the estimated acute exposure was determined
to result from the late season uses of formetanate hydrochloride on
apples, pears, oranges and grapefruit (particularly apples, and to a
lesser extent, pears).  When the late season uses are excluded from the
assessment, estimated dietary exposure (food + water) is below HED’s
level of concern for the U.S. population (32% of the aPAD) and all
population subgroups, except infants, whose estimated exposure
represents 110% of the aPAD.  Drinking water is the largest contributor
to overall dietary exposure when late season uses are excluded.  A
separate analysis of acute exposure to formetanate hydrochloride from
drinking water alone resulted in exposure estimates equivalent to 28% of
the aPAD for the overall U.S. population and 110% of the aPAD for
infants. 

Chronic Dietary Assessment:  A partially refined, Tier 3 chronic dietary
exposure assessment was also conducted for the supported food uses of
formetanate HCl and drinking water.  Anticipated residues were derived
using field trial data, incorporating  %CT data and, where available,
processing factors. 

For the chronic assessment, a single point estimate (0.08 ppb) of
formetanate HCl residues in surface water was used to assess exposure
from drinking water.  The estimated surface water concentration
represents the 90th percentile annual mean concentration generated by
the PRZM-EXAMS model for the Pennsylvania apple crop scenario, the crop
scenario resulting in the highest estimated annual mean concentration.

Chronic dietary risk estimates based on these assumptions are below
HED’s level of concern for the U.S. population and all population
subgroups.  Formetanate hydrochloride mean dietary (food + water)
exposure is estimated at 4.9% of the cPAD for the U.S. population and
28% of the cPAD for the most highly exposed population subgroup
(infants, <1 yr. old).  When late season uses on apples, pears, oranges
and grapefruit are excluded, estimated chronic dietary exposure
represents less than 1% of the cPAD for the U.S. population and all
population subgroups, except infants, whose estimated exposure
represents 1.3% of the cPAD.  Chronic dietary exposure from drinking
water alone is estimated to be less than 1% of the cPAD for all
populations.

Residential (non-occupational) Exposure and Risk Estimates

Currently, there are no registered residential uses of formetanate HCl.	
	

Aggregate Risk Estimates

The current uses for formetanate HCl encompass only agricultural use
sites; there are no non-occupational (residential) uses.  Therefore,
when addressing aggregate exposures, only the dietary pathways of food
and drinking water were considered.  Since drinking water was
incorporated directly into the acute and chronic dietary assessments,
the dietary risk estimates discussed above reflect total estimated acute
and chronic aggregate risk from formetanate Hcl.

Chronic aggregate exposure estimates for food and water are below
HED’s level of concern..

Acute aggregate exposure estimates for food and water exceed HED’s
level of concern. However, when residues resulting from late season uses
of formetanate HCL are excluded from the dietary assessment, acute
aggregate risk estimates are below HED’s level of concern for the U.S.
population (32% of the aPAD) and all population subgroups, except
infants, whose estimated exposure represents 110% of the aPAD.  

Drinking water is the largest contributor to the acute aggregate dietary
exposure when late season uses are excluded. Uncertainties associated
with the drinking water assumptions indicate that the estimated levels
of formetante HCL in drinking water are conservative and are not likely
to result in an underestimate of risk. Some assumptions include 1) The
lack of actual water monitoring data, which would have resulted in a
more refined estimate of drinking water exposure to formetanate HCl, 2)
The PRZM-EXAMS  model results assume that applications will be made at
maximum application rates every year for 30 years,  3) the PRZM-EXAMS
models are based on an actual reservoir/watershed system in Illinois
which is known to be a highly vulnerable configuration, 4) The
PRZM-EXAMS results were based on a single application to apples at the
maximum  application rate (1.15 lbs. a.i./A); as such, they do not take
into consideration potential late-season applications that are allowed
under certain circumstances.  Since typically only a single application
is made, and considering the conservative nature of the other model
assumptions, it is unlikely that the PRZM-EXAMS results based on a
single application underestimate drinking water residues.

The assumptions used for food residue inputs may also be considered
somewhat conservative. Although the field trial data are very limited in
terms of the number of trials and residue samples, it is still likely
that these data result in overestimates of dietary exposure to
formetanate, since they reflect maximum, rather than typical, usage. 
The availability and use of monitoring data reflecting current use
patterns and/or additional residue processing information (cooking,
peeling, etc.) would have resulted in a more refined estimate of dietary
exposure.		

Occupational Exposure and Risk Estimates - Handlers

EPA has determined that there are potential exposures to mixers,
loaders, applicators, and other handlers during usual use-patterns
associated with formetanate hydrochloride.   Based on the allowed use
patterns, 7 major exposure scenarios were identified for formetanate
hydrochloride: mixing/loading wettable powders in soluble bags for
groundboom, airblast, and aerial application; applying sprays by those
methods, and flagging spray operations.  Workers reentering formetanate
HCl-treated orchards or fields may be exposed to residues.  Only short
(1-30 days) and intermediate (1-6 months) duration exposures are
anticipated for formetanate HCl handlers and reentry workers.

Risks to mixer/loaders and applicators were calculated for scenarios
using the  recommended rate per application per acre.  All baseline,
i.e., typical single layer work clothing, applicator scenarios had
estimated exposures resulting in risks of concern. Even with maximum
personal protection or enclosed cockpit, some scenarios still produced
combined route (dermal + inhalation) risks of concern (MOEs <100). 

Mixing/loading scenarios for large acreage (alfalfa) by aerial
application resulted in risks of concern (MOE = 57) that were not
mitigated with addition of coveralls, gloves, and respirator. The
mixing/loading scenario for aerial application to alfalfa assumed the
default acreage of 1200 acres treated per day. An additional assessment
was performed using an estimate of 328 acres treated per day based on
data from the California Agricultural Commissioner (letter dated
11/29/2005 to D. Fuller from R. Melnicoe, College of Agricultural and
Environmental Science, University of California, Davis). Total MOEs were
69 using WSB and 210 using WSB plus double layer protection(coveralls),
gloves, and respirator.

It should be noted that the use of water soluble bags (a closed system)
is intended to negate the need for maximum PPE as PPE can be
uncomfortable to wear (respiratory protection) and also cause thermal
discomfort (chemical resistant coveralls). Use of engineering controls
also avoids the constellation of  problems associated with PPE (heat
stress, decreased mobility, physical stress, lack of fine motor skill,
false sense of security). Therefore additional PPE generally defeats the
purpose of putting the  product in water soluble bags.

With maximum PPE as prescribed by the MOA and the label (coveralls,
gloves, respirator and hood), airblast applicators for orchards still
had risks of concern (MOE = 73).  All applicator scenarios, except for
aerial application to alfalfa, had combined MOEs >100 with engineering
controls added in the form of enclosed vehicles.  Aerial applicators for
high-acreage (1200 acres per day) alfalfa crops had risks of concern
(MOE = 54) even with closed cockpit. However, when assuming an estimate
of 328 acres of alfalfa treated per day based on data from the
California Agricultural Commissioner, the total MOE was 200.

Occupational Exposure and Risk Estimates - Postapplication

Postapplication exposure and risk were estimated using standard residue
transfer coefficients for the crops assessed, and dislodgeable foliar
residue (DFR) data from a formetanate-HCl study on citrus.  Based on the
available data, re-entry activity MOEs equal to or over 100 are not
achieved until 12 days after the second application of the ai to tree
fruits (evergreen or deciduous) and 9 days after application to alfalfa.
The product label includes pre-harvest intervals (PHIs) greater than the
intervals needed to attain re-entry MOEs of 100 and/or prohibits
applications after fruit has begun to develop, except in the case of
second late season applications allowed to pome fruit, which do not
specify a PHI. 

Incident Reports

A review of available incident reports on formetanate HCl was completed
in 1997. Systemic poisoning has been reported in applicators who were
not properly protected and skin rashes have been reported in field
workers exposed to residues.  Based on the epidemiological review,
incident data do support the need for personal protective equipment for
those that handle formetanate HCl and reentry intervals for workers
returning to orchards or fields where this active ingredient has been
applied. A 2003 review of the EPA Incident Data System showed no
additional incident reports since 1996.

Data Gaps and Tolerance Reassessment

Refer to Section 8.0 of this document for specific data gaps and
tolerance reassessment.

2.0 Physical/chemical Properties Characterization

TABLE 2.1	Formetanate Hydrochloride Nomenclature

Compound	

Chemical Structure

Common name	

Formetanate HCl

Company experimental name	

Carzol®

IUPAC name	

3-dimethylaminomethyleneaminophenyl methylcarbamate monohydrochloride

CAS name	

Methanimidamide,
N,N-dimethyl-N(-[3-[[(methylamino)carbonyl]oxy]phenyl]-,
monohydrochloride

CAS #	

23422-53-9

Chemical Class	

Carbamate

End-use formulation

(EUP)	

Carzol® SP (92%WP in  water soluble packaging)



TABLE 2.2	Physicochemical Properties 

Parameter	

Value

Melting point/range	

191.2 C

pH	

(2.5 (10% solution)

Density	

200-450 g/L

Water solubility (25(C)	

82.2 g/100mL

Solvent solubility (g/100mL at 20(C)	

n-hexane 	<0.00005

ethylacetate	0.0001

toluene		0.001

acetone		0.007

dichloromethane	0.03

methanol		28.3

Vapor pressure at 25(C	

1.6 x 10-6 mmHg

Dissociation constant (pKa)	

8.0

Octanol/water partition coefficient (KOW)	

<0.002

UV/visible absorption spectrum 	

(max:  Molar 

  Absorbance	Absorbance

Media	  Maximum	Coefficient

Acidic	    208 nm	                  22130

    250 nm	                  16603

Neutral	    208 nm	                  21934

    250 nm	                  16540

Basic	    236 nm	                  23015

Results indicate no significant change in absorption in acidic and
neutral media; however, a significant change in the wavelength maximum
was observed in basic media.

Formetanate HCl is a white crystalline solid with a faint odor and a
melting point of 191-202(C. Formetanate HCl has a low vapor pressure and
exposure to the gaseous state should be negligible. Formetanate HCl is
highly  soluble in water and only slightly soluble in organic solvents
(dichloromethane, acetone, toluene, ethyl acetate, and n-hexane). Data
on the product identity and composition are inadequate. A nominal
concentration for nitrosamines as manufacturing impurities should be
added to the Confidential Statement of Formulation (CSF).

3.0 Hazard Characterization

3.1 Hazard Profile tc \l2 "3.1 Hazard Profile 

-Acute Toxicity.  Adequacy of data base for acute toxicity:  The data
base for acute toxicity consists of studies considered invalid and will
need replacement.  Formetanate is a carbamate inhibitor of
cholinesterase and the onset of typical cholinesterase inhibition
clinical signs is rapid and transient.  The acute toxicity data on the
formetanate technical are summarized below in Table 3.1.1.

Table 3.1.1. Acute Toxicity Data on Formetanate

Guideline

 No.	

Study Type	

MRID #(s)	

Results	

Toxicity Category

81-1	

Acute Oral	

00077666	

LD50 = 

26.4±3.4 mg/kg (

14.8±2.6 mg/kg (	

I*

81-2	

Acute Dermal	

00077666	

LD50 > 10.2 gm/kg	

III*

81-3	

Acute Inhalation	

00776668	

LC50 = 0.29 mg/L	

II*

81-4	

Primary Eye Irritation	

41208501	

Non-irritating	

IV

81-5 	

Primary Skin Irritation	

00077666	

PIS = 3.9/8.0	

III*

81-6	

Dermal Sensitization	

42089802

	

Sensitizer (guinea pig/Buehler test)

*IBT study and needs replacement.

-Subchronic/Chronic/Developmental/Reproductive/Carcinogenicity/Mutagenic
ity/and General Metabolism

Table 3.1.2.  Toxicity Profile for Formetanate Hydrochloride

Guideline No./ Study Type	

MRID No. (year)/ Classification /Doses	

Results

870.3100

90-Day oral toxicity rodents	

42664401 (1992). Unacceptable/Non-Guideline. 0, 0.07, 0.69, 1.43 or 3.48
mg/kg/day (males only). 	

NOAEL and LOAEL not established.  Refer to subchronic neurotoxicity
study below. 

870.3150

90-Day oral toxicity in nonrodents	

There is an acceptable chronic feeding study that supercedes the
requirement for this study. 

870.3200

21/28-Day dermal toxicity	

44948501 (2000)

Acceptable/Non-Guideline. 

0, 10, 20 or 500 mg/kg (single dose).

44948501 (1999) 

0, 10, 15 or 20 mg/kg/day. 	

NOAEL = 10 mg/kg/day

LOAEL = 20 mg/kg/day based on consistent decrease in whole blood
cholinesterase in males of 12-18%.  

No NOAEL and LOAEL assigned for this study. 

870.3250

90-Day dermal toxicity	

No study available and not required. 

870.3465

90-Day inhalation toxicity	

No study available and a study is being required. 

870.3700a

Prenatal developmental in rats	

00151570 (1985). Acceptable/Guideline. 

0, 1, 3, or 5 mg/kg/day	

Maternal NOAEL = 1 mg/kg/day

LOAEL = 3 mg/kg/day based mainly on body weight decreases. 

Developmental NOAEL > 5  mg/kg/day (no effects noted at the HDT). 

870.3700b

Prenatal developmental in nonrodents	

00151571 (1985). Acceptable/Non-Guideline.  0, 5, 15 or 30 mg/kg/day. 	

Maternal NOAEL = 5 mg/kg/day

LOAEL = 15 mg/kg/day based on body weight decrease and ataxia.  

Developmental NOAEL > 30  mg/kg/day (no effects noted at the HDT). 

870.3800

Reproduction and fertility effects	

40411801, -02 and -03  (1987). Acceptable/Guideline.

0, 0.9, 4.5 or 22.75 mg/kg/day.  	

Parental/Systemic NOAEL = 4.5 mg/kg/day

LOAEL = 22.75 mg/kg/day based on decreases in body weight and apparent
inhibition of whole blood cholinesterase. 

Reproductive NOAEL > 22.75  mg/kg/day.

Offspring NOAEL = 4.5 mg/kg/day

LOAEL = 22.75 mg/kg/day based on decreased pup weight and viability
index. 

870.4100a

Chronic toxicity rodents	

See combined chronic toxicity and carcinogenicity study below. 

870.4100b

Chronic toxicity dogs	

00164341 (1986). Acceptable/Guideline.

0, 0.37-both sexes, 1.74(/1.78(, or 8.45(/9.20( mg/kg/day.   	

Systemic toxicity:

  NOAEL =  0.37  mg/kg/day.

  LOAEL =   1.74  mg/kg/day based on clinical signs. 

Cholinesterase inhibition:

  NOAEL =   0.37  mg/kg/day.

  LOAEL =   1.74  mg/kg/day based on plasma and whole blood inhibition. 
LOAEL = 8.45 mg/kg/day. 

870.4200

Carcinogenicity rats	

40640901 (1988). Acceptable/Guideline. 

0, 0.45(/0.58(,  2.3(/2.9( or 12( /15( mg/kg/day.	

Systemic toxicity:

   NOAEL =  2.3  mg/kg/day

   LOAEL =  12  mg/kg/day based on decreased body weight. 

Cholinesterase inhibition. 

   No assignment of the NOAEL and LOAEL since this will be based on the
weight-of-evidence from all studies with rats. 

No evidence of carcinogenicity.

870.4300

Carcinogenicity mice	

40707101 (1988). Acceptable/Guideline.

0, 1.4(/1.9(, 7(/9.3( or 70(/98( mg/kg/day.	

Systemic effects:

    NOAEL =  7 mg/kg/day

    LOAEL =   70 mg/kg/day based on decreased body weight. 

No evidence of carcinogenicity

870.6200a

Acute neurotoxicity screening battery	

45314201 (2000)

Acceptable/Guideline.

0, 0.1, 1 or 10 mg/kg/day.	

Systemic effects:

    NOAEL = 1 mg/kg/day

    LOAEL =  10 mg/kg/day based on multiple FOB findings and decreased
motor activity. 

Cholinesterase inhibition:

    NOAEL = 0.1 mg/kg/day

    LOAEL = 1 mg/kg/day based on whole blood, plasma and brain
cholinesterase inhibition.

870.6200b

Subchronic neurotoxicity screening battery	

45314202 (2002)

Acceptable/Guideline.

0, 0.6(/0.7(, 3.0(/3.5( or 18.4(/ 20.9( mg/kg/day. 	

Systemic:

    NOAEL = 3  mg/kg/day

    LOAEL = 18.4 mg/kg/day based on decreased body weight gains and food
consumption. 

Cholinesterase inhibition:

    NOAEL > 18.4 mg/kg/day in males and 20.9 mg/kg/day in females. 

870.6300

Special non-guideline comparative ChE inhibition study. 	

46618901 (2005)

Acceptable/Non-guideline.

0, 0.6, 1.5 or 3 mg/kg for definitive study.	

Systemic NOAEL > 3 mg/kg.

Cholinesterase: 

 RBC AChE: poor dose responses - possible inhibition at all doses. 

 Brain AChE: Inhibition at all doses in pups and adults.

LOAEL = 0.6 mg/kg.  NOAEL - not established. 

A BMD analysis was conducted (TXR #0053699, memo from P. Villanueva and
A. Lowit, December 15, 2005) and the BMDL10 of 0.065 mg/kg based on
female pup brain AChE inhibition data was established. 

870.7485

Metabolism and pharmacokinetics	

42684601, 42684602, 42684603,  42684604

and 42909701	

The absorption, excretion, distribution and characterization of the
metabolites has been described. 

870.7600

Dermal penetration	

No study available.  

Special studies	

No special studies required for reregistration. 



-Hazard Characterization.	

Toxicologically significant adverse effects.  Formetanate hydrochloride
is a carbamate insecticide belonging to a class of chemicals that
inhibits cholinesterase.  Exposure to formetanate hydrochloride resulted
in decreased plasma, whole blood and/or brain cholinesterase. 
Cholinesterase inhibition and related toxicity appears to be the only
manifestation of exposure in the variety of studies run to support
registration. The clinical signs following acute and chronic exposure to
formetanate HCl in rats and dogs are consistent with cholinesterase
inhibition. The clinical signs following acute exposure to formetanate
and at the time of peak effect included decreased motor activity, slight
to moderate tremors, slight to moderate ataxic gait, slight to extreme
incapacity, decreased arousal and rearing, pinpoint pupils, decreased
response to toe or tail pinch, salivation, altered visual placing after
vibrissae touch, altered startle response, decreased body temperature
and decreased forelimb grip strength.  Following subchronic and chronic
exposure to formetanate HCl the clinical signs in rats (decreased body
weight) and in dogs (excessive salivation, wheezing, labored breathing,
trembling, vomiting, coughing, and abnormal quietness) are consistent
with cholinesterase inhibition. 

A special study comparing the sensitivity of inhibition of RBC and brain
AChE  in 11 day old neonatal pups with young adult pups demonstrated
that, based mainly on brain data, the pups were more sensitive to the
inhibitory effects of formetanate than adults. 

The toxicity database for formetanate HCl  indicates that the magnitude
of ChEI does not increase with continued exposure because of the rapid
reversibility of ChEI. Generally, recovery of RBC AChEI and brain AChEI 
occurred within 8 to 24 hours following a single gavage dose of
formetanate. Therefore, chronic exposures to formetanate may be
considered as a series of acute exposures.

Dermal toxicity/Dermal absorption. A dermal toxicity study demonstrating
inhibition of whole blood and plasma ChE is available and was used for
route specific dermal exposure risk assessments. Although a dermal
absorption study for formetanate HCl is not available, a dermal
absorption factor is not necessary for the risk assessment because a
route specific dermal toxicity study is available.

Inhalation toxicity.   There is no subchronic inhalation toxicity study
available. An oral endpoint has to be used for inhalation risk
assessments until an appropriate inhalation study is provided. 100%
inhalation absorption relative to oral absorption is assumed for risk
assessment purposes.

Developmental and reproductive effects.   Rat and rabbit developmental
toxicity studies clearly showed maternal toxicity at dose levels lower
than dose levels showing any indications of fetal toxicity or
developmental effects. There were no indications of treatment related
developmental toxicity or reproductive effects in the rat
multi-generation reproduction study. In the rat multi- generation
reproduction study the LOAEL and NOAEL for both parental and
developmental toxicity were the same. There was no indication of
increased susceptibility in these studies. 

Mutagenicity and carcinogenicity.   There were no concerns for
mutagenicity based on a battery of mutagenicity studies.  There were no
indications of increased neoplastic tissue in either the rat or mouse
carcinogenicity studies. Formetanate HCl is classified as a Group
‘E’ carcinogen (no evidence of carcinogenicity) (6/27/89 HED
Reference Dose/Peer Review Committee).

Endocrine disruption and immunotoxicity.  There were also no obvious
effects on the immune or endocrine systems.  

Metabolism.  The metabolism and excretion of formetanate as well as the
identification of its metabolites in rats is considered characterized.
In the rat metabolism study, greater than 90% of the dose was recovered
in the urine within 24 hours and less than 10% was recovered in the
feces.  Intravenous dosing, repeated oral dosing or a high dose had no
significant effects on the disposition of formetanate.  Terminal
disposition of radioactivity demonstrated the highest levels in liver,
gastrointestinal tract, adrenals, fat, residual carcass and eyes.  In
most cases these organs had levels near the lower limit of detection. At
the low dose, the major metabolites were identified as conjugates of
3-formanidophenol, 3-acetamidophenol and
3-dimethylaminomethylene-aminophenol.  At the high dose, there appeared
to be alteration in the metabolic profile. A conjugate of 3-aminophenol
was identified as a major metabolite.  

Overall, the studies supporting the toxicity data base for formetanate
are considered adequate and there is confidence in the hazard and dose
response assessments. 

Incident Reports. A review of available incident reports on formetanate
hydrochloride has been completed (J. Blondell to C. Lang, dated August
1, 1997). Systemic poisoning has been reported in applicators who were
not properly protected and skin rashes have been reported in field
workers exposed to residues.  Based on the epidemiological review,
incident data do support the need for personal protective equipment for
those that handle formetanate HCl and reentry intervals for workers
returning to orchards or fields where this active ingredient has been
applied.

A  2003 review of the EPA Incident Data System showed no additional
incident reports since 1996.		

3.2 FQPA Considerations    

Special Sensitivity to Infants and Children

The HIARC previously concluded that there is no concern for pre-and/or
postnatal toxicity resulting from exposure to formetanate hydrochloride
(4/21/03). However,  a comparative cholinesterase assay (CCA) study in
neonates and adult rats has since been submitted, as required, in lieu
of a developmental neurotoxicity study (MRID#46618901).  The CCA
demonstrated that the pups were more sensitive to the inhibitory effects
of formetanate than the adults.  Thus, there is now a concern for
special sensitivity to infants and children.   

A. Determination of Susceptibility

The HIARC previously concluded that there was no quantitative or
qualitative increase in the susceptibility of young animals in either
the rat or rabbit developmental toxicity studies based on the following:
 In the rat multigeneration reproduction study, there was no indication
of a quantitative susceptibility.  However, there was a slight decrease
in the viability index (survival index PostNatal Day 1 to 21) in F2a and
F2b generations noted at the same dose as maternal toxicity.  In
particular,  the F2a generation had 87, 78, 82 and 74% survival on
lactation day 21 for the control, 10, 50 and 250 ppm dose groups
respectively.  Similarly, the F2b generation had 84, 73, 76 and 64%
survival indicating that the lowest survival was in the high dose group
in both generations.  

However, a recently submitted CCA study compared the inhibition of both
RBC and brain AChE in 11 day old pups and adults.  The pups were
demonstrated to be more sensitive than the adults based upon both the
extent of inhibition at the lowest dose tested and benchmark dose (BMD)
analysis. 

B. Degree of Concern Analysis and Residual Uncertainties	

Although some indication of an apparent qualitative susceptibility was
seen in the two-generation reproduction study, the concern for postnatal
toxicity based on this study is low and indicates no residual
uncertainties.   For example, the apparent decrease in viability index
is seen only in the F2 generations and not in the F1 generation; there
was maternal toxicity at the same dose; decreased viability was also
seen in the control, low, and mid dose groups that was only a little
less than in the high dose (i.e. the magnitude of the effect in the high
dose is small).  

There is, however, a concern for increased sensitivity to the inhibitory
effects of formetanate in pups relative to adults based on the CCA
study.  

C.  Hazard-based Special FQPA Safety Factors

The HIARC (5/21/03) determined that the hazard-based special FQPA
safety factor can be reduced to 1X because of a lack of concern and no
residual uncertainties for pre- and post-natal toxicity.  However, a
comparative ChE inhibition study was subsequently performed and
benchmark dose (BMD) estimates were calculated from the submitted data
(TXR 0053699, D323943, 12/14/05). The results demonstrated that the pups
were more sensitive than the adults to the inhibitory effects of
formetanate.   In particular, based on the BMD for inhibition of brain
AChE, the male pups are approximately 2.7 times more sensitive than the
male adults and the female pups are approximately 5 times more sensitive
than the female adults.  Using the BMDL10 values, the male pups are
approximately 2.4 times more sensitive than the male adults and female
pups are approximately 4.77 times more sensitive than the female adults.
 A special FQPA safety factor of 1X is appropriate for use in
formetanate risk assessment scenarios where the endpoint and dose is
based on female pup brain AChE inhibition data. However, in those
residential (non-occupational) scenarios where it is more appropriate to
use a toxicity endpoint from a route-specific study performed on adult
animals (i.e. dermal toxicity study) versus using the BMDL10 value based
on the effects of oral dosing on AChE in the female pup brain, an
additional special FQPA safety factor would need to be applied.  Since
the current acute and chronic dietary dose and endpoints are based on
the BMDL10 and there are no residential uses of formetanate HCl, there
are presently no risk assessment scenarios requiring a special FQPA
factor greater than 1X.

Database Uncertainty Factor

The HIARC concluded that there is not a concern for developmental
neurotoxicity per se resulting from exposure to formetanate
hydrochloride. Therefore, a series 870.6300 developmental neurotoxicity
study is not required.  This decision was based on the following
considerations:

there was no developmental toxicity at the highest doses tested in the
rat and rabbit studies;

the effects (decrease in pup viability) in the two-generation
reproduction study were marginal and were seen in the presence of
maternal toxicity at a dose (LOAEL = 23 mg/kg/day) that causes blood
cholinesterase inhibition; and 

the behavioral effects in adult animals in the acute neurotoxicity study
were seen at a dose 10-fold higher than the dose where cholinesterase
inhibition occurred indicating that the behavioral effects in pups
measured in the DNT may also occur at higher doses than cholinesterase
inhibition [i.e., the DNT would not be testing the most sensitive
endpoint (ChEI)]. 

Formetanate hydrochloride, a carbamate, has been demonstrated to be an
inhibitor of cholinesterase and at higher doses to demonstrate signs of
toxicity related to cholinesterase inhibition.  Thus, based on structure
activity relationships and the demonstration of toxicity related to
cholinesterase inhibition a comparative ChE inhibition study was
requested.  This study was conducted and reviewed and determined to be
Acceptable/Non-Guideline and to satisfy the HED’s request for this
comparative analysis for potential inhibition in pups and adults. Since
the study was classified as Acceptable/Non-Guideline, and to satisfy the
HED’s request for the study, the 10X database uncertainty factor is
removed.  



3.3 Dose-Response Assessment

Table 3.3.1. Summary of Toxicological Endpoints Selected for Formetanate
Hydrochloride  

Exposure

Scenario	

Dose 

UF /MOE	

Hazard Based Special FQPA Safety Factor	

Endpoint for Risk Assessment

Dietary Risk Assessments

Acute Dietary

females 13-50 years of age	

	Not applicable; the endpoint selected for the general population (see
below) will include this population subgroup. 

Acute Dietary

general population 	

BMDL110 = 0.065 mg/kg

UF = 100 (a)

aRfD = 0.00065 mg/kg	

	1 X

Acute PAD = 0.00065 mg/kg.	

BMDL10 for female pup brain AChE in the  Comparative ChE study.  The 
FQPA SF is reduced to 1X because an endpoint based on the most sensitive
effect in the most sensitive population was used.

Chronic Dietary

	

BMDL110 = 0.065 mg/kg

UF = 100 (a)

cRFD = 0.00065 mg/kg	

	1 X

Chronic PAD = 0.00065 mg/kg.	

BMDL10 for female pup brain AChE in the  Comparative ChE study. The 
FQPA SF is reduced to 1X because an endpoint based on the most sensitive
effect in the most sensitive population was used.

Incidental Oral

Short and intermediate terms	

Not applicable.  There are no current registrations for residential
uses.  		

(Occupational) Non-Dietary Risk Assessments (b)

Dermal - Occupational

Short-Term 

(1 - 30 days)	

Dermal NOAEL= 

       10 mg/kg

	MOE = 100 (a)	

	1 X	

Special single dose time to peak effect dermal application study (2000,
MRID # 45311901).

LOAEL = 20 mg/kg based on whole blood cholinesterase inhibition. 

Dermal - Occupational 

Intermediate-Term 

(1 - 6 Months)	

Dermal NOAEL= 

       10 mg/kg

	MOE - 100 (a)	

	1 X	

Special single dose time to peak effect dermal application study (2000,
MRID # 45311901).

LOAEL = 20 mg/kg based on whole blood cholinesterase inhibition. 

Dermal - occupational

Long-Term 

(> 6 Months)	

Dermal NOAEL=       10 mg/kg

	MOE = 100 (a)	

	1 X	

Special single dose time to peak effect dermal application study (2000,
MRID # 45311901).

LOAEL = 20 mg/kg based on whole blood cholinesterase inhibition. 

Inhalation (c) - occupational 

Short-Term 

(1 - 30 days)	

Oral NOAEL =            0.1 mg/kg 

	MOE = 100 (a)	

	1 X	

Acute Neurotoxicity Screen (2000, MRID # 45314201) 

LOAEL = 1 mg/kg based on plasma, whole blood and brain cholinesterase
inhibition. 

Inhalation (c)- occupational

Intermediate-Term  

(1 - 6 Months)	

Oral NOAEL =           0.1 mg/kg 

	MOE = 100(a)

	

	1 X	

Acute Neurotoxicity Screen (2000, MRID # 45314201) 

LOAEL = 1 mg/kg based on plasma, whole blood and brain cholinesterase
inhibition. 

Inhalation (c) - occupational 

Long-Term 

(>6 Months)	

Oral NOAEL  =          0.1 mg/kg 

	MOE = 100(a)	

	1 X	

Acute Neurotoxicity Screen (2000, MRID # 45314201) 

LOAEL = 1 mg/kg based on plasma, whole blood and brain cholinesterase
inhibition. 

Cancer 	

Classification:  "Not likely".   Q1* = N/A

(a)   Based on 10X for interspecis extrapolation and 10X for
intraspecies variability

(b)There are no registered residential uses of formetante HCl. 
Endpoints were selected for    occupational exposure only.  

(c)   Absorption via the inhalation route is presumed to be equivalent
to oral absorption.



-Endpoint Selection Rationale and Discussion. 

Dose-response modeling (i.e. benchmark dose, or BMD, analysis)  is
preferred over the use of NOAEL/LOAELs 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).  In
order to evaluate the appropriate point of departure (PoD) for ChEI, EPA
performed a benchmark dose analysis (TXR No. 0053699)   ChEI data from
the comparative ChE study (2005, MRID No.: 46618901) with formetanate in
neonates and adult rats were analyzed.  

The estimated dose at which 10% ChE inhibition  is observed (BMD10) and
the lower 95% confidence interval (BMDL10) were estimated by fitting the
ChE data to an exponential dose-response model using generalized
nonlinear least squares.  The BMDL10 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. 
The exponential model was used in the Preliminary OP Cumulative Risk
Assessment (USEPA, 2001) to determine relative potency factors and
points of departure.  The exponential model and statistical methods used
to calculated the BMD10s and BMDL10s have been supported by the FIFRA
Science Advisory Panel (FIFRA, 2002) for analysis of ChE inhibition data
similar to that of OPs and N-methyl carbamates, including formetanate. 
Technical description of the statistical methods can be found in the
cumulative hazard assessment of the Preliminary OP Cumulative Risk
Assessment (USEPA, 2001).  Model fits and model parameters specific to
this analysis can be found in the memo from P. Villanueva and A. Lowit
dated December 15, 2005 (TXR No.: 0053699). 

The BMD analysis indicates that for single oral gavage dosing of
formetante HCl based on the comparative ChE study in neonatal and adult
rats, brain ChE inhibition is the more sensitive endpoint compared to
red blood cell (RBC) ChE, female pups are more sensitive than male pups
and male and female adults, and the 10% inhibition of ChE is the
appropriate benchmark response to consider. 

For formetanate endpoint selection, the BMDL10 from female pup brain
AChE inhibition data from the comparative ChE study was selected for
establishing the acute oral and chronic oral exposure endpoints and
doses.  This selection is justified because the BMDL10 would protect
against potential toxicity occurring at higher doses and for longer
exposures. The toxicity database for formetanate HCl  indicates that the
magnitude of ChEI does not increase with continued exposure because of
the rapid reversibility of ChEI. Generally, recovery of RBC and brain
AChEI occurred within 8 to 24 hours following a single gavage dose of
formetanate. Therefore, chronic exposures to formetanate could be
considered as a series of acute exposures. While this indicates that
neither a chronic dietary exposure assessment nor an intermediate -term
occupational assessment may be necessary, the risk assessment team has
provided these endpoints and exposure assessments for informational
purposes.

The CCA study indicated that there was inhibition of brain AChE at all
doses and that the female pup brain AChE data resulted in the lowest
BMDL10 (benchmark dose lower limit) of 0.065 mg/kg.   This dose and
endpoint was  selected for the oral exposure scenarios.   Since this
value was based on pup data (oral endpoint based on the most sensitive
effect in the most sensitive population was used ) a special FQPA safety
factor of 1X is appropriate for risk assessment purposes when this value
is used.   

The risk assessment team determined that the route-specific dermal
toxicity study is the most appropriate study for selecting the dose and
endpoint for dermal occupational risk assessments. The LOAEL is 20 mg/kg
based on consistent decrease of whole blood cholinesterase in males of
12 to 18%.  The NOAEL is 10 mg/kg. 

There are no inhalation toxicity studies available that assess for
cholinesterase inhibition. The risk assessment team determined that the
occupational inhalation risk endpoint should be retained from the acute
neurotoxicity study since there was no appropriate route-specific study
available. The LOAEL from the acute neurotoxicity study is 1 mg/kg base
on cholinesterase inhibition (whole blood, plasma, and brain). The
resulting NOAEL of 0.1 mg/kg is not much different from the BMDL10 of
0.065 mg/kg and is appropriate for use in occupational risk assessments
as it is derived from a study using adult animals.  Since an oral
endpoint was selected, absorption via inhalation is assumed to be
equivalent to oral absorption. Risk assessments for dermal and
inhalation occupational scenarios only are being presented as there are
no currently registered residential uses of formetanate HCl.  

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 scientific
bases 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 formetanate HCl, there was no evidence of endocrine disruptor
effects.  When additional appropriate screening and/or testing protocols
being considered under the Agency’s EDSP have been developed,
formetanate HCl may be subjected to further screening and/or testing to
better characterize effects related to endocrine disruption.

4.0 Exposure Assessment

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

Formetanate hydrochloride {m-[[(dimethylamino)methylene]amino]phenyl
methylcarbamate hydrochloride} is a carbamate miticide/insecticide used
on a variety of orchard fruits and alfalfa grown for seed. The 92%
wettable powder formulation (Carzol® SP) contains formetanate HCl as
the sole active ingredient (ai) and is registered for foliar or dormant
applications using ground or aerial equipment. There are no registered
residential uses.

According to the aformentioned 10/99 MOA, formetanate HCl may be applied
once to apple, pear, peach, nectarine, orange, grapefruit, lemon, lime,
tangerine and tangelo at a maximum seasonal application rate of 1.15 lb
a.i./A. Use is prohibited in Florida.

Formetanate HCl may not usually be applied to apple and pear after
bloom. However, a late season application may be made to control stink
bugs, lygus bugs, and pear rust mites in CA, OR, WA, and ID, upon
written approval on a case-by-case basis by the State agency responsible
for enforcement of FIFRA, or authorized by that State agency.

Formetanate HCl may not be applied to peach and nectarine after shuck
fall (i.e. when all flower parts, shucks, have fallen from the newly
formed fruit) .

For orange, lemon, lime, grapefruit, tangelo and tangerine, formetanate
HCl may usually not be applied after fruit reach one inch in diameter.
However, formetanate HCl may be applied to overcropped  grapefruit and
Valencia oranges above one inch in diameter, provided that a preharvest
interval ("PHI") of 30 days is observed. A 60 day PHI is required for
lemons (AZ).

 Formetanate HCl may be applied to alfalfa grown for seed at a maximum
rate of 0.92 lb a.i./A with a 21 day preharvest interval.

4.2 Dietary Exposure/Risk Pathway

4.2.1 Residue Profile tc \l3 "4.2.1 Residue Profile 

Tolerances are established for residues of formetanate hydrochloride per
se in or on apple; pear; peach; nectarine; orange; lemon; lime;
grapefruit; tangerine; and  plum, prune, fresh [40CFR 180.276].
According to the 10/99 MOA, the only food/feed uses allowed are those on
apple, pear, peach, nectarine, orange, lemon, lime, grapefruit, tangelo,
tangerine, and alfalfa grown for seed. Formetanate HCl tolerances are
reassessed in this document for the permitted food/feed uses (Table
8.1). The tolerances were reassessed based on limited field trial data
performed at the required  reduced rate and increased PHIs. In general
the field trial data did not satisfy the requirements for number of
field trials (see D324543, 12/14/05, D.Drew for deficiencies). At such
time as the additional field trials are received and deemed adequate,
the reassessed tolerances will be reevaluated.

The nature of the residue of formetanate HCl in livestock and plants
has been adequately delineated. Parent formetanate was not identified in
the ruminant and poultry metabolism studies.  The two
cholinesterase-inhibiting metabolites (3-formamidophenyl methylcarbamate
[SN 35902] and 3-aminophenyl methylcarbamate [SN 38075]) found in dairy
milk, liver, and kidney have been determined to be not of significant
toxicological concern as a result of an in vitro study. The study found
that these metabolites were 86 and 48 times less potent as
cholinesterase inhibitors than parent formetanate. These findings, along
with the fact that these two metabolites are found in rats and thus
their toxicity is assessed when the parent compound is assessed,
indicate that the tolerance expression does not need to include these
metabolites (J.Doherty, 12/10/98, DP: D249197; MARC Decisions 1/12/99,
D252123 and 3/15/99, D254395). Therefore, no tolerances are required for
formetanate hydrochloride and its metabolites for  milk and the fat,
meat, and meat byproducts of cattle, goats, horses, and sheep. No
formetanate HCl tolerances are required for poultry or hog commodities
as there are no registered uses on poultry or swine feed items.

An adequate method is available for data collection in livestock
commodities.  This method is similar to Method I of PAM (Pesticide
Analytical Manual) Vol. II. Because tolerances for livestock commodities
are not required, the registrant is not required at this time to submit
an independent laboratory validation of this method. 

The results of the alfalfa, lemon, and orange seedling metabolism
studies indicate that the metabolic pathway in plants is similar with
resulting metabolites containing the formamidine moiety. Formetanate HCl
was the only compound identified in the extractable radioactivity in/on
peaches.  The majority of the terminal residue in plants consists mainly
of parent compound. The majority of formetanate residues appear on the
surface (peel) of fruit. Parent formetanate HCl is the residue of
concern to be included in the tolerance expression and the dietary risk
assessment. 

An adequate method is available for tolerance enforcement for plant
commodities.  The gas chromatography/electron capture detection (GC/ECD)
Method I is listed in the PAM Vol. II and involves hydrolysis of
residues to 3-aminophenol and, therefore, determines residues of
formetanate HCl and all metabolites convertible to 3-aminophenol.

An adequate method for data collection for plant commodities has been
submitted by the registrant. The high performance liquid chromatography
(HPLC) method determines residues of the parent compound formetanate
only. An independent laboratory validation (ILV) of the method was also
submitted and found adequate. If the registrant proposes that this be a
new enforcement method then the method should be radiovalidated and an
Agency method validation should be performed.

USDA’s Pesticide Data Program (PDP), at HED’s request, collected
and analyzed oranges, apples and nectarines for residues of formetanate
HCl in 2000 and 2001; and HED used the 2001 data in its previous 2003
dietary exposure assessment.  Although these data were collected after
the 10/99 MOA which mandated lower application rates and longer PHIs,
the registrant argued that the PDP data did not reflect these label
changes, since most of the formetanate HCl product in the channels of
trade at the time still bore labeling with the previously approved rates
and PHIs.  Therefore, the registrant recommended that field trial data
reflecting current label rates and PHIs be used to assess dietary
exposure.  HED considered the registrant’s arguments and agreed to
reassess dietary exposure using the available field trial data. 

4.2.2  Acute and Chronic Dietary Exposure Assessments

Acute probabilistic and chronic dietary risk assessments were conducted
using the Dietary Exposure Evaluation Model (DEEM-FCID, Version 2.03),
which uses food consumption data from the USDA’s Continuing Surveys of
Food Intakes by Individuals (CSFII) from 1994-1996 and 1998. 

Food Residues:

Anticipated residues for formetanate HCl in foods were derived in
accordance with established Agency policies and guidance for chronic and
acute dietary exposure assessments.  Chronic anticipated residues were
generally based on the mean residue from field trials conducted at the
maximum label rate and minimum PHI with appropriate adjustments for
percent crop treated and residue concentration/reduction from
processing.  For the acute assessment, residue distribution files (RDFs)
were generated based on field trial data and maximum percent crop
treated information.  A certain number of “zero” residue values were
included to account for the untreated portion of the crop, and residues
equal to ½ the method Limit of Quantitation (LOQ) were assigned to
field trial samples with no detectable residues in accordance with
guidance in HED SOP 99.6 (Classification of Food Forms with Respect to
Level of Blending (8/20/99)).  Percent crop treated (%CT) data were
provided by the Biological and Economic Analysis Division (Screening
Level Usage Analysis (SLUA), 11/17/05; as modified by the email
communication from Jihad Alsadek to Danette Drew, 11/21/05).  %CT
estimates were based on national data for all crops, except nectarines. 
The estimate for nectarines was based on recent (2003) California data,
since 99% of U.S. nectarines are grown in California and the older
(1997) national data were not considered to reflect current usage.

Formetanate HCl is generally applied to fruit trees as an early season
treatment (i.e., before petal fall on apples, pears, peaches and
nectarines; and before citrus fruit reaches one inch in diameter). 
However, late season uses are permitted on apples, pears, Valencia
oranges and grapefruit as follows:  On apples and pears, a second, later
season, application may be made to control stink bugs, lygus bugs and
pear rust mites in CA, OR, WA and ID with prior State approval.  No PHI
is specified for this late season use.  On grapefruit and Valencia
oranges, if unharvested fruit are present from the previous crop, an
application may be made to the new crop, provided a 30-day PHI is
observed for the unharvested crop.  Field trial data reflecting these
late season uses showed considerably higher residues than those
reflecting only early season uses.  To assess the impact of the
late-season uses on dietary exposure, separate acute and chronic
assessments were conducted - one based on late-season field trial data
and one based on early-season field trial results only.  Both
assessments were conducted for food alone and for food plus drinking
water.

Data Translation:

Field trial and %CT data were available for apples, pears, peaches,
nectarines, oranges, grapefruit and lemons.  The data for lemons were
translated to both limes and tangerines, based on fruit size
similarities.  Because residues are found primarily on the surface of
fruits, size (i.e., surface-to-volume ratio) was considered more
important than taxonomic similarity within the citrus group for the
purposes of  residue data translation.

Analytical Methods and LOQs Used in the Assessments:

Two analytical methods were used to determine residues in/on collected
field trial samples.  One method (HPLC/UV) is a single analyte method
which measured only parent formetanate HCl; the other method (GC/ECD) is
a common moiety method, slightly modified from PAM Volume II enforcement
Method I, which measured parent and several metabolites convertible to
3-aminophenol.  The LOQ of the single analyte method is 0.1 ppm for
nectarines and 0.03 ppm for apples, pears, peaches and citrus.  The LOQ
of the common moiety method is 0.02 ppm for all crops.  In cases where
residues were non-detectable using both methods, HED assigned the sample
a residue value equal to ½ the LOQ of the common moiety method
(0.01ppm), based on the conclusion that residues of parent formetanate
could not be any greater than the combined residues of parent and its
metabolites.  In cases where residues were non-detectable using the
single analyte method but detectable using the common moiety method, HED
assigned the sample a residue value equal to ½ the LOQ of the single
analyte method (0.05ppm for nectarines and 0.015 ppm for other crops),
since the residue of concern consists of parent formetanate HCl only.

Processing Factors:

Processing data indicate that residues in apple juice are reduced by a
factor of 0.31x compared to fresh apples (MRID 00077702, memo 8/13/70,
PP0F0961).  This factor was applied to both apple and pear juice. 
Similarly, a processing factor of 0.03x, based on a citrus processing
study (MRID 00077702), was applied to grapefruit, lemon, orange, lime
and tangerine juice in the acute and chronic assessments.  A 40x
concentration factor for citrus peel was calculated from the same study.
 DEEM default processing factors of 8x for dried apples, 6.25x for dried
pears and 7x for dried peaches were assumed in the absence of processing
data for these commodities. 

Drinking Water Residues:  Reference:  Revised Tier II Drinking Water
Assessment for Formetanate HCL; DP Barcode 289182; Ibrahim Abdel-Saheb;
03/27/03)		

The Tier II screening models PRZM and EXAMS with the Index Reservoir
and Percent Crop Area adjustment (IR-PCA PRZM/EXAMS) were used to
determine estimated surface water concentrations of formetanate HCL. 
Modeling results were provided for three crop scenarios-apples grown in
North Carolina, Pennsylvania and Oregon.  

Since the NC apple scenario resulted in the highest estimated peak
concentration in surface water (7.67 ppb), HED selected this scenario
for the acute analysis.  Rough, preliminary calculations indicated that
water exposure would likely exceed HED’s level of concern for acute
exposure; therefore, HED asked EFED to provide the entire distribution
of estimated daily exposure values from the PRZM-EXAMS run for this
worst-case crop scenario.  This distribution was then incorporated in
the acute probabilistic exposure analyses.

For the chronic assessment, HED selected the highest annual mean EEC for
surface water based on the PA apple crop scenario (0.08 ppb) and
incorporated it as a point estimate in the chronic analyses.

EFED’s drinking water assessment is discussed in more detail below in
section 4.3 (“Water Exposure/Risk Pathway”).



4.2.3 Acute Dietary Assessment Results

Results in Tables 4.2.3.1 (food + water, including late season uses),
4.2.3.2 (food + water, without late season uses), 4.2.3.3 (food only,
including late season uses), 4.2.3.4 (food only, without late season
uses) and 4.2.3.5 (water only) are reported at the 95th, 99th and 99.9th
percentiles of exposure.

The acute dietary exposure estimates for food and water exceed HED’s
level of concern for the U.S. population and all reported population
subgroups at the 99.9th percentile of exposure.  Formetanate acute
dietary exposure (food + water) at the 99.9th percentile was estimated
at 0.005424 mg/kg/day for the U.S. population (830% of the aPAD) and
0.016665 mg/kg/day (2600% of the aPAD) for the most highly exposed
population subgroup (infants).  Most of the estimated acute exposure was
determined to result from the late season uses of formetanate
hydrochloride on apples, pears, oranges and grapefruit (particularly
apples, and to a lesser extent, pears).  When the late season uses are
excluded from the assessment, estimated dietary exposure (food + water)
is below HED’s level of concern for the U.S. population (32% of the
aPAD) and all population subgroups, except infants, whose estimated
exposure represents 110% of the aPAD.  Drinking water is the largest
contributor to overall dietary exposure when late season uses are
excluded.  A separate analysis of acute exposure to formetanate
hydrochloride from drinking water alone resulted in exposure estimates
equivalent to 28% of the aPAD for the overall U.S. population and 110%
of the aPAD for infants. 

Analyses were also conducted for food alone (with and without late
season uses).  Estimated exposure to formetanate hydrochloride at the
99.9th percentile from food alone exceeds HED’s level of concern for
all populations when the late season uses are included (840% of the aPAD
for the U.S. population and 2600% of the aPAD for infants) but is below
HED’s level of concern for all populations when they are excluded from
consideration (17% and 41% of the aPAD for the U.S. population and
infants, respectively).

At the 99th percentile, estimated exposure due to the late season uses
of formetanate HCl still exceeds HED’s level of concern for the U.S.
population and all infants’ and children’s subgroups.  Estimated
combined food and drinking water exposure is below HED’s level of
concern for all populations when the late season uses are excluded. 
Estimated exposure from all food uses (including late season uses) and
drinking water is below HED’s level of concern at the 95th percentile
of exposure. 



Table 4.2.3.1  Results of Acute Dietary Exposure Analysis: Food + Water,
Including Late Season Uses on Apples, Pears, Oranges and Grapefruit

Population Subgroup	

aPAD (mg/kg/day)	

95th Percentile	

99th Percentile	

99.9th Percentile

Exposure (mg/kg/day)	

% aPAD	

Exposure (mg/kg/day)	

% aPAD	

Exposure (mg/kg/day)	

% aPAD

General U.S. Population	

0.00065	

0.000014	

2.1	

0.000820	

130	

0.005424	

830

All Infants (< 1 year old)

0.000067	

10	

0.006212	

960	

0.016665	

2600

Children 1-2 years old

0.000111	

17	

0.005861	

900	

0.013953	

2100

Children 3-5 years old

0.000073	

11	

0.004433	

680	

0.010942	

1700

Children 6-12 years old

0.000031	

4.7	

0.001892	

290	

0.005939	

910

Youth 13-19 years old

0.000008	

1.3	

0.000182	

28	

0.002722	

420

Adults 20-49 years old

0.000008	

1.2	

0.000222	

34	

0.002329	

360

Females 13-49 years old

0.000010	

1.5	

0.000232	

36	

0.002596	

400

Adults 50+ years old

0.000014	

2.2	

0.000631	

97	

0.002560	

390

Table 4.2.3.2  Results of Acute Dietary Exposure Analysis: Food + Water,
Without Late Season Uses on Apples, Pears, Oranges and Grapefruit

Population Subgroup	

aPAD (mg/kg/day)	

95th Percentile	

99th Percentile	

99.9th Percentile

Exposure (mg/kg/day)	

% aPAD	

Exposure (mg/kg/day)	

% aPAD	

Exposure (mg/kg/day)	

% aPAD

General U.S. Population	

0.00065	

0.000002	

0.28	

0.000045	

6.9	

0.000209	

32

All Infants (< 1 year old)

0.000014	

2.2	

0.000146	

23	

0.000706	

110

Children 1-2 years old

0.000018	

2.7	

0.000120	

19	

0.000355	

55

Children 3-5 years old

0.000010	

1.6	

0.000101	

16	

0.000345	

53

Children 6-12 years old

0.000003	

0.48	

0.000058	

8.9	

0.000232	

36

Youth 13-19 years old

0.000001	

0.12	

0.000027	

4.2	

0.000142	

22

Adults 20-49 years old

0.000001	

0.18	

0.000032	

5.0	

0.000180	

28

Females 13-49 years old

0.000001	

0.19	

0.000033	

5.1	

0.000177	

27

Adults 50+ years old

0.000003	

0.39	

0.000036	

5.5	

0.000184	

.28



Table 4.2.3.3  Results of Acute Dietary Exposure Analysis: Food Only,
Including Late Season Uses on Apples, Pears, Oranges and Grapefruit

Population Subgroup	

aPAD (mg/kg/day)	

95th Percentile	

99th Percentile	

99.9th Percentile

Exposure (mg/kg/day)	

% aPAD	

Exposure (mg/kg/day)	

% aPAD	

Exposure (mg/kg/day)	

% aPAD

General U.S. Population	

0.00065	

0.000008	

1.3	

0.000826	

130	

0.005461	

840

All Infants (< 1 year old)

0.000045	

7.0	

0.006121	

940	

0.016725	

2600

Children 1-2 years old

0.000091	

14	

0.005918	

910	

0.013976	

2200

Children 3-5 years old

0.000055	

8.5	

0.004421	

680	

0.010859	

1700

Children 6-12 years old

0.000021	

3.2	

0.001917	

290	

0.005970	

920

Youth 13-19 years old

0.000004	

0.66	

0.000159	

24	

0.002724	

420

Adults 20-49 years old

0.000004	

0.55	

0.000160	

25	

0.002312	

360

Females 13-49 years old

0.000004	

0.64	

0.000182	

28	

0.002575	

400

Adults 50+ years old

0.000006	

0.95	

0.000628	

97	

0.002568	

400

Table 4.2.3.4  Results of Acute Dietary Exposure Analysis: Food Only,
Without Late Season Uses on Apples, Pears, Oranges and Grapefruit

Population Subgroup	

aPAD (mg/kg/day)	

95th Percentile	

99th Percentile	

99.9th Percentile

Exposure (mg/kg/day)	

% aPAD	

Exposure (mg/kg/day)	

% aPAD	

Exposure (mg/kg/day)	

% aPAD

General U.S. Population	

0.00065	

0.000000	

0.04	

0.000023	

3.5	

0.000113	

17

All Infants (< 1 year old)

0.000001	

0.13	

0.000104	

16	

0.000266	

41

Children 1-2 years old

0.000004	

0.68	

0.000100	

15	

0.000243	

37

Children 3-5 years old

0.000002	

0.26	

0.000080	

12	

0.000219	

34

Children 6-12 years old

0.000001	

0.09	

0.000039	

6.0	

0.000126	

19

Youth 13-19 years old

0.000000	

0.02	

0.000010	

1.5	

0.000051	

7.8

Adults 20-49 years old

0.000000	

0.02	

0.000016	

2.5	

0.000069	

11

Females 13-49 years old

0.000000	

0.03	

0.000019	

2.9	

0.000082	

13

Adults 50+ years old

0.000000	

0.05	

0.000020	

3.1	

0.000067	

10



Table 4.2.3.5  Results of Acute Dietary Exposure Analysis: Water Only,
Based on NC Apple Crop Scenario

Population Subgroup	

aPAD (mg/kg/day)	

95th Percentile	

99th Percentile	

99.9th Percentile

Exposure (mg/kg/day)	

% aPAD	

Exposure (mg/kg/day)	

% aPAD	

Exposure (mg/kg/day)	

% aPAD

General U.S. Population	

0.00065	

0.000000	

0.01	

0.000017	

2.7	

0.000184	

28

All Infants (< 1 year old)

0.000000	

0.02	

0.000045	

6.9	

0.000687	

110

Children 1-2 years old

0.000000	

0.01	

0.000025	

3.8	

0.000289	

44

Children 3-5 years old

0.000000	

0.01	

0.000024	

3.7	

0.000261	

40

Children 6-12 years old

0.000000	

0.01	

0.000016	

2.5	

0.000183	

28

Youth 13-19 years old

0.000000	

0.01	

0.000011	

1.8	

0.000136	

21

Adults 20-49 years old

0.000000	

0.01	

0.000017	

2.6	

0.000173	

27

Females 13-49 years old

0.000000	

0.01	

0.000016	

2.5	

0.000173	

27

Adults 50+ years old

0.000000	

0.01	

0.000019	

2.9	

0.000173	

27

A Critical Exposure Contribution (CEC) Analysis was conducted to
determine the foods contributing most heavily to acute exposure at the
99.9th percentile of exposure.  Table 4.2.3.6 below summarizes the
results of this analysis.  Note that this analysis considered all food
uses, including the late season uses on apples, pears, oranges and
grapefruit.

Table 4.2.3.6.  Major Food Contributors to Formetanate HCl Acute
Exposure at the 99.9th Percentile (The numbers in parentheses indicate
the food’s approximate contribution as a percent of total exposure.)

U.S. Population	

All Infants1	

Children, 1-2 Years Old

Apples (84)	

Apples (74)	

Apples (85)

Pears (14)	

Pears (25.6)	

Pears (15)

Oranges (1.7)	

Oranges (0.05)	

Oranges (0.13)

Drinking Water (0.03)	

Drinking Water (0.01)	

1The population subgroup with the highest estimated acute dietary
exposure.

The results of the CEC analysis indicate that most of the estimated
acute dietary exposure is due to the late season uses on apples and, to
a lesser extent, pears.

4.2.4 Chronic Dietary Assessment Results					

Chronic dietary exposure estimates are below HED’s level of concern
for the U.S. population and all population subgroups.  Formetanate
hydrochloride mean dietary exposure (food + water) is estimated at
0.000032 mg/kg/day for the U.S. population (4.9% of the cPAD) and
0.000180 mg/kg/day (28% of the cPAD) for the most highly exposed
population subgroup (infants, <1 yr. old).  When late season uses on
apples, pears, oranges and grapefruit are excluded, estimated chronic
dietary exposure represents less than 1% of the cPAD for the U.S.
population and all population subgroups, except infants, whose estimated
exposure represents 1.3% of the cPAD.  Chronic dietary exposure from
drinking water alone is estimated to be less than 1% of the cPAD for all
populations.

The results of the chronic dietary exposure assessment are presented
below in Tables 4.2.4.1 and 4.2.4.2.

Table 4.2.4.1.  Results of Chronic Dietary Exposure Analysis for Food
(including Late Season Uses) and Drinking Water

Population Subgroup	

cPAD

(mg/kg/day)	

Food	

Drinking Water	

Food + Drinking Water

Exposure

(mg/kg/day)	

% cPAD	

Exposure

(mg/kg/day)	

% cPAD	

Exposure

(mg/kg/day)	

% cPAD

General U.S. Population	

0.00065	

0.000030	

4.7	

0.000002	

0.3	

0.000032	

4.9

All Infants (< 1 year old)

0.000174	

27	

0.000006	

0.9	

0.000180	

28

Children 1-2 years old

0.000171	

26	

0.000003	

0.4	

0.000173	

27

Children 3-5 years old

0.000119	

18	

0.000002	

0.4	

0.000121	

19

Children 6-12 years old

0.000050	

7.7	

0.000002	

0.2	

0.000052	

8.0

Youth 13-19 years old

0.000014	

2.2	

0.000001	

0.2	

0.000016	

2.4

Adults 20-49 years old

0.000013	

1.9	

0.000002	

0.2	

0.000014	

2.2

Females 13-49 years old

0.000014	

2.2	

0.000002	

0.2	

0.000016	

2.4

Adults 50+ years old

0.000018	

2.8	

0.000002	

0.3	

0.000020	

3.0



Table 4.2.4.2.  Results of Chronic Dietary Exposure Analysis for Food
(without Late Season Uses) and Drinking Water

Population Subgroup	

cPAD

(mg/kg/day)	

Food	

Drinking Water	

Food + Drinking Water

Exposure

(mg/kg/day)	

% cPAD	

Exposure

(mg/kg/day)	

% cPAD	

Exposure

(mg/kg/day)	

% cPAD

General U.S. Population	

0.00065	

0.000001	

0.1	

0.000002	

0.3	

0.000002	

0.4

All Infants (< 1 year old)

0.000003	

0.5	

0.000006	

0.9	

0.000009	

1.3

Children 1-2 years old

0.000003	

0.5	

0.000003	

0.4	

0.000006	

0.9

Children 3-5 years old

0.000002	

0.4	

0.000002	

0.4	

0.000005	

0.7

Children 6-12 years old

0.000001	

0.2	

0.000002	

0.2	

0.000003	

0.4

Youth 13-19 years old

0.000000	

0.0	

0.000001	

0.2	

0.000002	

0.2

Adults 20-49 years old

0.000000	

0.1	

0.000002	

0.2	

0.000002	

0.3

Females 13-49 years old

0.000000	

0.1	

0.000002	

0.2	

0.000002	

0.3

Adults 50+ years old

0.000001	

0.1	

0.000002	

0.3	

0.000002	

0.3

4.2.5 Cancer Dietary

Formetanate HCl has been classified a Group “E” carcinogen (no
evidence of carcinogenicity). As such, a cancer dietary risk assessment
is not warranted.

4.2.6  Dietary Exposure Assessment - Discussion of Uncertainties 

This dietary assessment for formetanate HCl includes estimated exposure
from food and drinking water.  A characterization of the uncertainties
for each of these components is provided separately below:

Food:

The assessment for food incorporates partially refined anticipated
residue estimates for all commodities that were derived from field trial
data adjusted to account for the percent crop treated and, in some
cases, reduction/concentration during processing.  Although the field
trial data are limited in terms of the number of trials and residue
samples, it is still likely that these data result in overestimates of
dietary exposure to formetanate, since they reflect maximum, rather than
typical, usage.  The availability and use of monitoring data reflecting
current use patterns and/or additional residue processing information
(cooking, peeling, etc.) would have resulted in a more refined estimate
of dietary exposure.	

Percent crop treated data were provided by BEAD for all commodities. 
The %CT estimates are screening level estimates.  More refined %CT
estimates would result in more refined estimates of dietary exposure.

Drinking Water:

1.	Actual monitoring data are not available to estimate residues of
formetanate HCl in drinking water.  The availability and use of
monitoring data would have resulted in a more refined estimate of
drinking water exposure to formetanate HCl.  

2.	PRZM-EXAMS surface water modeling data were used probabilistically in
the acute analysis and deterministically in the chronic analysis.  The
estimates were partially refined in that they took into consideration
crop-specific percent cropped area (PCA).  Although the PRZM-EXAMS
models provide more refined estimates of surface water residues than the
Tier 1 FIRST model, the drinking water inputs may be considered
conservative for the following reasons.  

The model results assume that applications will be made at maximum
application rates every year for 30 years.  

The PRZM-EXAMS models are based on an actual reservoir/watershed system
in Illinois which is known to be a highly vulnerable configuration.  

2.	The PRZM-EXAMS results were based on a single application to apples
at the maximum  application rate (1.15 lbs. a.i./A); as such, they do
not take into consideration potential late-season applications that are
allowed under certain circumstances.  Since typically only a single
application is made, and considering the conservative nature of the
other model assumptions, it is unlikely that the PRZM-EXAMS results
based on a single application underestimate drinking water residues.

4.3 Water Exposure/Risk Pathway

Environmental Fate

According to the Environmental Fate and Effects Division (EFED memo
D256862, I. Saheb, 6/21/99), formetanate HCl may contaminate surface
waters via application spray drift. The low Kdads values and high water
solubility would indicate a high potential for dissolution in runoff
water. However, formetanate HCl rapidly degrades by hydrolysis and if
time and conditions allow for irreversible soil binding following
washoff of foliar applications, substantial fractions of applied
formetanate would not be available for runoff in dissolution, but
possibly through adsorption to eroding soil. Parent formetanate should
not be persistent in waters of neutral or alkaline pH due to its
susceptibilty to undergo rapid hydrolysis. However, parent formetanate
would be persistant in acidic waters, such as marshes. The major
hydrolysis degradates at all pHs are N,N-dimethyl-N-(3-hydroxy-phenyl)
formamidine (SN35867), 3-formaminophenyl – methyl-carbamate (SN35902),
and the terminal degradate, 3-formaminophenol (SN38075). (SN35902 and
SN38075 were determined to be not of toxicological concern as they are
86 and 48 times, respectively, less potent as cholinesterase inhibitors
than parent formetanate [3/15/99 MARC decision].)

Due to the rapid degradation of formetante HCl and soil binding
processes that would greatly reduce mobility it appears that the risk of
ground water contamination would be low. However, there is a short term
threat for formetanate and its degradates to move to ground water
because of low Kdads values and a limiting time factor required to
establish soil binding. If a rainfall event would occur immediately or
shortly after a formetanate application onto permeable soils of low
organic matter content, formetanate may have the potential to move to
shallow ground water before it would degrade or bind irreversibly to the
soils. Under these conditions it is not possible to state whether
formetanate leaching or biodegradation will be more rapid; the potential
risk of formetanate to move to groundwater will probably be determined
by the relative rates of these two processes, which in turn is
influenced by site specific conditions (EFED memo D256862, 6/21/99).

Estimated Environmental Concentrations (EECs)

Surface Water

EFED provided revised surface water EECs resulting from a single aerial
application of 1.15 lb a.i./A formetanate HCl to apples in North
Carolina, Pennsylvania, and Oregon (D289182, 3/27/03, I. Abdel-Saheb).
The Tier II screening models PRIZM and EXAMS with the Index Reservoir
and Percent Crop Area adjustment (0.87) were used. Monitoring data were
not available for formetanate in surface water. 

Table 4.3.1 Estimated Environmental Concentrations of Parent Formetanate
in Surface Water

1.15 lb a.i/A to Apples	

 Model EECs (ug/L)

	

NC	

PA	

OR

Peak (90th percentile annual daily max)	

7.68	

6.76	

6.83

90th percentile annual mean	

0.06	

0.08	

0.04

36-year overall mean	

0.04	

0.04	

0.03

The peak EECs for formetanate use on apples may be used for the acute
surface water-based drinking water risk assessment. The annual mean EECs
may be used for the chronic surface water-based drinking water risk
assessment.

Ground Water

EFED previously submitted  Tier I SCI-GROW modeling EEC for ground water
(1.17 ppb) based on formetanate HCl application to citrus at 4.61 lb
a.i./A which is 4x the currently allowed seasonal rate for use on
citrus. Given the current maximum application rate of 1.15 lb a.i./A,
and the linear nature of the SCI-GROW modeling, a ground water EEC of
0.29 ppb may be appropriate. Due to the rapid degradation of formetante
HCl and soil binding processes that would greatly reduce mobility it
appears that the risk of ground water contamination would be low.
Therefore, surface water estimated concentrations were considered more
appropriate for use in the assessment.

4.4 Residential Exposure/Risk Pathway

Only agricultural uses are registered for formetanate HCl.  There are no
uses that would result in residential or recreational exposures.
Assessments addressing residential and recreational risks are not
warranted at this time.

4.5 Spray Drift

Spray drift is always a potential source of exposure to residents nearby
to spraying operations.  This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from ground 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 air-blast 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.

5.0 Aggregate Risk Assessments And Risk Characterization

The current uses for formetanate HCl encompass only agricultural use
sites; there are no non-occupational (residential) uses.  Therefore,
when addressing aggregate exposures, only the dietary pathways of food
and drinking water were considered. Since drinking water was
incorporated directly into the acute and chronic dietary assessments,
the dietary risk estimates discussed above reflect total estimated acute
and chronic aggregate risk from formetanate HCl.

5.1 Acute Aggregate Risk

Acute aggregate risk estimates associated with exposure to formetanate
HCl residues in food and water exceed HED’s level of concern.
Formetanate acute dietary (food + water) exposure at the 99.9th
percentile was estimated at 830% of the aPAD for the U.S. population and
 2600% of the aPAD for the most highly exposed population subgroup
(infants).  Most of the estimated acute exposure was determined to
result from the late season uses of formetanate hydrochloride on apples,
pears, oranges and grapefruit (particularly apples, and to a lesser
extent, pears).  When the late season uses are excluded from the
assessment, estimated dietary exposure (food + water) is below HED’s
level of concern for the U.S. population (32% of the aPAD) and all
population subgroups, except infants, whose estimated exposure
represents 110% of the aPAD.   A separate analysis of acute exposure to
formetanate hydrochloride from drinking water alone resulted in exposure
estimates equivalent to 28% of the aPAD for the overall U.S. population
and 110% of the aPAD for infants. 

Drinking water is the largest contributor to the acute aggregate dietary
exposure when late season uses are excluded. Uncertainties associated
with the drinking water assumptions indicate that the estimated levels
of formetante HCL in drinking water are conservative and are not likely
to result in an underestimate of risk. Some assumptions include 1) The
lack of actual water monitoring data, which would have resulted in a
more refined estimate of drinking water exposure to formetanate HCl, 2)
The PRZM-EXAMS  model results assume that applications will be made at
maximum application rates every year for 30 years,  3) the PRZM-EXAMS
models are based on an actual reservoir/watershed system in Illinois
which is known to be a highly vulnerable configuration, 4) The
PRZM-EXAMS results were based on a single application to apples at the
maximum  application rate (1.15 lbs. a.i./A); as such, they do not take
into consideration potential late-season applications that are allowed
under certain circumstances.  Since typically only a single application
is made, and considering the conservative nature of the other model
assumptions, it is unlikely that the PRZM-EXAMS results based on a
single application underestimate drinking water residues.

The assumptions used for food residue inputs may also be considered
somewhat conservative. Although the field trial data are very limited in
terms of the number of trials and residue samples, it is still likely
that these data result in overestimates of dietary exposure to
formetanate, since they reflect maximum, rather than typical, usage. 
The availability and use of monitoring data reflecting current use
patterns and/or additional residue processing information (cooking,
peeling, etc.) would have resulted in a more refined estimate of dietary
exposure.		

5.2 Short-Term Aggregate Risk

There are no uses of formetante HCl that would result in short-term,
non-occupational exposures.  A short-term aggregate risk assessment for
formetanate HCl is not warranted.

5.3 Intermediate-Term Aggregate Risk

There are no uses of formetanate HCl that would result in
intermediate-term, non-occupational exposures.  An intermediate-term
aggregate risk assessment for formetanate HCl is not warranted.

5.4 Chronic Aggregate Risk

Chronic aggregate exposure estimates for food and water are below
HED’s level of concern.   Formetanate hydrochloride mean dietary (food
+ water) exposure is estimated at 4.9% of the cPAD for the U.S.
population and 28% of the cPAD for the most highly exposed population
subgroup (infants, <1 yr. old).  When late season uses on apples, pears,
oranges and grapefruit are excluded, estimated chronic dietary exposure
represents less than 1% of the cPAD for the U.S. population and all
population subgroups, except infants, whose estimated exposure
represents 1.3% of the cPAD.  Chronic dietary exposure from drinking
water alone is estimated to be less than 1% of the cPAD for all
populations.

5.5 Cancer Risk

Formetanate HCl has been classified a Group “E” carcinogen (no
evidence of carcinogenicity).  As such, a cancer aggregate risk
assessment is not warranted.

6.0 Cumulative 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.” 

Formetanate HCl is a member of the N-methyl carbamate class of
pesticides. This class also includes carbaryl, aldicarb, methomyl and
oxamyl among others. The N-methyl carbamates, as a group, have been
determined to share a common mechanism of toxicity (July 2001 memo from
Office Director Marcia Mulkey).  The preliminary cumulative risk
assessment for the N-methyl carbamate (NMC)  Cumulative Assessment
Group, which includes formetanate hydrochloride, was released in July
2005.  The preliminary cumulative risk assessment was reviewed by the
FIFRA SAP in August 2005.  The revised CRA is currently being developed
and will be released during 2006. The results of this NMC cumulative
assessment as well as the single chemical formetanate hydrochloride
assessment presented here will be considered during the formetanate
hydrochloride reregistration process in which decisions regarding
establishing, modifying, or revoking formetanate hydrochloride
tolerances will be made.     

7.0 Occupational Exposure and Risk

Formetanate hydrochloride is formulated as a  92% wettable powder (WP)
formulation (Carzol® SP) and is registered for foliar or dormant
applications to a variety of orchard fruits and alfalfa grown for seed
using ground or aerial equipment.

EPA has determined that there are potential exposures to mixers,
loaders, applicators, and other handlers during usual use-patterns
associated with formetanate hydrochloride.   Based on the use patterns,
7 major exposure scenarios were identified for formetanate
hydrochloride: 

mixing/loading wettable powders for aerial application;

mixing/loading wettable powders for airblast application;

mixing/loading wettable powders for groundboom application;

applying sprays with a fixed-wing aircraft; 

applying sprays with airblast equipment; 

applying sprays with a groundboom sprayer; and

flagging for aerial spray applications.

Postapplication exposures are anticipated for workers reentering fields
and orchards treated with  formetanate products.  Workers may enter
treated orchards to irrigate, scout, weed, prune, prop, harvest, or
perform other duties.  Workers may enter treated alfalfa fields to set
irrigation or scout for pests or diseases. Only short (1-30 days) and
intermediate (1-6 months) duration exposures are anticipated for
formetanate HCl reentry workers.

7.1 Occupational Handler tc \l2 "7.1 Occupational Handler 

No chemical-specific handler data were submitted, so short-term and
intermediate-term dermal and inhalation exposures for handlers were
developed using the Pesticide Handler Exposure Database (PHED) Version
1.1 surrogate data.

The daily dermal and inhalation exposures for mixers, loaders, and
applicators were calculated using surrogate field data from the PHED
tables and the following formula [inhalation doses in PHED are listed in
micrograms and so must be divided by 1000 to fit the formula]:	

Daily [dermal or inhalation] exposure (mg ai/day) =

Unit exposure (mg ai/lb ai) *  Use Rate (lb ai/A) * Daily Acres Treated
(A/day).

The daily dermal and inhalation doses are calculated using a 70 kg body
weight for short-term exposure and a 70 kg body weight for
intermediate-term exposure.

Daily [Dermal/Inhalation] Dose (mg ai/kg/day) = Daily
[Dermal/Inhalation] Exposure (mg ai/day) ( (body weight[kg])-1

These calculations of daily dermal dose of formetanate hydrochloride
received by handlers are used to assess the exposure risk to those
handlers.  The short-term and intermediate-term dermal margins of
exposure (MOEs) were calculated using a dermal NOAEL of 10 mg/kg/day in
the following formula:

MOE           =                         NOAEL [in mg/kg/day]

                                         Daily Dose [in mg/kg/day]

Because the NOAEL for the short-term and intermediate term dermal
exposures is the same (10 mg/kg/day) one occupational risk assessment
was conducted for these two exposure durations. The short-term and
intermediate-term inhalation MOEs were calculated by using an oral NOAEL
of 0.1 mg/kg/day in the same formula and assuming 100% absorption.	

The MOEs for dermal and inhalation exposure can be combined into a
common expression of risk,

Total MOE = 	1/ [(1/MOEDERMAL) + (1/MOEINHALATION)]

Exposure and risk estimates are the same for short-term and
intermediate-term exposure scenarios and are presented in Tables 7.1.1
through 7.1.4. Table 7.1.1 presents applicator and flagger short- (1-30
days) and intermediate-term (1-6 months) dermal and inhalation exposure
calculations for spray applications using the proposed daily maximum
application rates at baseline (single layer work clothing); Table 7.1.2
adds gloves for spray applicators; Table 7.1.3 shows the mixer/loader,
applicator, and flagger dermal and inhalation risk estimates when using
maximum personal protective equipment (PPE) as gloves and coveralls and
dust/mist respirator in addition to water soluble bags (WSB) when
handling the wettable powder (WP); Table 7.1.4 includes engineering
controls in the form of water soluble bags for mixer/loaders when
handling the wettable powder (WP) and closed vehicles for spray
applicators and flaggers (single layer clothing). 

Risks to mixer/loaders and applicators were calculated for scenarios
using the  recommended rate per application per acre.  All baseline,
i.e., typical single layer work clothing, applicator scenarios had
estimated exposures resulting in risks of concern. Even with maximum
personal protection or enclosed cockpit, some scenarios still produced
combined route (dermal + inhalation) risks of concern (MOEs <100). 

Mixing/loading scenarios for large acreage (alfalfa) by aerial
application resulted in risks of concern (MOE = 57) that were not
mitigated with addition of coveralls, gloves, and respirator. 

The mixing/loading scenario for aerial application to alfalfa assumed
the default acreage of 1200 acres treated per day. An additional
assessment was performed using an estimate of 328 acres treated per day
based on data from the California Agricultural Commissioner (letter
dated 11/29/2005 to D. Fuller from R. Melnicoe, College of Agricultural
and Environmental Science, University of California, Davis). Total MOEs
were 69 using WSB and 210 using WSB plus double layer
protection(coveralls), gloves, and respirator.

It should be noted that the use of water soluble bags (a closed system)
is intended to negate the need for maximum PPE as PPE can be
uncomfortable to wear (respiratory protection) and also cause thermal
discomfort (chemical resistant coveralls). Use of engineering controls
also avoids the constellation of  problems associated with PPE (heat
stress, decreased mobility, physical stress, lack of fine motor skill,
false sense of security). Therefore additional PPE generally defeats the
purpose of putting the  product in water soluble bags.

With maximum PPE as prescribed by the MOA and the label (coveralls,
gloves, respirator and hood), airblast applicators for orchards still
had risks of concern (MOE = 73).  All other applicator scenarios, except
for aerial application to alfalfa, had combined MOEs >100 with
engineering controls added in the form of enclosed vehicles. Aerial
applicators for high-acreage (1200 acres per day) alfalfa crops had
risks of concern (MOE = 54) even with closed cockpit. However, when
assuming an estimate of 328 acres of alfalfa treated per day based on
data from the California Agricultural Commissioner, the total MOE was
200.

Table 7.1.1.Formetanate HCL: Applicator& Flagger (spray application)
Short- and Intermediate-term Exposure and Risk Estimates: Single Layer
Protection

Exposure Scenario (Scenario #)	

Dermal Unit Exposure (mg/lb ai)1	

Inhalation Unit Exposure   (ug/lb ai)2	

Crop3	

Application Rate4	

Daily Area Treated5	

Dermal Dose (mg/kg/day)6	

Dermal MOE 7	

Inhalation Dose (mg/kg/day)8	

Inhalation MOE9	

Total MOE10

Applicator

Sprays for Aerial application (5)	

No Data	

No Data	

Alfalfa	

0.92  lb ai per acre	

1200  Acres per day	

No Data	

No Data	

No Data	

No Data	

No Data

Sprays for Aerial application (6)	

No Data	

No Data	

Pome, Stone, and Citrus Fruit	

1.15  lb ai per acre	

350  Acres per day	

No Data	

No Data	

No Data	

No Data	

No Data

Sprays for Airblast application (7)	

0.36	

4.5	

Pome, Stone, and Citrus Fruit	

1.15  lb ai per acre	

40  Acres per day	

0.24	

42	

0.0030	

34	

19

Sprays for Groundboom application (8)	

0.014	

0.74	

Alfalfa for seed	

0.92  lb ai per acre	

200  Acres per day	

0.037	

270	

0.0019	

51	

43

Flagger

Flagging for Sprays application (9)	

0.011	

0.35	

Alfalfa for seed	

0.92  lb ai per acre	

350  Acres per day	

0.051	

200	

0.0016	

62	

47

Flagging for Sprays application (10)	

0.011	

0.35	

Stone, Pome, and Citrus Fruit	

1.15  lb ai per acre	

350  Acres per day	

0.063	

160	

0.0020	

50	

38

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

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

3Crops and use patterns are from MOA and labels.

4Application rates are based on maximum values found on updated Carzol
SP®  labels.  In most scenarios, a range of maximum application rates
is used to represent the range of rates for different crops/sites/uses. 
Most application rates upon which the analysis is based are presented as
lb ai/A. 

5Amount treated is based on the area or gallons that can be reasonably
applied in a single day for each exposure scenario of concern based on
the application method and formulation/packaging type. (Standard
EPA/OPP/HED values).

6Dermal dose (mg/kg/day) = [unit exposure (mg/lb ai) * Dermal absorption
(100%) * Application rate (lb ai/acre or lb ai/gallon) * Daily area
treated (acres or gallons)] / Body weight (70 kg).

7Dermal MOE =  Dermal NOAEL  (10 mg/kg/day) / Daily Dermal Dose. Target
Dermal MOE is 100.

8Inhalation dose (mg/kg/day) = [unit exposure (ug/lb ai) * 0.001 mg/ g
unit conversion * Inhalation absorption (100%) * Application rate (lb
ai/acre or lb ai/gallon) * Daily area treated (acres or gallons)] / Body
weight (70 kg).

9Inhalation MOE = Oral NOAEL (0.1 mg/kg/day) / Daily Inhalation Dose.
Target Inhalation MOE is 100.

10Total MOE = 1 / [(1/MOEdermal) + (1/MOEinhalation)]

Table 7.1.2.Formetanate HCL: Applicator& Flagger (spray application)
Short- and Intermediate-term  Exposure and Risk Estimates: Single Layer
Protection, Gloves, No Respirator

Exposure Scenario (Scenario #)	

Dermal Unit Exposure (mg/lb ai)1	

Inhalation Unit Exposure   (ug/lb ai)2	

Crop3	

Application Rate4	

Daily Area Treated5	

Dermal Dose (mg/kg/day)6	

Dermal MOE 7	

Inhalation Dose (mg/kg/day)8	

Inhalation MOE9	

Total MOE10

Applicator

Sprays for Aerial application (5)	

No Data	

No Data	

Alfalfa	

0.92  lb ai per acre	

1200  Acres per day	

No Data	

No Data	

No Data	

No Data	

No Data

Sprays for Aerial application (6)	

No Data	

No Data	

Pome, Stone, and Citrus Fruit	

1.15  lb ai per acre	

350  Acres per day	

No Data	

No Data	

No Data	

No Data	

No Data

Sprays for Airblast application (7)	

0.24	

4.5	

Pome, Stone, and Citrus Fruit	

1.15  lb ai per acre	

40  Acres per day	

0.16	

63	

0.0030	

34	

22

Sprays for Groundboom application (8)	

0.014	

0.74	

Alfalfa for seed	

0.92  lb ai per acre	

200  Acres per day	

0.037	

270	

0.0019	

51	

43

Flagger

Flagging for Sprays application (9)	

0.01	

0.35	

Alfalfa for seed	

0.92  lb ai per acre	

350  Acres per day	

0.046	

220	

0.0016	

62	

48

Flagging for Sprays application (10)	

0.01	

0.35	

Stone, Pome, and Citrus Fruit	

1.15  lb ai per acre	

350  Acres per day	

0.058	

170	

0.0020	

50	

39

1PPE1 dermal unit exposures represent long pants, long sleeved shirts,
and chemical-resistant gloves.  Values are reported in the PHED
Surrogate Exposure Guide dated August 1998 or are from data submitted by
the Outdoor Residential Exposure Task Force dated May 2000.2PPE1
inhalation unit exposures represent no respirator.  Values are reported
in the PHED Surrogate Exposure Guide dated August 1998

3Crops and use patterns are from MOA and labels.

4Application rates are based on maximum values found on revised Carzol
SP® labels.  In most scenarios, a range of maximum application rates is
used to represent the range of rates for different crops/sites/uses. 
Most application rates upon which the analysis is based are presented as
lb ai/A.

5Amount treated is based on the area or gallons that can be reasonably
applied in a single day for each exposure scenario of concern based on
the application method and formulation/packaging type. (Standard
EPA/OPP/HED values).

6Dermal dose (mg/kg/day) = [unit exposure (mg/lb ai) * Dermal absorption
(100%) * Application rate (lb ai/acre or lb ai/gallon) * Daily area
treated (acres or gallons)] / Body weight (70 kg).

7Dermal MOE = Dermal NOAEL  (10 mg/kg/day) / Daily Dermal Dose. Target
Dermal MOE is 100.

8Inhalation dose (mg/kg/day) = [unit exposure (ug/lb ai) * 0.001 mg/ g
unit conversion * Inhalation absorption (100%) * Application rate (lb
ai/acre or lb ai/gallon) * Daily area treated (acres or gallons)] / Body
weight (70 kg).

9Inhalation MOE =   Oral NOAEL (0.1 mg/kg/day) / Daily Inhalation Dose.
Target Inhalation MOE is 100.

10Total MOE = 1 / [(1/MOEdermal) + (1/MOEinhalation)]

Table 7.1.3.Formetanate: Mixer-loader, Applicator, Flagger Short- and
Intermediate-term Exposure and Risk Estimates using WP in WSB plus
Double Layer Protection, Gloves, Dust/Mist Respirator (and Hood for
Airblast Applicators Only)

Exposure Scenario (Scenario #)	

Dermal Unit Exposure (mg/lb ai)1	

Inhalation Unit Exposure   (ug/lb ai)2	

Crop3	

Application Rate4	

Daily Area Treated5	

Dermal Dose (mg/kg/day)6	

Dermal MOE 7	

Inhalation Dose (mg/kg/day)8	

Inhalation MOE9	

Total MOE10

Mixer/Loader

Wettable Powders for Aerial application (1)	

0.0057	

0.048	

Pome, Stone, Citrus Fruit	

1.15  lb ai per acre	

350  Acres per day	

0.033	

305	

2.8E-04	

360	

170

Wettable Powders for Aerial application (2)	

0.0057	

0.048	

Alfalfa for seed	

0.92  lb ai per acre	

1200  Acres per day	

0.090	

110	

7.6E-04	

130	

57

Wettable Powders for Aerial application (2a)	

0.0057	

0.048	

Alfalfa for seed	

0.92  lb ai per acre	

328 Acres per day *	

0.025	

400	

2.0E-04	

500	

210

Wettable Powders for Airblast application (3)	

0.0057	

0.048	

Pome, Stone, and Citrus Fruit	

1.15  lb ai per acre	

40  Acres per day	

0.00375	

2700	

3.15E-05	

3200	

1500

Wettable Powders for Groundboom application (4)	

0.0057	

0.048	

Alfalfa	

0.92  lb ai per acre	

200  Acres per day	

0.015	

670	

1.3E-04	

790	

340

Applicator

Sprays for Aerial application (5)	

See Engineering Controls	

See Engineering Controls	

Alfalfa	

0.92  lb ai per acre	

1200  Acres per day	

	

	

	

	

Sprays for Aerial application (6)

	

Pome, Stone, and Citrus Fruit	

1.15  lb ai per acre	

350  Acres per day	

	

	

	

	

Sprays for Airblast application (7)	

0.12	

0.9	

Pome, Stone, and Citrus Fruit	

1.15  lb ai per acre	

40  Acres per day	

0.079	

130	

0.00059	

170	

73

Sprays for Groundboom application (8)	

0.011	

0.15	

Alfalfa for seed	

0.92  lb ai per acre	

200  Acres per day	

0.029	

350	

0.00039	

250	

150

Flagger

Flagging for Sprays application (9)	

0.01	

0.07	

Alfalfa for seed	

0.92  lb ai per acre	

350  Acres per day	

0.046	

220	

0.00032	

310	

130

Flagging for Sprays application (10)	

0.01	

0.07	

Stone, Pome, and Citrus Fruit	

1.15  lb ai per acre	

350  Acres per day	

0.058	

170	

0.00040	

250	

100

1Max label PPE dermal unit exposures represent coveralls worn over long
pants and long sleeved shirts; chemical-resistant gloves; plus (airblast
applicators only)  estimated 50% reduction in head/neck exposure using
hood.  Values are reported in the PHED Surrogate Exposure Guide dated
August 1998. Coveralls and hood estimated protection factor 0.5 (50%
exposure reduction).

2 Inhalation unit exposures represent a dust/mist respirator with a
protection factor of 5.  Values are reported in the PHED Surrogate
Exposure Guide dated August 1998.

3Crops and use patterns are from MOA and labels.

4Application rates are based on maximum values found on revised Carzol
SP® labels.  In most scenarios, a range of maximum application rates is
used to represent the range of rates for different crops/sites/uses. 
Most application rates upon which the analysis is based are presented as
lb ai/A. 

5Amount treated is based on the area or gallons that can be reasonably
applied in a single day for each exposure scenario of concern based on
the application method and formulation/packaging type. (Standard
EPA/OPP/HED values).

6Dermal dose (mg/kg/day) = [unit exposure (mg/lb ai) * Dermal absorption
(100%) * Application rate (lb ai/acre or lb ai/gallon) * Daily area
treated (acres or gallons)] / Body weight (70 kg).

7Dermal MOE = Dermal NOAEL  (10 mg/kg/day) / Daily Dermal Dose. Target
Dermal MOE is 100.

8Inhalation dose (mg/kg/day) = [unit exposure (ug/lb ai) * 0.001 mg/ g
unit conversion * Inhalation absorption (100%) * Application rate (lb
ai/acre or lb ai/gallon) * Daily area treated (acres or gallons)] / Body
weight (70 kg).

9Inhalation MOE =  NOAEL  (0.1 mg/kg/day) / Daily Inhalation Dose.
Target Inhalation MOE is 100.

10Total MOE = 1 / [(1/MOEdermal) + (1/MOEinhalation)]

* Estimated 328 acres treated per day of alfalfa grown for seed in CA
based on data from the California Agricultural Commissioner (letter
dated 11/29/2005 to D. Fuller from R. Melnicoe, College of Agricultural
and Environmental Science, University of California, Davis).



Table 7.1.4.Formetanate HCL: Mixer/Loader , Applicator and Flagger for
Short- and Intermediate-term  Exposure and Risk Estimates: Using
Engineering Controls: WP in Water Soluble Bags (WSB); Closed Cockpit
Airplane, Closed Cab Tractors

Exposure Scenario (Scenario #)	

Dermal Unit Exposure (mg/lb ai)1	

Inhalation Unit Exposure   (ug/lb ai)2	

Crop3	

Application Rate4	

Daily Area Treated5	

Dermal Dose (mg/kg/day)6	

Dermal MOE 7	

Inhalation Dose (mg/kg/day)8	

Inhalation MOE9	

Total MOE10

Mixer/Loader

Wettable Powders for Aerial application (1)	

0.0098	

0.24	

Pome, Stone, Citrus Fruit	

1.15  lb ai per acre	

350  Acres per day	

0.056	

180	

0.0014	

72	

51

Wettable Powders for Aerial application (2)	

0.0098	

0.24	

Alfalfa for seed	

0.92  lb ai per acre	

1200  Acres per day	

0.15	

65	

0.0038	

26	

19

Wettable Powders for Aerial application (2a)	

0.0098	

0.24	

Alfalfa for seed	

0.92  lb ai per acre	

328  Acres per day *	

.042	

240	

0.001	

100	

69

Wettable Powders for Airblast application (3)	

0.0098	

0.24	

Pome, Stone, and Citrus Fruit	

1.15  lb ai per acre	

40  Acres per day	

0.0064	

1600	

0.00016	

630	

450

Wettable Powders for Groundboom application (4)	

0.0098	

0.24	

Alfalfa	

0.92  lb ai per acre	

200  Acres per day	

0.026	

390	

0.00063	

160	

110

Applicator

Sprays for Aerial application (5)	

0.005	

0.068	

Alfalfa	

0.92  lb ai per acre	

1200  Acres per day	

0.079	

130	

0.0011	

93	

54

Sprays for Aerial application (5a)	

0.005	

0.068	

Alfalfa	

0.92  lb ai per acre	

328 Acres per day *	

0.022	

460	

0.00029	

340	

200

Sprays for Aerial application (6)	

0.005	

0.068	

Pome, Stone, and Citrus Fruit	

1.15  lb ai per acre	

350  Acres per day	

0.029	

350	

0.00039	

260	

150

Sprays for Airblast application (7)	

0.019	

0.45	

Pome, Stone, and Citrus Fruit	

1.15  lb ai per acre	

40  Acres per day	

0.012	

800	

0.00030	

340	

240

Sprays for Groundboom application (8)	

0.005	

0.043	

Alfalfa for seed	

0.92  lb ai per acre	

200  Acres per day	

0.013	

760	

0.00011	

890	

410

Flagger

Flagging for Sprays application (9)	

0.00022	

0.007	

Alfalfa for seed	

0.92  lb ai per acre	

350  Acres per day	

0.0010	

9900	

0.000032	

3100	

2400

Flagging for Sprays application (10)	

0.00022	

0.007	

Stone, Pome, and Citrus Fruit	

1.15  lb ai per acre	

350  Acres per day	

0.0013	

7900	

0.000040	

2500	

1900

1Engineering controls dermal unit exposures represent long pants and
long sleeved shirts. For mixers and loaders, chemical-resistant gloves
are also included.  For applicators, closed cab data are used.  Values
are reported in the PHED Surrogate Exposure Guide dated August 1998.

2Engineering controls inhalation unit exposures represent no respirator.
 Values are reported in the PHED Surrogate Exposure Guide dated August
1998; 98% PF assumed for closed cabs.

3Crops and use patterns are from MOA and labels.

4Application rates are based on maximum values found in revised labels. 
Most application rates upon which the analysis is based are presented as
lb ai/A. 

5Amount treated is based on the area or gallons that can be reasonably
applied in a single day for each exposure scenario of concern based on
the application method and formulation/packaging type. (Standard
EPA/OPP/HED values).

6Dermal dose (mg/kg/day) = [unit exposure (mg/lb ai) * Dermal absorption
(100%) * Application rate (lb ai/acre or lb ai/gallon) * Daily area
treated (acres or gallons)] / Body weight (70 kg).

7Dermal MOE = Dermal NOAEL  (10 mg/kg/day) / Daily Dermal Dose. Target
Dermal MOE is 100.

8Inhalation dose (mg/kg/day) = [unit exposure (ug/lb ai) * 0.001 mg/ g
unit conversion * Inhalation absorption (100%) * Application rate (lb
ai/acre or lb ai/gallon) * Daily area treated (acres or gallons)] / Body
weight (70 kg).

9Inhalation MOE = NOAEL (0.1 mg/kg/day) / Daily Inhalation Dose. Target
Inhalation MOE is 100.

10Total MOE = 1 / [(1/MOEdermal) + (1/MOEinhalation)]

* Estimated 328 acres treated per day of alfalfa grown for seed in CA
based on data from the California Agricultural Commissioner (letter
dated 11/29/2005 to D. Fuller from R. Melnicoe, College of Agricultural
and Environmental Science, University of California, Davis).

7.2 Occupational Postapplication Worker

Postapplication exposures are anticipated for workers reentering fields
and orchards treated with  formetanate products.  Workers may enter
treated orchards to irrigate, scout, weed, prune, prop, harvest, or
perform other duties.  Workers may enter treated alfalfa fields to set
irrigation or scout for pests or diseases. 

A dislodgeable foliar residue (DFR) study of formetanate hydrochloride
formulated as CARZOL® SP was conducted in orange and apple orchards. 
This study was reviewed and the procedures and analytical recoveries met
the Agency guideline criteria for use in risk assessment.  Only the
orange residue data were reported to the Agency, and these data were
normalized for application rate and translated to the other tree crops
and to alfalfa for exposure assessment.  Agency standard dermal transfer
coefficients were used with the normalized residue data to determine the
amount of time postapplication required to achieve the target MOE of 100
for each activity.

Daily dermal exposure is calculated as follows:

Potential dose =  DFR (ug/cm2) x Transfer Coefficient (cm2/hr) x Work
Day (8 hr)

Unit Adjustment from ug to mg (1000 ug/mg) x Body Wt (kg)

Post-application MOEs are calculated using the following formula: 

MOE = NOAEL (mg/kg/day)/ Daily Dermal Dose (mg/kg/day)

Although residues on citrus leaves may behave differently from
smooth-leaved trees, this assessment is based on the available orange
DFR study and is assumed to be representative for all registered tree
crops, and conservative for alfalfa. Re-entry activity MOEs equal to or
over 100 are not achieved until 12 days after the second application of
the ai to trees fruits (evergreen or deciduous) and 9 days after
application to alfalfa.  Current label REIs are:

16 days for hand labor activities (except weeding and propping) in
citrus, pome, and stone fruit trees.

10 days for hand labor activities (weeding and propping) in citrus,
pome, and stone fruit trees.

10 days for non-hand labor activities (irrigation and crop advisor
activities).

4 days when treating stone and pome fruit trees that are bare of
foliage.

48 hours for alfalfa (grown for seed)

Product label includes pre-harvest intervals (PHIs) greater than the
intervals needed to attain re-entry MOEs of 100  and/or prohibits
applications after fruit has begun to develop except in the case of
second late season applications allowed to pome fruit, which do not
specify a PHI.  The DFR data were translated from the citrus study, but
the application method and rate are similar to, and adjusted to the
product label. 

Tables 7.2.1-7.2.2 : Worker Reentry Exposure to Formetanate
Hydrochloride and AEF132314 Residues Following Second Application to
Fruit Trees (18 Days After The First Application)

Table 7.2.1. Crop Groupings: Selected Transfer Coefficients, Treated
Crops, and Rates

Transfer Coefficient Group (1)	

Specific Transfer Coefficient (cm2/hr) (1)	

Formetanate Specific Crops (2)	

Max Foliar Rate (lb ai/acre)

	

High end activities	

Low end activities

Field / row crops, low / medium	

2500

486 - 2,760	

100

TBD	

Alfalfa	

0.92

Trees, fruit, deciduous	

1500-3000

1,421 - 4,393	

1000

197 - 2,302	

Apples, Peaches	

1.15

Trees, fruit, evergreen	

1500-3000

363 - 4078	

1000

197 - 2,302	

Citrus	

1.15

Footnote:

  1. Crop groupings and transfer coefficients from Science Advisory
Council for Exposure: Policy Memo #003.1 'Agricultural Transfer
Coefficients', August 17, 2000.

  2. Maximum label rates from end use product labels.

Table 7.2.2. Short-term Post Application Assessment for Formetanate
Treated Agricultural Crops (including ornamentals)

DAT (1)	

Crop Groupings: MOEs for Highest Activity Level (2,3)

	

Field / row crops, low / medium

 (1 crop) (TC=2500 cm2/hr)	

Trees, fruit, deciduous

 (2 crops) (TC=1500 cm2/hr)	

Trees, fruit, evergreen

	

(TC =1500 cm2/hr)	

(TC = 3000 cm2/hr)

0	

22	

29	

29	

14

1	

26	

35	

35	

17

2	

32	

43	

43	

21

3	

36	

49	

49	

24

4	

43	

58	

58	

29

5	

52	

69	

69	

34

6	

62	

82	

82	

41

7	

73	

98	

98	

49

8	

87	

120	

120	

58

9	

100	

-	

-	

69

10	

-	

-	

-	

83

11	

-	

-	

	

98

12	

-	

-	

	

120

Footnote:

  1. DAT = Days after treatment; DAT0 = On the day of treatment, after
sprays have dried; assumed approximately 12 hours.

  2. Crop groupings and transfer coefficients from Science Advisory
Council for Exposure: Policy Memo #003.1 'Agricultural Transfer
Coefficients', August 17, 2000.

  3. MOE = Dermal toxicity endpoint (mg/kg-day)/absorbed dermal dose
(mg/kg-d) where the absorbed dose = DFR (ug/cm2) x TC (cm2/hr) x
conversion factor (1 mg/1,000 ug) x exposure time (hrs) x dermal
absorption / body weight (kg).

8.0 Data Needs, Label Requirements, and Tolerance Reassessment

Toxicology

The acute toxicity data base is currently supported by older IBT
studies.  Replacement studies for the following acute toxicity studies
are required. 

870.1100.   Acute oral toxicity

870.1200.   Acute dermal toxicity 

870.1300.   Acute inhalation toxicity

870.2500.   Primary dermal irritation 

870.3465. 	28 day inhalation toxicity study.  The protocol for this
study should also be submitted to OPP for review prior to initiating
this study.  This study will require preliminary work to determine the
optimum time following removal from inhalation exposure and blood
sampling in order to assure maximum inhibition of cholinesterase.   

Chemistry

Residue Chemistry Deficiencies- 

860.1300 Nature of the Residue- Pending submission of adequate
information regarding the use of peach leaves to support the storage
stability of peach extract, the requirement for plant metabolism data
for formetanate HCl will be fulfilled.

860.1500 Crop Field Trials- Tolerances will be reassessed upon receipt
and acceptance of the following outstanding data:

Apple: Four additional field trials in Regions 1, 5, and 11 must be
conducted (the trials should include an early and late season
application as allowed in the MOA);

Pear: Two additional field trials in Regions 10 and 11 must be
conducted (the trials should include an early and late season
application as allowed in the MOA);

Peach: Three additional field trials in Regions 1 (or 2), 5, and 10 must
be submitted.	

Nectarine: Details pertaining to the field procedures used in the
at-harvest study (i.e., application method and timing, equipment, spray
volumes, tank mix adjuvants) and multiple application rates must be
provided.;

Citrus Fruit: Five additional orange field trials in Regions 6 and 10
must be conducted. An additional lemon trial (Region 10) and 2
additional grapefruit trials (Regions 6, 10) are also required.

Product Chemistry Deficiencies- 

Data on the formetanate HCl product identity and composition are
inadequate. A nominal concentration for nitrosamines as manufacturing
impurities should be added to the Confidential Statement of Formulation
(CSF).

Occupational

As stated above, risk estimates based on PHED are considered of variable
confidence, depending on the number and quality of exposure replicates
available for each exposure scenario and suite of PPE or engineering
controls.  However, this data set is considered the best available and
is used internationally for similar risk assessments.  

Postapplication worker risk estimates were based on the citrus data,
which are considered sufficiently similar to other tree crops based on
application method and application rates in the studies, although all
trees differ in architecture and leaf characteristics.  Translation of
the citrus data for other tree fruits is appropriate, while use of the
data for alfalfa is considered a conservative approach.  Therefore, the
estimated postapplication intervals to reach a MOE of 100 should be
adequately protective of workers.  The proposed PHIs and application
timing generally support the calculated reentry intervals. No additional
data are required at this time.

TOLERANCE REASSESSMENT

The tolerances listed in 40 CFR §180.276 are expressed in terms of
formetanate hydrochloride {m-[[(dimethylamino) methylene] -amino]phenyl
methylcarbamate hydrochloride} and are summarized in Table 8.1 below.
The reassessed tolerances for formetanate HCl residues are based on new
field trials (apple, pear, peach, nectarine, orange, grapefruit, lemon)
submitted in response to the 10/99 MOA. While those field trials
generally reflect the new maximum rate and minimum PHIs, the number of
field trials were insufficient. When the additional required field
trials are submitted, the tolerance reassessment will be reevaluated.

The established 3 ppm tolerance for residues of formetanate HCl in
apple and pear may be reduced to 0.50 ppm based on the new residue data
for apples where formetanate HCl was applied at the maximum rate and
included a late season application (total 2.3 lb a.i/A and 14 day PHI). 

The available data for nectarine and peach indicate the established
tolerances (4 ppm and 5 ppm, respectively) may be reduced to 0.40 ppm.
Nectarine data were translated to peach data for tolerance reassessment.
Even though there were no detectable residues (<0.03) in the peach
trials, only two trials were performed (2 samples per trial). Since
there were a significant number of detectable residues in nectarines at
the new rate of 1.15 lb ai/A, it cannot automatically be assumed that
there would be no detects in peaches without an adequate number of peach
samples tested.

Based on the 30 day PHI residue data for mature-treated (overcropped)
oranges, grapefruit and lemons (1.15 lb a.i/A), the tolerances for
grapefruit and orange may be reassessed at 1.5 ppm. 

Based on the 42 day PHI residue data for mature-treated (overcropped)
oranges, grapefruit and lemons (1.15 lb a.i/A), the tolerances for lemon
(60 day PHI required)  may be reassessed at 0.60 ppm.

Tolerances for residues of formetanate HCl on lime, tangerine and
tangelo may be reduced to 0.03 ppm [LOQ] based on 207 day PHI residue
data for lemons.

Tolerances for residues of formetanate HCl in plums, prune, fresh should
be revoked as use on plums is no longer permitted.

Apple processing data demonstrate that a tolerance must be proposed for
residues in apple, wet pomace.  Based on a HAFT residue value of 0.38
ppm from the apple field trials (2 applications, one of them late
season, for a total of 2.3 lb ai/A; 14 day PHI) and an average
concentration factor of 4X from four processing studies, a tolerance of
1.5 ppm would be appropriate for residues of formetanate HCl in apple,
wet pomace.

No maximum residue limits (MRLs) for formetanate HCl have been
established by Codex for any agricultural commodity.  Therefore, there
should be no significant trade concern for U.S. growers. 

Table 8.1. Tolerance Reassessment Summary for Formetanate Hydrochloride

Commodity	

Current Tolerance (ppm)	

Tolerance Reassessment (ppm)1	

Comment/

[Correct Commodity Definition]

Tolerances Listed Under 40 CFR §180.276

Apple	

3	

0.50	

Pear	

3	

0.50	

Grapefruit	

4	

1.5	

Lemon	

4	

0.60	

Lime	

4	

0.03	

Oranges	

4	

1.5	

[orange]

Tangerine	

4	

0.03	

Nectarine	

4	

0.40	

Peach	

5	

0.40	

Plum, prune, fresh	

2	

revoke	

no longer a registered use

Tolerances To Be Proposed Under 40 CFR §180.276

Apple, wet pomace	

None	

1.5	

Tangelo	

None	

0.03	

 1 Reassessed tolerances are based on  insufficient field trial data .
When additional acceptable field trial data are received, the tolerance
reassessment will be reevaluated.

	

cc: D. Drew, C. Eiden,

RDI: C. Eiden (12/24/05)

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