	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 <IP_ADDRESS> (food + water, including late season uses), <IP_ADDRESS> (food + water, without late season uses), <IP_ADDRESS> (food only, including late season uses), <IP_ADDRESS> (food only, without late season uses) and <IP_ADDRESS> (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 <IP_ADDRESS>  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 <IP_ADDRESS>  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 <IP_ADDRESS>  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 <IP_ADDRESS>  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 <IP_ADDRESS>  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 <IP_ADDRESS> 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 <IP_ADDRESS>.  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 <IP_ADDRESS> and <IP_ADDRESS>.

Table <IP_ADDRESS>.  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 <IP_ADDRESS>.  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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