Document ID: EPA-HQ-OPP-2006-0239-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-03-28T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

  SEQ CHAPTER \h \r 1 WASHINGTON, D.C.  20460

		

							            OFFICE OF  PREVENTION, PESTICIDES 

		                    AND TOXIC SUBSTANCES 

February 28, 2007

  SEQ CHAPTER \h \r 1 MEMORANDUM

SUBJECT:	Fomesafen Sodium: HED Registration Review Problem Formulation
Document.

		PC Code:123802, DP Barcode: D306022.			

		

FROM:	Whang Phang, Toxicologist

	Reregistration Branch 1

	Health Effects Division (7509P)

THROUGH:	Michael S. Metzger, Branch Chief

	Reregistration Branch 1

	Health Effects Division (7509C)

TO:		Wilhelmena Livingston, Chemical Review Manager		

Special Review and Reregistration Division (7508P)

Attached is the Health Effects Division chapter of the fomesafen sodium
problem formulation document in supporting the registration review of
this chemical.  

Section 1.   Introduction

The HED Fomesafen Registration Review Team has evaluated the human
health assessments for the herbicide fomesafen to determine the scope of
work necessary to support the registration review.  The team considered
the current use profile, the toxicity, and exposure databases for this
chemical.  The primary source for the status update was the most recent
HED human health risk assessment (Donna Davis, D325797, 2/28/06). The
purpose of this screen is to determine whether sufficient data are
available to assess the safety of this pesticide and whether any new
data have been submitted since the last assessment which would
necessitate conducting a new human health risk assessment to support
registration review.  A comprehensive listing of the documents
considered is presented in Section 12 of this document.  The HED
Registration Review team includes Donna Davis, Toiya Goodlow, Matt
Lloyd, and Whang Phang.   

Fomesafen is currently registered for use on several crops including
cotton, dry beans, snap beans, and soybeans. Tolerances are established
in 40 CFR 180.433 for these commodities. Fomesafen is not registered for
use on any sites that would result in residential exposure. 

Section 2.  Chemical Identity

Table 1.  Fomesafen and its Sodium Salt Nomenclature

Chemical structure	 

Common name	Fomesafen

Molecular formula	C15H10ClF3N2O6S

Molecular weight	438.77

PC Code	N/A

IUPAC name
5-(2-chloro-,,-trifluoro-p-tolyloxy)-N-methylsulfonyl-2-nitrobe
nzamide

CAS name
5-[2-chloro-4-(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitrobenzam
ide

CAS registry number	72178-02-0

Chemical structure	 

Common name	Sodium salt of fomesafen

Molecular formula	C15H9ClF3NaN2O6S

Molecular weight	460.75

PC Code	123802

IUPAC name
5-(2-chloro-,,-trifluoro-p-tolyloxy)-N-methylsulfonyl-2-nitrobe
nzamide, sodium salt

CAS name
5-[2-chloro-4-(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitro-benza
mide, sodium salt

CAS registry number	108731-70-0

	

Section 3.  Toxicology

Fomesafen has low acute toxicity by oral route of exposure. It is
severely irritating to the eye and is a moderate skin irritant. In the
subchronic and chronic feeding studies, the consistent finding is the
effect in the liver characterized by increases in liver weight and in
associated enzymes including alkaline phosphatase, alanine transaminase,
and aspartate transaminase. Hyalinization of the liver is also observed.

Currently, the toxicity database is adequate in establishing the
toxicity endpoints for risk assessment.  No toxicity studies have been
received since the last human health risk assessment (D. Davis, D325797,
2/28/06). Acute inhalation and dermal toxicity studies and a skin
sensitization study were identified as data gaps.  

The risk assessment team has reevlauated the toxicity endpoints and
doses according to the current policies on selecting toxicity endpoints
and uncertainty factors. These conclusions are summarized below. 

Cancer classification:  The Cancer Assessment Review Committee (CARC)
has classified fomesafen as “Not Likely to be Carcinogenic to
Humans”. A quantitative cancer risk assessment is not needed. 		

FQPA safety factor: Based on the available toxicology data, the
fomesafen risk assessment team recommended the FQPA SF be reduced to 1x
because there was no concern and/or residual uncertainty with regard to
pre- and/or postnatal toxicity.  Since no new data are available to
necessitate any changes to this conclusion and it concurs with the
current FQPA policy, the conclusion remains unchanged. 

Table 2.  Summary of Toxicological Doses and Endpoints for Fomesafen for
Use in Human Risk Assessments

Exposure

Scenario	Point of Departure	Uncertainty/

FQPA

Safety

Factor  	RfD, PAD, Level of Concern for RA	Study and Toxicological
Effects

Acute Dietary

(females 13-49) and General population		

	

No toxic effects attributable to a single dose of fomesafen were found
in the database.

Chronic Dietary

(all populations)	NOAEL = 0.25 mg/kg/day

	UFA  = 10x

UHH = 10x

FQPA SF = 1x	RfD  = 0.0025

mg/kg/day

cPAD = 0.0025 mg/kg/day

	Chronic toxicity - rat

LOAEL = 5 mg/kg/day based on hyalinization of the liver in males

Dermal 

Short-Term (1-30 days) and Intermediate-Term (1-6 months)

	NOAEL = 100 mg/kg/day

(Dermal absorption rate = 20%)*	UFA  = 10x

UHH = 10x

FQPA SF = 1x	LOC for MOE  = 100  (Occupational)

	Prenatal developmental – rat

LOAEL = 200 mg/kg/day based on postimplantation loss

Inhalation 

Short-Term

(1 - 30 days) and Intermediate-Term (1-6 months)

	NOAEL = 0.5 mg/kg/day

(Inhalation adsorption rate = 100% oral equivalent)	UFA  = 10x

UHH = 10x

FQPA SF = 1x	LOC for MOE  = 100

(Occupational)	90-Day - rat

LOAEL = 10 mg/kg/day based on hyalinization of hepatocytes, increased
eosinophilia, reduced granulation,   increased liver weights in males
and females, and increases in plasma alkaline phosphatase, alanine
transaminase and aspartate transaminase in males.

Cancer Classification	“Not Likely to be Carcinogenic to Humans.”

NOAEL = no observed adverse effect level.  LOAEL = lowest observed
adverse effect level.  UF = uncertainty factor.  UFA = extrapolation
from animal to human (interspecies). UHH = potential variation in
sensitivity among members of human population (intraspecies). FQPA SF=
FQPA safety factor.  PAD = population adjusted dose (a = acute, c =
chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level
of concern.  RA = risk assessment

* = The dermal absorption factor was estimated to be 20% based on the
results of structurally related chemicals: acifluorfen (20% absorption
rate) and oxifluorofen (18% absorption rate).

Section 3.  Residue Chemistry

The residue chemistry database is essentially complete except for
supporting data required as a condition of registration for certain new
uses (D. Davis, D325797, 2/28/2006). The supporting data are listed in
the Attachment.

Section 4.  Dietary Exposure

Acute dietary risk assessments were not required as there were no
endpoints identified attributable to a single exposure of fomesafen. 
Chronic dietary risk assessments were conducted for fomesafen sodium
using the Dietary Exposure Evaluation Model (DEEM-FCID™), Version
2.03, which used food consumption data from the United States Department
of Agriculture’s (USDA’s) Continuing Surveys of Food Intakes by
Individuals (CSFII) from 1994-1996 and 1998.  The assumptions of these
assessments were tolerance level residues and 100% crop treated.  The
highest exposure and risk estimates based on exposure from food only
were for the “children 1 - 2 years” population subgroup.  The
exposure for food was 0.000041 mg/kg/day, which utilized 1.6% of the
cPAD (chronic population adjusted dose).

Section 5.  Aggregate and Cumulative Exposure

There are no residential uses formulated with fomesafen. Therefore, the
aggregate assessment considers only chronic exposure for food and
drinking water.

	

An aggregate dietary assessment using DEEM-FCID™ was conducted in
which the estimated drinking water concentrations (EDWCs) for ground and
surface water from the Environmental Fate and Effects Division were
included directly in the assessment (Table 3). The dietary exposure
analyses in this assessment resulted in chronic dietary risk estimates
for food and water that were below the Agency’s level of concern.  The
highest exposure and risk estimates were for the “all infants”
population subgroup.  The exposure for food plus surface water was
0.000766 mg/kg/day, which utilized 31% of the cPAD; and the exposure for
food plus ground water was 0.000107 mg/kg/day, which utilized 4.3% of
the cPAD.  

Table 3.  	Summary of Chronic Dietary Exposure and Risk for Fomesafen
Sodium Incorporating    Food and Surface and Ground Water As Drinking
Water Sources

Population Subgroup 1	Surface Water  	Ground Water  

 	EDWC (ppb)	 Exposure (mg/kg/day)	% cPAD 	EDWC (ppb)	 Exposure

(mg/kg/day)	% cPAD  

General U.S. Population	10.535	0.000239	9.5	1.0	0.000038	1.5

All Infants (< 1 year old) 	10.535	0.000766	31	1.0	0.000107	4.3

Children 1-2 years old	10.535	0.000371	15	1.0	0.000072	2.9

Children 3-5 years old	10.535	0.000344	14	1.0	0.000064	2.6

Children 6-12 years old	10.535	0.000236	9.4	1.0	0.000044	1.7

Youth 13-19 years old	10.535	0.000175	7.0	1.0	0.000030	1.2

Adults 20-49 years old	10.535	0.000221	8.8	1.0	0.000033	1.3

Adults 50+ years old	10.535	0.000231	9.2	1.0	0.000033	1.3

Females 13-49 years old	10.535	0.000219	8.8	1.0	0.000032	1.3

1 The values for the population with the highest dietary exposure and
risk estimates are bolded.

Section 6.  Occupational Exposure

There is potential for occupational exposure to fomesafen during mixing,
loading, application, and postapplication activities. The occupational
database is adequate, and all relevant occupational scenarios are
assessed for all existing uses.  The latest risk assessment (M. Lloyd,
D294458, 215/2006) indicated most of the occupational scenarios did not
result in risks of concern, with the exception of inhalation risks to
mixer/loader scenario for aerial application.  Inhalation MOEs for the
mixer/loader scenarios for aerial application were of concern with
baseline PPE (includes long-sleeve shirt, long pants, and gloves).  PF5
respirators are required to achieve acceptable MOEs (i.e., greater than
the target MOE of 100).  All of the dermal MOEs are greater than the
target MOE of 100 with single layer PPE for handlers and baseline PPE
for applicators and flaggers. Single layer PPE is mandated on the
proposed fomesafen label under consideration. All of the
post-application MOEs are greater than 100 on Day 0, and the risks are
not of concern.

Section 7.   Incident Report of human Health Effects Caused by
Fomesafen.

The available incident report data bases (1982 to the present) indicate
skin irritation in four cases and no reports of other ill effects (M. S.
Hawkins, D331945, 7/25/2006).

Section 8.  Anticipated Data Needs

HED anticipates that a revised risk assessment for fomesafen will not be
needed for registration review.  Additional data have been previously
required as conditions of registration for certain new uses. These are
listed in the Attachment to this document for informational purposes. 

Section 10.  Tolerances

Tolerances are established under 40 CFR §180.433 for the residues of
fomesafen 5-[2-chloro-4-(trifluoromethyl)
phenoxy]-N-(methylsulfonyl)-2-nitrobenzamide from the application of its
sodium salt as shown in the table below. 

No Codex maximum residue limits (MRLs) have been established for
residues of fomesafen.  Canadian MRLs have been established for residues
of fomesafen in/on dry beans, lima beans, snap beans, and soybeans at
0.05 ppm.

Commodity	U.S.  

(ppm)	Codex 

(mg/kg)	Canada

(ppm)

Soybean	0.050

0.05

Cotton,  undelineated  seed	0.025

Cotton,  gin byproducts	0.025 

Bean dry 		0.025 

0.05

Bean, snap, succulent	0.025 

0.05

Lima beans

	0.05

Section 11.  Overall Conclusions

HED anticipates no additional human health risk assessments will be
needed for the existing uses of fomesafen.  

Section 12.  Reference Memoranda

The memoranda listed in the following table were considered in the
development of this document.

HED Memoranda Relevant to Registration Review

Author	Barcode	Date

	D. Davis	D325797	2/28/06	Fomesafen Sodium. Human Health Risk Assessment
for a Proposal to Amend Use on Soybeans, and Proposal to Add uses on
Cotton, Dry Bean, and Snap Bean.  

D. Davis 

4/25/06	Fomesafen Sodium. Addendum to the 2/28/02  Human Health Risk
Assessment for a Proposal to Amend Use on Soybeans, and Proposal to Add
uses on Cotton, Dry Bean, and Snap Bean.  

J. Kidwell 	TXR # 0053835	11/3/05	Second report of the Cancer Assessment
Review Committee

M. Lloyd	D294458	2/15/06	Fomesafen: Occupational and  Residential
Exposure and Risk assessment for the Registration for New  Uses on Dry
Beans, Snap Beans, and Cotton.

T. Goodlow	D325798	2/15/06	Chronic Dietary Exposure Assessment for the
HED Human Health Risk Assessment. 

W. Greear	TXR # 0052977	1/20/06	Fomesafen: Toxicological Assessment for
Incorporation into Risk Assessment Document.

D. Davis 	D325801	4/25/06	Fomesafen Sodium: Residue Chemistry Summary
for Human Health Risk Assessment, a Proposal to Amend use on Soybeans,
and Proposals to Add uses on Cotton, Dry Bean, and Snap Bean.

J. Hetrick	D314014	9/27/05	Tier II Drinking water Assessment for
Fomesafen use
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1.	Upgrade the cotton metabolism study with additional information
(actual 	      	application rate for higher treatment rate, date of
sample analysis).

2	Submit raw data to support the submitted method validation data.

3	Modifications for enforcement method to incorporate specific
information on dry 	bean, snap bean, and soybean aspirated fraction.

4.	Submit multiresidue method testing data for fomesafen.

5.	Data on the stability of residues of fomesafen in/on cotton gin
byproducts, 	soybean hulls and oil, and field corn or sorghum forage &
stover.

6.	Additional data to upgrade the available cotton crop field trial data
including soil 	characteristic data, summary of weather conditions at
individual sites, indications 	as to whether irrigation was used, &
average historical data for temperature & 	rainfall for the duration of
the field trial intervals. 

		

Guideline   869.1200	Acute dermal toxicity study

Guideline   870.1300	Acute inhalation toxicity study

Guideline   869.2600	Skin sensitization study

	

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