Document ID: EPA-HQ-OPP-2007-0431-0008
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-06-20T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF PREVENTION, PESTICIDES 

AND TOXIC SUBSTANCES

  SEQ CHAPTER \h \r 1 MEMORANDUM			

May 30, 2007								

SUBJECT:	Mefluidide, Diethanolamine Mefluidide, and Potassium
Mefluidide- Phase 2 ( 30- Day Error only Correction), HED Chapter of the
Re-registration Eligibility Decision Document (RED).  PC Code: 114001,
114002, 114003.  Reregistration Case No. 2370.  DP Barcode D334500.

	  SEQ CHAPTER \h \r 1 

								

FROM:	  SEQ CHAPTER \h \r 1 Yan Donovan, Chemist and Risk Assessor

          		Reregistration Branch 4

		Health Effects Division (7509C)

		And

		Abdallah Khasawinah, Toxicologist

		Reregistration Branch 4

Health Effects Division (7509C))

THROUGH:	Susan Hummel

		  SEQ CHAPTER \h \r 1 Branch Senior Scientist

		Reregistration Branch 4

		Health Effects Division (7509C)

TO:		  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 Wilhemena Livingston,
Chemical Review Manager

		Reregistration Branch I

		Special Review & Reregistration Division (7508W)

		

Attached is Health Effect Division’s phase II risk assessment for  
SEQ CHAPTER \h \r 1 mefluidide RED.  This is a revised risk assessment
(from phase I) incorporating registrant’s error only comments dated
May 22, 2007.  The team reviewers who contributed to the disciplinary
chapters and the risk assessment are listed below: 

Hazard Identification Assessment; Abdallah Khasawinah, D322246, 1/31/07.

Occupational and Residential Exposure Assessment; Yan Donovan, D324823,
2/28/07.

	Incident Report; M. Hawkins, D324824, 07/25/06.

Drinking Water Assessment; James Hetrick from EFED, D334508, 03/08/07.

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc163291251"  1.0      
Executive Summary	  PAGEREF _Toc163291251 \h  4  

  HYPERLINK \l "_Toc163291252"  2.0	Ingredient Profile	  PAGEREF
_Toc163291252 \h  8  

  HYPERLINK \l "_Toc163291253"  2.1.	Summary of Registered/Proposed Uses
  PAGEREF _Toc163291253 \h  8  

  HYPERLINK \l "_Toc163291254"  2.2  	Structure and Nomenclature	 
PAGEREF _Toc163291254 \h  10  

  HYPERLINK \l "_Toc163291255"  2.3	Physical and Chemical Properties	 
PAGEREF _Toc163291255 \h  12  

  HYPERLINK \l "_Toc163291256"  3.0	Metabolism Assessment	  PAGEREF
_Toc163291256 \h  15  

  HYPERLINK \l "_Toc163291257"  3.1 	Rat Metabolic Profile	  PAGEREF
_Toc163291257 \h  15  

  HYPERLINK \l "_Toc163291258"  3.2	Nature of the Residue in Foods	 
PAGEREF _Toc163291258 \h  15  

  HYPERLINK \l "_Toc163291259"  3.3 	Environmental Degradation	  PAGEREF
_Toc163291259 \h  16  

  HYPERLINK \l "_Toc163291260"  4.0	Hazard Characterization/Assessment	 
PAGEREF _Toc163291260 \h  16  

  HYPERLINK \l "_Toc163291261"  4.1 Hazard characterization	  PAGEREF
_Toc163291261 \h  16  

  HYPERLINK \l "_Toc163291262"  4.2 Hazard considerations For Women and
Children	  PAGEREF _Toc163291262 \h  24  

  HYPERLINK \l "_Toc163291263"  4.2.1. Adequacy of the Toxicity Database
  PAGEREF _Toc163291263 \h  24  

  HYPERLINK \l "_Toc163291264"  4.2. 2. Evidence of Neurotoxicity	 
PAGEREF _Toc163291264 \h  24  

  HYPERLINK \l "_Toc163291265"  4.2.3. Developmental Toxicity Study
Conclusions	  PAGEREF _Toc163291265 \h  24  

  HYPERLINK \l "_Toc163291266"  4.2.4. Reproductive Toxicity Study	 
PAGEREF _Toc163291266 \h  25  

  HYPERLINK \l "_Toc163291267"  4.2.5. Additional Information from
Literature sources	  PAGEREF _Toc163291267 \h  27  

  HYPERLINK \l "_Toc163291268"  4.3. Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc163291268 \h  27  

  HYPERLINK \l "_Toc163291269"  4.3.1. Acute Reference Dose (aRfD)	 
PAGEREF _Toc163291269 \h  27  

  HYPERLINK \l "_Toc163291270"  4.3.2. Chronic Reference Dose (cRfD)	 
PAGEREF _Toc163291270 \h  28  

  HYPERLINK \l "_Toc163291271"  4.3.3. Incidental Oral Exposure
(Short-and Intermediate-term durations: 1 day – 6 months)	  PAGEREF
_Toc163291271 \h  28  

  HYPERLINK \l "_Toc163291272"  4.3.4. Dermal Absorption Factor	 
PAGEREF _Toc163291272 \h  28  

  HYPERLINK \l "_Toc163291273"  4.3.5. Dermal Exposure (Short and
Intermediate:  (1-30 days and 30 d-180 days)	  PAGEREF _Toc163291273 \h 
28  

  HYPERLINK \l "_Toc163291274"  4.3.6. Inhalation (Short- and
Intermediate-Term)	  PAGEREF _Toc163291274 \h  29  

  HYPERLINK \l "_Toc163291275"  4.3.7. Margins of Exposure	  PAGEREF
_Toc163291275 \h  29  

  HYPERLINK \l "_Toc163291276"  4.3.8. Classification of Carcinogenic
Potential	  PAGEREF _Toc163291276 \h  29  

  HYPERLINK \l "_Toc163291277"  5.0	Public Health Data	  PAGEREF
_Toc163291277 \h  31  

  HYPERLINK \l "_Toc163291278"  5.1	Incident Reports	  PAGEREF
_Toc163291278 \h  31  

  HYPERLINK \l "_Toc163291279"  6.0  	Exposure
Characterization/Assessment	  PAGEREF _Toc163291279 \h  32  

  HYPERLINK \l "_Toc163291280"  6.1	Dietary Exposure/Risk Pathway	 
PAGEREF _Toc163291280 \h  32  

  HYPERLINK \l "_Toc163291281"  6.1.1 	Food Exposure/Risk Pathway	 
PAGEREF _Toc163291281 \h  32  

  HYPERLINK \l "_Toc163291282"  6.1.2   Water Exposure/Risk Pathway	 
PAGEREF _Toc163291282 \h  32  

  HYPERLINK \l "_Toc163291283"  6.2	Dietary Exposure Estimates	  PAGEREF
_Toc163291283 \h  33  

  HYPERLINK \l "_Toc163291284"  6.3	Residential (Non-Occupational)
Exposure/Risk Pathway	  PAGEREF _Toc163291284 \h  34  

  HYPERLINK \l "_Toc163291285"  6.3.1.  Residential Handler Exposure and
Risks	  PAGEREF _Toc163291285 \h  34  

  HYPERLINK \l "_Toc163291286"  6.3.2.  Residential Post Application
Exposure and Risks	  PAGEREF _Toc163291286 \h  36  

  HYPERLINK \l "_Toc163291287"  7.0	Aggregate Risk Assessments and Risk
Characterization	  PAGEREF _Toc163291287 \h  38  

  HYPERLINK \l "_Toc163291288"  7.1	Aggregate Risk	  PAGEREF
_Toc163291288 \h  38  

  HYPERLINK \l "_Toc163291289"  7.2	Cancer Risk	  PAGEREF _Toc163291289
\h  39  

  HYPERLINK \l "_Toc163291290"  8.0	Cumulative Risk
Characterization/Assessment	  PAGEREF _Toc163291290 \h  39  

  HYPERLINK \l "_Toc163291291"  9.0	Occupational Exposure/Risk Pathway	 
PAGEREF _Toc163291291 \h  39  

  HYPERLINK \l "_Toc163291292"  9.1	Short/Intermediate-Term Handler Risk
  PAGEREF _Toc163291292 \h  39  

  HYPERLINK \l "_Toc163291293"  9.2	Post-application Exposure and Risk	 
PAGEREF _Toc163291293 \h  41  

  HYPERLINK \l "_Toc163291294"  10.0  	Data Needs and Label Requirements
  PAGEREF _Toc163291294 \h  42  

 

1.0      	Executive Summary	

  SEQ CHAPTER \h \r 1 A risk assessment is being conducted for
mefluidide, mefluidide diethanolamine salt, and mefluidide potassium
salt to support the mefluidide RED.  For the purposes of this
assessment, all of the three active ingredients are collectively
referred to as mefluidide.  SEQ CHAPTER \h \r 1 

Mefluidide is a member of the class of anilide.  Mefluidide is a plant
growth regulator that is applied postemergence when needed.  It is used
to control ornamental and non-ornamental woody plants, ground cover,
hedges trees, turf grasses, grass and broadleaf weeds by inhibiting
plant cell division, stem elongation and seed head development.  It is
also registered for growth control of low maintenance turf on
rights-of-ways, airports, public and industrial sites.  Mefluidide
products can also be used on residential lawns.  There are multiple
active ingredient products that contain an additional plant growth
regulator and herbicides such as paclobutrazol, imazapyr, and
imazethapyr.  These ingredients are not assessed in this document. 
Current formulations include granular, liquid ready- to- use, and
soluble concentrate/liquid.   Mefluidide can be applied as a band
treatment, broadcast, spot treatment, and spray.  The equipment used to
apply mefluidide includes backpack sprayer, groundboom, hand held pump
sprayer, handgun sprayer, hose-end sprayer, power sprayer, high pressure
handwand, and spreader (push-type and belly grinder).

Based on the structural similarities of mefluidide and its
diethanolamine (DEA) and potassium salts, where they all share the same
anion- anilide, and the physical and chemical properties of the DEA and
potassium salts, where they dissociate 100% back to free mefluidide in
aqueous environments, the risk assessment team concluded that mefluidide
DEA and potassium salts are biologically equivalent to mefluidide and
thus they share the same toxicity as the free mefluidide.  Therefore, it
is reasonable to bridge mefluidide toxicity data to mefluidide salts and
vice versa.

The toxicology data base of mefluidide and its salts is considered
adequate for the purposes of hazard and dose response assessment. 
Mefluidide has low acute toxicity by the oral, dermal and inhalation
routes (toxicity category III and IV).  It is a weak eye or dermal
irritant (toxicity category III and IV).  Mefluidide did not cause
dermal sensitization in the guinea pig.  In rats and rabbits, critical
effects of acute toxicity were tremors, hunched posture, salivation,
reduced body weight and body weight gain.

Subchronic and chronic toxicity of mefluidide is manifested by decreased
body weight and body weight gain in several species tested (rats,
rabbits and dogs).  Dogs appeared to be most sensitive species with the
critical toxicological effects of cortical nephrosis and body weight
loss.  In rats and rabbits, critical effects observed were tremors,
hunched posture, salivation, reduced body weight and body weight gain. 
Based on lack of evidence of carcinogenicity in both rats and mice,
mefluidide was considered as not likely to be carcinogenic to humans. 
Mefluidide exhibited a negative response in various genotoxicity
screening assays. 

Developmental effects of mefluidide in rats included increased number of
early resorptions and mean postimplantation loss.  These effects were
observed at the same dose that caused maternal toxicity indicating there
was no increased susceptibility to fetuses (LOAEL = 115 mg/kg/day, NOAEL
= 58 mg/kg/day).  The maternal toxicity included tremors, decreased body
weight, weight gain and mortality.  In rabbit, the LOAEL/NOAEL for
developmental toxicity were above the highest dose tested (60
mg/kg/day).  Although this study is not acceptable alone, taking into
the consideration of the results from the 14-day rabbit oral study where
mortality was seen at 100 mg/kg/day, and tremors and 100% mortality were
noted at 200 mg/kg/day, the NOAEL from the rabbit developmental study is
acceptable.  In the 3-generation rat reproduction toxicity study, the
offspring toxicity was characterized by decreased body weights in both
sexes and both litters in all generations.  The reproductive LOAEL was
not observed (NOAEL = 346/604 mg/kg bw/day in males and females). 

Endpoints and dose responses have been selected for all exposure routes
and durations, except for dermal exposure, where it was determined that
no quantitative dermal risk assessment is needed. 

There are no agricultural or any food related pesticide uses of
mefluidide.   Therefore, no dietary exposure from food is expected. 
However, there is potential for drinking water exposure due to the
outdoor uses of mefluidide.   A drinking water assessment was conducted
by the Environmental Fate and Effects Division (EFED) using Tier II
(PRZM-EXAMS) for surface water modeling and Tier 1 (SCI-GROW) for
groundwater modeling.  The mefluidide acid concentrations in surface
water are not expected to exceed 32 μg/L (= 32 ppb) for the 1 in 10
year daily peak concentration, 10 μg/L (= 10 ppb) for the 1 in 10 year
annual concentration, and 5 μg/L for the 30 year annual average
concentration.  Mefluidide acid concentrations in ground water are not
expected to exceed 1.0 μg/L.

Dietary (Water only) Exposure and Risk Estimates

Acute and chronic dietary (water only) risk assessments were conducted
using the Dietary Exposure Evaluation Model (DEEM).  The dietary
exposure assessments were performed using exposures from surface water
only, as there are no food uses for this chemical.  The estimated
surface drinking water concentration (32 ppb) was used in acute dietary
while the 10 ppb was used for chronic.  The analysis results indicated
that the dietary risks are below the Agency’s level of concern.  At
the 95th percentile, the acute dietary exposure to U.S. population was
0.0017 mg/kg/day, which utilized < 1% of the acute reference dose
(aRfD).  The exposure for all infants, which was the most highly exposed
population subgroup, was 0.006 mg/kg/day, which utilized 1% of the aRfD.
  For chronic dietary exposure, the exposure for U.S. population was
0.0002 mg/kg/day, which utilized 1% of the chronic reference dose
(cRfD).  The exposure for all infants, which was the most highly exposed
population subgroup, was 0.0007mg/kg/day, which utilized 5% of the cRfD.

Residential Exposure and Risk Estimates	

None of the labels prohibit use by homeowners.  The residential handler
risks were assessed using standard assumptions, maximum label rates,
Outdoor Residential Exposure Task Force (ORETF) studies and Pesticide
Handlers Exposure Database (PHED) unit exposure data.   The MOEs are all
>100, which means the risks are not of concern.

Residential Post Application Exposure and Risk Estimates

Since no dermal endpoints were selected, the residential post-
application assessments were only conducted for Children (through
incidental oral).   Incidental oral exposures include exposures from
hand- to- mouth, object- to- mouth and soil ingestion of treated turf
(all considered short-term).  Calculations used the Residential SOPs and
maximum label rates.  The combined MOE is >100 which means that the risk
is below EPA’s level of concern.  The residential post- application
exposures to toddlers from ingesting granules that have been applied to
residential turf were also assessed using a standard method as outlined
in the Residential SOPs.  The MOE was then calculated using the acute
dietary NOAEL of 58 mg/kg/day and it is > 100.   This means that the
risks for toddler exposures from granular ingestion are not of concern.

Aggregate Risk Assessment (food + water + residential exposure)

Although an aggregate risk assessment is not required under current
Agency policies for non-food use chemicals, to ensure that the public
health is adequately protected, a screening level aggregate risk
assessment was conducted for mefluidide.  For acute and chronic
aggregate risks, the only exposure is from drinking water.  As stated
above, the dietary exposures (drinking water only) do not exceed 1% of
the aRfD/cRfD for adult and 5% of the aRfD/cRfD for children.  For
short- term, no aggregate is needed for adults since there are no
residential post- application exposures to adults.  When considering the
dietary exposure (drinking water only) as a background exposure to
Children for short-term risk,  the level of dietary exposure (0.0007
mg/kg/day from chronic food) is negligible when compared to the combined
incidental oral exposure (0.019 mg/kg/day) or the granule ingesting dose
(0.098 mg/kg/day).  No intermediate-term residential risk was
identified.  Therefore, short- and intermediate- term aggregate is not
of concern.

Occupational Exposure and Risk Estimates	

The MOEs for occupational handler exposures were calculated for
short/intermediate term inhalation exposures using standard assumptions
and unit exposure data.  The unit exposure data were taken from the PHED
and the ORETF studies for professional lawn care operators. All of the
MOEs are > 100 with baseline personal protective equipment (PPE) which
means that the risks are not of concern and respiratory protection is
not needed. 

Occupational post application dermal risks were not assessed because
there is not likely to have occupational post-application scenario.   In
addition, no dermal endpoints were selected.  Mefluidide is only applied
outdoors and it is not a volatile compound, inhalation exposures are
negligible.

Risk Characterization

All MOEs for occupational and residential handlers are greatly above
100.  No refinement is needed.  The risk assessments for post-
application exposures for Children are conservative because they are
based upon day 0 TTRs and soil residue values and did not account for
dissipation.  

Environmental Justice Considerations:

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, "Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations,"   HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures. 
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Survey of Food Intake by Individuals (CSFII) and are used in pesticide
risk assessments for all registered food uses of a pesticide.  These
data are analyzed and categorized by subgroups based on age, season of
the year, ethnic group, and region of the country.  Additionally, OPP is
able to assess dietary exposure to smaller, specialized subgroups and
exposure assessments are performed when conditions or circumstances
warrant.  Whenever appropriate, non-dietary exposures based on home use
of pesticide products and associated risks for adult applicators and for
toddlers, youths, and adults entering or playing on treated areas
postapplication are evaluated.  Further considerations are currently in
development as OPP has committed resources and expertise to the
development of specialized software and models that consider exposure to
bystanders and farm workers as well as lifestyle and traditional dietary
patterns among specific subgroups.

Review of Human Research:

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.  These studies (listed in Appendix B) have been determined to
require a review of their ethical conduct, and have received that
review.



2.0	Ingredient Profile

Mefluidide is a plant growth regulator that is applied postemergence
when needed.  It is used to control the growth of ornamental and
non-ornamental woody plants, ground cover, hedges, trees, turf grasses,
grass and broadleaf weeds by inhibiting plant cell division, stem
elongation and seed head development.  It is registered for uses on low
maintenance turf on rights-of-ways, airports, and industrial sites.  It
can also be used on ornamental and or shade trees, ornamental ground
cover, ornamental herbaceous plants, golf course, hospitals/medical
institutions premises ornamental lawns and turf, and residential lawns.
There are multiple active ingredient products that contain an additional
plant growth regulator and herbicides such as paclobutrazol, imazapyr
and imazethapyr.  Current formulations include granular, liquid ready-
to- use, and soluble concentrate/liquid.   Mefluidide can be applied as
a band treatment, broadcast, spot treatment, and spray.  The equipment
used to apply mefluidide includes backpack sprayer, groundboom, hand
held pump sprayer, handgun sprayer, hose-end sprayer, power sprayer,
high pressure handwand, and spreader (push-type and belly grinder).  The
two registrants for mefluidide, PBI/Gordon (technical and end-use
registrant) and The Scotts Company (end-use registrant) are supporting
all of the existing uses for reregistration on their respective labels.

	2.1.	Summary of Registered/Proposed Uses

Based on the information provided by the registrant at the 11-08-06
SMART meeting, all existing mefluidide label uses (total 11 product
labels) are supported by the registrant.  The registrant also indicated
that among all labels, only three have active sales: Embark 2S (EPA Reg
# 2217-759), Embark T&O (EPA Reg#2217-768), and Stronghold (EPA
Reg#2217-802).

HED has analyzed all existing mefluidide product labels.  The label
suggested use patterns, formulations, application methods and maximum
application rates are summarized in Table 2.1 below.

Table 2.1 – Summary of Use Patterns, Formulations, and Application
Rates for Mefluidide.

Product Type	Product Label/names	Application Equipment	Use Sites

	Maximum application rates	Maximum Spray dilution 

Liquid	2217-759

(EMBARK 2-S)	High pressure handwand 	Ornamental trees, 	1.0 lbs ai/A
0.01 lbs ai/gallon

Groundboom, Turfgun	Turfgrass, golf course, rights-of-ways

0.067 lbs ai/gallon

Liquid	2217-763

(EMBARK 1-S)	Groundboom, Backpack sprayer	Turf, commercial-industrial,
public area	1.0 lbs ai/A	0.067 lbs ai/gallon

Liquid	2217-765

(EMBARK 1-L)	Groundboom,

Backpack sprayer	Turf, commercial-industrial, public area	1.0 lbs ai/A
0.067 lbs ai/gallon

Liquid	2217-766

(EMBARK 2-L)	Groundboom, Backpack sprayer	Turf, commercial-industrial,
public area	1.0 lbs ai/A	0.067lbs ai/gallon

Liquid	2217-768

(EMBARK E-Z-TU-USE)	Hand pump (pressure spray),

Hose end sprayers	Turf grass

	1.0 lbs ai/A	0.008 lbs ai/gallon

	Ornamentals	0.43 lbs ai/A	0.01 lbs ai/gallon

Liquid	2217-802

(EH1135 PGR)	Conventional power spray	Turf, commercial-industrial	0.43
lbs ai/A	0.029 lbs ai/gallon

Granules	538-181

(St. Aug.GR w/Fertilizer)	Spreader	Lawn	0.50 lbs ai/A	N/A

Granules	538-200

(Scotts Turf Manager)	Spreader	Lawn 	0.04 lbs ai/A	N/A

RTU	2217-787

(EMBARK R-T-U Northern)	 Sprinkler can	Residential areas	0.11 lbs ai/A
N/A

RTU	2217-788

(EMBARK R-T-U Southern)	Sprinkler can	Residential areas	1.23 lbs ai/A
N/A

RTU	2217-809

(ER 721)	Sprinkler can	Residential areas	1.0 lbs ai/A	N/A

	RTU = Ready- to- Use 

  SEQ CHAPTER \h \r 1 2.2  	Structure and Nomenclature

TABLE 2.2a.	Test Compound Nomenclature (Mefluidide)

Chemical Structure	

 

Empirical Formula	C11H13F3N2O3S

Common name	Mefluidide

Company experimental name	MBR 12325

IUPAC name
5′-(1,1,1-trifluoromethanesulfonamido)acet-2′,4′-xylidide

CAS name
N-[2,4-dimethyl-5-[[(trifluoromethyl)sulfonyl]amino]phenyl]acetamide

CAS Registry Number	53780-34-0

End-use product/EP	St. Aug.GR w/Fertilizer (Reg. #538-181), Scotts Turf
Manager (Reg.#538-200)

Chemical Class	Plant growth regulators 

Known Impurities of Concern	None

TABLE 2.2b.	Test Compound Nomenclature (Diethanolamine Mefluidide)

Chemical Structure	

 

5′-(1,1,1-trifluoromethanesulfonamido)acet-2′,4′-xylidide -
2,2′-iminodiethanol (1:1)

CAS name
N-[2,4-dimethyl-5-[[(trifluoromethyl)sulfonyl]amino]phenyl]acetamide
compound with 2,2′-iminobis[ethanol] (1:1)

CAS Registry Number	53780-36-2 (This substance is a derivative of
mefluidide [53780-34-0]).

End-use product/EP	EMBARK 2-S (Reg.# 2217-759), EMBARK 1-S (Reg.#
2217-763), EMBARK E-Z-TU-USE (Reg.# 2217-768), EH1135 PGR (Reg.#
2217-802), EMBARK R-T-U Northern (Reg.# 2217-787), EMBARK R-T-U Southern
(Reg.# 2217-788), ER 721 (Reg.# 2217-809)

Chemical Class	Plant growth regulators 

Known Impurities of Concern	None

TABLE 2.2c.	Test Compound Nomenclature (Potassium Mefluidide)

Chemical Structure	

 

Empirical Formula	C11H12F3KN2O3S

Common name	Mefluidide

Company experimental name	MBR 12325

IUPAC name	potassium
(EZ)-N-[5-(1,1,1-trifluoromethanesulfonamido)-2,4-xylyl]acetamide

CAS name
N-[2,4-dimethyl-5-[[(trifluoromethyl)sulfonyl]amino]phenyl]acetamide
monopotassium salt

CAS Registry Number	83601-83-6

End-use product/EP	EMBARK 1-L (Reg.# 2217-765), EMBARK 2-L (Reg.#
2217-766)

Chemical Class	Plant growth regulators 

Known Impurities of Concern	None

	Physical and Chemical Properties

TABLE 2.3.a	Physicochemical Properties  (Mefluidide)

Parameter	Value	Reference

Molecular Weight	310.3	HED memo of 3/13/89, A. Smith.  Accession No.
259274. RCB No. 126

Melting point/range	183-185 °C

	pH	4.6 @ 25°C (1% aqueous

dispersion)

	Density	Not available 

	Water solubility (25 °C)	0.18g/L at 25°C 

	Solvent solubility (temperature not specified)	N-Octanol.

= 17 g/L

	Vapor pressure (25°C)	<1.0E-4 mmHg  @ 25°C

	Dissociation constant, pKa	pKa  = 4.6

	Octanol/water partition coefficient,  Log(KOW) (25 °C)	Remain
outstanding 

	UV/visible absorption spectrum  	Max at 287 nm

	

TABLE 2.3b.	Physicochemical Properties (Diethanolamine Mefluidide)

Parameter	Value	Reference

Molecular Weight	413.3	HED memo of 3/2/93, C. Olinger, D166847 and
D179233.  MRIDs 41913301 and 02, 422513 01 through 04, 42309901,
42283301 through 03, 42331401 and 02.

Melting point/range	106-108 °C

	pH	6.98 @ 25°C (1% aqueous

dispersion)

	Density	0.69 g/cm3 typical @ 25°C 

	Water solubility (20 °C)	566 mg/g at 25°C 

	Solvent solubility (temperature not specified)	N-Octanol.

= 22 mg/g

	Vapor pressure (25°C)	<1.0 E-7 mmHg @ 25°C	HED memo of W. Smith,
2/16/93, D183266.  MRID Nos: 42355501.

Dissociation constant, pKa	100% dissociates in aqueous solution. 
Mefluidide pKa  = 4.6	HED memo of 3/2/93, C. Olinger, D166847 and
D179233. MRIDs 41913301 and 02, 422513 01 through 04, 42309901, 42283301
through 03, 42331401 and 02.

Octanol/water partition coefficient,  Log(KOW) (25 °C)	3.2 x10-2

	UV/visible absorption spectrum  	Max at 254 nm

	

TABLE 2.3c.	Physicochemical Properties (Potassium Mefluidide)

Parameter	Value	Reference

Molecular Weight	348.4	HED memo of 11/24/92, F. Toghrol, D179244. 
MRIDs: 42251401 through 05, 42282001, 42282002, 42302301, and 42323501.

Melting point/range	118- 120 °C

	pH	8.6 @ 25°C (1% aqueous

dispersion)

	Density	0.85 g/cm3 typical @ 25°C 

	Water solubility (25 °C)	510 mg/g 

	Solvent solubility (temperature not specified)	N-Octanol.

= 57 mg/g

	Vapor pressure (25°C)	< 1.0 E-7 mmHg @ 25°C

	Dissociation constant, pKa	100% dissociates in aqueous solution.
Mefluidide pKa  = 4.6

	Octanol/water partition coefficient,  Log(KOW) (25 °C)	Not available

	UV/visible absorption spectrum  	Not available

	

Based on the structural activities of mefluidide and its DEA and
potassium salts, where they all have similar structures (identical
benzene ring and functional groups, i.e., share the same anion-
anilide), and the above physical and chemical properties of the salts
where they dissociate 100% back to free mefluidide in aqueous
environment, the risk assessment team determined that mefluidide DEA and
potassium salts are biologically equivalent to mefluidide and thus they
share the same toxicity as the free mefluidide.  Therefore, it is
reasonable to bridge mefluidide toxicity data to mefluidide salts and
vice versa.

3	e	.0	Metabolism Assessment

	

3.1 	Rat Metabolic Profile

Mefluidide was almost completely absorbed following oral ingestion
(approximately 96%) and rapidly eliminated within 24 hours.  A majority
of dose was eliminated in urine (86-89 %) and remainder in feces after a
single oral dose in 24 hours. Residue consisted of mefluidide (97%) and
2 unidentified metabolites (1.2% and 0.5%) and unidentified polar
material (0.7%).  Excretion of the radioactivity in expired air was not
detected.  The chemical is unlikely to accumulate in body since it was
excreted almost completely within 24 hrs and steadily declined
thereafter. 

3.2	Nature of the Residue in Foods

	

	Not applicable.  There are no food uses.

3.3 	Environmental Degradation

	

The only identified degradation product was 5-amino-2,
4-dimethyltrifluoromethanesulfonilide.  It was found at a maximum daily
concentration of 2.8% of applied dose (MRID 43162201, aerobic soil). 
The risk assessment team concluded that this degradate is not of concern
based on its structure (structurally similar to the parent, there fore
it is not likely to be significantly more toxic than the parent), and
the fact that it is a minor degradate (<10% of the applied dose).  The
residue of concern for drinking water assessment is parent only.

4.0	Hazard Characterization/Assessment 

	4.1 Hazard characterization

Mefluidide has shown low acute toxicity by the oral, dermal and
inhalation routes (Toxicity Category III and IV).  It is a weak eye or
dermal irritant (Toxicity Category III and IV).  However, the precursor
of mefluidide (S-15733: manufacturing starting material) caused eye
irritation (Toxicity Category II).  Mefluidide did not cause dermal
sensitization in the guinea pig.  In rats and rabbits, critical effects
of acute oral toxicity (occurring at doses of 100 mg/kg/day and above)
were tremors, hunched posture, salivation, reduced body weight and body
weight gain.

Mefluidide and its diethanolamine salt subchronic and chronic toxicity
are manifested by decreased body weight and body weight gain in several
species tested (rats, rabbits and dogs). Dogs are most sensitive to
these effects, which occur at doses as low as 15 mg/kg/day in diets fed
for one year. In addition, dogs fed with mefluidide for one year
exhibited chronic cortical nephrosis at doses of 150 mg/kg/day.
Increased incidence of liver hyperplastic nodules in both sexes was
observed in mice fed with mefluidide at doses of 270 mg/kg/day and
higher, but there was no oncogenic response in mice at doses as high as
900 mg/kg/day.  Rats fed with mefluidide at doses up to 300 mg/kg/day
did not exhibit any carcinogenic response either.  Based on lack of
carcinogenic response in both rats and mice, mefluidide is considered as
not likely to be carcinogenic to humans. 

Mefluidide exhibited a negative response in various genotoxicity
screening assays (bacterial reverse mutation, in vitro mouse lymphoma
gene mutation, in vitro mammalian chromosome aberration, in vivo sister
chromatid exchange, unscheduled DNA synthesis).

Mefluidide and its DEA salt were not dermally toxic when tested in
rabbits at limit doses of 1000 mg/kg/day for 21 days. Effects were
limited to slight erythema at the application site at the 1000 mg/kg/day
dose.

Mefluidide or its DEA salt has not been tested for subacute or
subchronic inhalation toxicity.  However, both of them are in category
IV for acute inhalation toxicity.

  

Developmental effects of Mefluidide in rats included increased number of
early resorptions and mean postimplantation loss.  These effects were
observed at the same dose that caused maternal toxicity indicating there
was no increased susceptibility to fetuses.  The maternal toxicity
included tremors, decreased body weight, weight gain and mortality.  In
rabbit, the LOAEL/NOAEL for developmental toxicity were above the
highest dose tested (60 mg/kg/day).  In the 3-generation reproduction
toxicity study in rats, the offspring toxicity was characterized by
decreased body weights in both sexes and both litters in all
generations.  The reproductive LOAEL was not observed (NOAEL = 346/604
mg/kg bw/day).  The offspring toxicity was observed at the highest dose
tested (346 mg/kg/day) that also produced maternal toxicity indicating
there was no increased post-natal susceptibility for the mefluidide.

There is no evidence of increased pre- or post-natal susceptibility in
the developmental study or in the multi-generation reproduction study in
rat.  Although the LOAEL/NOAEL for developmental toxicity in the rabbits
were not established, the concern is low for the increased
susceptibility to the rabbit fetuses since the developmental effects
were not seen at the highest dose tested (60 mg/kg/day) which is above
the developmental NOAEL in rat (58 mg/kg/day) and well above (40X) the
dose that is used to establish chronic RfD (1.5 mg/kg/day).  Therefore,
there is no residual uncertainty for pre- and/or post natal
susceptibility.

The toxicology profile of mefluidide does not indicate a potential
concern for estrogens, androgen and/or thyroid mediated toxicity.

The toxicology profile of mefluidide and its DEA salt is adequate for
the purposes of hazard and dose response assessment.

Table 4.1a.  Acute Toxicity of Mefluidide and its salts (114001, 114002,
114003)

Guideline

 No.	

Study Type	

MRID	Results (LD50/LC50)	

Toxicity Category

870.1100

(81-1)	Acute Oral (female rat)

Mefluidide tech	>4000 mg/kg

MRID 00047118	

III

870.1100

(81-1)	Acute Oral (mouse) Mefluidide tech	1920.2 mg/kg

MRID 00047117 	

III

870.1100

(81-1)	Acute Oral (mouse) Mefluidide tech	829.8 mg/kg

MRID 00047116 	

III

870.1100

(81-1)	Acute Oral (dog)

Mefluidide tech	Not established

MRID 00049627;  emesis precluded evaluation at 100, 500, 2000 mg/kg
doses	

III

870.1200

(81-2)	Acute Dermal (female rabbit)

Mefluidide tech	>4000 mg/kg

MRID 00047122 & 00049628 & 00083817	

IV

870.1300

(81-3)	Acute inhalation – rat 

DEA salt of Mefluidide       	>5.2 mg/L

MRID 41888801	IV

870.1300

(81-3)	Acute inhalation – rat 

Mefluidide tech.  	>5.4 mg/L

MRID 41964601	IV

870.2400

(81-4)	Primary Eye Irritation (rabbit) Mefluidide tech	minimal
irritation

MRID 00047126, 00049630	

III

870.2400

(81-4)	Primary Eye Irritation (rabbit) DEA Mefluidide	minimal irritation

MRID43481203	III

870.2500

(81-5 )	

Primary Skin Irritation (rabbit), Mefluidide tech	

Not a dermal irritant

MRID 00047124, 00049629, 00083819	

IV

87.2600

(81-6)	Dermal Sensitization (guinea pig), Mefluidide 	Not a dermal
sensitizer

MRID 41887701	

N/A

87.2600

(81-6)	Dermal Sensitization (guinea pig), Mefluidide 	Not a dermal
sensitizer

MRID 00082076	

N/A



Table 4.1b  Toxicity Profile of Mefluidide and its salts (114001,
114002, 114003)

Guideline No./ Study type	

MRID No.(year)/Doses/ classification	

Results

Non-guideline

21-day Oral - dog	00047137, (1975)

0, 1000, 3000, 10000 ppm Vistar tech, 93% a.i./d (0, 25, 75, 250
mg/kg/d)

One dog/sex/dose

range finding

Acceptable/non-guideline

	LOAEL = not established.

NOAEL > 250 mg/kg/d, 

Non-guideline

5-week - mouse	00082072, (1976)

0, 1800, 6000 ppm Vistar tech, 93% a.i./d (0, 270, 900 mg/kg/d)

(Dietary 5/sex/dose)

range finding

Acceptable/non-guideline	LOAEL = not established

NOAEL  = 900 mg/kg/d, 

None-guideline

28-Day oral dietary [rat]	00047135, (1973), 

0, 1000, 3000 or 10000 ppm Vistar tech, 93% a.i. (0, 100, 300, 1000
mg/kg/d)

 (Dietary 5 rats/sex/dose)

range finding

Acceptable/non-guideline

	LOAEL = not established.

NOAEL > 1000 mg/kg/d, 

870.3100

(82-1a) 

90-Day oral dietary [rat]	00047136, (1975), 

0, 300, 1000 or 6000 ppm Vistar tech, 93% a.i. (0, 15, 50, 300 mg/kg/d)
(10 rats/sex/dose)

00047140 (1975)

0, 300, 1000, 3000 ppm (0, 15, 50, 150 mg/kg/day). (10 females/dose)

Acceptable/Guideline

	

LOAEL = 300 mg/kg/d, based on decreased body weight, body weight gain
and food consumption in the females.

NOAEL = 150 mg/kg/d (in conjunction with MRID # 00047140), 

870.3150

82-1(b) 

90-Day oral dietary [dog]	00047141, (IBT Study, 1977), 

0, 300, 1000 or 6000 ppm Vistar tech, 93% a.i. (0, 7.5, 25, 150 mg/kg/d)

(4/sex/dose)

Unacceptable/guideline (LOAEL was not observed)

	LOAEL = not established.

NOAEL = 150 mg/kg/d.  

870.3200

82-2 

21-Day  Dermal toxicity - rabbit	00082073, (1977)

0, 1, 3, 10 ml of 2S formulation/kg/day (Formulation containing 24%
a.i., equivalent to  0, 240, 720, or 2400 mg mefluidide/kg/day)

(4 rabbits/sex/dose)

Acceptable/Non-guideline

(NOAEL was not observed)

Note: This study assessed the dermal toxicity of 24 % formulation
mefluidide	Dermal LOAEL = 240 mg/kg/day, based on irritation,
inflammation and necrosis at test sites.

Systemic LOAEL = 240 mg/kg/day, based on clinical chemistry (increased
alkaline phosphatase and alanine aminotransferase) and organ weights
(decreased spleen weight in females and increased liver weights in
males).  Edema and swelling with myelin loss in sciatic nerve was seen
in 720 and 2400 mg/kg/day dose group. Dehydration observed at 2400
mg/kg/day dose. 

Dermal and systemic NOAELs were not established.

870.3200

82-2 

21-Day  Dermal toxicity - rabbit	42029601 (1991)

0, 100, 500 or 1000 mg a.i./kg/d

Mefluidide 58.2% a.i.

(5/rabbits/sex/dose)

Acceptable/guideline

	Dermal toxicity LOAEL = 1000 mg/kg/day based on erythema at the test
site.

Dermal toxicity NOAEL = 500 mg/kg/day

Systemic toxicity LOAEL was not established.  Minor hematological and
clinical chemistry findings at 1000 mg/kg/day dose reported, that were
within normal biological variation and did not correlate to
histopathological findings.

Systemic toxicity NOAEL = 1000 mg/kg/day

870.3200

82-2 

21-Day  Dermal toxicity - rabbit	41972901 (1991)

0, 100, 500 or 1000 mg a.i./kg/d

Mefluidide DEA salt 28.78% a.i.

(5/rabbits/sex/dose)

Acceptable/ guideline

	Dermal and systemic toxicity LOAEL was not established.  Minor
incidences of erythema at 500 mg and 1000 mg/kg/day dose. Increased
liver weight (absolute and relative) noted at 1000 mg/kg dose but no
correlating histopathological findings. Minor statistical increases in
liver enzymes AST and ALT.

Dermal and systemic NOAEL = 1000 mg/kg/day

Non-guideline

1-year feeding (Rat)	00132993, (1981)

0, 60, 200, 600 ppm Vistar tech, 93% a.i. (0, 3, 10, 30 mg/kg/d)

(20 rats/sex/dose)

Addendum to 2-year feeding study.

Acceptable/non-guideline

	LOAEL = not established

NOAEL = 30 mg/kg/d,

870.4100b 

83-1b 

Chronic Oral Feeding [dog]	00132995, (1982)

0, 60, 600, 6000 ppm Vistar tech, 93% a.i. (0, 1.5, 15, 150 mg/kg/d)

(6 dogs/sex/dose)

Acceptable/guideline

	LOAEL = 15 mg/kg/d, based on decreased body weight (15%) and body
weight gain (50%) in the males. Chronic cortical nephrosis was observed
at 150 mg/kg/day dose.

NOAEL = 1.5 mg/kg/d,

870.4100b 

83-2b

 Carcinogenicity Dietary [mouse]	00082747, (1979)

0, 600, 1800, 6000 ppm Vistar tech, 93% a.i. (0, 90, 270, 900 mg/kg/d)

(60 mice/sex/dose)

Acceptable/guideline

	LOAEL = 270 mg/kg/day, based on increased incidence of liver
hyperplastic nodules in both sexes.  

NOAEL = 90 mg/kg/day. 

No oncogenicity up to and including the highest dose tested.

870.4300

83-5

 2-year feeding/carcinogenicity [rat]	00061930, 00082737 (1979)

0, 600, 1800, 6000 ppm Vistar tech, 93% a.i. (0, 30, 90, 300 mg/kg/d)

(50 rats/sex/dose)

Acceptable/guideline

	LOAEL = 30 mg/kg/d, based on body weight loss.

NOAEL < 30 mg/kg/d,  

No oncogenicity up to and including the highest dose tested.

870.3700a 

83-3(a) 

Developmental Toxicity, gavage [rat]	

00132992, (1981)

0, 15, 30, 60 mg/kg/d

Unacceptable/guideline

(LOAEL was not observed)

	

Maternal LOAEL = not established.

Maternal NOAEL > 60 mg/kg/day, 

 

Developmental NOAEL > 60 mg/kg/day, Developmental LOAEL = not
established.

870.3700a

83-3(a)

Developmental Toxicity

Gavage [rat]	

42097201 (range finding)

42097701 (teratology), 1991

Range finding: 0, 100, 200, 400, 600 or 800 mg a.i./kg/d

Teratology study: 0, 50, 200 or 400 mg a.i./kg/d

Mefluidide technical 58.2% a.i.

Acceptable/Guideline	

Maternal LOAEL = 400 mg/kg/d based on reduced gain and food consumption.
Higher dose in the range finding study of 600 mg/kg/day produced
excessive mortality.

Maternal NOAEL = 200 mg/kg/d

Developmental LOAEL = 400 mg/kg/d based on slight fetal toxicity as
indicated by a slight nonstatistical increase in 14th rib.

Developmental NOAEL = 200 mg/kg/d

Non-guideline

Range Finding Developmental Toxicity , gavage[rat]	42026101, (1991)

0, 100, 200, 400, 600or 800 mg diethanolamine salt of mefluidide
(28.78%)/kg/d

(6 female rats/dose)

Range finding

Acceptable/non-guideline

	Maternal LOAEL: 115 mg a.i./kg/day based on clinical signs (tremors,
hunched posture, and salivation), maternal body weight gain and food
consumption.

Maternal NOAEL: 58 mg a.i./kg/day; 

Developmental LOAEL: 230 mg a.i. /kg/day based on significantly
decreased fetal body weight.

Developmental NOAEL: 173 mg a.i. /kg/day, 

The dosage levels of 0, 50, 200 and 400 mg of the 28.78%
formulation/kg/day were selected for the definitive developmental study.

870.3700a 

83-3(a) 

Developmental Toxicity, gavage [rat]	42026102, (1991)

0, 50, 200 400 mg diethanolamine salt of mefluidide (28.78%)/kg/d

(25 females/dose)

Doses adjusted for 100 % purity were 0, 14, 58, or 115 mg/kg/day. 

Acceptable/guideline	Maternal LOAEL = 115 mg a.i./kg/day based on
mortality, clinical signs (tremors, stained nose, urine and vaginal
discharge), decreased body weight and weight gain.

Maternal NOAEL = 58 mg a.i./kg/day), 

Developmental LOAEL = 115 mg a.i./kg/day based on increased number of
early resorptions and mean post-implantation loss.

Developmental NOAEL: 58mg a.i./kg/day 

Non-guideline

14-Day Oral gavage [rabbit]	00047138, (1975)

0, 100, 200, 400, 800 mg/kg/d Vistar tech, 93% a.i.

4 females/dose

range finding

Acceptable/non-guideline	LOAEL = < 100 mg/kg/day (females), based on
mortality (1/3 deaths) at 100 mg/kg/d.  Tremors and 100% mortality were
noted at the levels of 200 mg/kg/d and above. Histopathology not
reported.

NOAEL: not established, 

870.3700b

83-3(b) Developmental Toxicity, gavage [rabbit]

	00047139, (1975)

0, 15, 30, 60 mg technical MBR 12325/kg/d (purity not reported).

Unacceptable by itself, however, if combined with the 14-day oral study
(00047138), it is acceptable.	Maternal LOAEL = not established.

Maternal NOAEL = 60 mg/kg/day, 

Developmental LOAEL = not established.

Developmental NOAEL = 60 mg/kg/day, 

870.3800

(83-4 )

3-generation reproduction [rat]	

00082748, (1979)

0, 600, 1800, 6000 ppm, 93% a.i. (M/F: 0/0, 34/60, 102/183, 346/604
mg/kg/d)

Acceptable/guideline	

The parental systemic LOAEL = 346/604 mg/kg bw/day (M/F), based on
decreased body weights.  

The parental systemic NOAEL = 102/183 mg/kg bw/day in males/females.

The offspring LOAEL = 346/604 mg/kg bw/day in males/females, based on
decreased body weights in both sexes and both litters in all
generations.  The offspring NOAEL = 102/183 mg/kg bw/day in
males/females. 

The reproductive LOAEL was not observed.  

The reproductive NOAEL = 346/604 mg/kg bw/day in males/females. 

870.5100

84-2 

Bacterial reverse mutation 	00132996, (1983)

EL-565 (Lily compound 151065: mefluidide technical) tested at 0.1 –
1000 µg/ml 

Acceptable/Guideline	No reverse mutations were noted in any of 8 tester
strains of Salmonella typhimurium and two tryptophan autotrophs of E.
coli with or without metabolic activation 

870.5100

84-2 

Bacterial reverse mutation 	41888804, (1991)

0, 100, 333, 667, 1000, 3330, or 5000 µg/plate diethanolamine salt of
mefluidide (28.78%)/

Acceptable/guideline	DEA mefluidide did not increase the number of
histidine revertants per plate in any of the tester strains with or
without metabolic activation.

870.5300

84-2 

In-vitro Mouse lymphoma - gene mutation 	00132996, (1983)

EL-565 (Lily compound 151065: mefluidide technical)0, 1, 25, 50, 100,
250, 500, 750 or 1000 µg/ml 

Acceptable/guideline	There was no evidence of mutation in the presence
or absence of metabolic activation.

870.5375

84-2 

In-vitro mammalian chromosome aberration test	41888803, (1991)

Diethanolamine salt of mefluidide (28.8%)

500,- 5010 µg a.i. /ml (without S9 mix) or 500, - 5000 (with S9 mix)

Acceptable/guideline 	No significant increase in structural chromosomal
aberration with or without metabolic activation was seen, however, the
results were considered equivocal.

(84-2 In-vitro mammalian chromosome aberration test	(1992)

concentrations of 1250 to 5000 (g/ml (w S9 mix) or 200-1600 (wt S9 mix)

	Not mutagenic in Chinese Hamster Ovary cells

870.5550

84-2 

Unscheduled DNA Synthesis	41888802, (1991)

Diethanolamine salt of mefluidide (28.8%)

Concentrations of 100, 250, 500, 1000, 2000, 3000 µg/ml in trial 1;
1000, 1500, 2000, 3000, 3500 µg/ml in trial 2.

Acceptable/guideline	No unscheduled DNA synthesis response in the
absence of moderate to severe cytotoxicity.

870.5550

84-2

Unscheduled DNA Synthesis	00132996, (1983)

EL-565 (Lily compound 151065: mefluidide technical)

Tested at 0.5 to 1000 nmoles/mL	No indication of DNA repair synthesis
was observed in cultured rat heapatocytes treated with the test material
(EL-565 (Lily compound 151065: mefluidide technical))

870.5915

84-2 

In-vivo Sister Chromatid Exchange	00132996, (1983)

EL-565 (Lily compound 151065: mefluidide technical)

(0, 12.5, 25, 50, or 100 mg/kg.

Acceptable/Guideline	Negative in sister chromatid exchange in in-vivo
bone marrow of Chinese hamster assay.

870.5915

85-1 

Metabolism- male rat	

MRID is not known: Steifer, LJ (1978). 3M Company Report Number 852
(1-26-78)

Dose: 1 or 10 mg/kg of C-14, labeled mefluidide

Acceptable/None-Guideline 

	

By 24 hrs of post-treatment, 86-89% of the dose was found in urine with
the remainder in the feces.  Residue consisted of mefluidide (97%) and 2
unidentified metabolites (1.2% and 0.5%) and unidentified polar material
(0.7%).

870.6200

81-8

 Demyelination study - Chicken

	

0097684 (1977)

1000, 3000, 5000, 10,000 and 20,000 mg/kg/day.

Non-Acceptable/Non-Guideline	

NOAEL< 1000 mg/kg/day; LOAEL: 1000 mg/kg/day based on clinical signs
(hypoactivity, ataxia, tremors, lethargy and dyspnea) that were subsided
by 48 hrs following dosing.  The test material did not induce delayed
neurotoxicity in hens at the LD 50 dosage of 8500 mg/kg.  (Limit dose -
1 g/kg).

  

M = Males; F = Females



4.2 Hazard considerations For Women and Children  tc \l1 "2.2	Food
Quality Protection Act (FQPA) HAZARD CONSIDERATIONS 

	4.2.1. Adequacy of the Toxicity Database

 tc \l2 "1. Adequacy of the Toxicity Database 

The toxicology database for mefluidide is considered adequate.  The
following acceptable studies are available:

- Developmental toxicity studies in rats

- Developmental toxicity studies in rabbits

- Two-generation reproduction study in rats

	4.2. tc \l2 "2.2.  2. Evidence of Neurotoxicity

Acute and subchronic neurotoxicity studies were not performed.  Clinical
signs of neurotoxicity (such as tremors, ataxia, atonia, decreased limb
tone, salivation) were seen in several studies (14-day oral in rabbit at
or above 200 mg/kg/day, demyelination study in chickens at 1000
mg/kg/day and two developmental toxicity studies in rats at 115
mg/kg/day.  Edema and swelling with myelin loss in sciatic nerve was
observed in a dermal toxicity study in rabbits at doses of 720 mg/kg and
above. However, these effects were not seen in an additional dermal test
of similar duration using a 58.2% mefluidide formulation or
diethanolamine salt of mefluidide 28.8%.

	4.2.3. Developmental Toxicity Study Conclusions tc \l2 "2.2.3.
Developmental Toxicity Study Conclusions 

Developmental Toxicity Study - Rabbits:

In a developmental toxicity study (MRIDs 00047139 and 00047138),
technical MBR 12325 (Lot #9) in 4% gum acacia was administered to 16-20
New Zealand White rabbits/dose group via gavage at dose levels of 0, 15,
30, or 60 mg/kg bw/day from gestation days (GD) 6-18.

There were no treatment-related effects on survival, clinical signs,
body weight, food consumption, or cesarean parameters.

The maternal LOAEL was not observed.  The maternal NOAEL is 60 mg/kg
bw/day (the highest dose tested).

There were no effects of treatment on the numbers of litters, live
fetuses, dead fetuses, or resorptions, or on fetal body weights, sex
ratio, or post-implantation loss.  There were no treatment-related
external, visceral, or skeletal variations or malformations.

The developmental LOAEL was not observed.  The developmental NOAEL is 60
mg/kg bw/day (the highest dose tested).

This developmental toxicity study in rabbits has a number of
deficiencies:  a LOAEL was not observed; test material purity was not
provided; no information on dose formulation preparation or storage was
provided; and no analyses of homogeneity, stability, or concentration
were reported. However, when combined with the 14-day oral gavage study
in rabbits (MRID 00047138), where a LOAEL of <100 mg/kg bw/day based on
mortality and tremor was established, this developmental toxicity study
is considered acceptable and satisfies the guideline for a developmental
toxicity study (OPPTS 870.3700b; OECD 414) in rabbits.

Developmental Toxicity Study - Rats:

In a developmental toxicity study (MRID 42026102), Diethanolamine salt
of Mefluidide (28.78% a.i. Lot # JB0624) in distilled water was
administered to pregnant Sprague Dawley Crl:CD BR VAF/Plus (25/dose) by
gavage at dose levels of 0, 50, 200 or 400 mg/kg bw/day (adjusted doses
for 100 % purity were 0, 14, 58, or 115 mg/kg/day, respectively) from
days 6 through 15 of gestation.  

Animals were checked daily for clinical signs, mortality.  Body weights
were measured on gestation day 0, 6, 9, 12, 16 and 20.  Unscheduled
deaths, scheduled sacrifice and c-sections were subjected to gross
necropsy examination. Each fetus was examined for
external/visceral/skeletal anomalies, sexed and then weighed.

Evidence of maternal toxicity included transient clinical signs
(tremors, dark material around the nose, few feces, urine stain and
reddish vaginal discharge), decreased body weight gain (11-61%),
decreased food consumption and mortality (2/25 females found dead on GD
11 and 16) observed at the 400 mg/kg/day levels.  At the 400 mg/kg dose,
the clinical signs of toxicity appeared within 2 days after dosing in
few animals, and after few days of dosing in some others and more than
half of the animals at this dose were free from clinical signs of
toxicity. No external malformations or developmental variations were
observed associated with any fetus. Fetal toxicity was manifested by
increase in the number of early resorptions which resulted in increase
in mean postimplantation loss at 400 mg/kg/day dose. 

After adjusting to the pure active ingredient, the maternal NOAEL is 58
mg/kg/day and the LOAEL is 115 mg/kg/day based on clinical signs
(tremors, dark material around the nose, urine stain and reddish vaginal
discharge), decreased body weight gain, decreased food consumption and
mortality (2/25 females).   The developmental toxicity NOAEL is also 58
mg/kg/day, the LOAEL is 115 mg/kg/day based on increase in the number of
early resorptions and increase in mean postimplantation loss. 

	This developmental toxicity study is classified acceptable/Guideline
and it does satisfy the guideline requirement for a developmental
toxicity study (OPPTS 870.3700; OECD 414) in the rat.

	4.2.4. Reproductive Toxicity Study

In a three-generation reproduction study (MRID 00082748), MBR 12325
(Mefluidide; 93% a.i., Lot #25) was administered in the diet to 20 male
and 40 female Charles River CD® rats/dose group at dose levels of 0,
600, 1800, or 6000 ppm (equivalent to Males/Females - 0/0, 34/60,
102/183, and 346/604 mg/kg bw/day).  When approximately 100 days old,
the P generation animals were mated (1 male: 2 females) for up to 15
days to produce the F1a litter.  Following weaning of the F1a litters,
50 F1a offspring/sex/dose were selected for a 2-year chronic feeding
study, and the remaining F1a offspring were discarded.  The P generation
was reduced to 10 males/20 females per dose group.  After a 10-day
post-weaning rest period, these P animals were mated again to produce
the F1b litter.  Upon weaning, 10 male and 20 female F1b offspring/dose
group were selected to be parents of the F2 generation.  This study
design was continued for three generations with 2 litters per
generation.

There were no effects on food consumption, organ weights, gross
pathology, or histopathology.

Numerous absolute and relative (to bw) organ weights in the 6000 ppm
parents were significantly (p<0.05) different from the controls,
however, none of these differences were corroborated by any macroscopic
or microscopic findings indicating these decreases were most likely not
related to treatment.  Thus, it is likely that they were attributable to
decreased body weights at this dose. 

The only deaths included one 6000 ppm F1 female, one 6000 ppm F2 male,
and one 1800 ppm F2 female.  It was stated that macroscopic and
microscopic findings in these animals were unremarkable.  Therefore,
these deaths were considered incidental and were not treatment related.

At 6000 ppm, body weights were decreased by 1-8% in males and 1-12% in
females throughout the study in the P generation, attaining significance
(p<0.05) at Week 18 in the males and Weeks 8, 18, 19, and 27 in the
females.  In the F1 generation at this dose, body weights were decreased
throughout the study in the males (decr. 13-21%) and females (decr.
10-21%), attaining significance (p<0.01) at Weeks 27, 37, and 56 in both
sexes.  Similarly in the F2 generation, body weights were decreased
throughout the study in the 6000 ppm males (decr. 14-21%) and females
(decr. 11-23%), attaining significance (p<0.01) at Weeks 57, 66, and 85
in both sexes.

At 1800 ppm, only minor and infrequent decreases in body weights were
noted.  There were no treatment-related findings at 600 ppm.

The parental systemic LOAEL is 6000 ppm (346/604 mg/kg bw/day in
males/females), based on decreased body weights in both sexes in all
generations.  The parental systemic NOAEL is 1800 ppm (102/183 mg/kg
bw/day in males/females). 

There were no effects of treatment on post-natal survival (i.e.,
viability and lactation) indices in the pups at any dose.  There were no
treatment-related findings at 600 or 1800 ppm.

At 6000 ppm, body weights were decreased by up to 27% compared to
controls throughout the post-natal period in both litters in each
generation (i.e., F1a, F1b, F2a, F2b, F3a, and F3b litters). These
decreases attained significance in both sexes at PND 21.

The offspring LOAEL is 6000 ppm (346/604 mg/kg bw/day in males/females),
based on decreased body weights in both sexes and both litters in all
generations.  The offspring NOAEL is 1800 ppm (102/183 mg/kg bw/day in
males/females). 

There were no effects of treatment on male or female fertility indices
or gestation survival index.

The reproductive LOAEL was not observed.  The reproductive NOAEL is 6000
ppm (346/604 mg/kg bw/day in males/females). 

This study is acceptable/guideline and satisfies the guideline
requirement for a three-generation reproductive study (OPPTS 870.3800;
OECD 416) in rats.

	4.2.5. Additional Information from Literature sources

There was no published information on this subject.

4.3. Hazard Identification and Toxicity Endpoint Selection

 tc \l2 "2.4	Hazard Identification and Toxicity Endpoint Selection 

4.3.1. Acute Reference Dose (aRfD)

Females age 13-49 : Acute dietary endpoint for child bearing females
(females 13+ years old) was determined from the developmental toxicity
study in rat (MRID 42026102).  A NOAEL of 58 mg/kg/day was derived based
on developmental toxicity (increased number of early resorptions and
mean post-implantation loss) at a LOAEL of 115 mg/kg/day.  An UF of 100X
(10-fold for inter-species extrapolation, 10-fold for intra-species
variability) was applied to the NOAEL of 58 mg/kg/day to derive the
aRfD.  

 

Acute Reference Dose (aRfD) - General Population

The acute RfD for the general population including infants and children
was determined from the developmental toxicity study in rat (MRID
42026102).  A NOAEL of 58 mg/kg/day was derived based on maternal
toxicity (clinical signs: tremors)  at a LOAEL of 115 mg/kg/day.  An UF
of 100X (10- fold for inter-species extrapolation, 10-fold for
intra-species variability) was applied.  The selected endpoint of
toxicity is appropriate for this exposure since clinical signs of
toxicity occurred within two days of dosing.

4.3.2. Chronic Reference Dose (cRfD)  

The cRfD of 0.015 mg/kg/day was determined on the basis of the Chronic
Oral Feeding – dog (MRID 00132995); NOAEL of 1.5 mg/kg/day and LOAEL
of 15.0 mg/kg/day based on decreased body weight (15%) and body weight
gain (50%) in the males.  This study provided the lowest NOAEL (1.5
mg/kg/d) in the database that provides the most protective limits for
human effects.  An UF of 100X (10-fold for interspecies extrapolation,
10-fold for intraspecies variability) was applied to the NOAEL of 1.5
mg/kg/day to derive the cRfD to give and RfD of 0.015 mg/kg/day. 

	4.3.3. Incidental Oral Exposure (Short-and Intermediate-term durations:
1 day – 6 months)  

Points of departure for these scenarios were based on the rat
developmental study (MRID 42026102).  NOAEL = 58 mg/kg bw/day, LOAEL =
115 mg/kg bw/day based on mortality and clinical signs.  These data were
also supported by the rabbit developmental study (NOAEL = 60 mg/kg
bw/day) and rabbit 14 day oral study (LOAEL = 100 mg/kg bw/day based on
mortality).  The level of concern for residential exposure is for MOEs =
100 and for occupational exposure is for MOEs =100.  

	4.3.4. Dermal Absorption Factor 

A dermal penetration study is not available.  A dermal absorption factor
is derived by extrapolation from the rabbit 21-day dermal (MRID
41972901) and rabbit 14 day oral (MRID 00082073) studies.  The dermal
systemic NOAEL in the 21-day study is 1000 mg/kg/day based on minor
increases in liver enzymes.   In the 14 day rabbit oral study(MRID
00047138), the LOAEL is less than 100 mg/kg/day based on mortality and
clinical signs (tremors) and the NOAEL is <100 mg/kg/day, therefore, the
calculated dermal absorption factor would at the most be (100/1000) x
100 = 10%. 

	4.3.5. Dermal Exposure (Short and Intermediate:  (1-30 days and 30
d-180 days) 

Three subacute (21-day) dermal toxicity studies were considered.  The
two more recent studies (MRID 42029601 and 41972901) showed no systemic
effects at the limit dose.  Only one study (MRID 00082073) with 24%
active ingredient showed toxic effects (Edema and swelling with myelin
loss in sciatic nerve at 720 and 2400 mg/kg/day).  These effects were
not seen in the more recent GLP dermal studies using a 58.2% mefluidide
formulation (MRID 42029601) or diethanolamine salt of mefluidide 28.8%
(MRID 41972901).  The risk assessment team determined that no
quantitative dermal assessment is needed due to the following:

1) Two 21-day dermal toxicity studies with rabbits indicated no dermal
systemic toxicity at 1000 mg/kg/day (the highest dose tested).  The one
study that showed toxicity indicated that effects only occurred at high
doses.

2) The rat developmental study indicated no developmental concern
(developmental NOAEL equals to maternal NOAEL),

3) The acute dermal toxicity of mefluidide, where the acute dermal LD50
is >4000 mg/kg, it is not a skin irritant and is not a dermal
sensitizer.  

	4.3.6. Inhalation (Short- and Intermediate-Term) 

Endpoint for this scenario was determined from the rat developmental
study.  NOAEL = 58 mg/kg bw/day, LOAEL = 115 mg/kg bw/day based on
mortality and clinical sings.  These data were also supported by the
rabbit developmental study (NOAEL = 60 mg/kg bw/day) and rabbit 14 day
oral study (LOAEL = 100 mg/kg bw/day based on mortality).  Since oral
study was selected for inhalation exposure assessment an
inhalation-absorption factor of 100% oral equivalent should be used.   

 	4.3.7. Margins of Exposure

These are summarized in the following table:

Route

                                    	       Duration	Short-Term

(1-30 Days)	Intermediate-Term

(1 - 6 Months)

 

Occupational (Worker) Exposure

Dermal	NA	NA

Inhalation	100	100

Residential (Non-Dietary) Exposure

Oral	100	100

Dermal	NA	NA

Inhalation	100	100

 	4.3.8. Classification of Carcinogenic Potential 

Mefluidide was negative for carcinogenicity in mouse (MRID 00082747) and
rat (MRID 00061930 7 00082737) bioassays.  It was also evaluated for
genotoxicity in several tests and found negative. It is unlikely that
mefluidide will pose a cancer risk to humans.



Table 4.3.  Summary of Toxicological Dose and Endpoints for Mefluidide
and its salt (114001, 114002, 114003) Used in Human Risk Assessment

Exposure

Scenario	

Point of Departure 	

Uncertainty Factors	

Level of Concern for Risk Assessment	

Study and Toxicological Effects

Acute Dietary (general population)	

NOAEL = 58 mg/kg/day 

	UFA = 10X

UFH = 10X	

Acute RfD = 

Maternal NOAEL   

UncertaintyFactor

= 0.58 mg/kg /day	

MRID 42026102

Developmental toxicity - rat;

LOAEL= 115.0 mg/kg/day based on mortality(within 5 days of dosing) and
clinical signs (within 2 days of dosing), and the NOAEL of 58 mg/kg/day.

Acute Dietary (Females 13+)	

NOAEL = 58 mg/kg/day 

	UFA = 10X

UFH = 10X	

Acute RfD =

Develop. NOAEL   

UncertaintyFactor

= 0.58 mg/kg	

MRID 42026102

Developmental toxicity - rat;

LOAEL= 115.0 mg/kg/day based on increased number of early resorptions
and mean postimplantation loss. NOAEL = 58 mg/kg/day

Chronic Dietary

(All populations)	

NOAEL = 1.5 mg/kg/day

	UFA = 10X

UFH = 10X	

Chronic RfD = 

NOAEL__ 

Uncertainty Factor

= 0.015 mg/kg/day	

MRID 00132995

Chronic Oral Feeding - dog;

LOAEL= 15.0 mg/kg/day based on decreased body weight (15%) and body
weight gain (50%) in the males at 15 mg/kg/day.

Short-Term 

Incidental Oral (1-30 days)	

NOAEL = 58 mg/kg/day 

	UFA = 10X

UFH = 10X	

Residential LOC for MOE = 100

	MRID 42026102

Developmental toxicity - rat;

NOAEL = 58 mg/kg bw/day, LOAEL = 115 mg/kg bw/day based on mortality and
clinical sings.  These data were also supported by the rabbit
developmental study (MRID 00047139) (NOAEL = 60 mg/kg bw/day) and rabbit
14 day oral study (LOAEL = 100 mg/kg bw/day based on mortality). 

Intermediate-Term 

Incidental Oral (1- 6 months)

Short-Term Dermal (1 to 30 days)

	

Dermal  NOAEL = 1000 mg/kg/day 

	UFA = 10X

UFH = 10X	

No quantitative dermal assessment is needed.

	

Three subacute (21-day) dermal toxicity studies were considered. The
risk assessment team determined that no quantitative dermal assessment
is needed due to the following:

1) Two 21-day dermal toxicity studies with rabbits indicated no dermal
systemic toxicity at 1000 mg/kg/day (the highest dose tested).  The one
study that showed toxicity indicated that effects only occurred at high
doses.

2) the rat developmental study indicated no developmental concern
(developmental NOAEL = maternal NOAEL),  

3) Acute toxicity of mefluidide, where acute dermal LD50 is >4000 mg/kg,
not a skin irritant and is not a dermal sensitizer.

Intermediate-Term

Dermal (1 to 6 months)

Short-Term Inhalation (1 to 30 days)	

Oral NOAEL = 58 mg/kg/day

(inhalation- absorption rate = 100% oral equivalent)	UFA = 10X

UFH = 10X	

Residential LOC for MOE = 100;

Occupational LOC for MOE = 100

	

MRID 42026102

Developmental toxicity - rat;

NOAEL = 58 mg/kg bw/day, LOAEL = 115 mg/kg bw/day based on mortality and
clinical sings.  These data were also supported by the rabbit
developmental study (NOAEL = 60 mg/kg bw/day) and rabbit 14 day oral
study (LOAEL = 100 mg/kg bw/day based on mortality).

Intermediate-Term Inhalation (1 to 6 months)

Cancer	Mefluidide was negative for carcinogenicity in mouse (MRID
00082747) and rat (MRID 00061930 7 00082737) bioassays.  It was also
evaluated for genotoxicity in several tests and found negative.

Point of Departure (POD) = a data point or an estimated point that is
derived from observed dose-response data and used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  UF = uncertainty factor, UFA = extrapolation
from animal to human (intraspecies), UFH = potential variation in
sensitivity among members of the human population (interspecies), NOAEL
= no observed adverse effect level, LOAEL = lowest observed adverse
effect level, RfD = reference dose (a = acute, c = chronic), MOE =
margin of exposure, LOC = level of concern, NA = Not Applicable. Safety
Factor = UF = 100.

5.0	Public Health Data	

	

Incident Reports 

(HED memo of 07/25/06, M. Hawkins, D324824)

The following data bases have been consulted for the poisoning incident
data on the active ingredient Mefluidide and salts:

1)  OPP Incident Data System (IDS) - No reports for mefluidide or its
salts in the Incident Data System.

2)  Poison Control Centers - No reports located in the Poison Control
Center records from 1993 through 2003 involving mefluidide.

3)  California Department of Pesticide Regulation - Detailed description
of 1 case submitted to the California Pesticide Illness Surveillance
Program (1982-2003) was reviewed.  In the case, a worker reported a rash
on the side of their face after several workers passed a vehicle that
sprayed the product.

4)  National Pesticide Information Center (NPIC) - From 1984-1991
inclusively, mefluidide was not reported to be involved in human
incidents.

5) National Institute of Occupational Safety and Health’s Sentinel
Event Notification System for Occupational Risks (NIOSH SENSOR) - Of
5,899 reported cases from 1998-2003, none involved mefluidide.

In conclusion, there was only one report of an ill effect from exposure
to mefluidide in the available data bases.

6.0  	Exposure Characterization/Assessment

	

6.1	Dietary Exposure/Risk Pathway

	

	6.1.1 	Food Exposure/Risk Pathway

	

None.  No food uses.

	6.1.2   Water Exposure/Risk Pathway	

Drinking water Assessment; James Hetrick (D334508, 03/08/07)

Possible routes of dissipation for mefluidide are photodegradation on
soil surfaces and microbial-mediated degradation.   Mefluidide is not
prone to abiotic hydrolysis or photolysis in sterile buffer solutions
within the environmentally relevant pH range of 4 to 9.  There are data
showing mefluidide undergoes rapid photodegradation (t1/2 = 2 to 3 days)
in natural well water.  On soil surfaces, mefluidide photodegraded with
a half-life of 116.4 hours.  Mefluidide in aerobic soils degraded with a
half-life of 12 days.  The only degradation product was
5-amino-2,4-dimethyltrifluoromethanesulfonilide.  It was found at a
maximum daily concentration of  2.8% of applied dose (MRID 43162201,
aerobic soil).   Mefluidide dissipated  with a half-life of  2.0 to 3.3
days in warm-season turf soil in Georgia and  1.2 to 1.4 days in
cool-season grass soil in Missouri.  Mefluidide dissipated from grass
foliage at half-lives of 1.7 to 6.91 days (upper 90th percentile of mean
half-life= 4.0414 day, k= 0.1715 days-1).

No surface or ground water monitoring data were found for mefluidide. 
Drinking water assessment was conducted using Tier II (PRZM-EXAMS) for
surface water modeling and Tier 1 (SCI-GROW) for groundwater modeling. 
Because mefluidide use is associated with turf, the aquatic exposure
assessment was conducted using the PA  and FL turf scenarios.  These use
scenarios were selected to represent of rights-of-way, residential turf,
industrial areas with turf (i.e., airports, etc.), and golf courses. 
The turf scenarios are expected to be conservative estimate of
mefluidide runoff potential because they assume 100% of the watershed is
treated with mefluidide as well as the runoff scenarios are located in
areas with high runoff potential. The mefluidide acid concentrations in
surface water are not expected to exceed 32 μg/L for the 1 in 10 year
daily peak concentration, 10 μg/L for the 1 in 10 year annual
concentration, and 5 μg/L for the 30 year annual average concentration.
 Mefluidide acid concentrations in ground water are not expected to
exceed 1.0 μg/L. These concentrations have not been adjusted for any
crop area factor (CAF) because the crop area factors do not account for
non-agricultural uses such as turf, ornamentals, etc.  Uncertainty in
the assessment is the persistence of mefluidide acid in aerobic aquatic
environments.  This assessment was conducted using an estimated aerobic
aquatic half-life of 72 days (Guidance for Chemistry and Management
Practice Input Parameters for Use in Modeling the Environmental Fate and
Transport of Pesticides, Version 2, 11/7/2000).  Because this estimated
half-life was designed to approximate upper 90th percentile of the mean
half-life, it is anticipated to be a conservative estimate of mefluidide
acid persistence in aquatic environments.     

6.2	Dietary Exposure Estimates

isk assessments were conducted using the Dietary Exposure Evaluation
Model (DEEM-FCID™, Version 2.03) which uses food consumption data from
the U.S. Department of Agriculture’s Continuing Surveys of Food
Intakes by Individuals (CSFII) from 1994-1996 and 1998.

Acute Dietary Exposure from Drinking Water

An acute dietary exposure assessment was performed for mefluidide
considering exposures from surface water only, as there are no food uses
for this chemical.  An estimated drinking water concentration (EDWC) for
surface water (32 ppb) provided by the Environmental Fate and Effects
Division (EFED) was used in this assessment.  Ground water sources were
not included, as the EDWCs for this water source are minimal in
comparison to surface water.  The drinking water exposure analysis
result in dietary risk estimates for surface water only are below the
Agency’s level of concern for acute exposure.  At the 95th percentile,
the exposure to U.S. population was 0.0017 mg/kg/day, which utilized <1%
of the acute reference dose (aRfD).  The exposure for all infants, which
was the most highly exposed population subgroup, was 0.006 mg/kg/day,
which utilized 1% of the aRfD.  Conservative screening-level drinking
water estimates were used in this assessment (i.e., the highest peak
surface water level for a one in ten year concentration), therefore the
dietary risk estimates were reported at the 95th percentile of exposure.
 

Chronic Dietary Exposure from Drinking Water

A chronic dietary exposure from drinking water only was also performed
using surface water EDWC value (10 ppb).   For the U.S. population the
exposure was 0.0002 mg/kg/day, which utilized 1% of the chronic
reference dose (cRfD).  The exposure for all infants, which was the most
highly exposed population subgroup, was 0.0007mg/kg/day, which utilized
5% of the cRfD.

Table 6.2.  Summary of Drinking Water Exposure and Risk for Mefluidide

Population Subgroup	Acute Dietary

95th  Percentile	Chronic Dietary

	aRfD (mg/kg/day)	Dietary Exposure (mg/kg/day)	% aRfD	cRfD (mg/kg/day)
Dietary Exposure

(mg/kg/day)	% cRfD

General U.S. Population	0.58

	0.001672	<1	0.015	0.000211	1

All Infants (< 1 year old)

0.006303	1

0.000691	5

Children 1-2 years old

0.002623	<1

0.000313	2

Children 3-5 years old

0.002396	<1

0.000293	2

Children 6-12 years old

0.001668	<1

0.000202	1

Youth 13-19 years old

0.001356	<1

0.000152	1

Adults 20-49 years old

0.001549	<1

0.000197	1

Adults 50+ years old

0.001399	<1

0.000207	1

Females 13-49 years old

0.001558	<1

0.000196	1

For detailed DEEM input and result files, please see Attachment I.

6.3	Residential (Non-Occupational) Exposure/Risk Pathway

Occupational and Residential Exposure Assessment; Yan Donovan, D324823,
2/28/07.

Mefluidide is intended for both occupational and residential uses.  None
of the labels prohibit use by homeowners. The residential products are
typically formulated as granules, or as liquid concentrates, or ready-
to- use sprinkler can sprays.  Spot and broadcast treatments are both
included on the labels.  Exposures are expected to be short term in
duration.

	6.3.1.  Residential Handler Exposure and Risks

Residential Handler Scenarios, Data Sources and Assumptions

Scenarios

Based on the product labels, the following scenarios were assessed.

1.  Load/Apply Granules with Belly Grinder

2.  Load/Apply Granules with a Broadcast Spreader

3.  Mix/Load/Apply with a Hose-end Sprayer (Mix your own)

4.  Mix/Load/Apply with Hand Held Pump Sprayer.

Data Sources

	

      Exposure data for scenario #1 was taken from PHED because no unit
exposure data is available from ORETF for this specific scenario. 
Exposure data for scenarios #2 and #3 were taken from the residential
portion of the ORETF Handler Study.  Exposure data for scenario #4 was
taken from MRID 44459801, a study involved low pressure handwand and RTU
trigger sprayer application of carbaryl to home vegetable plants.  This
study was reviewed by Jeff Dawson in document D287251, has since been
purchased by ORETF.  

Assumptions Regarding Residential Applicators

Broadcast spreaders and hose end sprayers would be used for broadcast
treatments and the other application methods would be used for spot
treatments only.

The application rate of 1.0 lb ai/acre is from mefluidide labels. 

An area of 0.023 acre (1000 square feet) would be treated per
application during spot treatments and an area of 0.5 acre would be
treated during broadcast applications.

Residential Handler Exposure and Risk Estimates

	 A summary is included in Table 6.3.1.  The MOEs are > 100 and the
risks are below EPA’s level of concern.



Table 6.3.1- Mefluidide Short Term MOEs for Homeowner Applications to
Lawns

Scenario	Application Rate	Area Treated or Amount Applied	Inhalation Unit
Exposure (per lbs ai handled)	Inhalation Dose (mg/kg/day)	Inhalation MOE

 Load/Apply granules with Belly Grinder (spot treatment)	0.5 lb ai/acre
0.023 acre/day	62 µg

(PHED)	1.0E-05	6,000,000

Load/Apply Granules with a Broadcast Spreader	0.5 lb ai/acre	0.5
acre/day	0.91 µg

(ORETF)	3.3E-06	18,000,000

 Mix/Load/Apply with a Hose-end Sprayer (Mix your own)		1.0 ai/acre	0.5
acre/day	16 µg

(ORETF)	1.1E-04	500,000

 Mix/Load/Apply with Hand Held Pump Sprayer (use on turf)	1.0 lb ai/acre
0.023 acre/day	9 µg

(MRID44459801)	3.0E-06	20,000,000

Mix/Load/Apply with Hand Held Pump Sprayer (use on ornamentals)	0.01 lbs
ai

/gallon	5 gallons	9 µg

(MRID44459801)	6.0E-06	9,000,000

	6.3.2.  Residential Post Application Exposure and Risks

Residential Post Application Exposure Scenarios, Data Sources and
Assumptions

Scenarios

The following exposure scenario was assessed for residential turf post
application risks:

Short Term Incidental Oral Exposures of Toddlers Playing on Treated Turf

	  

General Assumptions

The following general assumptions are taken from the Standard Operating
Procedure (SOPs) of December 18, 1997 and ExpoSAC Policy #12
“Recommended Revisions to the Standard Operating Procedures for
Residential Exposure Assessments of February 22, 2001. 

An assumed initial TTR value of 5% of the application rate is used for
assessing hand to mouth exposures.

An assumed initial TTR value of 20% of the application rate is used for
assessing object to mouth exposures.

Soil residues are contained in the top centimeter and soil density is
0.67 mL/gram.

Three year old toddlers are expected to weigh 15 kg.

Hand-to-mouth exposures are based on a frequency of 20 events/hour and a
surface area per event of 20 cm2 representing the palmar surfaces of
three fingers.

Saliva extraction efficiency is 50 percent meaning that every time the
hand goes in the mouth approximately ½ of the residues on the hand are
removed.

An exposure duration of 2 hours per day is assumed for toddlers playing
on turf. 

Assumptions Specific to Mefluidide

The following assumptions that are specific to mefluidide are used for
assessing residential post application exposures.	

The application rate of 1.0 lbs ai/acre as stated in the label was used.
 Although RTU product (EPA Reg # 2217-788) has the highest application
rate of 1.23 lbs ai/acre, this product is considered to be used as spot
treatment.  As a result, the 1.23 lbs ai/acre is not considered a
representative rate for turf use. 

Calculation Methods 

	The above factors were used in the standard residential SOP formulas to
calculate the incidental oral exposures from hand- to- mouth, object-
to- mouth and soil ingestion on treated turf.  These formulas are
described in the cited ORE memo.  The MOEs were calculated using the
short/intermediate term incidental oral endpoint which has a NOAEL of 58
mg/kg/day.  

	The MOEs are summarized in Table 6.3.2A.  All of the MOEs exceeded 100.
 This means that the risks are below EPA’s level of concern. 

Table 6.3.2A - Mefluidide MOEs for Residential Post Application Turf
Exposures 

(Application Rate = 1.0 lb ai/acre)

Toddler Exposure Scenario

	TTR and soil Residue Levels	Dose (mg/kg/day)	MOE

Hand to Mouth Ingestion	0.56 ug/cm2	0.0150	4,000

Object to Mouth Ingestion 	2.2 ug/cm2	0.0037	16,000

Soil Ingestion 	7.5 ppm	5.0E-05	1,000,000

Total of Above

0.019	3,000

 

The risk assessment for toddler turf exposures are conservative because
it is based on day zero TTRs and soil residues and does not account for
dissipation.   The combined MOE is considered highly conservative since
each of the single scenarios (hand-to-mouth, object-to-mouth, or soil
ingestion) is assessed based on conservative assumptions, and that the
likelihood of all three scenarios occur at the same time is very rare.

Residential Turf Granule Ingestion Exposure and Risks

Scenarios

The following exposure scenario was assessed

Acute Exposures of Toddlers from Incidental Oral Ingestion of Granules

Assumptions

The following assumptions were used to assess the risk of incidental
oral ingestion of granules: 

The assumed ingestion rate is 0.3 gram/day based on the Residential SOP
2.3.1.  This is based on the assumption that if 150 lbs of product were
applied to a ½ acre lawn, the amount of product per square foot would
be 3 g/ft2 and a child would consume one-tenth of the product available
in a square foot.

Three year old toddlers are expected to weigh 15 kg.

The granules contain a maximum of 0.49 percent mefluidide ai based upon
product #538-181.  

Calculation Methods and Risks 

	The above factors were used to calculate the potential dose rate and
the absorbed dose using the Residential SOP 2.3.1 formulas as shown in
Table 6.3.2B.    MOEs were then calculated using the acute dietary NOAEL
of 58 mg/kg/day and they exceed 100.   This means that the risks for
toddler exposures from granular ingestion are below EPA’s level of
concern. 

Table 6.3.2B - Granule Ingestion Risks for Mefluidide

Percent ai	Potential Dose Rate1 (mg/day)	Absorbed Dose2 

(mg/kg/day)	Acute MOE3

0.49	1.47	0.098	590

1. Potential Dose Rate (PDR) = 0.3 gram/day * (Percent ai/100)* 1000
mg/gram

2. Absorbed Dose = PDR/BW

3. MOE = NOAEL/Dose where the NOAEL = 58 mg/kg/day

	

7.0	Aggregate Risk Assessments and Risk Characterization	

7.1	Aggregate Risk  tc "7.5	Cancer Risk " \l 2 

Aggregate Risk Assessment (food + water + residential exposure)

Although an aggregate risk assessment is not required under current
Agency policies for non-food use chemicals, to ensure that the public
health is adequately protected, a screening level aggregate risk
assessment was conducted for mefluidide.  For acute and chronic
aggregate risks, the only exposure is from drinking water.  As stated
above, the dietary exposures (drinking water only) do not exceed 1% of
the aRfD/cRfD for adult and 5% of the aRfD/cRfD for children.  For
short- term, no aggregate is needed for adults since there are no
residential post- application exposures to adults.  When considering the
dietary exposure (drinking water only) as a background exposure to
Children for short-term risk, the level of dietary exposure (0.0007
mg/kg/day) is negligible when compared to the combined incidental oral
exposure (0.019 mg/kg/day, Table 6.3.2A above) or the granule ingesting
dose (0.098 mg/kg/day, Table 6.3.2B above).  No intermediate-term
residential post application exposure was identified.  Therefore, short-
and intermediate- term aggregate is not of concern.

7.2	Cancer Risk  tc "7.5	Cancer Risk " \l 2 

Based on lack of evidence of carcinogenicity in both rats and mice,
mefluidide was considered as not likely to be carcinogenic to humans. 
No cancer assessment is needed.

8.0	Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to mefluidide and any other
substances and mefluidide does not appear to produce a toxic metabolite
produced by other substances. For the purposes of this action,
therefore, EPA has not assumed that mefluidide has a common mechanism of
toxicity with other substances.  For information regarding EPA’s
efforts to determine which chemicals have a common mechanism of toxicity
and to evaluate the cumulative effects of such chemicals, see the policy
statements released by EPA’s Office of Pesticide Programs concerning
common mechanism determinations and procedures for cumulating effects
from substances found to have a common mechanism on EPA’s website at  
HYPERLINK http://www.epa.gov/pesticides/cumulative/.
http://www.epa.gov/pesticides/cumulative/. 

9.0	Occupational Exposure/Risk Pathway

(Occupational and Residential Exposure Assessment; Yan Donovan, D324823,
2/28/07).

Mefluidide products are intended for both occupational and residential
uses.  

  SEQ CHAPTER \h \r 1 9.1	Short/Intermediate-Term Handler Risk

Based upon the application methods listed in Table , the following
exposure scenarios were identified and assessed. 

Mix/Load Liquid Formulations

Groundboom Application

Turfgun Application

Right of Way Application

Mix/Load/Apply Liquids with a Backpack Sprayer

Mix/Load/Apply Liquids with a Turfgun

Load/Apply Granules with a Push Cyclone

		

Occupational Handler Exposure Assumptions and Data Sources 

Exposure Assumptions

The following assumptions and factors were used in order to complete the
exposure and risk assessments for occupational handlers/applicators:

The daily acreages treated were taken from EPA Science Advisory Council
for Exposure Standard Operating Procedure  #9 “Standard Values for
Daily Acres Treated in Agriculture,” Revised July 5, 2000.  

The maximum application rate for turf areas is 1.0 lbs ai per acre as
listed in the Mefluidide labels.

The maximum application rate for ornamental trees is 0.01 lbs ai per
gallon based upon the Label #2217-759.

A body weight of 70 kg was assumed because the endpoint is not gender
specific.	

The inhalation absorption rate is 100%.	

Baseline indicates that no respirator is worn.

Handler Exposure Data Sources

	

	The handler exposure data were taken from the Pesticide Handler
Exposure Database (PHED) and the Outdoor Residential Exposure Task Force
(ORETF).  The PHED data were used primarily for the golf course,
ornamental trees, and rights- of - ways (ROW) scenarios and the ORETF
data were used for lawn care scenarios.  The detailed values specific to
each exposure scenario can be found in the above cited ORE memo.

Occupational Handler Exposure and Risk Estimates

Daily inhalation doses and Margins of Exposure (MOEs) were calculated
using standard HED methodology.  The MOEs for occupational handlers are
summarized in Table 9.1.   All of the MOEs are > 100 with baseline PPE
which means that the risks are not of concern and respiratory protection
is not needed. 



Table 9.1 – Mefluidide Inhalation MOEs for Occupational Handlers

Exposure Scenario 	Use Site	Application Rate	Daily Amount Treated or
Applied	Inhalation Unit Exposure at Baseline

(µg/lb ai handled)	MOE

 at Baseline Level1

Mixer/Loader (M/L)

M/L Liquids for Turfgun (20 PCOs)	PCO2 Turf	1.0 lb ai/acre	100 acres	1.2
34,000

M/L Liquids for High pressure Handwand	Ornamental trees	0.01lb ai/gallon
1000 gallons	1.2	340,000

M/L Liquids for Groundboom 	Golf Courses	1.0 lb ai/acre	40 acres	1.2
85,000

M/L Liquids for ROW Sprayer	Right of Way	0.067 lb ai/gallon	1000 gallons
1.2	50,000

Applicator

Groundboom Application	Golf Courses	1.0 lb ai/acre	40 acres	0.74	140,000

ROW Sprayer Application	Non Turf Areas3	0.067 lb ai/gallon	1000 gallons
3.9	16,000

Turfgun Application	PCO Turf	1.0 lb ai/acre	5 acres	1.0	812,000

Mixer/Loader/Applicator (M/L/A)

M/L/A Liquid Flowables with Turfgun 	PCO Turf	1.0 lb ai/acre	5 acres	1.9
427,000

M/L/A Liquids with Backpack Sprayer 	Non Turf Areas	0.067 lb ai/gallon
40 gallons	30	50,000

M/L/A Granules with Push Cyclone 	PCO Turf	0.5 lb ai/acre	5 acres	7.5
217,000

1. Baseline PPE indicates no respirator.  

2. PCO Turf includes residential lawns, commercial lawns and other lawn
areas treated by a Pest Control Operator (PCO).

3. Non Turf Areas include roadsides, Rights of Way (ROW) and other
similar non-crop areas.

Occupational Handler Risk Characterization

All the MOEs for occupational handlers are greatly above HED’s level
of concern (100), no refinement is needed.   However, HED recommends the
level of PPE required on the current labels are not to be changed as a
result of this assessment.

  SEQ CHAPTER \h \r 1 9.2	Post-application Exposure and Risk 

Occupational post application dermal risks were not assessed because
there is not likely to have occupational post-application scenario.   In
addition, no dermal endpoints were selected.  Mefluidide is only applied
outdoors and it is not a volatile compound, inhalation exposures are
negligible (Vapor pressures are < 1.0E-4 torr at 25o C for mefluidide, <
1.0E-7 torr at 25o C for mefluidide DEA salt and potassium salt).

10.0  	Data Needs and Label Requirements	

None.

Attachment I

Filename: C:\Documents and Settings\ydonovan\DEEM
Files\Mefluidide\Mefluidide.R98

Chemical: Mefluidide and Salts

RfD(Chronic): .015 mg/kg bw/day  NOEL(Chronic): 1.5 mg/kg bw/day

RfD(Acute): .58 mg/kg bw/day  NOEL(Acute):  58 mg/kg bw/day

Date created/last modified: 03-22-2007/09:27:32/8          Program ver.
2.03

Comment: Acute Exposure from drinking water only

------------------------------------------------------------------------
--------

  EPA    Crop                                   Def Res     Adj.Factors 
 Comment

  Code    Grp  Commodity Name                    (ppm)       #1    #2   

-------- ---- -------------------------------  ----------  ------ ------
 -------

86010000 O    Water, direct, all sources         0.032000   1.000  1.000
 

86020000 O    Water, indirect, all sources       0.032000   1.000  1.000



U.S. Environmental Protection Agency                                 
Ver. 2.02

DEEM-FCID ACUTE Analysis for MEFLUIDIDE AND SALTS               
(1994-98 data)

Residue file: Mefluidide.R98                      Adjustment factor #2
NOT used.

Analysis Date: 03-22-2007/09:46:53    Residue file dated:
03-22-2007/09:44:59/8

NOEL (Acute) =  58.000000 mg/kg body-wt/day

Daily totals for food and foodform consumption used.

Run Comment: "Exposure from drinking water only"

========================================================================
=======

Summary calculations (per capita):

      95th Percentile             99th Percentile             99.9th
Percentile

 Exposure  % aRfD     MOE    Exposure  % aRfD     MOE    Exposure  %
aRfD     MOE  

---------- ------- -------- ---------- ------- -------- ----------
------- --------

U.S. Population:

  0.001672    0.29   34696    0.003140    0.54   18472    0.006282   
1.08    9232  

All infants:

  0.006303    1.09    9202    0.009035    1.56    6419    0.016185   
2.79    3583  

Children 1-2 yrs:

  0.002623    0.45   22112    0.004380    0.76   13240    0.006371   
1.10    9104  

Children 3-5 yrs:

  0.002396    0.41   24206    0.003756    0.65   15443    0.006130   
1.06    9462  

Children 6-12 yrs:

  0.001668    0.29   34771    0.002774    0.48   20912    0.003788   
0.65   15312  

Youth 13-19 yrs:

  0.001356    0.23   42768    0.002282    0.39   25420    0.004104   
0.71   14133  

Adults 20-49 yrs:

  0.001549    0.27   37449    0.002594    0.45   22362    0.004692   
0.81   12362  

Adults 50+ yrs:

  0.001399    0.24   41469    0.002000    0.34   28997    0.003244   
0.56   17881  

Females 13-49 yrs:

  0.001558    0.27   37238    0.002507    0.43   23137    0.004446   
0.77   13046  

Filename: C:\Documents and Settings\ydonovan\DEEM
Files\Mefluidide\Mefluidide-Chronic.R98

Chemical: Mefluidide and Salts

RfD(Chronic): .015 mg/kg bw/day  NOEL(Chronic): 1.5 mg/kg bw/day

RfD(Acute): .58 mg/kg bw/day  NOEL(Acute):  58 mg/kg bw/day

Date created/last modified: 03-22-2007/09:44:59/8          Program ver.
2.03

Comment: Chronic Exposure from drinking water only

------------------------------------------------------------------------
--------

  EPA    Crop                                   Def Res     Adj.Factors 
 Comment

  Code    Grp  Commodity Name                    (ppm)       #1    #2   

-------- ---- -------------------------------  ----------  ------ ------
 -------

86010000 O    Water, direct, all sources         0.010000   1.000  1.000
 

86020000 O    Water, indirect, all sources       0.010000   1.000  1.000
 



U.S. Environmental Protection Agency                                
Ver. 2.00

DEEM-FCID Chronic analysis for MEFLUIDIDE AND SALTS             (1994-98
data)

Residue file name: C:\Documents and Settings\ydonovan\DEEM
Files\Mefluidide\Mefluidide-Chronic.R98

                                                 Adjustment factor #2
NOT used.

Analysis Date 03-22-2007/10:15:37     Residue file dated:
03-22-2007/10:14:22/8

Reference dose (RfD, Chronic) = .015 mg/kg bw/day

COMMENT 1: Chronic Exposure from drinking water only

========================================================================
=======

                    Total exposure by population subgroup

------------------------------------------------------------------------
-------

                                                    Total Exposure

                                        
-----------------------------------

          Population                         mg/kg             Percent
of   

           Subgroup                       body wt/day             Rfd   
   

--------------------------------------   -------------      
---------------

U.S. Population (total)                     0.000211                
1.4%

U.S. Population (spring season)             0.000209                
1.4%

U.S. Population (summer season)             0.000226                
1.5%

U.S. Population (autumn season)             0.000204                
1.4%

U.S. Population (winter season)             0.000204                
1.4%

Northeast region                            0.000192                
1.3%

Midwest region                              0.000213                
1.4%

Southern region                             0.000200                
1.3%

Western region                              0.000241                
1.6%

Hispanics                                   0.000239                
1.6%

Non-hispanic whites                         0.000206                
1.4%

Non-hispanic blacks                         0.000200                
1.3%

Non-hisp/non-white/non-black                0.000258                
1.7%

All infants (< 1 year)                      0.000691                
4.6%

Nursing infants                             0.000256                
1.7%

Non-nursing infants                         0.000856                
5.7%

Children 1-6  yrs                           0.000294                
2.0%



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Females 13-19 (not preg or nursing)         0.000148                
1.0%

Females 20+ (not preg or nursing)           0.000210                
1.4%

Females 13-50 yrs                           0.000204                
1.4%

Females 13+ (preg/not nursing)              0.000205                
1.4%

Females 13+ (nursing)                       0.000292                
1.9%

Males 13-19 yrs                             0.000155                
1.0%

Males 20+ yrs                               0.000189                
1.3%

Seniors 55+                                 0.000207                
1.4%

Children 1-2 yrs                            0.000313                
2.1%

Children 3-5 yrs                            0.000293                
2.0%

Children 6-12 yrs                           0.000202                
1.3%

Youth 13-19 yrs                             0.000152                
1.0%

Adults 20-49 yrs                            0.000197                
1.3%

Adults 50+ yrs                              0.000207                
1.4%

Females 13-49 yrs                           0.000196                
1.3%

------------------------------------------------------------------------
------- 

Appendix B:  Review of Human Research TC \l1 " Appendix D:  Review of
Human Research 

Studies reviewed for ethical conduct:

No MRID - PHED Surrogate Exposure Guide

00031050    Feldman, R.J., Maibach, H.I. (1974) Percutaneous penetration
of some pesticides and herbicides in man.  Toxicology and Applied
Pharmacology 28(?):126-132.  (Also In unpublished submission received
Apr 23, 1980 under 10279-7; submitted by Purdue Frederick Co., Norwalk,
Conn.; CLD:242321-R)

Studies reviewed by the Human Studies Review Board:

44416201  Gledhill, A. (1997) Dichlorvos: A Study to Investigate
Erythrocyte Cholinesterase Inhibition Following Oral Administration to
Healthy Male Volunteers: Lab Project Number: XH5170: Y09341: C05743. 
Unpublished study prepared by Zeneca Central Toxicology Lab. 104 p. 

 PAGE   

Page   PAGE  2  of   NUMPAGES  47 

Acute RfD (general population)  =      58 mg/kg (NOAEL)   = 0.58 mg/kg

		    	100 (UF)

Acute RfD (Females 13-50 years old)  =      58 mg/kg (NOAEL)   = 0.58
mg/kg

		    	         100 (UF)