Document ID: EPA-HQ-OPP-2007-0596-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-05-07T04:00Z

<EPA BIOPESTICIDES AND POLLUTION PREVENTION DIVISION COMPANY NOTICE OF
FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 
(7/1/2006)>

<EPA Biopesticides and Pollution Prevention Division contact: [insert
name and telephone number with area code]>

 

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<SUBMISSION: E-mail the completed template to: hollis.linda@epa.gov.>

<TEMPLATE:>

<[Hercon Environmental]>

<[Insert petition number]>

	EPA has received a pesticide petition ([insert petition number]) from
[Hercon Environmental], [PO Box 435, Emigsville, PA 17318] proposing,
pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act
(FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 to establish an
exemption from the requirement of a tolerance for biochemical pesticide
[(Z)-7,8-epoxy-2-methyloctadecane].

	Pursuant to section 408(d)(2)(A)(i) of the FFDCA, as amended, [Hercon
Environmental] has submitted the following summary of information, data,
and arguments in support of their pesticide petition. This summary was
prepared by [Hercon Environmental] and EPA has not fully evaluated the
merits of the pesticide petition. The summary may have been edited by
EPA if the terminology used was unclear, the summary contained
extraneous material, or the summary unintentionally made the reader
conclude that the findings reflected EPA’s position and not the
position of the petitioner.

<I. [Hercon Environmental]  Petition Summary>

<	[Insert petition number]>

<A. Product Name and Proposed Use Practices>

<[((Z)-7,8-epoxy-2-methyloctadecane,( commonly referred to as
(Disparlure,( is the technical grade active ingredient.

>

<B. Product Identity/Chemistry>

>

>

	>

<C. Mammalian Toxicological Profile>

	<[Studies to evaluate the safety to mammals were conducted on the
technical grade active ingredient (Disparlure( and are summarized as
follows:>

1.	Acute Oral Toxicity (OPPTS 870.1100):  No adverse effects  or deaths
were seen in rats that received an oral gavage dose of undiluted
Disparlure at 34,600 mg/kg bw (MRID No. 00047224).  Additionally, no
adverse effects  or deaths were seen in rats that received an oral
gavage limit dose of Disparlure at 5,000 mg/kg bw (MRID No. 45529801). A
LD50 >34,600 mg/kg was established.  

2.	Acute Dermal Toxicity (OPPTS 870.1200):  No adverse effects or deaths
were seen in rabbits  that received a dermal dose of 2,025 mg/kg bw of
undiluted Disparlure (MRID No. 00047224).  Local skin reactions observed
after the 24-hour exposure period were characterized by erythema and
edema.  After 7 days, skin lesions included escharosis, desquamation,
hemorrhaging and fissures, and after 14 days skin lesions remained, but
appeared less severe.  Necropsy of all subjects revealed no gross
pathological alterations other than the dermal alterations noted above. 
A LD50 >2,025 mg/kg was established.  

3.	Acute Inhalation Toxicity (OPPTS 870.1300):  No adverse effects or
deaths were seen in rats that were exposed to Disparlure as an aerosol
in a concentration of 5.0 mg/L of air for 1 hour (MRID No. 0004224).  No
effects on appearance, behavior or body weight were observed in any rats
any time after exposure.   A LD50 >5 mg/L was established.  

4.	Primary Eye Irritation (OPPTS 870.2400):  In an eye irritation study
on rabbits, Disparlure was classified as mildly irritating to the eye
(MRID Nos. 00047224 and 00144038).  The active ingredient was instilled
into the right eye of six healthy rabbits.  Three of the six rabbits had
redness of the conjunctiva at 24 hours, but no effects were observed in
any of the rabbits at 48 and 72 hours.  No effects were observed 7 days
after exposure.  

5.	Primary Dermal Irritation (OPPTS 870.2500):  In a skin irritation
study on rabbits, Disparlure was classified as moderately irritating to
the skin.  A concentration of 0.5 mL of undiluted active ingredient was
applied to each of two test sites on six healthy rabbits.  At 24 hours
after test material application all treated sites exhibited erythema and
all test sites except one animal exhibited edema.  At 72 hours erythema
was observed in all animals and edema was observed in four animals.  

6. 	Genotoxicity (OPPTS 870.5000):   A bacterial reverse mutation assay
using Salmonella typhimurium  and Escherichia coli was conducted on
Disparlure with and without metabolic activation (MRID No. 45309502). 
The study concluded that Disparlure has no mutagenicity to bacteria
under the conditions of the study.

	A waiver has been previously accepted by EPA for the dermal
sensitization data requirement for Disparlure.  A waiver of 90-day oral
toxicity, 90-day dermal toxicity, 90-day inhalation toxicity,
teratogenicity and immunotoxicity data requirements has been requested
based on the facts that 1) Disparlure is nontoxic by all routes of
exposure; 2) Disparlure is similar in chemical structure to compounds of
low chronic toxicity; and, 3) the potential for human exposure to
Disparlure is low, as follows:

	1) Disparlure is nontoxic by all routes of exposure.  The acute
toxicity studies and the genotoxicity study summarized herein
demonstrate the very low mammalian toxicity of Disparlure that is
characteristic of insect pheromones (FR Notice dated August 30, 1995.
Volume 60 number 168; pages 45060-45062. Lepidopteran Pheromones:
Tolerance Exemptions).  

	2) Disparlure is similar in chemical structure to compounds of low
chronic toxicity.  Disparlure is an aliphatic hydrocarbon compound, 18
carbons in length, with a single epoxide bond.  Disparlure is similar in
structure to epoxylated fatty acids present in epoxylated soybean oil, a
mixture that has undergone toxicity testing.  The structural similarity
between Disparlure and epoxylated soybean oil supports the use of
chronic oral toxicity data for epoxylated soybean oil as a surrogate for
Disparlure toxicity data.  Epoxylated soybean oil contains epoxylated
fatty acids derived from oleic, linoleic and linolenic acids which
differ from one another in the number of epoxide bonds present, either
one, two or three.  Each of these epoxylated fatty acids in epoxylated
soybean oil contains 18 carbons, and the epoxy bond is in the place of
the double bonds normally present in the fatty acids.  These three fatty
acids make up approximately 86% of soybean oil (Opinion of the
Scientific Panel on Food Additives, Flavorings Processing Aids and
Materials in Contact with Food [AFC on a request from the Commission
related to the use of Epoxidised soybean oil in food contact materials].
  EFSA Journal (2004) 64, 1-17. Adopted 26 May 2004 by written
procedure.).  The presence of an equal or greater number of epoxide
bonds in the soybean oil compared to Disparlure suggests that this test
article would not be less toxic than Disparlure, given the likely
assumption that the epoxide portion of the molecule mediates any
potential toxicity. 

	The Scientific Panel on Food Additives (European Commission on Food
Safety) presented a summary of the toxicity of epoxidized soybean oil
(ESFA, 2004).  The acute oral toxicity was similar to that of
Disparlure, with an LD50 in rats greater than 5,000 mg/kg bw.  A chronic
oral study was conducted in rats fed a diet containing up to 5%
epoxylated soybean oil for 2 years.  The no observed adverse effect
level (NOAEL) was approximately 140 mg/kg/day and the lowest observed
adverse effect level (LOAEL) was approximately 1,400 mg/kg/day.  The
effects observed were slight changes in the uterus, liver and kidney
weights and no alteration in blood parameters, indicating a lack of
effects on the immune system.  A tolerable daily intake of 1 mg/kg/day
was derived for epoxylated soybean oil. Also, data shows that the
epoxide bond is likely metabolized by an epoxide hydrolase enzyme. 
Soluble epoxide hydrolase has been detected in a variety of mammalian
tissues including liver, kidney, intestine, lungs vascular endothelium
and skin (Newman JW, Morisseau C, Hammock BD, 2005.  Epoxide hydrolases:
their roles and interactions with lipid metabolism.  Progress in Lipid
Research 44; 1-51).  The presence of epoxide hydrolase in the intestine,
liver, vascular endothelium and the skin suggests that similar
metabolites would likely be formed no matter what the exposure route. 
Given the similarity in chemical structure of Disparlure and epoxylated
soybean oil, the similarity in acute oral toxicity values, and the fact
that a 2-year toxicity study was conducted on epoxylated soybean oil,
Hercon believes the chronic toxicity data on epoxylated soybean oil is
an appropriate surrogate to characterize the safety of Disparlure in
place of sub-chronic, teratogencity and immunotoxicity studies.

	3) The potential for human exposure to Disparlure is low.  The
potential for Disparlure exposure to humans from treatment of forests,
recreation areas and trees and shrubs near pastures or other non-target
vegetation is low.  The application rates currently used are 6, 15 or 30
grams of active ingredient per acre, depending on the level of gypsy
moth infestation.  Label instructions indicate that under unusual
conditions a second application may be made in a year, for a maximal
application of 60 grams/acre/year.    In the event that Disparlure
applied to sites near pastures or other non-target vegetation drifts
into pastures where cattle are grazing, cattle may be exposed resulting
in potential human exposure.  

 	An exposure scenario based on the method for ecological exposure
characterization and risk assessment described by the EPA, using on the
Hoerger, Kenaga and Fletcher nomogram, was derived to estimate the
highest potential exposure to grazing cattle
(http://www.epa.gov/oppefed1/ecorisk_ders/toera_analysis_exp.htm).  The
nomogram presents the maximum and average estimated concentration of
pesticide in tall grass, short grass and broadleaf forage after
application of 1 pound per acre by spray.  The concentrations from the
nomogram were multiplied by the ratio of the anticipated application
rate/acre divided by 453 g/acre (453g equals 1 pound).  Assuming a
grazing area of short grass was impacted by the maximum single day
Disparlure application of 30 g/acre, the average Disparlure
concentration would be 5.63 mg/kg grass (long grass would be 2.38 mg/kg
and forage crops would be 2.98 mg/kg).  Assuming a cow eats 13.6 kg
short grass/day and weighs 544 kg, the Disparlure consumption level of
the cow would be approximately 0.14 mg/kg bw/day.  This could occur
twice per year and assumes that all the Disparlure applied is consumed
by grazing cattle, and all the grass consumed is impacted by drifting
Disparlure at the highest application rate. Grazing cattle could
maintain this level of exposure for only a short time, since the
assumptions basically require that all the applied Disparlure be
consumed in a matter of days after application, otherwise as the grass
grows the concentration of the Disparlure decreases.   More realistic
assumptions would be that only a portion of the pasture is impacted by
Disparlure drift, and this occurs once or perhaps twice per year.  Thus
consumption of Disparlure by cattle is more likely to be approximately
10% or less of the previous estimate, or a maximum of 0.014 mg/kg/day. 
Mammals are known to have metabolic pathways to breakdown aliphatic
epoxides, including ubiquitous epoxide hydrolase enzymes, so Disparlure
consumed by cattle is not expected to bioaccumulate (Newman et al 2005).
 Even if a conservative assumption is used to estimate the levels of
Disparlure that might remain in food products derived from cattle, say
10 or 100 times the level ingested on a mg/kg basis, human exposure to
Disparlure from this pathway would still be low.   The potential human
exposure to Disparlure from consuming products from exposed cattle is
significantly lower than the tolerable daily intake of 1 mg/kg body
weight for the related epoxylated soybean oil adopted by the Scientific
Committee for Food (European Commission on Food Safety).  Thus
incidental cattle exposure to Disparlure from application to areas near
pastures or other non-target vegetation would result in the potential
for very low exposure to humans. 

<D. Aggregate Exposure>

<1. Dietary exposure. 

>

<	i. Food. [Dietary exposure from use Disparlure, as proposed, is
minimal.  Disparlure is intended for application to non-crop areas such
as forests; residential, municipal and shade tree areas; recreational
areas such as campgrounds, golf courses, parks and parkways; ornamental
and shade tree forest plantings; and shelter belts, rights of way and
other easements.  The product is not applied directly to fruits,
vegetables or other food commodities; however,  unintentional spray or
drift from application when treating trees and shrubs along or within
pastures, as well as unintentional spray and drift to non-target
vegetation, may occur. 

>

<	ii. Drinking Water. [Similarly, exposure to humans from residues of
Disparlure in consumed drinking water would be unlikely.  Potential
exposure to surface water would be negligible and exposure to drinking
water (well or ground water) would be impossible to measure. Disparlure
is intended for application to non-crop areas such as forests;
residential, municipal and shade tree areas; recreational areas such as
campgrounds, golf courses, parks and parkways; ornamental and shade tree
forest plantings; and shelter belts, rights of way and other easements. 
The product is not applied directly to water.

>

<	2. Non-dietary exposure. [The potential for non-dietary exposure to
the general population, including infants and children, is limited.  to
non-crop areas such as forests; residential, municipal and shade tree
areas; recreational areas such as campgrounds, golf courses, parks and
parkways; ornamental and shade tree forest plantings; and shelter belts,
rights of way and other easements.  

>

<E. Cumulative Effects>

<	[It is not expected that, when used as proposed, Disparlure would
result in residues that are of toxicological concern. 

	Disparlure is intended for application to non-crop areas such as
forests; residential, municipal and shade tree areas; recreational areas
such as campgrounds, golf courses, parks and parkways; ornamental and
shade tree forest plantings; and shelter belts, rights of way and other
easements.  The product is not applied directly to food commodities;
however,  unintentional spray or drift from application when treating
trees and shrubs along or within pastures, as well as unintentional
spray and drift to non-target vegetation, may occur. 

>

<F. Safety Determination>

>

>

<G. Effects on the Immune and Endocrine Systems>

<	

	>

<H. Existing Tolerances>

>

<I. International Tolerances>

  >

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