Document ID: EPA-HQ-OPP-2007-1187-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-02-25T05:00Z

<EPA BIOPESTICIDES AND POLLUTION PREVENTION DIVISION COMPANY NOTICE OF
FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

(7/1/2007)>

<EPA Biopesticides and Pollution Prevention Division contact: [Todd
Peterson and (703) 308-7224]>

 

<INSTRUCTIONS:  Please utilize this outline in preparing the pesticide
petition.  In cases where the outline element does not apply, please
insert “NA-Remove” and maintain the outline. Please do not change
the margins, font, or format in your pesticide petition. Simply replace
the instructions that appear in green, i.e., “[Repar Corporation],”
with the information specific to your action.>

<SUBMISSION: E-mail the completed template to: duggard.mari@epa.gov.>

<TEMPLATE:>

<[Repar Corporation]>

<[7F7296]>

<	EPA has received a pesticide petition ([insert petition number]) from
[Repar Corporation], [c/o Mandava Associates, LLC, 1730 M Street, N.W.,
Suite 906, Washington, D.C. 20036] 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.>

<(Options (pick one)>

<	1. by establishing a tolerance for residues of>

<	2. to establish an exemption from the requirement of a tolerance for>

	

<	3. to establish an amendment/expansion of an existing tolerance
exemption for the>

<(Options (pick one)>

<	1. microbial pesticide  [insert name of active ingredient]>

<	2. biochemical pesticide [Homobrassinolide]>

	

<	3. plant-pesticide [Insert name of active ingredient] in or on [insert
commodity].>

<	Pursuant to section 408(d)(2)(A)(i) of  FFDCA, as amended, [Repar
Corporation] has submitted the following summary of information, data,
and arguments in support of their pesticide petition. This summary was
prepared by [Repar Corporation] 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. [Repar Corporation] Petition Summary>

<	[7F7296]>

<A. Product Name and Proposed Use Practices>

<	[The product name is Homobrassinolide Technical which contains
homobrassinolide as new active ingredient. It is a naturally occurring
plant growth regulator proposed for use in or on all agricultural
commodities for increasing the crop growth and efficiency, and crop
yield. The Agency classified homobrassinolide as a biochemical
pesticide. Homobrassinolide has been shown to increase cell elongation
and cell division thus contributing to over-all growth of the treated
crops.  Homobrassinolide is proposed for use on all agronomic and
horticultural crops including but not limited to all agricultural crops,
grasses, vines, ornamental and forest trees. Homobrassinolide Technical
is a manufacturing-use product intended for reformulations into end-use
products for application to target plants as foliar spray or for ground
applications and for seed treatment. The proposed maximum application
rate for all crops is less than 20 grams of the active ingredient per
acre per growing season.]>

<B. Product Identity/Chemistry>

α, 3α, 22S, 23S,
24S)-2,3,22,23-tetrahydroxy-24-ethyl-B-homo-7-oxa-5α-cholestan-6-one.
It is also called 22S, 23S-homobrassinolide. The CAS Registry Number is
80483-89-2. It is a naturally occurring substance and belongs to a group
of more than 50 other naturally occurring sterols which are collectively
known as Brassinosteroids. Brassinolide, epibrassinolide and
homobrassinolide are the most active substances in brassinosteroids
which undergo rapid metabolic changes in the plants. The metabolic
pathways of brassinosteroids including homobrassinolide,  produce
structural modifications to natural brassinosteroids that affect their
activity, function and transport in plants. Currently, 42
brassinosteroids metabolites are known.  The metabolic pathways vary
according to (i) plant species, (ii) developmental stages, and (iii)
structural changes. Based on the published information on
brassinosteroids, the metabolic pathway can be classified into two
types: (1) modification of the steroidal skeleton and (2) modification
of the side chain. Active brassinosteroids including homobrassinolide
are metabolized to inactive metabolites by such different processes in
the plants as: (a) dehydrogenation at C-3 or C-23; (b) dealkylation at
C-26 or C-28; (c) epimerization at C-2 or C-3; (d) esterification at
C-3; (e) glycosylation at C-2, C-3, C-23, C-25 or C-26; (f)
hydroxylation at C-20, C-25 or C-26; (g) side chain cleavage at C-20 or
C-22; and (h) sulfonation at C-22. Based on the published information,
brassinosteroids are biosynthesized from plant sterols and the
endogenous active brassinosteroids,  including homobrassinolide are
rapidly metabolized to inactive forms, some of which may give rise to
active forms by de-esterification and de-glycosylation. Since the
naturally occurring active brassinosteroids are present at
parts-per-billion levels in plants to elicit the desired biological
activity, the residues as a result of degradation (undergoing metabolic
changes to give inactive forms) are also present at such low levels.]>

<	2. Magnitude of residues at the time of harvest and method used to
determine the residue. [Homobrassinolide and other brassinosteroids are
naturally occurring substances and are ubiquitous to plants. They are
present in minute amounts (micrograms to picograms or even less) in all
parts of plants (edible and non-edible portions). Humans and animals are
exposed to these substances through the food channels.  An exogenous
supply of homobrassinolide is unlikely to have accumulation in the form
of residues because it is rapidly metabolized in plants to several
metabolic products which are the inactive forms. Since the proposed
applications of homobrassinolide to crops are so low (less than 20
grams/acre and in some cases it is applied at 1-5 grams per acre), the
residues in food crops at the time of harvest are expected to be
negligible. There are no analytical methods to estimate the residues
from the treated crops. Additionally, it is difficult to differentiate
the exogenous and endogenous levels of homobrassinolide and the
resulting degradates, metabolites or other residues in crops after
harvest.  At these low levels, it is difficult to measure the residues
which are unlikely to cause any harm to humans and the environment.]>



<	3. A statement of why an analytical method of detecting and measuring
the levels of the pesticide residue are not needed. [An analytical
method for detection of homobrassinolide residues in treated crops is
not required.  The proposed uses of homobrassinolide on all agricultural
crops are for a single season and homobrassinolide is applied at less
than 20 grams per acre for all treatments combined to enhance plant
growth, and to increase the crop efficiency and yields. An analytical
method for enforcement purposes to detect the residues was not submitted
since this petition proposes an exemption from the requirement of a
tolerance. Also there are no analytical methods available for
determination of residues of homobrassinolide because they are present
in minute amounts which are of no toxicological concern. ]>

<C. Mammalian Toxicological Profile>

<	[1. Acute toxicity.  Homobrassinolide  Technical has low acute oral,
dermal and inhalation toxicity. The oral lethal dose (LD50) in rats is
>5,000 milligrams/kilogram (mg/kg) body weight (bw); the acute oral LD50
in mice is >5,000 mg/kg bw; the dermal LD50 is >2,000 mg/kg bw; and the
inhalation 4-hour lethal concentration (LC50) in rats is 2.26
milligrams/Liter (mg/L) air. It is a mild irritant to the eyes of
rabbits and non-irritant to the skin of rabbits. It is not a skin
sensitizer in Guinea pigs.

	2.  Genotoxicity. Homobrassinolide Technical does not induce gene
mutations in bacterial and mammalian cells, chromosome aberrations in
mammalian cells or deoxyribonucleic acid (DNA) damage in bacterial cells
in in vitro test systems. Similarly, it does not exhibit a clastogenic
effect in vivo in the mice micronucleus test.  Therefore, there is no
evidence to suggest a genotoxic hazard at any of the three main levels
of genetic organization.

	3.  Subchronic toxicity. Subchronic (90-day) feeding studies were
conducted with Wistar rats.  There were no signs and no mortality, no
gain in body weight, no significant change in food consumption, and no
haematological and biochemical changes as a result of homobrassinolide
treatment.  Gross and histopathological examination of the rats did not
reveal any test material related lesions. Based on this study, it was
concluded that rats treated with 1000 mg/kg bw showed no significant
changes in haematological, blood biochemicals, body weight or food
consumption. Therefore, the NOAEL for Homobrassinolide Technical was
established at 1,000 mg a.i./kg/day for 90-day subchronic feeding study
in rats.

	4.  Other toxicity studies. Waivers are being requested for
developmental toxicity, 2-year chronic toxicity and carcinogenicity
studies based on homobrassinolide’s ubiquity in nature and negligible
exposure from low use rates.  Since homobrassinolide is not acutely
toxic, does not elicit genotoxic effects and shows high NOEAL (1000
mg/kg/day) in subchronic (90-day) study in rats, it is unlikely that it
will show any other toxic effects at the proposed use levels. Since
homobrassinolide is naturally occurring in plants, plants are part of a
normal human diet, and low use rates of homobrassinolide are proposed as
a plant regulator, such low use rates are not expected to significantly
increase the dietary intake over that anticipated from consumption of a
normal diet.]>

<D. Aggregate Exposure>

	 [Under Food Quality Protection Act (FQPA), the petitioner needs to
consider available information concerning exposures from the pesticide
residues in food and drinking water and all other non-occupational
exposures.]

<	1. Dietary exposure. [The mammalian toxicology data for
homobrassinolide indicate low acute toxicity following oral exposure
(Toxicity Category IV). At the levels used (less than 20
grams/acre/season) as plant growth regulator, human dietary exposure is
expected to be negligible and acute toxicity from such exposure is not
expected.  Subchronic (90-day) studies indicated that the toxicity did
not occur as a result of repeated oral doses at or above 1,000 mg/kg of
body weight, and no mutagenic activity was observed. Therefore, it is
unlikely that chronic exposures would be high enough to result in
effects harmful to humans. As to homobrassinolide, the lack of concern
regarding toxic effects, plus its low application rates, and its intake
above normally consumed levels demonstrates that there is reasonable
certainty of no harm from its use as plant growth regulator.]>

<	i. Food. [Residue analysis data, if any are available, are not a
component of this determination since homobrassinolide either is
naturally occurring in many food plants and is, therefore, a component
of the normal human diet, and/or is used at very low rates. The
petitioner believes that use of homobrassinolide will result in
negligible to nonexistent residues in or on foods or feed.]>

<	ii. Drinking water. [For the purposes of assessing the potential
dietary exposure under these exemptions, the petitioner considered that
under these exemptions homobrassinolide could be present in all food
commodities. Other potential sources of dietary exposure of the general
population to residues of pesticides are residues in drinking water.
Because of low use rates and the fate of the applied homobrassinolide in
the environment (degradation in soil and water), the petitioner does not
anticipate residues of homobrassinolide in drinking water.]>

<	2. Non-dietary exposure. [For homobrassinolide, the toxicity data in a
90-day feeding study in rats demonstrated no toxic endpoints upon which
to base a risk characterization at or below 1,000 mg/kg of body
weight/day (the limit dose).  Any non-occupational risk is expected to
be not significant because of the non-toxic mode of action and low
exposure resulting from the low plant growth regulator application
rates.  Also homobrassinolide is naturally occurring in foods, turf and
other plant species.  If required, appropriate label precautions will
mitigate risk from exposure through residential (home and garden) use.

	1. Dermal exposure. The mammalian toxicity data for homobrassinolide
indicate low acute toxicity following dermal exposure (Toxicity Category
III).

	2. Inhalation exposure.  The mammalian toxicity data for
homobrassinolide indicate low acute toxicity following inhalation
exposure (Toxicity Category III).]>

<E. Cumulative Effects>

<	[There are no other products (brassinosteroids) similar to
homobrassinolide registered as active ingredients for food use, so
dietary exposure from other pesticidal uses is not likely. Humans are
exposed to homobrassinolide through diet from plant sources and
cumulative effects are not expected from either other brassinosteroids
or other natural plant growth regulators. Consideration of a common
mechanism of toxicity is not necessary because there is no indication
that toxic effects of homobrassinolide would be cumulative with those of
any other plant growth regulators. Therefore, the petitioner believes it
is appropriate to consider only the potential risks of homobrassinolide
in aggregate risk assessment.]>

<F. Safety Determination>

<	1. U.S. population. [Homobrassinolide is a naturally occurring
substance ubiquitous to all plants which are the sources for food for
human consumption.  This substance has a low toxicity as demonstrated by
acute oral toxicity studies in rats and mice (LD50 > 5,000 mg/kg bw) and
the NOAEL of 1000 mg/kg/day in sub-chronic (90-day feeding) study in
rats. For chronic exposure, similar NOAEL (1000 mg/kg/day) value would
be considered.  Based on this information, the petitioner is of the
opinion that the aggregate exposure to homobrassinolide over a lifetime
should not change with application of homobrassinolide to crops at low
application rates (less than 20 grams/ acre/season). Thus, there is a
reasonable certainty that no harm will result from aggregate exposure to
homobrassinolide.]>

<	2. Infants and children. [FFDCA section 408 provides that EPA shall
apply an additional ten-fold margin of exposure (safety) for infants and
children in the case of threshold effects to account for pre- and
post-natal toxicity and the completeness of the database, unless EPA
determines that a different margin of exposure (safety) will be safe for
infants and children. Margins of exposure (safety) are often referred to
as uncertainty factors.  There are reliable data to support the
conclusion that homobrassinolide when used as a plant growth regulator
is practically non-toxic to mammals including infants and children, and
thus, there are no threshold effects, and the petitioner has not used a
margin of exposure (safety) approach to assess its safety. As a result,
the provision requiring an additional margin of exposure (safety) does
not apply.]>

<G. Effects on the Immune and Endocrine Systems>

<	[There is no information to suggest that homobrassinolide will have an
effect on the immune and endocrine systems. The Agency is not requiring
information on the endocrine effects of this natural plant regulator at
this time. Because of the long-term history of natural exposure in the
diet, it is not anticipated that homobrassinolide will require endocrine
effects screening.]>

<H. Existing Tolerances>

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There are no known existing tolerances for the use of homobrassinolide
as a plant growth regulator.]>

<I. International Tolerances>

<	[There are no CODEX, Canadian, or Mexican maximum residue limits
(MRLs) or no international tolerance exemptions for homobrassinolide,
when used as a plant growth regulator, at this time.]>

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