[Federal Register Volume 63, Number 59 (Friday, March 27, 1998)]
[Notices]
[Pages 14926-14936]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-8065]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-799; FRL-5579-6]
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces the initial filing of pesticide
petitions proposing the establishment of regulations for residues of
certain pesticide chemicals in or on various food commodities.
DATES: Comments, identified by the docket control number PF-799, must
be received on or before April 27, 1998.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Division
(7506C), Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 1132, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically by following
the instructions under ``SUPPLEMENTARY INFORMATION.'' No confidential
business information should be submitted through e-mail.
Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment that does not contain CBI must be submitted
for inclusion in the public record. Information not marked confidential
may be disclosed publicly by EPA without prior notice. All written
comments will be available for public inspection in Rm. 1132 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: The product reviewer listed in the
table below:
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Office location/
Product Manager telephone number Address
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Ann Sibold.................... Rm. 212, CM #2, 703- 1921 Jefferson
305-6502, e- Davis Hwy,
mail:[email protected] Arlington, VA
il.epa.gov.
Joseph M. Tavano.............. Rm. 214, CM #2, 703- Do.
305-6411, e-mail:
[email protected]
.epa.gov.
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SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as
follows proposing the establishment and/or amendment of regulations for
residues of certain pesticide chemicals in or on various food
commodities under section 408 of the Federal Food, Drug, and Comestic
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these petitions
contain data or information regarding the elements set forth in section
408(d)(2); however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data supports granting of
the petition. Additional data may be needed before EPA rules on the
petition.
The official record for this notice of filing, as well as the
public version, has been established for this notice of filing under
docket control number [PF-799] (including comments and data submitted
electronically as described below). A public version of this record,
including printed, paper versions of electronic comments, which does
not include any information claimed as CBI, is available for inspection
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal
holidays. The official record is located at the address in
``ADDRESSES'' at the beginning of this document.
Electronic comments can be sent directly to EPA at:
opp-docket@epamail.epa.gov
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comment and data
will also be accepted on disks in
[[Page 14927]]
Wordperfect 5.1 file format or ASCII file format. All comments and data
in electronic form must be identified by the docket number (insert
docket number) and appropriate petition number. Electronic comments on
notice may be filed online at many Federal Depository Libraries.
List of Subjects
Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: March 19, 1998
Peter Caulkins,
Acting Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Petitioner summaries of the pesticide petitions are printed below
as required by section 408(d)(3) of the FFDCA. The summaries of the
petitions were prepared by the petitioners and represent the views of
the petitioners. EPA is publishing the petition summaries verbatim
without editing them in any way. The petition summary announces the
availability of a description of the analytical methods available to
EPA for the detection and measurement of the pesticide chemical
residues or an explanation of why no such method is needed.
1. American Cyanamid Company
PP 6F4623
EPA has received a pesticide petition (PP 6F4623) from American
Cyanamid Company, P.O. Box 400, Princeton, NJ 08543-0400, proposing
pursuant to section 408(d) of the Federal Food, Drug and Cosmetic Act,
21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance
of 0.5 ppm for residues of 4-bromo-2-(4-chlorophenyl)-1-(ethoxymethyl)-
5-(trifluoromethyl)-1-pyrrole-3-carbonitrile, (chlorfenapyr) in or on
the raw agricultural commodity citrus. As citrus processed commodities
fed to food animals may be transferred to milk and edible tissues,
tolerances are also proposed for the following ruminant food items:
milk at 0.01 parts per million (ppm); milk fat at 0.15 ppm; meat at
0.01 ppm; and meat by-products (including fat) at 0.10 ppm.
The proposed analytical method is capillary gas chromatography
using an electron capture detector. EPA has determined that the
petition contains data or information regarding the elements set forth
in section 408(d)(2) of the FFDCA; however, EPA has not fully evaluated
the sufficiency of the submitted data at this time or whether the data
supports granting of the petition. Additional data may be needed before
EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The nature of the residues of chlorfenapyr in
plants is adequately understood and the residue of concern in citrus
consists of the parent molecule. Expressed on a whole basis, the parent
compound accounted for 56-75% of the total radioactive residue (TRR),
98% of which was associated with the external rinse and peel.
2. Analytical method. The GC analytical method, M2284, which is
proposed as the enforcement method for the residues of chlorfenapyr in
citrus, has a limit of detection (LOD) of 0.01 ppm (0.025 ppm for
juice) and a limit of quantitation (LOQ) of 0.05 ppm.
3. Magnitude of residues. Extensive citrus field trials have been
conducted over multiple growing seasons in all major citrus growing
regions of the US. The results of these studies indicate that at the
highest proposed use rate of 1.05 lbs ai/A, the maximum expected
chlorfenapyr residues are 0.4 ppm in oranges, 0.38 ppm in lemons and
0.27 ppm in grapefruit in/on citrus samples harvested 7 days following
the last application. These field trial data are adequate to support
the proposed tolerance of 0.5 ppm in/on citrus harvested 7-days
following the last application. The results of processing studies
indicate that chlorfenapyr residues do not concentrate in molasses and
juice. The actual concentration factors in dried pulp (2.4x) and citrus
oil (70x) are well below the maximum theoretical concentration factors
for these commodities. Although citrus oil is not considered to be a
ready-to-eat item and is not expected to contribute to the dietary
exposure, a tolerance at 35 ppm (0.5 ppm x 70) is proposed for
enforcement purposes.
B. Toxicological Profile
1. Acute toxicity. Based on the EPA's toxicity category criteria,
the acute toxicity category for chlorfenapyr technical is Category II
or moderately toxic (signal word WARNING) and the acute toxicity
category for the 2SC formulation is Category III or slightly toxic
(signal word CAUTION). Males appear to be more sensitive to the effects
of chlorfenapyr than females. The acute toxicity profile indicates that
absorption by the oral route appears to be greater than by the dermal
route. The following are the results from the acute toxicity tests
conducted on the technical material:
i. Rat Oral LD50: 441/1152 milligram/kilograms (mg/kg)
bwt.(M/F) -- Tox. Category II
ii. Rabbit Dermal LD50: >2,000 mg/kg bwt.(M/F) -- Tox.
Category III
iii. Acute Inhal. LC50: 0.83/>2.7 mg/L (M/F) -- Tox.
Category III
iv. Eye Irritation: Moderately Irritating -- Tox. Category III
v. Dermal Irritation: Non-Irritating -- Tox. Category IV
vi. Dermal Sensitization: Non-Sensitizer -- Non Sensitizer
vii. Acute Neurotoxicity: NOEL 45 mg/kg bwt. -- Not An Acute
Neurotoxicant
2. Genotoxicty. Chlorfenapyr technical (94.5% a.i.) was examined in
a battery ofin vitro and in vivo tests to assess its genotoxicity and
its potential for carcinogenicity. These tests are summarized below.
Microbial/Microsome Mutagenicity Assay: Non-mutagenic
Mammalian Cell CHO/HGPRT Mutagenicity Assay: Non-mutagenic
In Vivo Micronucleus Assay: Non-genotoxic
In Vitro--Chromosome Aberration Assay in CHO: Non-clastogenic
In Vitro--Chromosome Aberration Assay in CHLC: Non-clastogenic
Unscheduled DNA Synthesis (UDS) Assay: Non-genotoxic.
3. Reproductive and developmental toxicity. Chlorfenapyr is neither
a reproductive or developmental toxicant and is not a teratogenic agent
in the Sprague-Dawley rat or the New Zealand white rabbit. This is
demonstrated by the results of the following studies:
Rat Oral Teratology -- No-Observed-Effect-Level (NOEL) for maternal
toxicity 25 mg/kg bwt./day and NOEL for fetal/develop. toxicity 225
milligram/kilograms body weight/day (mg/kg bwt./day)
Rabbit Oral Teratology -- NOEL for maternal toxicity 5 mg/kg bwt./
day and NOEL for fetal/develop. toxicity 30 mg/kg bwt./day
Rat 2-Generation Reproduction -- NOEL for parental toxicity /growth
and offspring development 60 ppm (5 mg/kg bwt./day)
NOEL for reproductive performance 600 ppm (44 mg/kg bwt./day).
4. Subchronic toxicity. The following are the results of the
subchronic toxicity tests that have been conducted with chlorfenapyr:
28-Day Rabbit Dermal -- NOEL 100 mg/kg bwt./day
28-Day Rat Feeding -- NOEL >600 ppm (< 71.6="" mg/kg="" bwt./day)="" 28-day="" mouse="" feeding="" --="" noel="">160 ppm (<32 mg/kg="" bwt./day)="" 13-week="" rat="" dietary="" --="" noael="" 150="" ppm="" (11.7="" mg/kg="" bwt./day)="" [[page="" 14928]]="" 13-week="" mouse="" dietary="" --="" noel="" 40="" ppm="" (8.2="" mg/kg="" bwt./day)="" 13-week="" dog="" dietary="" --="" noael="" 120="" ppm="" (4.2="" mg/kg="" bwt./day)="" 5.="" chronic="" toxicity.="" chlorfenapyr="" is="" not="" oncogenic="" in="" either="" sprague="" dawley="" rats="" or="" cd-1="" mice="" and="" is="" not="" likely="" to="" be="" carcinogenic="" in="" humans.="" the="" following="" are="" the="" results="" of="" the="" chronic="" toxicity="" tests="" that="" have="" been="" conducted="" with="" chlorfenapyr:="" 1-year="" neurotoxicity="" in="" rats="" --="" noel="" 60="" ppm="" (2.6/3.4="" mg/kg="" bwt./day="" m/f)="" 1-year="" dog="" dietary="" --="" noel="" 120="" ppm="" (4.0/4.5="" mg/kg="" bwt./day="" m/f)="" 24-month="" rat="" dietary="" --="" noel="" for="" chronic="" effects="" 60="" ppm="" (2.9/3.6="" mg/kg="" bwt./day="" m/f)="" and="" noel="" for="" oncogenic="" effects="" 600="" ppm="" (31/37="" mg/kg="" bwt./day="" m/f)="" 18-month="" mouse="" dietary="" --="" noel="" for="" chronic="" effects="" 20="" ppm="" (2.8/3.7="" mg/kg="" bwt./day="" m/f)="" and="" noel="" for="" oncogenic="" effects="" 240="" ppm="" (34.5/44.5="" mg/kg="" bwt./day="" m/f)="" 6.="" animal="" metabolism.="" a="" metabolism="" study="" was="" conducted="" in="" sprague="" dawley="" rats="" at="" approximately="" 20="" and="" 200="" mg/kg="" bwt.="" using="" radiolabeled="" chlorfenapyr.="" approximately="" 65%="" of="" the="" administered="" dose="" was="" eliminated="" during="" the="" first="" 24="" hours="" (62%="" in="" feces="" and="" 3%="" in="" urine)="" and="" by="" 48="" hours="" following="" dosing,="" approximately="" 85%="" of="" the="" dose="" had="" been="" excreted="" (80%="" in="" feces="" and="" 5%="" in="" urine).="" the="" absorbed="" chlorfenapyr-related="" residues="" were="" distributed="" throughout="" the="" body="" and="" detected="" in="" tissues="" and="" organs="" of="" all="" treatment="" groups.="" the="" principal="" route="" of="" elimination="" was="" via="" feces,="" mainly="" as="" unchanged="" parent="" plus="" minor="" n-dealkylated,="" debrominated="" and="" hydroxylated="" oxidation="" products.="" the="" metabolic="" pathway="" of="" chlorfenapyr="" in="" the="" laying="" hen="" and="" the="" lactating="" goat="" was="" also="" similar="" to="" that="" in="" laboratory="" rats.="" 7.="" metabolite="" toxicology.="" the="" parent="" molecule="" is="" the="" only="" moiety="" of="" toxicological="" significance="" which="" needs="" regulation="" in="" plant="" and="" animal="" commodities.="" 8.="" endocrine="" effects.="" collective="" organ="" weights="" and="" histopathological="" findings="" from="" the="" 2-generation="" rat="" reproduction="" study,="" as="" well="" as="" from="" the="" subchronic="" and="" chronic="" toxicity="" studies="" in="" two="" or="" more="" animal="" species,="" demonstrate="" no="" apparent="" estrogenic="" effects="" or="" effects="" on="" the="" endocrine="" system.="" there="" is="" no="" information="" available="" which="" suggests="" that="" chlorfenapyr="" would="" be="" associated="" with="" endocrine="" effects.="" c.="" aggregate="" exposure="" 1.="" dietary="" exposure--="" i.="" food.="" for="" purposes="" of="" assessing="" the="" potential="" dietary="" exposure,="" a="" theoretical="" maximum="" residue="" contribution="" (tmrc)="" has="" been="" calculated="" from="" the="" tolerance="" of="" chlorfenapyr="" in/on="" citrus="" at="" 0.5="" ppm.="" this="" exposure="" assessment="" is="" based="" on="" very="" conservative="" assumptions,="" namely="" 100%="" of="" all="" citrus="" is="" treated="" with="" chlorfenapyr="" and="" that="" the="" residues="" of="" chlorfenapyr="" in="" citrus="" are="" at="" the="" tolerance="" level.="" although="" there="" are="" no="" other="" established="" us="" permanent="" tolerances="" for="" chlorfenapyr,="" a="" petition="" for="" a="" permanent="" tolerance="" at="" 0.5="" ppm="" in="" cottonseed="" is="" pending="" at="" the="" agency.="" therefore,="" the="" dietary="" exposures="" to="" residues="" of="" chlorfenapyr="" in="" or="" on="" food="" will="" be="" limited="" to="" residues="" in="" cottonseed,="" citrus="" and="" food="" and="" feed="" items="" derived="" from="" them.="" as="" dried="" citrus="" pulp="" is="" a="" dairy="" and="" beef="" cattle="" feed="" item,="" a="" cold="" feeding="" study="" with="" dairy="" cattle="" was="" conducted.="" since="" this="" study="" demonstrated="" that="" measurable="" residues="" of="" chlorfenapyr="" may="" occur="" in="" milk,="" meat="" and="" meat="" by="" products,="" appropriate="" residue="" tolerances="" for="" these="" items="" are="" proposed.="" the="" contribution="" of="" the="" citrus="" tolerances="" alone="" to="" the="" daily="" consumption="" uses="" only="" 0.23%="" of="" the="" reference="" dose="" (rfd)="" for="" the="" overall="" us="" population.="" the="" combined="" contributions="" of="" the="" citrus="" and="" the="" pending="" cottonseed="" tolerances="" to="" the="" daily="" consumption="" uses="" less="" than="" 1%="" (actual="" 0.85%)="" of="" the="" reference="" dose="" for="" the="" overall="" us="" population="" and="" less="" than="" 3%="" (actual="" 2.23%)="" and="" less="" than="" 1%="" (actual="" 0.89%)="" of="" the="" reference="" doses="" for="" children="" aged="" 1-6="" and="" for="" non-nursing="" infants,="" respectively.="" ii.="" drinking="" water.="" there="" is="" no="" available="" information="" about="" chlorfenapyr="" exposures="" via="" levels="" in="" drinking="" water.="" there="" is="" no="" concern="" for="" exposure="" to="" residues="" of="" chlorfenapyr="" in="" drinking="" water="" because="" of="" its="" extremely="" low="" water="" solubility="" (120="" ppb="" at="" 25="" deg.).="" chlorfenapyr="" is="" also="" immobile="" in="" soil="" and="" does="" not="" leach="" because="" it="" is="" strongly="" adsorbed="" to="" all="" common="" soil="" types.="" in="" addition,="" the="" label="" explicitly="" prohibits="" applications="" near="" aquatic="" areas="" there="" is="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" from="" dietary="" exposure="" to="" chlorfenapyr,="" because="" dietary="" exposure="" to="" residues="" on="" food="" will="" use="" only="" a="" small="" fraction="" of="" the="" (rfd)="" (including="" exposure="" of="" sensitive="" subpopulations),="" and="" exposure="" through="" drinking="" water="" is="" expected="" to="" be="" insignificant.="" 2.="" non-dietary="" exposure.="" there="" is="" no="" available="" information="" quantifying="" non-dietary="" exposure="" to="" chlorfenapyr.="" however,="" based="" on="" the="" physico-chemical="" characteristics="" of="" the="" compound,="" the="" proposed="" use="" pattern="" and="" available="" information="" concerning="" its="" environmental="" fate,="" non-dietary="" exposure="" is="" expected="" to="" be="" negligible.="" the="" vapor="" pressure="" of="" chlorfenapyr="" is="" less="" than="" 1="" x="">-7 mm of Hg; therefore,
the potential for non-occupational exposure by inhalation is
insignificant. Moreover, the current proposed registration is for
outdoor, terrestrial uses which severely limit the potential for non-
occupational exposure.
D. Cumulative Effects
The pyrrole insecticides represent a new class of chemistry with a
unique mechanism of action. The parent molecule, AC 303,630 is a pro-
insecticide which is converted to the active form, CL 303,268, via
rapid metabolism by mixed function oxidases (MFOs). The active form
uncouples oxidative phosphorylation in the insect mitochondria by
disrupting the proton gradient across the mitochondrial membrane. The
production of ATP is inhibited resulting in the cessation of all
cellular functions. Because of this unique mechanism of action, it is
highly unlikely that toxic effects produced by chlorfenapyr would be
cumulative with those of any other pesticide chemical.
In mammals, there is a lower titer of MFOs, and chlorfenapyr is
metabolized by different pathways (including dehalogenation, oxidation
and ring hydroxylation) to other polar metabolites without any
significant accumulation of the potent uncoupler, CL--303,268. In the
rat, approximately 85 % of the administered dose is excreted in the
feces within 48-hours, thereby reducing the levels of AC 303,630 and CL
303,268 that are capable of reaching the mitochondria. This
differential metabolism of AC 303,630 to CL 303,268 in insects versus
to other polar metabolites in mammals is responsible for the selective
insect toxicity of the pyrroles.
E. Safety Determination
1. U.S. population. The RfD of 0.03 mg/kg bwt./day for the residues
of chlorfenapyr in citrus is calculated by applying a 100-fold safety
factor to the overall NOEL of 3 mg/kg bwt./day. This NOEL is of based
on the results of the chronic feeding studies in the rat and mouse and
the 2-generation reproduction study in the rat (see Item 2). The TMRC
for the proposed tolerances in citrus alone, (0.0000692 mg/kg bwt./
day), will utilize only 0.23% of the RfD for the general U.S.
population and the combined TMRC for the proposed chlorfenapyr
tolerances in cottonseed, citrus, milk and meat (0.0002558 mg/kg bwt./
day) will utilize approximately 0.85% of the RfD for the general U.S.
population.
2. Infants and children. The TMRC in milk consumed by a non-nursing
infant
[[Page 14929]]
(>1-year of age) is 0.0002435 mg/kg bwt./day. The combined tolerances
will use less than 1% (actual 0.89%) of the RfD for non-nursing
infants. The TMRC in milk consumed by a child (1-6 years of age) is
0.0003886 mg/kg bwt./day. The combined TMRC for the proposed
chlorfenapyr tolerances in cottonseed, citrus meat and milk consumed by
a child 1-6 years of age is 0.0006708 mg/kg bwt./day, which is less
than 3% (actual 2.23%) of the RfD. Therefore, the results of the
toxicology and metabolism studies support both the safety of
chlorfenapyr to humans based on the intended use as an insecticide-
miticide on citrus and cottonseed and the granting of the requested
tolerances in cottonseed, citrus, milk, milk fat solids, meat and meat
by-products.
Based on the conservative assumptions used in proposing the above
tolerances and the absence of other non-dietary routes of exposure to
chlorfenapyr, and since the calculated exposures are well below 100% of
the reference dose, there is a reasonable certainty that no harm will
result from aggregate exposure to residues of chlorfenapyr, including
all anticipated dietary exposure and all other non-occupational
exposures. The use of a 100-fold safety factor ensures an acceptable
margin of safety for both the overall U. S. population as well as
infants and children. As the toxicology database (reproduction/
developmental and teratology studies) is complete, valid and reliable,
no additional safety factor is needed.
The 100-fold margin of safety is adequate to assure a reasonable
certainty of no harm to infants and children from the proposed use. As
stated earlier, the NOEL is based on the effects observed in the rat
and mouse chronic oncogenicity studies, (reduced body weight gains,
increased globulin and cholesterol values and increased liver weights
in the rat and reduced body weight gains and vacuolation of white
matter of the mouse brain), the one-year neurotoxicity study in the
rat, (reduced body weight gains and vacuolar myelinopathy of the brain
and spinal cord that is completely reversible following termination of
treatment and is not associated with any damage to neuronal cell bodies
or axons; vacuolation of the white matter is a consequence of edema
(water) formation between the myelin layers which result from the
unrestricted movement of ions across the cell membranes) and the 2-
generation rat reproduction study, (reduced body weight gains for
parental animals and reduced pup body weights for the F1 and F2
litters; however no behavioral changes were observed in either F1 or F2
offsprings in the 2-generation reproduction study). Moreover, as the
NOELs for fetal/developmental toxicity are significantly higher than
those for maternal toxicity, the results indicate that chlorfenapyr is
neither a developmental toxicant nor a teratogenic agent in either the
Sprague-Dawley rat or New Zealand White rabbit. Thus, there is no
reliable information to indicate that there would be a variability in
the sensitivities of infants and children and adults to the effects of
exposure to chlorfenapyr.
F. International Tolerances
Section 408 (b)(4) of the amended FFDCA requires EPA to determine
whether a maximum residue level has been established for the pesticide
chemical by the Codex Alimentarius Commission.
There is neither a Codex proposal, nor Canadian or Mexican
tolerances/limits for residues of chlorfenapyr in/on citrus. Therefore,
a compatibility issue is not relevant to the proposed tolerance.
2. Rohm and Haas Company
PP 6G4681
EPA has received a pesticide petition (PP 6G4681) from Rohm and
Haas Company, 100 Independence Mall West, Philadelphia, PA 19106-2399.
proposing pursuant to section 408(d) of the Federal Food, Drug and
Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR part 180 by
establishing a tolerance for residues of tebufenozide, benzoic acid,
3,5-dimethyl-,1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl)hydrazide in or
on the raw agricultural commodity pears at 1.5 (ppm). EPA has
determined that the petition contains data or information regarding the
elements set forth in section 408(d)(2) of the FFDCA; however, EPA has
not fully evaluated the sufficiency of the submitted data at this time
or whether the data supports granting of the petition. Additional data
may be needed before EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The metabolism of tebufenozide in plants
(grapes, apples, rice and sugar beets) is adequately understood for the
purposes of these tolerances. The metabolism of tebufenozide in all
crops was similar and involves oxidation of the alkyl substituents of
the aromatic rings primarily at the benzylic positions. The extent of
metabolism and degree of oxidation are a function of time from
application to harvest. In all crops, parent compound comprised the
majority of the total dosage. None of the metabolites were in excess of
10% of the total dosage. The metabolism of tebufenozide in goats
proceeds along the same metabolic pathway as observed in plants. No
accumulation of residues in tissues or milk occurred. Because apple
pomace is not fed to poultry, there is no reasonable expectation that
measurable residues of tebufenozide will occur in eggs, poultry meat or
poultry meat by-products.
2. Analytical method. A high performance liquid chromatographic
(HPLC) analytical method using ultraviolet (UV) or mass selective
detection have been validated for apples. The method involves
extraction by blending with solvents, purification of the extracts by
liquid-liquid partitions and final purification of the residues using
solid phase extraction column chromatography. The limits of
quantitation is 0.02 ppm for apples.
B. Toxicological Profile
1. Acute toxicity. Tebufenozide has low acute toxicity.
Tebufenozide Technical was practically non-toxic by ingestion of a
single oral dose in rats and mice (LD50 > 5,000 milligram/
kilograms (mg/kg) and was practically non-toxic by dermal application
(LD50 > 5,000 mg/kg). Tebufenozide Technical was not
significantly toxic to rats after a 4-hr inhalation exposure with an
LC50 value of 4.5 mg/L (highest attainable concentration),
is not considered to be a primary eye irritant or a skin irritant and
is not a dermal sensitizer. An acute neurotoxicity study in rats did
not produce any neurotoxic or neuropathologic effects.
2. Genotoxicty. Tebufenozide technical was negative (non-mutagenic)
in an Ames assay with and without hepatic enzyme activation and in a
reverse mutation assay with E. coli. Tebufenozide technical was
negative in a hypoxanthine guanine phophoribosyl transferase (HGPRT)
gene mutation assay using Chinese hamster ovary (CHO) cells in culture
when tested with and without hepatic enzyme activation. In isolated rat
hepatocytes, tebufenozide technical did not induce unscheduled DNA
synthesis (UDS) or repair when tested up to the maximum soluble
concentration in culture medium. Tebufenozide did not produce
chromosome effects in vivo using rat bone marrow cells or in vitro
using Chinese hamster ovary cells (CHO). On the basis of the results
from this battery of tests, it is concluded that tebufenozide is not
mutagenic or genotoxic.
3. Reproductive and developmental toxicity--i. NOELs for
developmental and maternal toxicity to tebufenozide
[[Page 14930]]
were established at 1,000 milligram/kilograms/day (mg/kg/day) highest
dose tested (HDT) in both the rat and rabbit. No signs of developmental
toxicity were exhibited.
ii. In a 2-generation reproduction study in the rat, the
reproductive/developmental toxicity (NOEL) of 12.1 mg/kg/day was 14-
fold higher than the parental (systemic) toxicity NOEL 10 ppm 0.85 mg/
kg/day. Equivocal reproductive effects were observed only at the 2,000
ppm dose.
iii. In a second rat reproduction study, the equivocal reproductive
effects were not observed at 2,000 ppm (the NOEL equal to 149-195 mg/
kg/day) and the NOEL for systemic toxicity was determined to be 25 ppm
(1.9-2.3 mg/kg/day).
4. Subchronic toxicity-- i. The NOEL in a 90-day rat feeding study
was 200 ppm (13 mg/kg/day for males, 16 mg/kg/day for females). The
lowest-observed-effect-level (LOEL) was 2,000 ppm (133 mg/kg/day for
males, 155 mg/kg/day for females). Decreased body weights in males and
females was observed at the LOEL of 2,000 ppm. As part of this study,
the potential for tebufenozide to produce subchronic neurotoxicity was
investigated. Tebufenozide did not produce neurotoxic or
neuropathologic effects when administered in the diets of rats for 3-
months at concentrations up to and including the limit dose of 20,000
ppm (NOEL = 1330 mg/kg/day for males, 1,650 mg/kg/day for females).
ii. In a 90-day feeding study with mice, the NOEL was 20 ppm (3.4
and 4.0 mg/kg/day for males and females, respectively). The LOEL was
200 ppm (35.3 and 44.7 mg/kg/day for males and females, respectively).
Decreases in body weight gain were noted in male mice at the LOEL of
200 ppm.
iii. A 90-day dog feeding study gave a NOEL of 50 ppm (2.1 mg/kg/
day for males and females). The LOEL was 500 ppm (20.1 and 21.4 mg/kg/
day for males and females, respectively). At the LOEL, females
exhibited a decrease in rate of weight gain and males presented an
increased reticulocyte
iv. A 10-week study was conducted in the dog to examine the
reversibility of the effects on hematological parameters that were
observed in other dietary studies with the dog. Tebufenozide was
administered for 6-weeks in the diet to 4 male dogs at concentrations
of either 0 or 1,500 ppm. After the 6-week, the dogs receiving treated
feed were switched to the control diet for 4- weeks. Hematological
parameters were measured in both groups prior to treatment, at the end
of the 6-weeks treatment, after 2-weeks of recovery on the control diet
and after 4-weeks of recovery on the control diet. All hematological
parameters in the treated/recovery group were returned to control
levels indicating that the effects of tebufenozide on the hemopoietic
system are reversible in the dog.
v. In a 28-day dermal toxicity study in the rat, the NOEL was 1,000
mg/kg/day, (HDT). Tebufenozide did not produce toxicity in the rat when
administered dermally for 4-weeks at doses up to and including the
limit dose of 1,000 mg/kg/day.
5. Chronic toxicity--i. A 1-year feeding study in dogs resulted in
decreased red blood cells, hematocrit, and hemoglobin and increased
Heinz bodies, reticulocytes, and platelets at the (LOEL) of 8.7 mg/kg/
day. The NOEL in this study was 1.8 mg/kg/day.
ii. An 18-month mouse carcinogenicity study showed no signs of
carcinogenicity at dosage levels up to and including 1,000 ppm, the
highest dose tested.
iii. In a combined rat chronic/oncogenicity study, the NOEL for
chronic toxicity was 100 ppm (4.8 and 6.1 mg/kg/day for males and
females, respectively) and the LOEL was 1,000 ppm (48 and 61 mg/kg/day
for males and females, respectively). No carcinogenicity was observed
at the dosage levels up to 2,000 ppm (97 mg/kg/day and 125 mg/kg/day
for males and females, respectively).
6. Animal metabolism. The adsorption, distribution, excretion and
metabolism of tebufenozide in rats was investigated. Tebufenozide is
partially absorbed, is rapidly excreted and does not accumulate in
tissues. Although tebufenozide is mainly excreted unchanged, a number
of polar metabolites were identified. These metabolites are products of
oxidation of the benzylic ethyl or methyl side chains of the molecule.
These metabolites were detected in plant and other animal (rat, goat,
hen) metabolism studies.
7. Metabolite toxicology. Common metabolic pathways for
tebufenozide have been identified in both plants (grape, apple, rice
and sugar beet) and animals (rat, goat, hen). The metabolic pathway
common to both plants and animals involves oxidation of the alkyl
substituents (ethyl and methyl groups) of the aromatic rings primarily
at the benzylic positions. Extensive degradation and elimination of
polar metabolites occurs in animals such that residue are unlikely to
accumulate in humans or animals exposed to these residues through the
diet.
8. Endocrine disruption. The toxicology profile of tebufenozide
shows no evidence of physiological effects characteristic of the
disruption of the hormone estrogen. Based on structure-activity
information, tebufenozide is unlikely to exhibit estrogenic activity.
Tebufenozide was not active in a direct in vitro estrogen binding
assay. No indicators of estrogenic or other endocrine effects were
observed in mammalian chronic studies or in mammalian and avian
reproduction studies. Ecdysone has no known effects in vertebrates.
Overall, the weight of evidence provides no indication that
tebufenozide has endocrine activity in vertebrates.
C. Aggregate Exposure
1. Dietary exposure. Use of an agricultural pesticide may result,
directly or indirectly in pesticide residues in food. These residues
are determined by chemical analysis. Data from field studies are
evaluated to determine the appropriate level of residue that would not
be exceeded if the pesticide were used according to the label use
directions.
2. Plant and animal metabolism. The metabolism of tebufenozide in
plants (grapes, apples, rice and sugar beets) is adequately understood
for the purposes of these tolerances. The metabolism of tebufenozide in
all crops was similar and involves oxidation of the alkyl substituents
of the aromatic rings primarily at the benzylic positions. The extent
of metabolism and degree of oxidation are a function of time from
application to harvest. In all crops, parent compound comprised the
majority of the total dosage. None of the metabolites were in excess of
10% of the total dosage. The metabolism of tebufenozide in goats
proceeds along the same metabolic pathway as observed in plants. No
accumulation of residues in tissues or milk occurred. Because apple
pomace is not fed to poultry, there is no reasonable expectation that
measurable residues of tebufenozide will occur in eggs, poultry meat or
poultry meat by-products.
3. Analytical methods. A high performance liquid chromatographic
(HPLC) analytical method using ultraviolet (UV) or mass selective
detection have been validated for apples. The method involves
extraction by blending with solvents, purification of the extracts by
liquid-liquid partitions and final purification of the residues using
solid phase extraction column chromatography. The limits of
quantitation is 0.02 ppm for apples.
4. Food. Tolerances for residues of tebufenozide are currently
expressed as benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2(4-
ethylbenzoyl) hydrazide. Tolerances currently exist for residues on
apples at 1.0 ppm (import
[[Page 14931]]
tolerance) and on walnuts at 0.1 ppm (see 40 CFR 180.482).
5. Acute risk--i. No appropriate acute dietary endpoint was
identified by the Agency. This risk assessment is not required.
ii. Chronic risk. For chronic dietary risk assessment, the
tolerance and temporary tolerance values are used and the assumption
that all walnuts, imported apples and pears which are consumed in the
U.S. will contain residues at the tolerance level. The theoretical
maximum residue contribution (TMRC) using existing tolerances and
temporary tolerances for tebufenozide on food crops is obtained by
multiplying the tolerance level residues by the consumption data which
estimates the amount of those food products consumed by various
population subgroups and assuming that 100% of the food crops are
treated with tebufenozide. The Theoretical Maximum Residue Contribution
(TMRC) from current tolerances and temporary tolerances (MRID 44319101)
is calculated using the Dietary Exposure Evaluation Model (Version
5.03b, licensed by Novigen Sciences Inc.) which uses USDA food
consumption data from the 1989-1992 survey.
With the current and proposed uses of tebufenozide, the TMRC
estimate represents 4.31% of the Reference dose (RfD) for the U.S.
population as a whole. The subgroup with the greatest chronic exposure
is non-nursing infants (less than 1-year old), for which the TMRC
estimate represents 20.3% of the RfD. The chronic dietary risks from
these uses do not exceed EPA's level of concern.
6. Drinking water. An additional potential source of dietary
exposure to residues of pesticides are residues in drinking water.
Review of environmental fate data by the Environmental Fate and Effects
Division concludes that tebufenozide is moderately persistent to
persistent and mobile, and could potentially leach to groundwater and
runoff to surface water under certain environmental conditions.
However, in terrestrial field dissipation studies, residues of
tebufenozide and its soil metabolites showed no downward mobility and
remained associated with the upper layers of soil. Foliar interception
(up to 60% of the total dosage applied) by target crops reduces the
ground level residues of tebufenozide. There is no established Maximum
Concentration Level (MCL) for residues of tebufenozide in drinking
water. No drinking water health advisory levels have been established
for tebufenozide.
There are no available data to perform a quantitative drinking
water risk assessment for tebufenozide at this time. However, in order
to mitigate the potential for tebufenozide to leach into groundwater or
runoff to surface water, precautionary language has been incorporated
into the product label. Also, to the best of our knowledge, previous
experience with more persistent and mobile pesticides for which there
have been available data to perform quantitative risk assessments have
demonstrated that drinking water exposure is typically a small
percentage of the total exposure when compared to the total dietary
exposure. This observation holds even for pesticides detected in wells
and drinking water at levels nearing or exceeding established MCLs.
Considering the precautionary language on the label and based on our
knowledge of previous experience with persistent chemicals, significant
exposure from residues of tebufenozide in drinking water is not
anticipated.
7. Non-dietary exposure. Tebufenozide is not registered for either
indoor or outdoor residential use. Non-occupational exposure to the
general population is therefore not expected and not considered in
aggregate exposure estimates.
D. Cumulative Effects
The potential for cumulative effects of tebufenozide with other
substances that have a common mechanism of toxicity was considered.
Tebufenozide belongs to the class of insecticide chemicals known as
diacylhydrazines. The only other diacylhydrazine currently registered
for non-food crop uses is halofenozide. Tebufenozide and halofenozide
both produce a mild, reversible anemia following subchronic/chronic
exposure at high doses; however, halofenozide also exhibits other
patterns of toxicity (liver toxicity following subchronic exposure and
developmental/systemic toxicity following acute exposure) which
tebufenozide does not. Given the different spectrum of toxicity
produced by tebufenozide, there is no reliable data at the molecular/
mechanistic level which would indicate that toxic effects produced by
tebufenozide would be cumulative with those of halofenozide (or any
other chemical compound).
In addition to the observed differences in mammalian toxicity,
tebufenozide also exhibits unique toxicity against target insect pests.
Tebufenozide is an agonist of 20-hydroxyecdysone, the insect molting
hormone, and interferes with the normal molting process in target
lepidopteran species by interacting with ecdysone receptors from those
species. Unlike other ecdysone agonists such as halofenozide,
tebufenozide does not produces symptoms which may be indicative of
systemic toxicity in beetle larvae (Coleopteran species). Tebufenozide
has a different spectrum of activity than other ecdysone agonists. In
contrast to the other agonists such as halofenozide which act mainly on
coleopteran insects, tebufenozide is highly specific for lepidopteran
insects.
Based on the overall pattern of toxicity produced by tebufenozide
in mammalian and insect systems, the compound's toxicity appears to be
distinct from that of other chemicals, including organochlorines,
organophosphates, carbamates, pyrethroids, benzoylureas, and other
diacylhydrazines. Thus, there is no evidence to date to suggest that
cumulative effects of tebufenozide and other chemicals should be
considered.
E. Safety Determination
1. U.S. population. Using the conservative exposure assumptions
described above and taking into account the completeness and
reliability of the toxicity data, the dietary exposure to tebufenozide
from the current and proposed tolerances will utilize 4.31% of the RfD
for the U.S. population and 20.3% for non-nursing infants under 1-year
old. EPA generally has no concern for exposures below 100% of the RfD
because the RfD represents the level at or below which daily aggregate
dietary exposure over a lifetime will not pose appreciable risks to
human health. Rohm and Haas concludes that there is a reasonable
certainty that no harm will result from aggregate exposure to
tebufenozide residues to the U.S. population and non-nursing infants.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of tebufenozide, data
from developmental toxicity studies in the rat and rabbit and 2-
generation reproduction studies in the rat are considered. The
developmental toxicity studies are designed to evaluate adverse effects
on the developing organism resulting from pesticide exposure during
prenatal development to 1 or both parents. Reproduction studies provide
information relating to effects from exposure to the pesticide on the
reproductive capability of mating animals and data on systemic
toxicity. Developmental toxicity was not observed in developmental
studies using rats and rabbits. The NOEL for developmental effects in
both rats and rabbits was 1,000 mg/kg/day, which is the limit dose for
testing in developmental studies.
[[Page 14932]]
In the 2-generation reproductive toxicity study in the rat, the
reproductive/ developmental toxicity NOEL of 12.1 mg/kg/day was 14-fold
higher than the parental (systemic) toxicity NOEL (0.85 mg/kg/day). The
reproductive (pup) LOEL of 171.1 mg/kg/day was based on a slight
increase in both generations in the number of pregnant females that
either did not deliver or had difficulty and had to be sacrificed. In
addition, the length of gestation increased and implantation sites
decreased significantly in F1 dams. These effects were not replicated
at the same dose in a second 2-generation rat reproduction study. In
this second study, reproductive effects were not observed at 2,000 ppm
(the NOEL equal to 149-195 mg/kg/day) and the NOEL for systemic
toxicity was determined to be 25 ppm (1.9-2.3 mg/kg/day).
Because these reproductive effects occurred in the presence of
parental (systemic) toxicity and were not replicated at the same doses
in a second study, these data do not indicate an increased pre-natal or
post-natal sensitivity to children and infants (that infants and
children might be more sensitive than adults) to tebufenozide exposure.
FFDCA section 408 provides that EPA shall apply an additional safety
factor for infants and children in the case of threshold effects to
account for pre- and post-natal toxicity and the completeness of the
data base unless EPA concludes that a different margin of safety is
appropriate. Based on current toxicological data discussed above, an
additional uncertainty factor is not warranted and the RfD at 0.018 mg/
kg/day is appropriate for assessing aggregate risk to infants and
children. Rohm and Haas concludes that there is a reasonable certainty
that no harm will occur to infants and children from aggregate exposure
to residues of tebufenozide.
F. International Tolerances
There are no approved CODEX maximum residue levels (MRLs)
established for residues of tebufenozide. At the 1996 Joint Meeting for
Pesticide Residues, the FAO expert panel considered residue data for
pome fruit and proposed an MRL (Step 3) of 1.0 mg/kg.
3. Valent U.S.A. Corporation
PP 7F4882
EPA has received a pesticide petition (PP 7F4882) from Valent
U.S.A. Corporation, 1333 N. California Blvd., Walnut Creek, CA 94596.
proposing pursuant to section 408(d) of the Federal Food, Drug and
Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR part 180 by
establishing a tolerance for residues pyriproxyfen, 2-[ 1-methyl-2-(4-
phenoxyphenoxy)ethoxy]pyridine in or on the raw agricultural commodity
Pome Fruits(Crop Group 11, including apples and pears) at 0.2 (ppm),
Walnuts at 0.02 ppm, and Apple Pomace,wet at 0.8 ppm. EPA has
determined that the petition contains data or information regarding the
elements set forth in section 408(d)(2) of the FFDCA; however, EPA has
not fully evaluated the sufficiency of the submitted data at this time
or whether the data supports granting of the petition. Additional data
may be needed before EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The nature of the residues in cotton, apples,
and animals is adequately understood. Metabolism of 14C-pyriproxyfen
labelled in the phenoxyphenyl ring and in the pyridyl ring was studied
in cotton, apples, lactating goats, and laying hens (and rats). The
nature of the residue is defined by the metabolism studies primarily as
pyriproxyfen. The major metabolic pathways in plants is hydroxylation
and cleavage of the ether linkage, followed by further metabolism into
more polar products by oxidation or conjugation reactions, however, the
bulk of the radiochemical residues was parent. Comparing metabolites
from cotton, apple, goat and hen (and rat) shows that there are no
significant metabolites in plants which are not also present in the
excreta or tissues of animals.
Ruminant and poultry metabolism studies demonstrated that transfer
of administered 14C residues to tissues was low. Total 14C residues in
goat milk, muscle and tissues accounted for less than 2% of the
administered dose, and were less than 1 ppm in all cases. In poultry,
total 14C residues in eggs, muscle and tissues accounted for about 2.7%
of the administered dose, and were less than 1 ppm in all cases except
for gizzard.
2. Analytical method. Practical analytical methods for detecting
and measuring levels of pyriproxyfen (and relevant metabolites) have
been developed and validated for the raw agricultural commodities,
their respective processing fractions, and animal tissues. The methods
have been independently validated in cottonseed and apples (and
oranges) and the extraction methodology has been validated using aged
radiochemical residue samples from metabolism studies. EPA has(personal
communication) successfully validated the analytical method for
analysis of cottonseed raw agricultural commodity. The limit of
detection of pyriproxyfen in the methods is 0.01 ppm which will allow
monitoring of food with residues at or above the levels set for the
proposed tolerance.
3. Magnitude of residues--i. Apples. A total of fifteen trials were
conducted in 1994, 1995, and 1996 to determine the magnitude of the
residue in apples and apple processing commodities from regions
representing approximately 97% of the commercial U.S. apple acreage.
The mean residue of pyriproxyfen found in these samples was 0.091 ppm
with a standard deviation (, n-1 degrees of freedom) of 0.035
ppm and a maximum residue of 0.18 ppm. Apples from two sites were
processed into juice and wet pomace. The results from the processing
samples show that pyriproxyfen was substantially retained with the wet
pomace fraction, resulting in a 5 x concentration in this fraction. The
average processing concentration factor for pyriproxyfen from fruit
into apple pomace, wet, was 4.89 x. No residues of pyriproxyfen above
the 0.01 LOD was detected in the juice fractions.
ii. Pears. A total of eight trials were conducted in 1994, 1995,
and 1996 to determine the magnitude of the residue of pyriproxyfen in
pears from regions representing approximately 95% of the commercial
U.S. pear acreage. The mean residue of pyriproxyfen found in these
samples was 0.039 ppm with a standard deviation (, n-1 degrees
of freedom) of 0.016 ppm and a maximum residue of 0.07 ppm.
iii. Walnuts. A total of 4 trials were conducted in 1996 to
determine the magnitude of the residue of pyriproxyfen in walnut
nutmeats all in region x where 98% of the commercial walnut acreage is
located. No residues of pyriproxyfen above the 0.01 ppm limit of
detection were found in any walnut nutmeat collected for this study.
4. Secondary residues. Since low residues were detected in animal
feed items (cotton gin byproducts, apple pomace, wet) and animal
metabolism studies do not show potential for significant residue
transfer, detectable secondary residues in animal tissues, milk, and
eggs are not expected. Therefore, tolerances are not needed for these
commodities.
B. Toxicological Profile
1. Acute toxicity. The acute toxicity of technical grade
pyriproxyfen is low by all routes, classified as Category III for acute
dermal and inhalation toxicity, and Category IV for acute oral
toxicity, and skin/eye irritation. Pyriproxyfen is not a skin
sensitizing agent.
[[Page 14933]]
2. Genotoxicty. Pyriproxyfen does not present a genetic hazard.
Pyriproxyfen was negative in the following tests for mutagenicity: Ames
assay with and without S9, in vitro unscheduled DNA synthesis in HeLa
S3 cells, in vitro gene mutation in V79 Chinese hamster cells, and in
vitro chromosomal aberration with and without S9 in Chinese hamster
ovary cells.
3. Reproductive and developmental toxicity. Pyriproxyfen is not a
developmental toxicant. In the rat teratology study, maternal toxicity
was observed at doses of 300 mg/kg/day and greater, the NOEL for
prenatal developmental toxicity was 100 mg/kg/day. A rabbit teratology
study resulted in a maternal NOEL of 100 mg/kg/day, with no
developmental effects observed in the rabbit fetuses.
In the study conducted with rats, technical pyriproxyfen was
administered by gavage at levels of 0, 100, 300, and 1,000 mg/kg/day
during gestation days 7-17. Maternal toxicity (mortality, decreased
body weight gain and food consumption and clinical signs of toxicity)
was observed at doses of 300 mg/kg/day and greater. The maternal NOEL
was 100 mg/kg/day. A transient increase in skeletal variations was
observed in rat fetuses exposed to 300 mg/kg/day and greater. These
effects were not present in animals examined at the end of the
postnatal period, therefore, the NOEL for prenatal developmental
toxicity was 100 mg/kg/day. An increased incidence of visceral and
skeletal variations was observed postnatally at 1,000 mg/kg/day. The
NOEL for postnatal developmental toxicity was 300 mg/kg/day. In the
study conducted with rabbits, technical pyriproxyfen was administered
by gavage at levels of 0, 100, 300, and 1,000 mg/kg/day during
gestation days 6-18. Maternal toxicity (clinical signs of toxicity
including one death, decreased body weight gain and food consumption,
and abortions or premature deliveries) was observed at oral doses of
300 mg/kg/day or higher. The maternal NOEL was 100 mg/kg/day. No
developmental effects were observed in the rabbit fetuses. The NOEL for
developmental toxicity in rabbits was 1,000 mg/kg/day.
Pyriproxyfen is not a reproductive toxicant. Pyriproxyfen was
administered in the diet at levels of 0, 200, 1,000, and 5,000 ppm
through 2- generations of rats. Adult systemic toxicity (reduced body
weights, liver and kidney histopathology, and increased liver weight)
was produced at the 5,000 ppm dose (453 mg/kg/day in males, 498 mg/kg/
day in females during the pre-mating period). The systemic NOEL was
1,000 ppm (87 mg/kg/day in males, 96 mg/kg/day in females). No effects
on reproduction were produced even at 5,000 ppm, the highest dose
tested.
4. Subchronic toxicity. Subchronic oral toxicity studies conducted
with pyriproxyfen technical in the rat, mouse and dog indicate a low
level of toxicity. Effects observed at high dose levels consisted
primarily of decreased body weight gain; increased liver weights;
histopathological changes in the liver and kidney; decreased red blood
cell counts, hemoglobin and hematocrit; altered blood chemistry
parameters; and, at 5,000 and 10,000 ppm in mice, a decrease in
survival rates. The NOELs from these studies were 400 ppm (23.5 mg/kg/
day for males, 27.7 mg/kg/day for females) in rats, 1,000 ppm (149.4
mg/kg/day for males, 196.5 mg/kg/day for females) in mice, and 100 mg/
kg/day in dogs.
In a 4-week inhalation study of pyriproxyfen technical in rats,
decreased body weight and increased water consumption were observed at
1,000 mg/m3 . The NOEL in this study was 482 mg/m3.
A 21-day dermal toxicity study in rats with pyriproxyfen technical
did not produce any signs of dermal or systemic toxicity at 1,000 mg/
kg/day, the highest dose tested. In a 21-day dermal study conducted
with KNACK Insect Growth Regulator the test material produced a NOEL of
1,000 mg/kg/day (highest dose tested) for systemic effects, and a NOEL
for skin irritation of 100 mg/kg/day.
5. Chronic toxicity. Pyriproxyfen technical has been tested in
chronic studies with dogs, rats and mice.
Pyriproxyfen technical was administered to dogs in capsules at
doses of 0, 30, 100, 300 and 1,000 mg/kg/day for 1-year. Dogs exposed
to dose levels of 300 mg/kg/day or higher showed overt clinical signs
of toxicity, elevated levels of blood enzymes and liver damage. The
NOEL in this study was 100 mg/kg/day.
Pyriproxyfen technical was administered to mice at doses of 0, 120,
600 and 3,000 ppm in diet for 78-weeks. The NOEL for systemic effects
in this study was 600 ppm (84 mg/kg/day in males, 109.5 mg/kg/day in
females), and a LOEL of 3,000 ppm (420 mg/kg/day in males, 547 mg/kg/
day in females) was established based on an increase in kidney lesions.
In a 2-year study in rats, pyriproxyfen technical was administered
in the diet at levels of 0, 120, 600, and 3,000 ppm. The NOEL for
systemic effects in this study was 600 ppm (27.31 mg/kg/day in males,
35.1 mg/kg/day in females). A LOEL of 3,000 ppm (138 mg/kg/day in
males, 182.7 mg/kg/day in females) was established based on a
depression in body weight gain in females.
EPA has established a RfD for pyriproxyfen of 0.35 mg/kg/day, based
on the rat 2-year chronic/oncogenicity study. Effects cited by EPA in
the RfD Tracking Report include negative trend in mean red blood cell
volume; increased hepatocyte cytoplasm and cytoplasm:nucleus ratios;
and decreased sinusoidal spaces.
Pyriproxyfen is not a carcinogen. Studies with pyriproxyfen show
that repeated high dose exposures produced changes in the liver, kidney
and red blood cells, but did not produce cancer in test animals. No
oncogenic response was observed in a rat 2-year chronic feeding/
oncogenicitystudy or in a 78-week study on mice.
Pyriproxyfen's oncogenicity classification is ``E'' (no evidence of
carcinogenicity for humans).
6. Animal metabolism. The mammalian metabolism of pyriproxyfen is
understood. The absorption, tissue distribution, metabolism and
excretion of 14C-labeled pyriproxyfen were studied in rats after single
oral doses of 2 or 1,000 mg/kg (phenoxyphenyl and pyridyl label), and
after a single oral dose of 2 mg/kg (phenoxyphenyl label only)
following 14 daily oral doses at 2 mg/kg of unlabelled material.
Both the phenoxyphenyl-label and pyridyl-label studies exhibited
very similar results. For all dose groups, most (88-96%) of the
administered radiolabel was excreted in the urine and feces within 2-
days after radiolabeled test material dosing, and 92-98% of the
administered dose was excreted within 7-days. 7-days after dosing,
tissue residues were generally low, accounting for no more than 0.3% of
the dosed 14C. 14C concentrations in fat were the
highest in tissues analyzed. Recovery in tissues over time indicates
that the potential for bioaccumulation is minimal. There are no
significant sex or dose-related differences in excretion or metabolism.
7. Endocrine disruption. Pyriproxyfen is specifically designed to
be an insect growth regulator and is known to produce juvenile hormone-
mediated effects in arthropods. However, this mechanism-of-action in
target insects has no relevance to the mammalian endocrine system.
While specific tests, uniquely designed to evaluate the potential
effects of pyriproxyfen on mammalian endocrine systems have not been
conducted, the toxicology of pyriproxyfen has been extensively
evaluated in acute, sub-chronic, chronic, developmental, and
reproductive toxicology studies. The results of these studies show no
[[Page 14934]]
evidence of any endocrine-mediated effects and no pathology of the
endocrine organs. Consequently, it is concluded that Sumilarv does not
possess estrogenic or endocrine disrupting properties applicable to
mammals.
C. Aggregate Exposure
1. Dietary exposure. A chronic dietary exposure and risk assessment
based on anticipated residues from samples from field residue studies
was performed in cotton, apple, pear, and walnut and assumed that 100%
of the crops were treated. The exposure analysis also reflected the
contribution of meat and milk residues, without regard to
detectability, based on commodities used for feed containing residues
at anticipated residue levels.
Using mean anticipated residue values and 100% of the crop treated,
exposure to the U.S. population - 48 States - all seasons is calculated
to be only 0.000049 mg/kg body-wt/day. The most exposed sub-population,
non-nursing infants (<1-year), is="" calculated="" to="" be="" 0.000273="" mg/kg="" bwt./="" day.="" these="" calculated="" exposures="" represent,="" respectively,="" 0.014,="" and="" 0.078="" percent="" occupancy="" of="" the="" rfd="" of="" 0.35="" mg/kg="" body-wt/day.="" chronic="" dietary="" risk="" from="" exposure="" to="" pyriproxyfen="" residues="" on="" the="" proposed="" crops="" may="" be="" characterized="" as="" negligible.="" 2.="" drinking="" water.="" since="" pyriproxyfen="" is="" to="" be="" applied="" outdoors="" to="" growing="" agricultural="" crops,="" the="" potential="" exists="" for="" the="" parent="" or="" its="" metabolites="" to="" reach="" ground="" or="" surface="" water="" that="" may="" be="" used="" for="" drinking="" water.="" 3.="" ground="" water.="" pyriproxyfen="" is="" extremely="" insoluble="" in="" water="" (0.367="" mg/l="" at="" 25="" deg.,="" with="" high="" octanol/water="" partitioning="" constant="" (log="" p="" o/w="5.37" at="" 25="" deg.,="" and="" relatively="" short="" soil="" half-life="" (aerobic="" soil="" metabolism="" t="" \1/2\="6" to="" 9="" days).="" given="" the="" low="" use="" rates,="" the="" immobility="" of="" the="" parent="" and="" the="" instability="" of="" the="" soil="" metabolites="" in="" soil,="" it="" is="" very="" unlikely="" that="" pyriproxyfen="" or="" its="" metabolites="" could="" leach="" to="" and="" contaminate="" potable="" groundwater.="" 4.="" surface="" water.="" in="" connection="" with="" the="" potential="" for="" dietary="" exposure="" from="" surface="" potable="" water,="" a="" simulation="" of="" expected="" exposure="" concentration="" (eec)="" values="" in="" aquatic="" systems="" has="" been="" performed="" using="" the="" pesticide="" root="" zone="" model="" (przm-3)="" and="" the="" exposure="" analysis="" modeling="" system,="" version="" 2.97="" (examsii).="" the="" simulation="" was="" designed="" to="" approximate="" as="" closely="" as="" possible="" the="" conditions="" associated="" with="" the="" high="" rate="" proposed="" use="" on="" tree="" crops.="" the="" results="" of="" the="" modelingdemonstrate="" that="" the="" maximum="" upper="" tenth="" percentile="" concentrations="" modeled="" in="" water="" adjacent="" to="" treated="" fields="" are="" instantaneous,="" 0.36="" ppb;="" 96-hour,="" 0.23="" ppb;="" and="" 21-day,="" 0.14="" ppb.="" to="" obtain="" a="" very="" conservative="" estimate="" of="" a="" possible="" dietary="" exposure="" from="" drinking="" water,="" it="" could="" be="" assumed="" that="" all="" water="" consumed="" contains="" pyriproxyfen="" at="" the="" maximum="" upper="" tenth="" percentile="" concentrations="" modeled="" in="" aquatic="" systems="" adjacent="" to="" treated="" orchards.="" the="" 21-day="" concentration,="" 0.14="" ppb="" (0.00014="" mg/kg),="" is="" used="" because="" drinking="" water="" is="" considered="" to="" be="" a="" chronic="" exposure,="" and="" there="" are="" no="" identified="" acute="" or="" short="" term="" endpoints="" of="" concern.="" using="" standard="" assumptions="" of="" body="" weight="" and="" water="" consumption="" (adult="" 70="" kg,="" 2="" kg="" water="" per="" day;="" child="" 10="" kg,="" 1="" kg="" water),="" the="" highest="" possible="" exposure="" would="" be="" 4.0="" x="" 10-6="" and="" 1.4="" x="" 10-5="" mg/kg="" bwt./day="" for="" the="" adult="" and="" child,="" respectively.="" this="" very="" small,="" but="" probably="" exaggerated,="" exposure="" would="" occupy="" 0.00114="" (adult)="" and="" 0.004="" (child)="" percent="" of="" the="" chronic="" reference="" dose="" of="" 0.35="" mg/kg="" body-wt/day.="" 5.="" non-dietary="" exposure.="" pyriproxyfen="" has="" numerous="" registered="" products="" for="" household="" use="" primarily="" of="" indoor,="" non-food="" applications="" by="" consumers.="" the="" consumer="" uses="" of="" pyriproxyfen="" typically="" do="" not="" involve="" chronic="" exposure.="" instead,="" consumers="" are="" exposed="" intermittently="" to="" a="" particular="" product="" (e.g.,="" pet="" care="" pump="" spray)="" containing="" pyriproxyfen.="" since="" the="" pharmacokinetics="" of="" pyriproxyfen="" indicate="" a="" relatively="" short="" elimination="" half-life,="" cumulative="" toxicological="" effects="" resulting="" from="" bioaccumulation="" are="" not="" plausible="" following="" these="" short-term,="" intermittent="" exposures.="" further,="" pyriproxyfen="" is="" very="" short-lived="" in="" the="" environment="" and="" this="" indoor="" domestic="" use="" of="" pyriproxyfen="" may="" provide="" only="" relatively="" short-term="" reservoirs.="" the="" most="" relevant="" exposure="" for="" non-dietary="" exposure="" assessment="" is="" short-term="" to="" intermediate="" average="" daily="" exposure="" estimates.="" the="" non-="" dietary="" exposure="" assessment="" for="" pyriproxyfen="" conservatively="" focuses="" on="" upper-bound="" estimates="" of="" potential="" applicator="" (adult)="" and="" post-="" application="" (adult="" and="" child="" -="" less="" than="" 1-year="" old)="" exposures="" on="" the="" day="" of="" application.="" subsequent="" days="" present="" no="" applicator="" exposure,="" and="" a="" decreasing="" contribution="" to="" short-term="" total="" exposure.="" the="" assessment="" presented="" herein="" estimates="" exposures="" for="" selected="" consumer="" uses="" that="" are="" considered="" representative,="" plausible,="" and="" reasonable="" worst="" case="" exposure="" scenarios.="" the="" scenarios="" selected="" include:="" (i)="" potential="" exposures="" associated="" with="" adult="" application="" (dermal="" and="" inhalation="" exposures)="" and="" post-application="" (adult="" and="" child="" inhalation="" exposures)="" of="" pyriproxyfen-containing="" pet="" care="" products;="" and="" (ii)="" potential="" adult="" application="" exposures="" (dermal="" and="" inhalation),="" and="" adult="" (inhalation)="" and="" child="" exposures="" (inhalation,="" dermal,="" incidental="" oral="" ingestion="" associated="" with="" hand-to-mouth="" behavior)="" post-="" application="" exposures="" associated="" with="" consumer="" use="" of="" a="" carpet="" spray="" product.="" using="" a="" combination="" of="" representative="" information="" from="" the="" phed="" data="" base="" for="" applicators="" (adult),="" and="" surrogate="" data="" from="" a="" study="" of="" exposure="" to="" indoor="" broadcast="" applications="" (post-application="" adult="" and="" child)="" a="" series="" of="" adsorbed="" dose="" estimates="" were="" calculated="" for="" adult="" applicators,="" and="" post-application="" exposures="" to="" adults="" and="" children="" by="" dermal,="" inhalation,="" and="" (hand-to-mouth)="" oral="" routes.="" the="" methodology,="" assumptions,="" and="" estimates="" are="" presented="" in="" detail="" in="" the="" full="" fqpa="" exposure="" analysis,="" the="" table="" below="" presents="" the="" results.="" summary="" of="" estimated="" human="" application="" and="" post-application="" exposures="" associated="" with="" use="" of="" pet="" spray="" and="" carpet="" spray="" products="" containing="" pyriproxyfen="" as="" the="" active="" ingredient="" --------------------------------------------------------------------------------------------------------------------------------------------------------="" daily="" dose="" (mg/kg="" bw/day)="" product="" population="" timing="" of="" exposure="" ---------------------------------------------------------------------------="" inhalation\1\="" dermal\2\="" oral\1\="" total="" --------------------------------------------------------------------------------------------------------------------------------------------------------="" pet="" spray........................="" adults..............="" application........="" 4.3="" x="">-6 0.085 3NA 0.085
Post-Application... 1.8 x 10-5 NA NA 1.8 x 10-5
TOTAL.............. 2.2 x 10-5 0.085 NA 0.085
Children............ Post-Application... 3.7 x 10-5 NA NA 3.7 x 10-5
Carpet Spray..................... Adults.............. Application........ 1.3 x 10-6 5.1 x 10-4 NA 5.1 x 10-4
Post-Application... 5.4 x 10-6 NA NA 5.4 x 10-6
[[Page 14935]]
TOTAL.............. 6.7 x 10-6 5.1 x 10-4 NA 5.2 x 10-4
Crawling Infant..... Post-Application... 1.5 x 10-5 1.3 x 10-3 2.1 x 10-4 1.5 x 10-3
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ 100 % adsorption.
\2\ Conservatively assumes a dermal absorption factor of 50%.
\3\ Exposure pathway not applicable.
It is important to emphasize that the exposures summarized in the
table are based on conservative assumptions and surrogate data.
Further, the exposures are calculated for the day of application.
Subsequent daily exposures would be less as pyriproxyfen is adsorbed
into substrate, or dissipates and becomes unavailable by other
mechanisms. Exposures to applicators on non-application days would be
zero.
Further, the Agency has not identified acute or short term toxicity
endpoints of concern. Endpoints that could be considered for short term
and intermediate exposures include a developmental toxicity no observed
effect level (NOEL) of 100 mg/kg/day (rat and rabbit), a rat 21-day
dermal systemic NOEL of 1,000 mg/kg/day (technical grade and end-use
products), a 4-week rat inhalation toxicity NOEL of 482 mg/m3, and a
90-day rat oral toxicity NOEL of 23.5 mg/kg/day. There are no dermal
absorption data for pyriproxyfen. The 1-day exposure calculated for the
applicator of the pet spray (0.085 mg/kg/day) is 57-times larger than
the next highest calculated exposure which is the total exposure to a
crawling infant on the day of application of the carpet spray (1.5 x
10-3 mg/kg/day). Furthermore, the return frequency is much different.
Label instructions allow treatment of the dog every 14-days during the
flea season, while the carpet can be treated only each 120-days. The 1-
day exposure can be compared to the smallest short term endpoint, that
from the 90-day rat oral toxicity NOEL of 23.5 mg/kg/day, and a Margin
of Exposure (MOE) can be calculated. This compares an acute exposure to
a sub-chronic endpoint.
MOE = Toxicity Endpoint (mg/kg/day) Daily Short Term
Exposure (mg/kg/day)
MOEPet Spray Applicator, One day = 276
Probably more realistic, a short term daily exposure to the adult
applicator can be calculated and compared to the same endpoint.
Daily Exposure (mg/kg/day) = Applicator Exposure (mg/kg/day)
Frequency (days)
MOEPet Spray Applicator = 3900
Based on the available toxicity data and the conservative exposure
assumptions, and because infants and children are not applicators in
the household, the smallest acute and short term MOE value for children
is based on post-application exposures. The day of application exposure
to a crawling infant is the sum of inhalation, dermal adsorption, and
oral (hand to mouth) exposures. Subsequent daily exposures are not
quantified, but because of dissipation of the active ingredient in the
home environment but must be smaller than on the day of application.
MOECarpet Spray, Crawling Infant = 15,700
There is usually no cause for concern if margins of exposure exceed
100. All other margins of exposure that can be calculated from the non-
occupational, non-dietary exposures summarized in the table above are
considerably larger than that for the pet spray applicator and (post
carpet spray application) crawling infant.
Summary of Aggregate Non-Occupational Exposures. Aggregate
exposure is defined as the sum all non-occupational exposures to the
general U.S. population and relevant sub-populations to the single
active ingredient, pyriproxyfen. These exposures can be classified as
acute, short term, and chronic.
Acute and Short Term Non-Occupational Potential acute and short
term non-occupational exposures to pyriproxyfen are associated with
household uses -- applicator, bystander, and post-application
exposures. For preliminary risk analysis, these exposures, oftentimes
calculated using conservative assumptions and surrogate data, are
compared to appropriate acute and short term toxicity endpoints to
yield margins of exposure (MOE). In general, if exposure estimates are
conservative and the resulting MOE values are greater than 100, the
Agency is not concerned. In contrast, if conservative MOE values are
less than 100, then more refined exposure estimates and/or exposure
mitigation are required.
The Agency has not identified acute or short term toxicity
endpoints of concern for pyriproxyfen. Valent has identified the 90-day
rat oral toxicity with a NOEL of 23.5 mg/kg/day as the short term study
with the lowest exposure endpoint. Comparing this endpoint with the
short term non-occupational exposures calculated for the household uses
of pyriproxyfen gives MOE values all much larger than 100. These acute
and short term exposures are small enough to be of little significance.
C. Chronic Exposures
Potential chronic exposures to pyriproxyfen are considered to be
derived from dietary exposures to primary and secondary residues in
food, and to potential residues in drinking water. To calculate the
total potential chronic exposure from food and drinking water, the
calculated exposures from both media can be summed. To assess risk
these totals can then be compared to the chronic RfD.
Summation of the Calculated Potential Chronic Exposure to Pyriproxyfen in Food and Drinking Water and Percent
Occupancy of the RfD for Two U.S. Populations
----------------------------------------------------------------------------------------------------------------
General
Medium(mg/kg body-wt/day) Population(adult) Non-NursingInfant ( 1)
----------------------------------------------------------------------------------------------------------------
Food.......................................................... 0.000049 0.000273
Drinking Water................................................ 0.000004 0.000014
[[Page 14936]]
Total......................................................... 0.000053 0.000287
%RfD(0.35 mg/kg body-wt/day).................................. 0.015 0.082
----------------------------------------------------------------------------------------------------------------
If the occupancy of the RfD is less than 100%, the Agency usually
has little cause for concern. From the table above, it can be seen that
the total potential chronic exposure to pyriproxyfen is truly
insignificant, and should not be cause for concern.
D. Cumulative Effects
Valent has considered the potential for cumulative exposure to
substances with a common mechanism of toxicity to pyriproxyfen.
However, a cumulative exposure assessment is not appropriate at this
time because there is no available information to indicate that the
effects of pyriproxyfen would be cumulative with those of any other
chemical compound. Therefore, Valent is considering only the potential
risk of pyriproxyfen in its aggregate exposure assessment.
E. Safety Determination
1. U.S. population. Based on a complete and reliable toxicity
database, EPA has established an RfD value of 0.35 mg/kg bwt./day using
the NOEL from the chronic rat feeding study and a 100-fold uncertainty
factor. The aggregate chronic exposure to pyriproxyfen will utilize
less than 0.1% of the RfD for the U.S. population. Because estimated
exposures are far below 100 percent of the RfD, Valent concludes that
there is a reasonable certainty that no harm will result from aggregate
exposure to pyriproxyfen residues.
2. Infants and children. Using the same conservative exposure
assumptions as for the general population, the percent of the RfD
utilized by aggregate chronic exposure to residues of pyriproxyfen is
0.082% for non-nursing infants, the most highly exposed population
subgroup. Valent concludes that there is a reasonable certainty that no
harm will result to infants and children from aggregate exposure to
residues of pyriproxyfen.
F. International Tolerances
There are presently no Codex maximum residue levels established
for residues of pyriproxyfen on any crop.
[FR Doc. 98-8065 Filed 3-26-98; 8:45 am]
BILLING CODE 6560-50-F
