[Federal Register Volume 63, Number 193 (Tuesday, October 6, 1998)]
[Notices]
[Pages 53656-53669]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-26782]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-837; FRL-6033-8]
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-837, must
be received on or before November 5, 1998.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Division
(7502C), Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 119, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically to: docket@epamail.epa.gov. Follow 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 manager listed in the
table below:
[[Page 53657]]
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Office location/
Product Manager telephone number Address
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Edith Minor................... Rm. 229, CM #2, 703- 1921 Jefferson
305-7390, e- Davis Hwy,
mail:[email protected] Arlington, VA
ail.epa.gov.
Joanne Miller................. Rm. 229, PM #23, 703-
306-6224, e-mail:
[email protected]
.epa.gov.
Joseph Tavano................. Rm. 214, 703-305-6411, Do.
e-
mail:tavano.joseph@ep.
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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-837] (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. Comments and data
will also be accepted on disks in 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: September 29, 1998.
James Jones,
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. Griffin Corporation
PP 7F4837
EPA has received a pesticide petition (PP 7F4837) from Griffin
Corporation, P.O. Box 1847, Valdosta, GA 31603-1847, 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 to establish an exemption from
the requirement of a tolerance for propazine 2-chloro-4,6-
bis(isopropylamine)-s-triazine and its two chloro metabolites, 2-amino-
4-chloro, 6-isopropylamino-s-triazine (G-30033) and 2,4-diamino-6-
chloro-s-triazine (G-28273) in or on the raw agricultural commodities
sorghum, stover, forage, and grain at 0.25 parts per million (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. In sorghum, metabolism occurs by the three
following reactions: N-dealkylation of the side-chains, hydrolytic
dehalogenation or nucleophilic displacement of the 2-chloro group with
glutathione (GSH). The dehalogenation and formation of GSH conjugates
are the two predominant pathways and only small amounts of the chloro
residues were found in forage and stover. No chloro residues were
detected in sorghum grain in two propazine metabolism studies that were
conducted. Griffin believes the metabolism is well characterized in
plants and animals and the pathways of metabolism are very similar to
those defined for other triazines. The metabolism profile supports the
use of an analytical enforcement method that accounts for parent
propazine and its two chloro metabolites, 2-amino-chloro-6-isopropyl-
amino-s-triazine (G-30033) and 2-chloro-4,6-di-amino-s-triazine (G-
28273) in the raw agricultural commodity (RAC's) of grain sorghum and
further supports the current tolerance of 0.25 ppm to include the two
chloro metabolites.
2. Analytical method. A practical analytical method has been
submitted. as a part of the sorghum residue study. The method involves
extraction, evaporation solid phase clean-up column and quantitation by
high performance liquid chromotography (HPLC) equipped with a
ultraviolet ray (UV) detector. One aliquot is used for assaying for
propazine and G-30033 and another aliquot is used for quantitating G-
27283. The limit of quanitation (LOQ) for propazine and each of its
chloro metabolites in each raw agricultural commodities (RAC) and each
chloro residue is 0.05 ppm.
3. Magnitude of residues. A total of 13 sorghum field residue
trails were conducted in the major sorghum growing areas of the United
States. No quantifiable residues of parent or the two chloro
metabolites were detected in the RAC's of the 13 field residue studies
when treated at the 1x rate. Only four samples for sorghum forage
contained residues of G-28273 which were quantifiable and residues
ranged from 0.05 ppm to 0.087 ppm. The treatment rate for these studies
exceeded the maximum proposed use rate and the extrapolated range of
residues for the four samples was 0.024 to 0.069 ppm.
The RAC's of sorghum are only used as feed for cattle and poultry.
Only the grain is fed to chickens and there were no chloro residues
present in grain; therefore no chloro residues would be expected in
eggs and poultry products. The level of chloro residues in forage
[[Page 53658]]
and fodder are sufficiently low in the metabolism and residue studies
to demonstrate that any potential transfer of propazine and its chloro
metabolites to milk and meat is not expected.
For rotational crops, no chloro residues were present in root and
grain crops when planted more than 129 days after treatment. Chloro
residues were present in leafy vegetables grown in soils with pH values
above 7 and under inclimate growing conditions. One field sample of
wheat forage contained low levels of parent propazine but this sample
was taken at an interval shorter than will be proposed on the label for
plant back and, in addition, the pH of the soil was above 7.
An amendment of the current tolerance of 0.25 ppm to include parent
propazine and its two chloro metabolites, G-30033 and G-28273, is
proposed for each of the RAC's of grain sorghum. The metabolism and
field residue results show that chloro residues of propazine should not
exceed 0.25 ppm in any of the RAC's. Potential transfer of propazine
and its two chloro metabolites to milk and meat is not expected.
Therefore, tolerances in milk, meat, poultry and eggs are not required.
The data show that root and grain crops can be rotated with sorghum
treated with propazine, but leafy vegetable crops should not be rotated
with sorghum in soils with pH values above 7.
B. Toxicological Profile
1. Acute toxicity. A complete battery of acute toxicity studies for
propazine technical was completed. The acute oral toxicity study
resulted in a LD50 of greater than 5,050 milligram kilogram
(mg/kg) for both sexes. The acute dermal toxicity in rabbits resulted
in an LD50 in either sex of greater than 5,050 mg/kg. The
acute inhalation study in rats resulted in an LC50 of
greater than 1.22 mg/l. Propazine was non-irritating to the skin of
rabbits in the primary dermal irritation study. In the primary eye
irritation study in rabbits, no irritation was noted. The dermal
sensitization study in guinea pigs indicated that propazine is not a
sensitizer. Based on these results, propazine technical is placed in
toxicity Category III.
2. Reproductive and developmental toxicity. The potential maternal
and developmental toxicity of propazine were evaluated in rabbits.
Propazine technical was suspended in corn oil and administered orally
by gavage to three groups of 20 artificially inseminated New Zealand
White rabbits as a single daily dose from gestation days 6-18. In the
range-finding study, rabbits were dosed at levels of 0, 10, 50, 100,
200, and 400 milligram kilogram day (mg/kg/day). Maternal toxicity was
exhibited by decreased defecation, body weight losses and decreased
food consumption during the treatment period at 50, 100, 200 and 400
mg/kg/day. Abortions also occurred at levels of 200 and 400 mg/kg/day.
Dose levels of 0, 2, 10, and 50 mg/kg/day were selected based on the
results of this study. In the definitive study, no test article related
deaths occurred at any dose level tested. The only clinical sign
observed was decreased defecation in the 50 mg/kg/day group. Inhibition
of body weight gain occurred during the first 6 days of dosing and
inhibition of food consumption occurred throughout the treatment period
in the 50 mg/kg/day group. No other treatment related findings were
noted in the dams at any dose level. Intrauterine parameters were
unaffected by treatment. There were no treatment related effects on
fetal malformations or developmental variations.
The data from the developmental toxicity studies on propazine show
no evidence of a potential for developmental effects (malformations or
variations) at doses that are not maternally toxic. The no observed
adverse effect level (NOAEL) for maternal toxicity in rabbits was 10
mg/kg/day and the NOAEL for developmental toxicity was 50 mg/kg/day.
3. Subchronic toxicity.. No test article related deaths occurred at
any dose level. Very minimal dermal irritation was noted in the 100 and
1,000 mg/kg/day females. Body weight gain was slightly inhibited in the
high dose group during weeks 0-1 (both sexes) and 2-3 (males only).
There were no treatment related effects on the clinical observations,
food consumption, hematology and serum chemistry parameters or organ
weights were observed at any dose level. Macroscopic and microscopic
examinations revealed no treatment related lesions at any dose level.
Based on the 21 day dermal study in rats, the NOAEL for systemic
toxicity was 100 mg/kg/day due to reduced body weight gain at 1,000 mg/
kg/day.
4. Chronic toxicity. Griffin conclude that the body weight gain and
survival data clearly indicate that the high dose female rats exceeded
the maximum tolerance dose (MTD), and therefore the high dose female
group should be excluded from any risk assessment or weight-of-evidence
arguments concerning this study. Additionally, the incidence of mammary
gland tumors in all doses in this study were within the range of
current laboratory historical control incidences and those reported by
the breeder, Charles River. No adverse treatment related effects were
observed at levels below the MTD.
5. Animal metabolism. The absorption, distribution, excretion, and
metabolism of propazine (ring-UL-14C propazine) was
investigated in Sprague-Dawley CD rats. One group of rats was
administered a single oral dose at 1.0 mg/kg (low dose), one group was
administered a single oral dose at 100 mg/kg (high dose), and a third
group was administered fourteen consecutive oral daily doses of non-
radioactive propazine at 1.0 mg/kg, followed by a single oral dose of
14C-propazine at 1.0 mg/kg (consecutive dose group). A
fourth group of animals (3 rats/sex) was administered a single oral
dose of the vehicle only (corn oil), and served as controls. Since
propazine is not soluble in water, it was not possible to include an
intravenous dose group.
Excretion patterns were very similar in all dose groups. Nearly all
of the radioactivity administered was recovered in the excreta within
24 to 48 hours after dosing. The majority of the administered
radioactivity was excreted in the urine (66.2 - 70.5%), and this
finding shows that the majority of the administered dose was
bioavailable and rapidly absorbed from the gastrointestinal tract. High
performance liquid chromotography (HPLC) analysis of the urine
indicated a similar profile among all dose groups and both sexes. The
excretion of radioactivity in the feces was significantly lower than in
the urine (range: 19.9 -28.6%) in all dose groups and both sexes.
Analysis of this radioactivity demonstrated a relatively consistent
pattern among the various dose groups with females containing a
quantitatively higher level of the parent compound. The recovery of
expired radioactivity was shown in a pilot study to be negligible
(<0.1%), indicating="" little="" or="" no="">14CO2 production
during the metabolism of propazine.
7 days post-treatment all animals were sacrificed and the total
radioactive residue was quantified in bone, brain, fat (visceral),
gastrointestinal tract (including contents), heart, kidney, liver,
lung, muscle (thigh), ovary, plasma, red blood cells (RBC), skin,
spleen, testis, thyroid, uterus, and residual carcass. Highest
concentrations were found in the RBCs of all dose groups (0.472 - 0.577
ppm parent equivalents at 1.0 mg/kg and 44.649 - 55.287 ppm at 100 mg/
kg). Residue concentration in the remaining tissues ranged from 0.007
to 0.468 ppm at the low and consecutive dose groups, and from 0.859 to
13.246 ppm at the high dose. Mean body burdens for the low,
[[Page 53659]]
high, and consecutive dose groups accounted for 10.3, 5.9 and 7.1% of
the dose, respectively. Material balances were quantitative and
accounted for 102.5, 101.1 and 96.3% of the dose, respectively.
Metabolite characterization of excreta indicated a
biotransformation pathway consistent with historical metabolism of
alkylated s-triazines. Confirmed metabolite identification showed that
propazine was metabolized via N-dealkylation mechanisms and excreted in
urine primarily as the G-27283 metabolite (approximately 27% of the
total dose). Unmetabolized parent propazine was the predominant
identified compound in the feces (13.8% in the high dose male group).
The fact that a greater percentage of administered 14C-
propazine was found in the feces of the high dose group probably
indicated some degree of saturation of the absorption mechanism.
Propazine technical is not metabolized to breakdown products which
accumulate in sufficient quantities that can be reasonably expected to
present any chronic dietary risk.
6. Metabolite toxicology. The hydroxy metabolite of atrazine, an
analog of propazine has been shown not to exhibit carcinogenic effects.
7. Endocrine disruption. There is no evidence that propazine has
endocrine-modulation characteristics as demonstrated by the lack of
endocrine effects in developmental, subchronic and chronic studies.
C. Aggregate Exposure
1. Dietary exposure--Food. A dietary risk exposure study dietary
risk evaluation system (DRES) for Griffin for the purpose of estimating
dietary exposure to propazine residues. Grain sorghum is the only
proposed food or food use of propazine. Therefore, there exists no
potential for human consumption of crops treated with propazine.
Sorghum (grain, forage and stover) is, however, fed to livestock. Grain
is the only sorghum commodity fed to poultry. There are no chloro
residues, the residues of toxicological concern, in the grain. In turn,
there is no potential for poultry to be exposed to propazine or related
residues. Beef and dairy cattle are fed all sorghum commodities: grain,
forage, stover, and aspirated grain fractions. Therefore, in evaluating
potential human dietary exposure to propazine, the potential exposure
via secondary residues in meat and milk must be considered. The total
chloro residues for a goat dosed at 9.9 ppm in a metabolism study were
low. Specifically, the highest total residue was observed in milk
(0.162 ppm), while the lowest residue of <0.002 ppm="" was="" observed="" in="" kidney.="" these="" tissue="" to="" feed="" ratios="" can="" then="" be="" combined="" with="" the="" worst-="" case="" diets="" derived="" from="" a="" sorghum="" only="" ration="" which="" includes="" propazine="" residues="" at="" the="" tolerance="" level="" of="" 0.25="" ppm.="" (it="" should="" be="" noted="" that="" this="" worst-case="" diet="" is="" not="" a="" ration="" that="" would="" be="" fed="" to="" cattle).="" the="" results="" of="" this="" indicate="" that="" even="" under="" theoretically="" worst-case="" conditions="" all="" meat="" and="" milk="" residues="" are="" extremely="" low="" (all="" less="" than="" 0.01="" ppm;="" the="" loq="" in="" plant="" matrices="" is="" 0.05="" ppm).="" in="" turn,="" there="" is="" no="" potential="" for="" dietary="" exposure="" to="" propazine="" via="" secondary="" residues="" in="" meat="" and="" milk.="" therefore,="" tolerances="" for="" meat="" and="" milk="" are="" not="" required="" for="" propazine.="" 2.="" drinking="" water.="" griffin="" conclude="" that="" environmental="" fate="" and="" behavior="" studies,="" including="" aerobic="" soil="" metabolism,="" field="" lysimeter,="" and="" long="" term="" soil="" dissipation,="" indicate="" little="" potential="" for="" propazine="" to="" reach="" surface="" or="" groundwater="" from="" its="" proposed="" use="" on="" grain="" sorghum.="" griffin="" concludes="" that="" there="" is="" little="" potential="" for="" dietary="" exposure="" to="" propazine="" residues="" in="" water="" exists.="" 3.="" non-dietary="" exposure.="" there="" are="" no="" residential="" uses="" for="" propazine="" in="" the="" u.s.="" therefore,="" there="" is="" no="" potential="" for="" residential="" exposure.="" 4.="" non-occupational.="" a="" registration="" application="" is="" pending="" for="" use="" of="" propazine="" in="" greenhouses="" on="" certain="" ornamental="" plants.="" the="" container="" sizes="" in="" which="" the="" product="" is="" to="" be="" distributed="" and="" channel="" of="" distribution="" make="" it="" unlikely="" that="" this="" use="" would="" result="" in="" any="" non-="" occupational="" exposure.="" d.="" cumulative="" effects="" because="" of="" the="" benefits="" of="" propazine,="" most="" of="" the="" propazine="" use="" on="" sorghum="" will="" be="" substituted="" for="" other="" triazines="" and="" since="" the="" proposed="" use="" rate="" is="" lower="" than="" the="" other="" triazines="" the="" cumulative="" will="" not="" increase="" and="" could="" possibly="" be="" reduced="" as="" a="" result="" of="" registering="" propazine="" for="" use="" on="" grain="" sorghum.="" e.="" safety="" determination="" the="" reference="" dose="" (rfd)="" is="" based="" on="" the="" rat="" chronic="" study.="" using="" the="" noael="" of="" 5="" mg/kg/day="" in="" this="" study="" and="" an="" uncertainty="" factor="" (uf)="" of="" 300,="" an="" rfd="" of="" 0.02="" mg/kg/day="" was="" established="" as="" the="" chronic="" dietary="" endpoint.="" 1.="" u.s.="" population--general="" u.s.="" population.="" in="" the="" dres="" analysis="" referenced="" above,="" it="" was="" determined="" that="" there="" is="" no="" potential="" exposure="" to="" propazine="" via="" dietary,="" water,="" or="" non-occupational="" routes.="" 2.="" infants="" and="" children.="" in="" assessing="" the="" potential="" for="" additional="" sensitivity="" of="" infants="" and="" children="" to="" residues="" of="" propazine,="" the="" available="" developmental="" toxicity="" study="" and="" the="" potential="" for="" endocrine="" modulation="" by="" propazine="" were="" considered.="" the="" data="" from="" the="" developmental="" toxicity="" studies="" on="" propazine="" show="" no="" evidence="" of="" a="" potential="" for="" developmental="" effects="" (malformations="" or="" variations)="" at="" doses="" that="" are="" not="" maternally="" toxic.="" the="" developmental="" no="" observed="" adverse="" effect="" levels="" (noaels)="" and="" loaels="" were="" at="" higher="" dose="" levels="" (less="" toxic),="" indicating="" no="" increase="" in="" susceptibility="" of="" developing="" organisms.="" no="" evidence="" of="" endocrine="" effects="" were="" noted="" in="" any="" study.="" it="" is="" therefore="" concluded="" that="" propazine="" poses="" no="" additional="" risk="" for="" infants="" and="" children="" and="" no="" additional="" uncertainty="" factor="" is="" warranted.="" federal="" food,="" drug="" and="" cosmetic="" act="" (ffdca)="" section="" 408="" provides="" that="" an="" additional="" safety="" factor="" for="" infants="" and="" children="" may="" be="" applied="" in="" the="" case="" of="" threshold="" effects.="" since,="" as="" discussed="" in="" the="" previous="" section,="" the="" toxicology="" studies="" do="" not="" indicate="" that="" young="" animals="" are="" any="" more="" susceptible="" than="" adult="" animals="" and="" the="" fact="" that="" the="" current="" rfd="" calculated="" from="" the="" noael="" from="" the="" rat="" chronic="" study="" already="" incorporates="" a="" 300x="" uncertainty="" factor,="" griffin="" believes="" that="" an="" adequate="" margin="" of="" safety="" is="" therefore="" provided="" by="" the="" rfd="" established="" by="" epa.="" there="" is="" no="" evidence="" that="" propazine="" has="" endocrine-modulation="" characteristics="" as="" demonstrated="" by="" the="" lack="" of="" endocrine="" effects="" in="" developmental,="" subchronic,="" and="" chronic="" studies.="" there="" is="" no="" potential="" exposure="" to="" propazine="" via="" dietary,="" water,="" or="" non-occupational="" routes="" based="" on="" the="" proposed="" use="" on="" grain="" sorghum.="" no="" additional="" uncertainty="" factor="" for="" infants="" and="" children="" is="" warranted="" based="" on="" the="" completeness="" and="" reliability="" of="" the="" database,="" the="" demonstrated="" lack="" of="" increased="" risk="" to="" developing="" organisms,="" and="" the="" lack="" of="" endocrine-modulating="" effects.="" f.="" international="" tolerances="" there="" are="" no="" codex="" alimentarius="" commission="" (codex)="" maximum="" residue="" levels="" (mrls)="" established="" for="" residues="" of="" propazine="" and="" its="" chloro="" metabolites="" in="" or="" on="" raw="" agricultural="" commodities.="" 2.="" k-1="" chemical="" u.s.a.,="" inc.="" pp="" 7f4821="" epa="" has="" received="" an="" amendment="" to="" pesticide="" petition="" (pp="" 7f4821)="" from="" k-i="" chemical="" u.s.a.,="" inc.,="" proposing="" pursuant="" to="" section="" 408(d)="" of="" the="" federal="" food,="" drug,="" and="" cosmetic="" act,="" 21="" u.s.c.="" [[page="" 53660]]="" 346a(d),="" to="" amend="" 40="" cfr="" part="" 180="" by="" establishing="" a="" tolerance="" for="" residues="" of="" herbicide="" and="" harvest="" aid="" fluthiacet-methyl="" in="" or="" on="" the="" raw="" agricultural="" commodities="" cottonseed="" at="" 0.02="" parts="" per="" million="" (ppm)="" and="" cotton,="" gin="" by-products="" at="" 0.5="" 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.="" on="" april="" 14,="" 1997,="" epa="" announced="" receipt="" of="" a="" pesticide="" petition="" (pp="" 7f4821)="" from="" k-1="" chemical="" u.s.a.,="" inc.,="" 11="" martine="" avenue,="" 9th="" floor,="" white="" plains,="" ny="" 10606,="" 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="" the="" herbicide="" fluthiacet-methyl:="" acetic="" acid,="" [[2-chloro-4-fluoro-5-="" [(tetrahydro-3-oxo-1h,3h-[1,3,4]thiadiazolo[3,4-a]="" pyridazin-1-="" ylidene)amino]phenyl]thio]-methyl="" ester="" in="" or="" on="" the="" raw="" agricultural="" commodities="" field="" corn="" grain="" and="" sweet="" corn="" grain="" (k="" +="" cwhir)="" at="" 0.02="" ppm="" and="" corn="" forage="" and="" fodder="" at="" 0.05="" ppm.="" on="" september="" 4,="" 1997="" k-i="" chemical,="" u.s.a.,="" inc.,="" amended="" pp="" 7f4821="" to="" include="" a="" proposed="" tolerance="" for="" popcorn="" grain="" at="" 0.02="" ppm.="" on="" august="" 14,="" 1998="" k-i="" chemical="" u.s.a.,="" inc.="" amended="" pp="" 7f4821="" to="" include="" proposed="" tolerances="" for="" cottonseed="" at="" 0.02="" ppm="" and="" for="" cotton,="" gin="" by-products="" at="" 0.5="" ppm.="" epa="" has="" determined="" that="" the="" amended="" 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="" corn="" is="" adequately="" understood="" following="" application="" of="" fluthiacet-methyl.="" residue="" levels="" and="" the="" metabolic="" pathway="" are="" consistent="" with="" those="" in="" soybeans.="" parent="" fluthiacet-methyl="" was="" the="" primary="" component="" of="" the="" residue="" seen="" in="" corn="" grain,="" forage,="" fodder="" and="" silage.="" results="" of="" these="" studies="" have="" been="" submitted="" to="" the="" epa.="" 2.="" analytical="" method.="" k-i="" chemical="" has="" submitted="" practical="" analytical="" methods="" (ag-603b="" and="" ag-624)="" for="" detecting="" and="" measuring="" the="" level="" of="" fluthiacet-methyl="" in="" or="" on="" corn,="" corn="" commodities,="" cotton,="" cotton="" commodities,="" and="" in="" animal="" tissues="" with="" a="" limit="" of="" detection="" that="" allows="" monitoring="" residues="" at="" or="" above="" the="" levels="" set="" for="" the="" proposed="" tolerance.="" the="" limit="" of="" quantitation="" of="" the="" crop="" method="" is="" 0.01="" ppm="" in="" corn,="" corn="" commodities,="" cotton,="" and="" cotton="" commodities,="" 0.05="" ppm="" in="" animal="" tissues="" and="" 0.01="" ppm="" in="" milk.="" the="" crop="" method="" involves="" extraction,="" filtration,="" and="" solid="" phase="" clean="" up.="" residue="" levels="" of="" fluthiacet-methyl="" are="" determined="" by="" gas="" chromatographic="" analysis="" utilizing="" a="" nitrogen="" phosphorus="" detector="" and="" a="" fused-silica="" column.="" the="" animal="" tissue="" method="" involves="" extraction,="" filtration,="" and="" partition.="" determination="" of="" residue="" levels="" in="" animal="" tissues="" is="" by="" high="" performance="" liquid="" chromotography="" (hplc)="" with="" ultraviolet="" ray="" (uv)="" detection="" via="" column="" switching="" using="" c1="" and="" c18="" columns.="" the="" analyte="" of="" interest="" in="" animal="" tissues="" and="" milk="" is="" the="" major="" animal="" metabolite="" cga-="" 300403.="" residues="" of="" fluthiacet-methyl="" in="" corn="" are="" determined="" by="" gas="" chromatography.="" 3.="" magnitude="" of="" residues.="" the="" residue="" of="" concern="" in="" corn="" is="" fluthiacet-methyl="" per="" se.="" twenty-one="" field="" residue="" studies="" were="" conducted="" with="" corn="" grown="" in="" nineteen="" states.="" fifteen="" of="" the="" studies="" were="" on="" field="" corn="" and="" six="" on="" sweet="" corn.="" no="" studies="" were="" conducted="" with="" popcorn,="" however="" k-i="" believes="" that="" the="" data="" on="" field="" and="" sweet="" corn="" support="" a="" tolerance="" in="" popcorn="" as="" well.="" because="" the="" proposed="" use="" rate="" and="" pattern="" is="" the="" same="" for="" popcorn,="" it="" is="" reasonable="" to="" conclude="" that="" residues="" in="" popcorn="" grain="" will="" not="" exceed="" the="" proposed="" tolerance="" of="" 0.02="" ppm.="" residues="" in="" field="" and="" sweet="" corn="" forage="" after="" the="" day="" of="" application="" were="" less="" than="" the="" proposed="" tolerance="" of="" 0.05="" ppm.="" popcorn="" forage="" is="" not="" a="" fed="" commodity.="" nonetheless,="" residues="" in="" popcorn="" forage="" or="" fodder="" are="" not="" expected="" to="" exceed="" the="" proposed="" tolerance="" of="" 0.05="" ppm.="" the="" proposed="" tolerances="" of="" 0.02="" ppm="" in="" field="" corn,="" sweet="" corn,="" and="" popcorn="" grain="" and="" 0.05="" ppm="" in="" field="" corn="" and="" sweet="" corn="" forage="" and="" fodder="" are="" adequate="" to="" cover="" residues="" likely="" to="" occur="" when="" action="" herbicide="" is="" applied="" to="" corn="" as="" directed.="" this="" position="" is="" based="" on="" 180.34(d)="" of="" the="" cfr="" which="" states="" that="" ``if="" the="" pesticide="" chemical="" is="" not="" absorbed="" into="" the="" living="" plant="" or="" animal="" when="" applied="" (is="" not="" systemic),="" it="" may="" be="" possible="" to="" make="" a="" reliable="" estimate="" of="" the="" residues="" to="" be="" expected="" on="" each="" commodity="" in="" a="" group="" of="" related="" commodities="" on="" the="" basis="" of="" less="" data="" than="" would="" be="" required="" for="" each="" commodity="" in="" the="" group,="" considered="" separately''.="" and,="" 180.34(e)="" states="" that="" ``each="" of="" the="" following="" groups="" of="" crops="" lists="" raw="" agricultural="" commodities="" that="" are="" considered="" to="" be="" related="" for="" the="" purpose="" of="" paragraph="" (d)="" of="" this="" section;="" field="" corn,="" popcorn,="" sweet="" corn="" (each="" in="" grain="" form)''.="" residues="" of="" fluthiacet-methyl="" in="" treated="" field="" and="" sweet="" corn="" grain="" and="" sweet="" corn="" ears="" were="" less="" than="" the="" method="" limit="" of="" quanitation="" (loq)=""><0.01 ppm).="" because="" the="" proposed="" use="" rate="" and="" pattern="" is="" the="" same="" for="" popcorn,="" it="" is="" reasonable="" to="" conclude="" that="" residues="" in="" popcorn="" grain="" will="" not="" exceed="" the="" proposed="" tolerance="" of="" 0.02="" ppm.="" residues="" in="" field,="" and="" sweet="" corn="" forage="" -after="" the="" day="" of="" application="" were="" less="" than="" the="" proposed="" tolerance="" of="" 0.05="" ppm.="" popcorn="" forage="" is="" not="" a="" feed="" commodity.="" nonetheless,="" residues="" in="" popcorn="" forage="" or="" fodder="" are="" not="" expected="" to="" exceed="" the="" proposed="" tolerance="" of="" 0.05="" ppm.="" the="" proposed="" tolerances="" of="" 0.02="" ppm="" in="" field="" corn,="" sweet="" corn,="" and="" popcorn="" grain="" and="" 0.05="" ppm="" in="" field="" corn,="" sweet="" corn="" forage,="" and="" fodder="" are="" adequate="" to="" cover="" residues="" likely="" to="" occur="" when="" fluthiacet-methyl="" herbicide="" is="" applied="" to="" corn="" as="" directed.="" twelve="" cotton="" field="" residue="" trials="" were="" conducted="" in="" which="" fluthiacet-methyl="" 4.75%="" wettable="" powder="" (wp)="" was="" applied="" as="" two="" broadcast="" foliar="" sprays,="" 7="" days="" apart.="" no="" residues="" were="" detected=""><0.01ppm) in="" undelinted="" seed,="" delinted="" seed,="" hulls,="" meal,="" or="" refined="" oil="" nor="" was="" there="" concentration="" of="" residues="" in="" processed="" fractions,="" even="" at="" 3x="" and="" 5x="" rates="" in="" 3="" day="" phi="" (="" preharvest="" interval)="" samples.="" fluthiacet-methyl="" residues="" were="" present="" in="" field="" trash="" at="" 0.32="" and="" 0.11ppm="" at="" 3="" and="" 8="" day="" phis,="" respectively,="" and="" in="" gin="" trash="" at="" 0.1="" 0="" and="" .086="" ppm="" at="" 4="" and="" 7="" day="" phis,="" respectively,="" in="" the="" 1x="" treatment="" rate.="" results="" were="" similar="" in="" two="" additional="" trials="" in="" which="" the="" magnitude="" of="" residues="" was="" compared="" following="" application="" of="" the="" 4.75%="" wp="" and="" 10.3%="" emulsifiable="" concentrate="" (ec)="" formulations="" of="" fluthiacet-="" methyl.="" residues="" from="" the="" proposed="" use="" of="" fluthiacet-methyl="" on="" cotton="" will="" not="" exceed="" the="" proposed="" tolerances="" of="" 0.02="" ppm="" and="" 0.5="" ppm="" for="" fluthiacet-methyl="" residues="" in/on="" the="" raw="" agricultural="" commodities="" cottonseed="" and="" cotton,="" gin="" by-products.="" b.="" toxicological="" profile="" 1.="" acute="" toxicity--i.="" a="" rat="" acute="" oral="" study="" with="" an="">50 > 50,000 milligram/kilogram (mg/kg).
ii. A rabbit acute dermal study with an LD50 > 2,000 mg/
kg.
iii. A rat inhalation study with an LC50 > 5.05 mg/
liter.
[[Page 53661]]
iv. A primary eye irritation study in the rabbit showing moderate
eye irritation.
v. A primary dermal irritation study in the rabbit showing no skin
irritation.
vi. A primary dermal sensitization study in the Guinea pig showing
no sensitization.
2. Acute neurotoxicity study in rats. Neurotoxic effects were not
observed. The no observed adverse effect level (NOAEL) was 2,000 mg/kg.
3. Genotoxicty. In vitro gene mutation tests: Ames test -negative;
Chinese hamster V79 test - negative; rat hepatocyte DNA repair test -
negative; E. Coli lethal DNA damage test - negative. In vitro
chromosomal aberration tests: Chinese hamster ovary -positive at
cytotoxic doses; Chinese hamster lung - positive at cytotoxic doses;
human lymphocytes - positive at cytotoxic doses. In vivo chromosome
aberration tests: Micronucleus assays in rat liver - negative; mouse
bone marrow test - negative.
4. Reproductive and developmental toxicity. Teratology study in
rats with a maternal and developmental NOAEL equal to or greater than
1,000 milligram/kilogram/day (mg/kg/day). Teratology study in rabbits
with a maternal NOAEL greater than or equal to 1,000 mg/kg/day and a
fetal NOAEL of 300 mg/kg based on a slight delay in fetal maturation.
2-generation reproduction study in rats with a NOAEL of 36 mg/kg/day,
based on liver lesions in parental animals and slightly reduced body
weight development in parental animals and pups. The treatment had no
effect on reproduction or fertility.
5. Subchronic toxicity. 90-day subchronic neurotoxicity study in
rats. The NOAEL was 0.5 mg/kg/day based on reduced body/weight/gain
(bwt/gain). No clinical or morphological signs of neurotoxicity were
detected at any dose level. 28 day dermal toxicity study in rats with a
NOAEL equal to or higher than the limit dose of 1,000 mg/kg.
6 week dietary toxicity study in dogs with a NOAEL of 162
milligram/kilogram/day (mg/kg/day) in males and 50 mg/kg/day in females
based on decreased body weight gain and modest hematological changes.
90 day subchronic dietary toxicity study in rats with a NOAEL of
6.2 mg/kg/day based on liver changes and hematological effects.
6. Chronic toxicity. 24 month combined chronic toxicity/
carcinogenicity study in rats with a NOAEL of 2.1 mg/kg/day. Based on
reduced bwt development and changes in bone marrow, liver, pancreas and
uterus the MTD was exceeded at 130 mg/kg/day. A positive trend of
adenomas of the pancreas in male rats treated at 130 mg/kg/day and
above may be attributable to the increased survival of the rats treated
at high doses. 18 month oncogenicity study in mice with a NOAEL of 0.
14 mg/kg/day. Based on liver changes, the MTD was reached at 1.2 mg/kg/
day. The incidence of hepatocellular tumors was increased in males
treated at 12 and 37 mg/kg/day.
7. Animal metabolism. The results from hen and goat metabolism
studies, wherein fluthiacet-methyl was fed at exaggerated rates, showed
that the transfer of fluthiacet-methyl residues from feed to tissues,
milk and eggs is extremely low. No detectable residues of fluthiacet-
methyl (or metabolite CGA-300403) would be expected in meat, milk,
poultry, or eggs after feeding the maximum allowable amount of treated
corn and soybeans. This conclusion is based on residue data from the
corn and soybean metabolism and field residue chemistry studies coupled
with the residue transfer from feed to tissues, milk and eggs obtained
in the goat and hen metabolism studies.
8. Endocrine disruption. Based on the results of short-term,
chronic, and reproductive toxicity studies there is no indication that
fluthiacet-methyl might interfere with the endocrine system.
Considering further the low environmental concentrations and the lack
of bioaccumulation, there is no risk of endocrine disruption in humans
or wildlife.
C. Aggregate Exposure
Aggregate exposure includes exposure from dietary exposure from
food and drinking water; and non-dietary exposure from non-dietary uses
of pesticides products containing the active ingredient, fluthiacet-
methyl.
1. Dietary exposure. Dietary exposure consists of exposures from
food and drinking water.
2. Food. In this assessment, K-1 Chemical has conservatively
assumed that 100% of all soybeans and corn used for human consumption
would contain residues of fluthiacet-methyl and all residues would be
at the level of the proposed tolerances. The potential dietary exposure
to fluthiacet-methyl was calculated on the basis of the proposed
tolerance which is based on an limit of quantitation (LOQ) of 0.01 ppm
in soybeans and 0.02 ppm in corn (2x LOQ). The anticipated residues in
milk, meat and eggs resulting from feeding the maximum allowable amount
of soybean and corn commodities to cattle and poultry were calculated,
and the resulting quantities were well below the analytical method LOQ.
Therefore, tolerances for milk, meat and eggs are not required.
Assuming 100% crop treated values, the chronic dietary exposure of the
general U.S. population to fluthiacet-methyl would correspond to 2.3%
of the Reference dose (RfD).
3. Drinking water. Although fluthiacet-methyl has a slight to
medium leaching potential; the risk of the parent compound to leach to
deeper soil layers is negligible under practical conditions in view of
the fast degradation of the product. For example, the soil metabolism
half-life was extremely short, ranging from 1.1 days under aerobic
conditions to 1.6 days under anaerobic conditions. Even in the event of
very heavy rainfalls immediately after application, which could lead to
a certain downward movement of the parent compound, parent fluthiacet-
methyl continues to be degraded during the transport into deeper soil
zones. Considering the low application rate of fluthiacet-methyl, the
strong soil binding characteristics of fluthiacet-methyl and its
degradates, and the rapid degradation of fluthiacet-methyl in the soil,
there is no risk of ground water contamination with fluthiacet-methyl
or its metabolites. Thus, aggregate risk of exposure to fluthiacet-
methyl does not include drinking water.
4. Non-dietary exposure. Fluthiacet-methyl is not registered for
any other use and is only proposed for use on agricultural crops. Thus,
there is no potential for non-occupational exposure other than
consumption of treated commodities containing fluthiacet-methyl
residue.
D. Cumulative Effects
A cumulative exposure assessment is not appropriate at this time
because there is no information available to indicate that effects of
fluthiacet-methyl in mammals would be cumulative with those of another
chemical compound.
E. Safety Determination
1. U.S. population. Using very conservative exposure assumptions
coupled with toxicity data for fluthiacet-methyl, K-1 Chemical
calculated that aggregate, chronic exposure to fluthiacet-methyl will
utilize no more than 1.42% of the RfD for the U.S. population, 2.47%
for nursing infants less than 1 year old, 5.09% for non-nursing infants
greater than 1 year, and 3.5% for children ages 1-6 years. Because the
actual anticipated residues are well below tolerance levels and the
percent crop treated with fluthiacet-methyl is expected to be less than
100% of planted corn, cotton or soybeans, a more realistic estimate is
that dietary exposure will be many times less than the conservative
estimate previously
[[Page 53662]]
noted (the margins of exposure (MOE) will be accordingly higher).
Exposures below 100% of the RfD are generally not of concern 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. K-1 Chemical concludes that there is a reasonable certainty
that no harm will result to infants and children from chronic aggregate
exposure to residues of fluthiacet-methyl.
Also the acute dietary risk to consumers will be far below any
significant level; the lowest NOAEL from a short term exposure scenario
comes from the teratology study in rabbits with a NOAEL of 300 mg/kg.
This NOAEL is 2,000-fold higher than the chronic NOAEL which provides
the basis for the RfD (see above). Acute dietary exposure estimates
which are based on a combined food survey from 1989 to 1992 predict MOE
of at least one million for 99.9% of the general population and for
women of child bearing age. MOE of 100 or more are generally considered
satisfactory. Therefore, K-1 Chemical concludes that there is a
reasonable certainty that no harm will result from acute aggregate
exposure to fluthiacet-methyl residues
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of fluthiacet-methyl,
K-1 Chemical considered data from developmental toxicity studies in the
rat and rabbit and a 2-generation reproduction study in the rat. A
slight delay in fetal maturation was observed in a teratology study in
rabbits at a daily dose of 1,000 mg/kg. In a 2-generation reproduction
study fluthiacet-methyl did not affect the reproductive performance of
the parental animals or the physiological development of the pups. The
NOAEL was 500 ppm for maternal animals and their offspring, which is
50,000 fold higher than the RfD.
F. International Tolerances
No international tolerances have been established under CODEX for
fluthiacet-methyl.
3. Rohm and Haas Company
PP 8F5004 and 8F5006
EPA has received pesticide petitions (PP 8F5004 and 8F5006) from
Rohm and Haas Company, 100 Independence Mall West., 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 methoxyfenozide[benzoic acid, 3-methoxy-2-methyl-,2-
(3,5-dimethylbenzoyl)-2-91,1-dimethylethyl) hydrazide in or on the raw
agricultural commodity cottonseed at 2.0 parts per million (ppm),
cotton gin trash at 25 ppm, pome fruit at 1.25 ppm, meat, kidney, meat
by-products and milk of cattle, goats, sheep, and hogs at 0.02 ppm and
in fat and liver at 0.1 ppm. The tolerance expression for kidney and
liver includes the glucuronide conjugate of methoxyfenozide (RH-1518).
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 ofthe petition.
Additional data may be needed before EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The metabolism of methoxyfenozide in plants
(apples,cotton, and grapes) is adequately understood for the purposes
of these tolerances. The metabolism of methoxyfenozide in all crops was
similar and involves cleavage of the methoxyl side chain to the free
phenol, RH-117236,or oxidation of the alkyl substituents of the
aromatic rings primarily at the benzylic positions. 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.
2. Analytical method. High performance liquid chromatographic
(HPLC) analytical methods using ultraviolet (UV) or mass selective (MS)
detection have been validated for cottonseed, cotton gin trash,
cottonseed processed fractions, pome fruit, apple processed fractions
and meat, kidney, liver, fat and milk. The methods involve 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 limit of quantitation (LOQ)
is 0.01 parts per million (ppm) for cottonseed processed fractions
(meal, hulls and oil), 0.025 ppm for cottonseed, 0.05 ppm for gin
trash, 0.01 ppm for pome fruit and apple processed fractions (wet
pomace and juice), 0.01 ppm for meat, kidney, liver, fat and milk. For
residues of the gluronide conjugate metabolite of methoxyfenozide (RH-
1518), the limit of quantitation in liver and kidney is 0.02 ppm.
3. Magnitude of residues. A total of twelve cotton residue trials
were conducted in the U.S. with the 80WP formulation of INTREPID at a
maximum seasonal rate of 2.0 lb. a.i./A (i.e., 5 applications at 0.4
lb. a.i./A). The label pre-harvest interval (PHI) is 14 days. In all
cases, cotton was harvested at 14-16 days after the last application.
Methoxyfenozide residues in cottonseed ranged from 0.1-1.75 ppm. The
average residue from all GAP trials is 0.5 0.40 ppm.
Residues of methoxyfenozide in gin trash ranged from 3.84 to 22.3 ppm
with an average of 12.1 6.35 ppm. Residues did not
concentrate in meal, hulls and refined oil.
4. Pome fruit. Six pears and twelve apples trials were conducted in
1996 and 1997 with INTREPID 80WP at an application rate of 0.3 lb. AI/
acre for a total of six applications. Samples of fruit collected 14-15
days after the last application. Residues of methoxyfenozide in apples
ranged from 0.16 to 1.18 ppm and in pears from 0.26 to 0.93 ppm. The
average residue in apples is 0.53 0.28 ppm and in pears is
0.43 0.24 ppm. The combined apple and pear residue average
is 0.50 0.26 ppm. Residues of methoxyfenozide did not
concentrated in apple juice but did concentrate in wet apple pomace.
5. Cattle feeding study. A 28 day feeding study was conducted in
which dairy cows were fed daily doses of 0, 15, 45 and 150 ppm
methoxyfenozide. Tissues and milk samples were collected analyzed using
validated analytical methods. The analytes of concern included parent
methoxyfenozide in all matrices and its metabolite, RH-1518, the
glucuronic acid conjugate of the free phenol in kidney and liver.
Overall, average methoxyfenozide residues (or sum of methoxyfenozide
and RH-1518 residues for kidney and liver) were < 0.05="" ppm="" in="" the="" tissues="" (fat,="" muscle="" and="" kidney)="" from="" the="" 45="" ppm="" dose="" level="" except="" in="" liver="" (0.066="" ppm).="" in="" milk,="" methoxyfenozide="" average="" residues="" were="" less="" than="" the="" loq,="" 0.01="" ppm,="" at="" the="" 45="" ppm="" dose="" levels.="" b.="" toxicological="" profile="" 1.="" acute="" toxicity--methoxyfenozide="" has="" low="" acute="" toxicity.="" methoxyfenozide="" was="" practically="" non-toxic="" by="" ingestion="" of="" a="" single="" oral="" dose="" in="" rats="" and="" mice="">50 < 5,000="" milligram/kilogram="" (mg/="" kg))="" and="" was="" practically="" non-toxic="" by="" dermal="" application="">50 < 5,000="" mg/kg).="" methoxyfenozide="" was="" not="" significantly="" toxic="" to="" rats="" after="" a="" 4="" hours="" inhalation="" exposure="" with="" an="">50 value of > 4.3 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 with a No
[[Page 53663]]
observed adverse effect level (NOAEL) > 2,000 mg/kg.
2. Genotoxicty. Methoxyfenozide tested negative (non-mutagenic,
non-genotoxic) in a battery of in vitro and in vivo assays, which
included an Ames assay with and without metabolic activation, a CHO/
HGPRT assay, an in vitro chromosome aberration assay in CHO cells with
and without a metabolic activation, an in vivo micronucleus assay in
mouse bone marrow cells.
3. Reproductive and developmental toxicity. NOAEL for developmental
and maternal toxicity to methoxyfenozide were established at 1,000
milligrams/kilogram/day (mg/kg/day) highest dose tested (HDT) in both
the rat and rabbit. No signs of developmental toxicity were exhibited.
In a 2-generation reproduction study in the rat, the reproductive/
developmental toxicity NOAEL of 1,552 mg/kg/day was 100-fold higher
than the parental (systemic) toxicity NOAEL of 200 ppm (15.5 mg/kg/
day).
4. Subchronic toxicity. The NOAEL in a 90-day rat feeding study was
1,000 ppm (69.3 mg/kg/day for males, 72.4 mg/kg/day for females). The
lowest-observed-effect-level (LOAEL) was 5,000 ppm (353 mg/kg/day for
males, 379 mg/kg/day for females). Increased liver weight and liver
histopathology were observed at the LOAEL of 5,000 ppm. Methoxyfenozide
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 (NOAEL = 1,318 mg/kg/day for males, 1,577
mg/kg/day for females).
i. In a 90-day feeding study with mice, the NOAEL was 2,500 ppm
(428 and 589 mg/kg/day for males and females, respectively). The LOAEL
was 7,000 ppm (1,149 and 1,742 mg/kg/day for males and females,
respectively). Decreases in body weight gain (bwt/gain) were noted in
both sexes of mice at the LOAEL of 7,000 ppm.
ii. A 90 day dog feeding study gave a NOAEL of 3,000 ppm, the
highest dose tested (HDT) (198 and 209 mg/kg/day for males and females,
respectively). Extension of treatment of the low dose animals for 6
weeks at 15,000 ppm (422 and 460 mg/kg/day for males and females,
respectively) produced no signs of systemic toxicity.
Methoxyfenozide 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. These findings correlate with the low
dermal penetration observed with 14C-methoxyfenozide,
formulated as the wettable powder, (i.e., after 24 hours 1-3% of the
administered dose was systemically absorbed).
5. Chronic toxicity--i. The NOAEL in a 1 year feeding study in dogs
was 300 ppm (9.8 and 12.6 mg/kg/day for male and females,
respectively). The LOAEL was 3,000 ppm (106 and 111 mg/kg/day for male
and females, respectively) based on minimal hematological effects.
ii. An 18 month mouse carcinogenicity study showed no signs of
carcinogenicity at dosage levels up to and including 7,000 ppm (1,020
and 1,354 mg/kg/day for male and females, respectively), HDT.
iii. In a combined rat chronic/oncogenicity study, the NOAEL for
chronic toxicity was 200 ppm (10.2 and 11.9 mg/kg/day for males and
females, respectively) and the LOAEL was 8,000 ppm (411 and 491 mg/kg/
day for males and females, respectively). No carcinogenicity was
observed at the dosage levels up to 20,000 ppm (1,045 and 1,248 mg/kg/
day for males and females, respectively).
6. Animal metabolism. In toxicokinetic and metabolism studies in
the rat, methoxyfenozide was rapidly absorbed following oral exposure
with peak plasma levels occurring within 0.5 hour of administration.
Methoxyfenozide does not bioaccumulate in that the compound is rapidly
and almost completely eliminated within 24 hours. Methoxyfenozide was
extensively metabolized in rats. Including parent compound, 32
metabolites, of which 26 were identified, were isolated from the rat
urine and feces. The primary pathway of methoxyfenozide metabolism
involves demethylation of the A-ring methoxyl moiety to form the
corresponding A-ring phenol, RH-117,236, which is readily conjugated
with glucuronic acid to RH-1518. Hydroxylation on the B-ring methyl
moieties is also an important metabolic pathway.
7. Metabolite toxicology. Common metabolic pathways for
methoxyfenozide have been identified in both plants (apple, cotton and
grape), and animals (,goat, hen, rat). Extensive degradation and
elimination of polar metabolites occurs in animals such that residues
are unlikely to accumulate in humans or animals exposed to these
residues through the diet. The rapid metabolism and excretion of
methoxyfenozide in part accounts for the compound's overall low
toxicity profile in animals. The main metabolite of methoxyfenozide in
plants and animals, the A-ring phenol, RH-117,236, produced no toxicity
in mice (LD50 > 5,000 mg/kg) and was negative when tested in
the Ames mutagenic assay. Other metabolites of methoxyfenozide (e.g.,
glucuronides) would be expected to produce minimal to no toxicity given
structure activity considerations.
8. Endocrine disruption. Based on structure-activity information as
well as the lack of developmental and reproductive toxicity,
methoxyfenozide is unlikely to exhibit estrogenic activity. No
indicators of estrogenic or other endocrine effects were observed in
mammalian chronic studies or in mammalian and avian reproduction
studies. Methoxyfenozide is within a class of chemistry
(diacylhydrazines) that is not known to bind to mammalian steroid
receptors. Overall, the weight of evidence provides no indication that
methoxyfenozide has endocrine activity in vertebrates.
C. Aggregate Exposure
1. Dietary exposure. Tolerances are proposed for the residues of
methoxyfenozide in or cottonseed, cotton gin trash, pome fruit, apple
pomace, and livestock commodities. Risk assessments were conducted by
Rohm and Haas to assess dietary exposures and risks from
methoxyfenozide as follows:
2. Acute exposure and risk. No acute endpoint of concern was
identified for methoxyfenozide and no acute risk assessment is
required.
3. Chronic exposure and risk. For chronic dietary risk assessment,
the proposed tolerance values and anticipated (average) residues are
used and the assumption that 100% of all cotton and pome fruit will
contain residues of methoxyfenozide at the tolerance or anticipated
residue levels. The Reference dose (RfD) used for the chronic dietary
analysis is 0.1 mg/kg/day based on the NOAEL of 9.8-10.0 mg/kg/day from
the rat and dogs chronic studies. Potential chronic exposures were
estimated using NOVIGEN'S Dietary Exposure Evaluation Model (DEEM
Version 5.03b) which uses USDA food consumption data from the 1989-1992
survey. With the proposed tolerances and anticipated residue levels for
methoxyfenozide, the percentage of the RfD utilized is as follows:
[[Page 53664]]
----------------------------------------------------------------------------------------------------------------
Population Subgroups Tolerance Levels Anticipated Residues
----------------------------------------------------------------------------------------------------------------
Total % RfD Total %RfD
----------------------------------------------------------------------------------------------------------------
U.S. Population - 48 States............. 1.7 0.3
Nursing Infants < 1="" year="" old............="" 1.5.7="" 0.7="" non-nursing="" infants="">< 1="" year="">2....... 19.0 1.7
Children 1-6 years old.................. 6.8 1.3
Children 7-12 years old................. .2.7 0.7
----------------------------------------------------------------------------------------------------------------
The chronic dietary risks from these uses do not exceed EPA's level
of concern.
4. Drinking water. Submitted environmental fate studies suggest
that methoxyfenozide is moderately persistent and mobile, and could
potentially leach to groundwater and runoff to surface water under
certain environmental conditions. However, in terrestrial field
dissipation and orchard dissipation studies, residues of
methoxyfenozide showed minimal mobility and remained associated with
the upper layers of soil. Foliar interception (up to 70% of the total
dosage applied) by target crops reduces the ground level residues of
methoxyfenozide.
Acute and chronic exposures to methoxyfenozide in drinking water
were estimated using the GEENEC V1.2 and SCI-GROW models, as directed
in OPP's Interim Approach for Addressing Drinking Water Exposure.
GEENEC is a highly conservative model used to estimate residue
concentrations in surface water. SCI-GROW is an equally conservative
model used to estimate residue concentrations in shallow, highly
vulnerable ground water (i.e., sites with sandy soils and depth to
ground water of 10 to 20 feet). As indicated in EPA's drinking water
exposure guidance, a very small percentage of people in the U.S. would
derive their drinking water from such sources. GEENEC (56 Day average)
and SCI-GROW water exposure values for methoxyfenozide utilize 1% or
less of the RfD for adults and children.
There is no established Maximum Concentration Level (MCL) for
residues of methoxyfenozide in drinking water. No drinking water health
advisory levels have been established for methoxyfenozide. There is no
entry for methoxyfenozide in the ``Pesticides in Groundwater Database''
(EPA 734-12-92-001, September 1992).
5. Chronic exposure and risk. There are insufficient water-related
exposure data to complete a comprehensive drinking water assessment for
methoxyfenozide at this time. However, in order to mitigate the
potential for methoxyfenozide to leach into groundwater or runoff to
surface water, precautionary language has been incorporated into the
proposed product label. Also, to the best of our knowledge, previous
experience at EPA with more persistent and mobile pesticides for which
there were available data to perform quantitative risk assessments
demonstrated that drinking water exposure was typically a small
percentage of 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 our knowledge of previous experience with persistent
chemicals, no risk from residues of methoxyfenozide in drinking water
is anticipated.
6. Non-dietary exposure. Methoxyfenozide is not currently
registered for any indoor or outdoor residential uses; therefore, no
non-dietary residential exposure is anticipated.
D. Cumulative Effects
Cumulative exposure to substances with common mechanism of
toxicity: The methodologies to resolve the complex scientific issues
concerning common mechanism of toxicity in a meaningful way are not
available at this time. EPA has begun a pilot process to study this
issue further through the examination of particular classes of
pesticides. The Agency hopes that the results of this pilot process
will increase the Agency's scientific understanding of this question
such that EPA will be able to develop and apply scientific principles
for better determining which chemicals have a common mechanism of
toxicity and evaluating the cumulative effects of such chemicals. The
Agency anticipates, however, that even as its understanding of the
science of common mechanisms increases, decisions on specific classes
of chemicals will be heavily dependent on chemical specific data, much
of which may not be presently available.
Although at present the Agency does not know how to apply the
information in its files concerning common mechanism issues to most
risk assessments, there are pesticides for which the common mechanism
issues can be resolved. These pesticides include pesticides that are
toxicologically dissimilar to existing chemical substances (in which
case the Agency can conclude that it is unlikely that a pesticide
shares a common mechanism of activity with other substances) and
pesticides that produce a common toxic metabolite (in which case common
mechanism of activity will be assumed).
At this time, no data are available to determine whether
methoxyfenozide [benzoic acid, 3-methoxy-2-methyl-, 2-(3,5-
dimethylbenzoyl)-2-(1,1-dimethylethyl) hydrazide] has a common
mechanism of toxicity with other substances. Thus, it is not
appropriate to include this pesticide in a cumulative risk assessment.
Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, methoxyfenozide
[benzoic acid, 3-methoxy-2-methyl-, 2-(3,5-dimethylbenzoyl)-2-(1,1-
dimethylethyl) hydrazide] does not produce a toxic metabolite produced
by other substances. For the purposes of this tolerance action,
therefore, methoxyfenozide [benzoic acid, 3-methoxy-2-methyl-, 2-(3,5-
dimethylbenzoyl)-2-(1,1-dimethylethyl) hydrazide] is assumed not to
have a common mechanism of toxicity with other substances.
E. Safety Determination
1. U.S. population--Acute exposure and risk. Since no acute
endpoint of concern has been identified for methoxyfenozide, no acute
risk assessment is required.
2. Chronic exposure and risk. Using the conservative exposure
assumptions described above and taking into account the completeness
and reliability of the toxicity data, the percentage of the RfD that
will be utilized by dietary (food only) exposure to residues of
methoxyfenozide from the proposed tolerances is 1.7% (tolerance levels)
and 0.3% (anticipated residues) for the U.S. population. Aggregate
exposure (food and water) are not expected to exceed 100%. EPA
generally has no concern for exposures below 100% of the RfD
[[Page 53665]]
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
methoxyfenozide residues to the U.S. population.
3. Infants and children-- Safety factor for infants and children--
i. In general. The potential for additional sensitivity of infants and
children to residues of methoxyfenozide are assessed using data from
developmental toxicity studies in the rat and rabbit and 2-generation
reproduction studies in the rat. The developmental toxicity studies are
designed to evaluate adverse effects on the developing organism
resulting from maternal pesticide exposure during gestation.
Reproduction studies provide information relating to effects from
exposure to the pesticide on the reproductive capability of mating
animals and data on systemic toxicity.
ii. Developmental toxicity studies-- Rats. In a developmental
toxicity study in rats, the maternal (systemic) NOAEL was 1,000 mg/kg/
day HDT. The developmental (pup) NOAEL was > 1,000 mg/kg/day HDT).
iii. Rabbits. In a developmental toxicity study in rats, the
maternal (systemic) NOAEL was 1,000 mg/kg/day HDT. The developmental
(pup) NOAEL was > 1,000 mg/kg/day HDT.
iv. Reproductive toxicity study rats. In a multigeneration
reproductive toxicity study in rats, the parental (systemic) NOAEL was
15.5 mg/kg/day, based on liver effects at the LOAEL of 153 mg/kg/day.
The reproductive (pup) NOAEL was 1,552 mg/kg/day HDT. No adverse
reproductive effects were observed.
v. Pre- and post-natal sensitivity--Pre-natal sensitivity. The
developmental NOAELs of >1,000 mg/kg/day HDT from the developmental
toxicity studies in rats and rabbits demonstrate that there is no
developmental (prenatal) toxicity present for methoxyfenozide.
Additionally, these developmental NOAELs are greater than 100-fold
higher than the NOAEL of 9.8-10.0 mg/kg/day from the rat and dogs
chronic studies which are the basis of the RfD.
vi. Post-natal sensitivity. In the reproductive toxicity study in
rats, the reproductive NOAEL (1,552 mg/kg/day) is about 100-fold higher
than the parental NOAEL (15.5 mg/kg/day). These developmental and
reproductive studies indicate that methoxyfenozide does not have
additional pre- and post-natal sensitivity for infants and children in
comparison to other exposed groups.
vii. Acute exposure and risk. No acute endpoint was identified for
methoxyfenozide, and therefore no acute risk assessment is required.
viii. Chronic exposure and risk. For chronic dietary risk
assessment, tolerances and anticipated residue values are used and the
assumption that 100% of all cotton and pome fruit will contain residues
at the tolerance or anticipated residue levels. The percentage RfD
utilized from the proposed tolerances and anticipated residues 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 proposed tolerances and anticipated residues for
methoxyfenozide, the percentage of the RfD that will be utilized by
dietary (food only) exposure to residues of methoxyfenozide is 9.0%
(tolerance levels ) and 1.7% (anticipated residues) for non-nursing
infants less than 1 year old. Aggregate exposure (food and water) are
not expected to exceed 100%. Rohm and Haas concludes that there is a
reasonable certainty that no harm will result from aggregate exposure
to methoxyfenozide residues to non-nursing infants.
F. International Tolerances
There are currently no CODEX, Canadian or Mexican maximum residue
levels (MRLs) established for methoxyfenozide in cottonseed, gin trash,
pome fruit, apple pomace, or livestock commodities so no harmonization
issues are required for this action.
4. Valent U.S.A. Company
PP 8F5022
EPA has received a pesticide petition (PP 8F5022) from Valent
U.S.A. Company, 1333 North California Boulevard, Suite 600, Walnut
Creek, CA 94596-8025., 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 pyriproxyfen,
2-[ 1-methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine in or on the raw
agricultural commodity almond hulls at 2.0 parts per million (ppm),
citrus fruits (crop group 10) at0.3 ppm, fruiting vegetables (crop
group 8) at 0.1 ppm, tree nuts (crop group 14) at 0.02 ppm, and in the
processed commodities citrus oil at 20 ppm and dried citrus pulp 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-- Nature of the residues in food, feed and
secondary residues. Metabolism of 14C-pyriproxyfen labelled
in the phenoxyphenyl ring and in the pyridyl ring has been studied in
cotton, apples, tomatoes, lactating goats, and laying hens (and rats).
The major metabolic pathways in plants is aryl hydroxylation and
cleavage of the ether linkage, followed by further metabolism into more
polar products by further oxidation and/or conjugation reactions.
However, the bulk of the radiochemical residue on RAC samples remained
as parent. Comparing metabolites detected and quantified from apple,
cotton, tomato, goat and hen (and rat) shows that there are no
significant aglycones in plants which are not also present in the
excreta or tissues of animals. The residue of concern is best defined
as the parent, pyriproxyfen. 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 parts per million (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--Priproxyfen and metabolites. Practical
analytical methods for detecting and measuring residue levels of
pyriproxyfen (and relevant metabolites) have been developed and
validated in/on all appropriate agricultural commodities, respective
processing fractions, milk, animal tissues, and environmental samples.
The extraction methodology has been validated using aged radiochemical
residue samples from metabolism studies. The methods have been
validated in cottonseed, apples, soil, and oranges at independent
laboratories. EPA has 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 the levels proposed for the
tolerances.
3. Magnitude of residues--i. Almonds. Data from six field trials in
almonds all conducted in 1997 in California showed that at the proposed
maximum
[[Page 53666]]
application rate there were no detectable residues in nutmeats (>0.01
ppm pyriproxyfen). In a single sample at twice the maximum rate,
pyriproxyfen was measured just at the limit of detection (0.01 ppm).
Almond hulls are exposed to application and are used as ruminant feed.
In/on almond hulls, the average measured residue was 0.78 ppm (n =
12,n-1 = 0.41 ppm) pyriproxyfen. A tolerance of
0.02 ppm in/on tree nutmeats and 2.0 in/on almond hulls is proposed.
The proposed nutmeat tolerance, twice the limit of detection, is
completely consistent with previously submitted data on walnut
nutmeats, and supports the proposed tree nut crop group tolerance.
ii. Citrus. Thirteen field trials in oranges were conducted in 1996
through 1998. Similarly, six field trials were conducted for lemons,
and seven field trials were conducted for grapefruit. The proposed use
pattern for the three citrus crops is identical. The analytical data
show that the average measured residue in/on orange samples was 0.155
ppm (n = 26, n-1 = 0.045 ppm) pyriproxyfen.
Similarly, the analytical data show that the average measured residue
in/on lemon samples was 0.128 ppm (n = 12, n-1 =
0.073 ppm), and in/on grapefruit samples was 0.123 ppm (n = 14,
n-1 = 0.025 ppm), pyriproxyfen. In one unfrozen
sample of oranges, peel was analyzed separately from pulp demonstrating
that the residue of pyriproxyfen is on the exterior of the citrus
fruit. A processing study in oranges demonstrated that pyriproxyfen
concentrated in orange oil (74-fold) and in dried orange pulp (6.3-
fold) but did not concentrate in orange juice (>0.03-fold). The highest
average residue (HAR) from field trials was 0.22 ppm. All these data
support proposed tolerances for pyriproxyfen in/on citrus fruit crop
group at 0.3 ppm, citrus oil at 20 ppm, and dried citrus pulp at 1.5
ppm
iii. Peppers. Data from ten field trials in bell and non-bell
peppers conducted in 1997 showed that the average measured residue was
0.025 ppm (n = 20, n-1 = 0.24 ppm) pyriproxyfen.
These data along with tomato data support a proposed fruiting vegetable
crop group tolerance of 0.1 ppm.
iv. Tomatoes. Data from thirteen field trials in tomatoes conducted
in 1996 and 1997 showed that the average measured residue was 0.016 ppm
(n = 26, n-1 = 0.010 ppm) pyriproxyfen. The
proposed use pattern is identical to that proposed for peppers and
allows a maximum seasonal application totaling 0.176 lb. ai/acre (80
grams ai./acre), with a maximum single application rate of 0.066 lb.
ai./acre (30 grams ai./acre), at a minimum 7 days interval between
applications, and with the last application no less than 14 days before
harvest. A processing study demonstrated that pyriproxyfen did not
concentrate in tomato puree or tomato paste and no processed product
tolerances are necessary. These data along with pepper data support a
proposed fruiting vegetable crop group tolerance of 0.1 ppm.
v. Secondary residues. Using proposed tolerances to calculate the
maximum feed exposure to fed animals, and using the very low potential
for residue transfer documented in the milk cow feeding residue study,
finite, detectable secondary residues in animal tissues, milk, and eggs
are not expected. Therefore, tolerances are not proposed for these
commodities.
vi. Rotational crops. The results of a confined rotational crops
accumulation study indicate that no rotational crop planting
restrictions or rotational crop tolerances are required.
B. Toxicological Profile
1. Acute toxicity. The acute toxicity of technical grade
pyriproxyfen is low by all routes. The compound is 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.
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 or reproductive toxicant. Developmental toxicity studies
have been performed in rats and rabbits, and multigenerational effects
on reproduction were tested in rats. These studies have been reviewed
and found to be acceptable to the Agency.
In the developmental toxicity study conducted with rats, technical
pyriproxyfen was administered by gavage at levels of 0, 100, 300, and
1,000 milligram kilogram body weight day (mg/kg/bwt/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/bwt/day and greater. The maternal no
observed adverse effect level (NOAEL) was 100 mg/kg/bwt/day. A
transient increase in skeletal variations was observed in rat fetuses
from females exposed to 300 mg/kg/bwt/day and greater. These effects
were not present in animals examined at the end of the postnatal
period, therefore, the NOAEL for prenatal developmental toxicity was
100 mg/kg/bwt/day. An increased incidence of visceral and skeletal
variations was observed postnatally at 1,000 mg/kg/bwt/day. The NOAEL
for postnatal developmental toxicity was 300 mg/kg/bwt/day.
In the developmental toxicity study conducted with rabbits,
technical pyriproxyfen was administered by gavage at levels of 0, 100,
300, and 1,000 mg/kg/bwt/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 bw/day or higher.
The maternal NOEL was 100 mg/kg bw/day. No developmental effects were
observed in the rabbit fetuses. The NOAEL for developmental toxicity in
rabbits was 1,000 mg/kg/bwt/day.
In the rat reproduction study, 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/bwt/day in males, 498 mg/kg/bwt/day in females)
during the pre-mating period. The systemic NOAEL was 1,000 ppm (87 mg/
kg/bwt/day in males, 96 mg/kg/bwt/day in females). No effects on
reproduction were produced at 5,000 ppm, the highest dose tested (HDT).
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 NOAELs from these studies were 400 ppm (23.5 mg/kg/
bwt/day for males, 27.7 mg/kg/bwt/day for females) in rats, 1,000 ppm
(149.4 mg/kg/bwt/day for males, 196.5 mg/kg/bwt/day for females) in
mice, and 100 mg/kg/bwt/day in dogs.
In a 4 week inhalation study of pyriproxyfen technical in rats,
decreased body weight and increased
[[Page 53667]]
water consumption were observed at 1,000 mg/m3. The NOAEL 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/bwt/day, the HDT. In a 21 day dermal study conducted with KNACK.
Insect Growth Regulator the test material produced a NOAEL of 1,000 mg/
kg/bwt/day (HDT) for systemic effects, and a NOAEL for skin irritation
of 100 mg/kg/bwt/day.
5. Chronic toxicity. Pyriproxyfen technical has been tested in
chronic studies with dogs, rats and mice. EPA has established a
reference dose (RfD) for pyriproxyfen of 0.35 mg/kg/bwt/day, based on
the NOAEL in female rats from the 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 have
shown 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/
oncogenicity study or in a 78 week study on mice. The oncogenicity
classification of pyriproxyfen is ``E'' (no evidence of carcinogenicity
for humans).
Pyriproxyfen technical was administered to dogs in capsules at
doses of 0, 30, 100, 300 and 1,000 mg/kg/bwt/day for 1 year. Dogs
exposed to dose levels of 300 mg/kg/bwt/day or higher showed overt
clinical signs of toxicity, elevated levels of blood enzymes and liver
damage. The NOAEL in this study was 100 mg/kg/bwt/day.
Pyriproxyfen technical was administered to mice at doses of 0, 120,
600 and 3,000 ppm in diet for 78 weeks. The NOAEL for systemic effects
in this study was 600 ppm (84 mg/kg/bwt/day in males, 109.5 mg/kg/bwt/
day in females), and a lowest observed adverse effect level (LOAEL) of
3,000 ppm (420 mg/kg/bwt/day in males, 547 mg/kg/bwt/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 NOAEL for
systemic effects in this study was 600 ppm (27.31 mg/kg/bwt/day in
males, 35.1 mg/kg/bwt/day in females). A LOAEL of 3,000 ppm (138 mg/kg/
bwt/day in males, 182.7 mg/kg/ bwt/day in females) was established
based on a depression in body weight gainin females.
6. Animal metabolism. 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/bwt
(phenoxyphenyl and pyridyl label), and after a single oral dose of 2
mg/kg/bwt (phenoxyphenyl label only) following 14 daily oral doses at 2
mg/kg/bwt of unlabelled material. 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. Radiocarbon concentrations in fat were the
higher than in other tissues analyzed. Recovery in tissues over time
indicates that the potential for bioaccumulation is minimal. There were
no significant sex or dose-related differences in excretion or
metabolism.
7. Metabolite toxicology. Metabolism studies of pyriproxyfen in
rats, goats and hens, as well as the fish bioaccumulation study
demonstrate that the parent is very rapidly metabolized and eliminated.
In the rat, most (88-96%) of the administered radiolabel was excreted
in the urine and feces within 2 days of dosing, and 92-98% of the
administered dose was excreted within 7 days. Tissue residues were low
7 days after dosing, accounting for no more than 0.3% of the dosed
14C. Because parent and metabolites are not retained in the
body, the potential for acute toxicity from in situ formed metabolites
is low. The potential for chronic toxicity is adequately tested by
chronic exposure to the parent at the MTD and consequent chronic
exposure to the internally formed metabolites.
Seven metabolites of pyriproxyfen, 4'-OH-pyriproxyfen, 5''-OH-
pyriproxyfen, desphenyl-pyriproxyfen, POPA, PYPAC, 2-OH-pyridine and
2,5-diOH-pyridine, have been tested for mutagenicity (Ames) and acute
oral toxicity to mice. All seven metabolites were tested in the Ames
assay with and without S9 at doses up to 5,000 micro-grams per plate or
up to the growth inhibitory dose. The metabolites did not induce any
significant increases in revertant colonies in any of the test strains.
Positive control chemicals showed marked increases in revertant
colonies. The acute toxicity to mice of 4'-OH-pyriproxyfen, 5''-OH-
pyriproxyfen, desphenyl-pyriproxyfen, POPA, and PYPAC did not appear to
markedly differ from pyriproxyfen, with all metabolites having acute
oral LD50 values greater than 2,000 mg/kg/bwt. The two
pyridines, 2-OH-pyridine and 2,5-diOH-pyridine, gave acute oral
LD50 values of 124 (male) and 166 (female) mg/kg/bwt, and
1,105 (male) and 1,000 (female) mg/kg/bwt, respectively.
8. Endocrine disruption. Pyriproxyfen is specifically designed to
be an insect growth regulator and is known to produce juvenoid effects
on arthropod development. However, this mechanism-of-action in target
insects and other some arthropods has no relevance to any 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 including detailed histopathology
of numerous tissues. The results of these studies show no evidence of
any endocrine-mediated effects and no pathology of the endocrine
organs. Consequently, it is concluded that pyriproxyfen does not
possess estrogenic or endocrine disrupting properties applicable to
mammals.
C. Aggregate Exposure
1. Dietary exposure. An evaluation of acute and chronic dietary
exposure to include drinking water has been performed for the U.S.
population and various sub-populations including infants and children.
Because of the lack of identified toxic endpoints of concern for acute
dietary exposure, the results of the acute evaluations are not reported
in this analysis.
2. Food. Chronic dietary exposure to pyriproxyfen residues was
calculated for the U.S. population and 26 population subgroups assuming
tolerance level residues and 100% of the crop treated. The results from
several representative subgroups are listed below. Chronic dietary
exposure was at or below 0.22 % of the reference dose with pome fruits,
fruiting vegetables and citrus the commodities contributing the most to
chronic exposure. Generally speaking, the Agency has no cause for
concern if total residue contribution for published and proposed
tolerances is less than 100% of the RfD.
Tier I Calculated Chronic Dietary Exposures to the total U.S.
Population and Selected Sub-Populations to Pyriproxyfen Residues in
Food
[[Page 53668]]
----------------------------------------------------------------------------------------------------------------
Population Subgroup Exposure Percent of
----------------------------------------------------------------------------------------------------------------
(mg/kg/bw/day) RfD
----------------------------------------------------------------------------------------------------------------
Total U.S. Population (all seasons)..... 0.000237 0.067
Females (13+/Nursing)................... 0.000310 0.089
Females (20+ years, not preg. or nursing 0.000188 0.054
Children (1-6 Years).................... 0.000544 0.154
All Infants (<1 year="" old)...............="" 0.000629="" 0.180="" non-nursing="" infants=""><1 year="" old).......="" 0.000771="" 0.220="" nursing="" infants=""><1 year="" old)...........="" 0.000293="" 0.084="" ----------------------------------------------------------------------------------------------------------------="" acute="" dietary="" risk="" assessments="" are="" performed="" for="" a="" food="" use="" pesticide="" if="" a="" toxicological="" study="" has="" indicated="" the="" possibility="" of="" an="" effect="" of="" concern="" occurring="" as="" the="" result="" of="" a="" 1="" day="" or="" single="" exposure.="" no="" acute="" dietary="" endpoint="" and="" dose="" was="" identified="" in="" the="" toxicology="" data="" base="" for="" pyriproxyfen,="" therefore="" the="" agency="" has="" concluded="" that="" there="" is="" a="" reasonable="" certainty="" of="" no="" harm="" from="" acute="" dietary="" exposure.="" 3.="" drinking="" water.="" since="" pyriproxyfen="" is="" applied="" outdoors="" to="" growing="" agricultural="" crops,="" the="" potential="" exists="" for="" pyriproxyfen="" or="" its="" metabolites="" to="" reach="" ground="" or="" surface="" water="" that="" may="" be="" used="" for="" drinking="" water.="" because="" of="" the="" physical="" properties="" of="" pyriproxyfen,="" it="" is="" unlikely="" that="" pyriproxyfen="" or="" its="" metabolites="" can="" leach="" to="" potable="" groundwater.="" to="" quantify="" potential="" exposure="" from="" drinking="" water,="" surface="" water="" concentrations="" for="" pyriproxyfen="" were="" estimated="" using="" geneec="" 1.3.="" the="" average="" 56="" day="" concentration="" predicted="" in="" the="" simulated="" pond="" water="" was="" 0.16="" ppb.="" using="" standard="" assumptions="" about="" body="" weight="" and="" water="" consumption,="" the="" chronic="" exposure="" to="" pyriproxyfen="" from="" this="" drinking="" water="" would="" be="" 4.57="" x="">-6 and 1.6 x
10-5 mg/kg/bwt/day for adults and children, respectively;
0.0046 percent of the RfD (0.35 mg/Kg/day) for children. Based on this
worse case analysis, the contribution of water to the dietary risk is
negligible.
4. Non-dietary exposure. Pyriproxyfen is the active ingredient in
numerous registered products for household use -- primarily for 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 pyriproxyfen has a relatively
short elimination half-life, cumulative toxicological effects resulting
from bioaccumulation are not plausible following short-term,
intermittent exposures. Further, pyriproxyfen is short-lived in the
environment and this indoor domestic use of pyriproxyfen provides only
relatively short-term reservoirs. Thus, consumer use of these products
results in acute and short term intermittent exposures. No acute
dermal, or inhalation dose or endpoint was identified in the toxicity
data for pyriproxyfen. Similarly, doses and endpoints were not
identified for short and intermediate term dermal or inhalation
exposure to pyriproxyfen. The Agency has concluded that there are
reasonable certainties of no harm from acute, short term, and
intermediate term dermal and inhalation occupational and residential
exposures due to the lack of significant toxicological effects
observed. Thus, no detailed exposure and risk analyses for non-dietary
exposures to pyriproxyfen are necessary.
D Cumulative Effects
Section 408(b)(2)(D)(v) requires that the Agency must consider
``available information'' concerning the cumulative effects of a
particular pesticide's residues and ``other substances that have a
common mechanism of toxicity''. Available information in this context
include not only toxicity, chemistry, and exposure data, but also
scientific policies and methodologies for understanding common
mechanisms of toxicity and conducting cumulative risk assessments. For
most pesticides, although the Agency has some information in its files
that may turn out to be helpful in eventually determining whether a
pesticide shares a common mechanism of toxicity with any other
substances, EPA does not at this time have the methodologies to resolve
the complex scientific issues concerning common mechanism of toxicity
in a meaningful way.
There are no other pesticidal compounds that are structurally
related to pyriproxyfen and have similar effects on animals. In
consideration of potential cumulative effects of pyriproxyfen and other
substances that may have a common mechanism of toxicity, there are
currently no available data or other reliable information indicating
that any toxic effects produced by pyriproxyfen would be cumulative
with those of other chemical compounds. Thus, only the potential risks
of pyriproxyfen have been considered in this assessment of aggregate
exposure and effects.
Valent will submit information for EPA to consider concerning
potential cumulative effects of pyriproxyfen consistent with the
schedule established by EPA at 62 FR 42020 (Aug. 4, 1997) and other
subsequent EPA publications pursuant to the Food Quality Protection
Act.
E. Safety Determination
1. U.S. population--Chronic dietary exposure and risk-- Adult sub-
populations. Using the Tier I dietary exposure assessment procedures
described above for pyriproxyfen, calculated chronic dietary exposure
resulting from residue exposure from existing and proposed uses of
pyriproxyfen is minimal. The estimated chronic dietary exposure from
food for the overall U.S. population and many non-child/infant
subgroups is from 0.000175 to 0.000310 mg/kg/bwt/day, 0.05 to 0.089% of
the RfD. Addition of the small but worse case potential chronic
exposure from drinking water (calculated above) increases exposure by
only 4.57 x 10 -6 mg/kg/bwt/day and does not change the
maximum occupancy of the RfD significantly. Generally, the Agency has
no cause for concern if total residue contribution is less than 100% of
the RfD. It can be concluded that there is a reasonable certainty that
no harm will result to the overall U.S. population and many non-child/
infant subgroups from aggregate, chronic exposure to pyriproxyfen
residues.
2. Acute dietary exposure and risk-- Adult sub-populations. An
acute dietary dose and endpoint was not identified. Thus, the risk from
acute aggregate exposure is considered to be negligible. Non-Dietary
Exposure and Aggregate Risk -- Adult Sub-Populations: Acute, short
term, and intermediate term dermal and inhalation risk assessments for
residential exposure are not required due to the lack of significant
toxicological effects observed.
3. Infants and children--i. Safety factor for infants and children.
In
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assessing the potential for additional sensitivity of infants and
children to residues of pyriproxyfen, FFDCA section 408 provides that
EPA shall apply an additional margin of safety, up to ten-fold, for
added protection for infants and children in the case of threshold
effects unless EPA determines that a different margin of safety will be
safe for infants and children.
The toxicological data base for evaluating pre- and post-natal
toxicity for pyriproxyfen is complete with respect to current data
requirements. There are no special pre- or post-natal toxicity concerns
for infants and children, based on the results of the rat and rabbit
developmental toxicity studies or the 2-generation reproductive
toxicity study in rats. Valent concludes that reliable data support use
of the standard 100-fold uncertainty factor and that an additional
uncertainty factor is not needed for pyriproxyfen to be further
protective of infants and children.
ii. Chronic dietary exposure and risk-- Infants and children. Using
the conservative Tier I exposure assumptions described above, the
percentage of the RfD that will be utilized by chronic dietary (food
only) exposure to residues of pyriproxyfen ranges from 0.000293 mg/kg/
bwt/day for Nursing Infants (<1 year="" old),="" up="" to="" 0.000771="" mg/kg/bwt/day="" for="" non-nursing="" infants=""><1 year="" old),="" 0.084="" to="" 0.220%="" of="" the="" rfd,="" respectively.="" adding="" the="" worse="" case="" potential="" incremental="" exposure="" to="" infants="" and="" children="" from="" pyriproxyfen="" in="" drinking="" water="" (1.6="" x="" 10="">-5 mg/kg/bwt/day) does not materially increase the
aggregate, chronic dietary exposure and only increases the occupancy of
the RfD by 0.0046% to 0.225% for Non-Nursing Infants (<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.="" it="" can="" be="" concluded="" that="" there="" is="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" to="" infants="" and="" children="" from="" aggregate,="" chronic="" exposure="" to="" pyriproxyfen="" residues.="" iii.="" acute="" dietary="" exposure="" and="" risk--="" infants="" and="" children.="" an="" acute="" dietary="" dose="" and="" endpoint="" was="" not="" identified.="" thus,="" the="" risk="" from="" acute="" aggregate="" exposure="" is="" considered="" to="" be="" negligible.="" non-dietary="" exposure="" and="" aggregate="" risk="" --="" infants="" and="" children:="" acute,="" short="" term,="" and="" intermediate="" term="" dermal="" and="" inhalation="" risk="" assessments="" for="" residential="" exposure="" are="" not="" required="" due="" to="" the="" lack="" of="" significant="" toxicological="" effects="" observed.="" f.="" international="" tolerances="" pyriproxyfen="" is="" a="" new="" compound="" scheduled="" for="" toxicological="" and="" residue="" evaluations="" at="" the="" 1999="" jmpr.="" therefore,="" there="" are="" no="" presently="" existing="" codex="" mrls="" for="" pyriproxyfen.="" [fr="" doc.="" 98-26782="" filed="" 10-5-98;="" 8:45="" am]="" billing="" code="" 6560-50-f="">