[Federal Register Volume 64, Number 32 (Thursday, February 18, 1999)]
[Notices]
[Pages 8102-8105]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-4024]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-861; FRL-6061-4]
Novartis Crop Protection; Pesticide Tolerance Petition Filing
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces the initial filing of a pesticide
petition proposing the establishment of regulations for residues of a
certain pesticide chemical in or on various food commodities.
[[Page 8103]]
DATES: Comments, identified by the docket control number PF-861, must
be received on or before March 22, 1999.
ADDRESSES: By mail submit written comments to: Information and Records
Integrity Branch, Public Information and Services Divison (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 by following
the instructions under ``SUPPLEMENTARY INFORMATION.'' No confidential
business information should be submitted through e-mail.
Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment that does not contain CBI must be submitted
for inclusion in the public record. Information not marked confidential
may be disclosed publicly by EPA without prior notice. All written
comments will be available for public inspection in Rm. 119 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: Cynthia Giles-Parker, Registration
Support Branch, Registration Division (7505W), Office of Pesticide
Programs, Environmental Protection Agency, 401 M St., SW, Washington,
DC 20460. Office location, telephone number, and e-mail address: Rm.
247, Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA
22202, (703) 305-7740; e-mail: giles-parker.cynthia@epamail.epa.gov.
SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition as
follows proposing the establishment and/or amendment of regulations for
residues of certain pesticide chemical 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 this petition
contains 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-861] (including comments and data submitted
electronically as described below). A public version of this record,
including printed, paper versions of electronic comments, which does
not include any information claimed as CBI, is available for inspection
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal
holidays. The official record is located at the address in
``ADDRESSES'' at the beginning of this document.
Electronic comments can be sent directly to EPA at:
opp-docket@epamail.epa.gov
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comment and data
will also be accepted on disks in Wordperfect 5.1/6.1 file format or
ASCII file format. All comments and data in electronic form must be
identified by the docket control number (PF-861) and appropriate
petition number. Electronic comments on this 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: February 9, 1999.
James Jones,
Director, Registration Division, Office of Pesticide Programs.
Summary of Petition
The petitioner summary of the pesticide petition is printed below
as required by section 408(d)(3) of the FFDCA. The summary of the
petition was prepared by the petitioner and represents the views of the
petitioner. 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.
Novartis Crop Protection
8F4974
EPA has received a pesticide petition (8F4974) from Novartis Crop
Protection, P.O. Box 18300, Greensboro, NC 27419 proposing, pursuant to
section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21
U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance
for residues of 1,2,3-Benzothiadiazole-7-carbothioic acid S-methyl
ester in or on the raw agricultural commodities leafy vegetables crop
group (excluding spinach), spinach, and fruiting vegetables at 0.25,
1.0, and 1.0 parts per million (ppm), respectively. 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. Novartis believes the metabolism of
acibenzolar-S-methyl has been well characterized. Only 4.6% and 14.9%
of the total radioactive residue (TRR) was non-extractable in lettuce
at the recommended application rate and three times the recommended
application rate, respectively. Non-extractables were also low in a
tomato metabolism study; 3.4% and 7.4% in tomatoes and foliage,
respectively. The metabolism in these crops proceeded via hydrolysis of
benzo [1,2,3] thiadiazole-7-carbothioic acid S-methyl ester to benzo
[1,2,3] thiadiazole-7-carboxylic acid (BTCA), followed by conjugation
as ester, glycoside and/or other plant constituents. The metabolism
profile supports the use of an analytical enforcement method that
accounts for acibenzolar-S-methyl and metabolites containing the benzo
[1,2,3] thiadiazole-7-carboxylic acid (BTCA) moiety.
2. Analytical method. Novartis Analytical Method AG-671A is a
practical and valid method for the determination and confirmation of
CGA-245704 in raw agricultural commodities (RAC) and processing
substrates from the tobacco, leafy and fruiting vegetable crop groups
at a limit of quantitation (LOQ) of 0.02 ppm. The method involves
extraction, solid phase cleanup of samples with analysis by high
performance liquid chromotography (HPLC) with ultraviolet (UV)
detection or confirmatory LC/MS. The validity is demonstrated by the
acceptable accuracy and precision obtained on numerous procedural
recovery samples (radiovalidation and field trial sample sets), and by
the extractability and accountability obtained by the analysis
[[Page 8104]]
of weathered radioactive substrates using Analytical Method AG-671A.
3. Magnitude of residues. This petition is supported by forty-four
field trials conducted on representative members of the Fruiting
Vegetable and the Leafy Vegetable Crop Groupings. All samples were
analyzed for by the total residue method (AG-671A) to determine the
combined residues of acibenzolar-S-methyl and metabolites which contain
the benzo [1,2,3] thiadiazole-7-carboxylic acid (BTCA) moiety. In
fruiting vegetables, the residues found for tomatoes, bell peppers, and
non-bell peppers ranged from 0.06 ppm to 0.61 ppm, from 0.16 ppm to
0.74 ppm, and from 0.26 ppm 0.68 ppm, respectively. Residues did not
concentrate in tomato puree (0.55 ppm). Residues did not concentrate
significantly in tomato paste (1.33 ppm); dilution-corrected residue
does not exceed the assumed tolerance for the RAC. A tolerance of 1.0
ppm for the fruiting vegetable crop group has been requested. In leafy
vegetables, the maximum residues found on representative commodities
were 0.09 ppm, 0.11 ppm, 0.20 ppm, and 0.69 ppm for celery, head
lettuce, leaf lettuce, and spinach, respectively. A tolerance of 0.25
ppm has been proposed for the Leafy Vegetable Crop Grouping (excluding
spinach). A tolerance of 1.0 ppm has been proposed for spinach.
B. Toxicological Profile
1. Acute toxicity. The risk from acute dietary exposure to
acibenzolar-S-methyl is considered to be very low. CGA-245704 and the
formulated 50 WG product have low orders of acute toxicity by the oral,
dermal and inhalation exposure routes. Results from acute studies all
fall within toxicity rating categories of III or IV. CGA-245704
technical has a low order of acute toxicity, is only slightly
irritating to skin and eyes, but may cause sensitization by skin
contact. An LD50 of greater than 5,000 milligram/kilogram
(mg/kg) was observed for the acute oral toxicity study in rats. The
lowest no-observed-adverse-effect level (NOAEL) in a short term
exposure scenario, identified as 50 mg/kg in the rabbit and rat
teratology studies, is 10-fold higher than the chronic NOAEL. Based on
worst case assumptions, the chronic exposure assessments (see below)
did not result in any margin of exposure (MOE) less than 3,330 for even
the most impacted population subgroup, Novartis believes the MOE is
greater than 100 for any population subgroups; EPA considers MOEs of
100 or more as satisfactory. The following are results from the acute
toxicity tests conducted on the technical material:
i. Rat oral LD50: > 5,000 mg/kg/bwt. (M/F) Tox. Category
IV
ii. Rat dermal LD50: > 2,000 mg/kg/bwt. (M/F) Tox.
Category III
iii. Acute Inhalation LC50: > 5,000 mg/L (M/F) Tox.
Category IV
iv. Rabbit Eye Irritation: Minimally irritating -- Tox. Category
III
v. Rabbit dermal irritation: Slightly irritating -- Tox. Category
IV
vi. Dermal Sensitization: Sensitizer
2. Genotoxicty. CGA-245704 technical was not mutagenic or
clastogenic and did not provoke unscheduled DNA synthesis when tested
thoroughly in a battery of standard in vivo, and in vitro independent
assays, using both eukaryotes and prokaryotes, and with or without
metabolic activation. These tests are summarized below:
i. Microbial/Microsome Mutagenicity Assay: Non-mutagenic
ii. Mammalian Cell CHO Mutagenicity Assay: Non-mutagenic; Non-
clastogenic
iii. CH Bone marrow: Non-clastogenic; negative for chromosome
aberrations
iv. Mouse Micronucleus Test: Non-clastogenic ; negative for
chromosome aberrations
v. DNA Damage and Repair Rat hepatocyte: Negative]
3. Reproductive and developmental toxicity. Acibenzolar-S-methyl is
not a teratogenic hazard except at, or close to, the maximum tolerated
dose. In the rat multigeneration study, CGA-245704 (acibenzolar-S-
methyl) technical had no effect on rat reproductive parameters
including gonadal function, estrus cycles, mating behavior, conception,
parturition, lactation, weaning, and sex organ histopathology. At 4,000
ppm, parental body weights (bwt) were reduced. This demonstrated by the
results of the following studies:
i. Rat oral teratology - Maternal NOAEL of 200 mg/kg based on
embryotoxicity and teratogenic effects; Fetal NOAEL of 50 mg/kg.
ii. Rabbit oral teratology study - Maternal NOAEL of 50 mg/kg based
on maternal toxicity and slightly delayed ossification; Fetal NOAEL of
300 mg/kg based on changes in bwt.
iii. Rat 2-generation reproduction study - NOAEL of 25 mg/kg based
on weight development in adults at 4,000 ppm and pups during lactation
at 2,000 ppm and above. No adverse effects on reproduction or
fertility.
4. Subchronic toxicity. No signs of neurotoxicity were noted with
CGA-245704 in both acute and subchronic studies even at the highest
dose levels of 800 mg/kg and 8,000 ppm, respectively. The evaluated
parameters included functional observation battery, motor activity
measurement and neurohistopathologic assessment. These tests are
summarized below:
i. Rat 28-day dermal study - NOAEL of 1,000 mg/kg/day
ii. Dog 90-day feeding study - NOAEL of 10 mg based on reduced bwt
gain at 50 mg/kg/day
iii. Mouse 90-day feeding - NOAEL of < 30="" mg/kg="" based="" on="" reduced="" bwt="" development="" at="" 1,000="" ppm="" and="" above="" iv.="" rat="" 90-day="" feeding="" study="" -="" noael="" of="" 25="" mg/kg="" based="" on="" inappetence="" and="" reduced="" bwt="" development="" at="" higher="" dose="" levels="" (4,000,="" and="" 8,000="" ppm).="" 5.="" chronic="" toxicity.="" based="" on="" the="" available="" chronic="" toxicity="" data,="" novartis="" crop="" protection,="" inc.="" believes="" the="" reference="" dose="" (rfd)="" for="" acibenzolar-s-methyl="" is="" 0.05="" mg/kg/day.="" acibenzolar-s-methyl="" is="" not="" oncogenic="" in="" rats="" or="" mice="" and="" is="" not="" likely="" to="" be="" carcinogenic="" in="" humans.="" no="" carcinogenic="" activity="" was="" detected="" in="" mice="" and="" rats="" at="" the="" maximum="" tolerated="" dose="" (mtd).="" there="" was="" no="" evidence="" of="" carcinogenicity="" in="" an="" 18-month="" feeding="" study="" in="" mice="" and="" a="" 24="" month="" feeding="" study="" in="" rats.="" dosage="" levels="" in="" both="" the="" mouse="" and="" the="" rat="" studies="" were="" adequate="" for="" identifying="" a="" cancer="" risk.="" novartis="" believes="" acibenzolar-s-methyl="" should="" be="" classified="" as="" a="" ``not="" likely''="" carcinogen="" based="" on="" the="" lack="" of="" carcinogenicity="" in="" rats="" and="" mice.="" 6.="" animal="" metabolism.="" metabolism="" proceeded="" primarily="" via="" hydrolysis="" to="" form="" the="" corresponding="" carboxylic="" acid="" (btca)="" which="" was="" subsequently="" conjugated="" with="" several="" amino="" acids="" including="" glycine,="" lysine="" and="" ornithine.="" elimination="" was="" rapid="" in="" all="" cases.="" oxidation="" of="" the="" aromatic="" ring="" of="" the="" acid="" was="" a="" very="" minor="" pathway="" observed="" in="" goats.="" the="" metabolic="" fate="" of="" cga-245704="" in="" plants="" paralleled="" that="" observed="" in="" animals.="" the="" major="" metabolite="" in="" all="" test="" systems="" was="" the="" same="" hydrolysis="" product="" btca.="" thus,="" the="" metabolism="" profile="" supports="" the="" use="" of="" an="" analytical="" enforcement="" method="" that="" accounts="" principally="" for="" parent="" and="" btca.="" 7.="" metabolite="" toxicology.="" in="" short-term="" toxicity="" studies="" in="" rats,="" cga-210007="" was="" found="" to="" be="" of,="" at="" most,="" equal="" or="" less="" toxicity="" than="" the="" parent="" compound.="" as="" with="" parent="" cga-245704,="" the="" subchronic="" noael="" for="" cga-210007="" was="" 100="" mg/kg="" bwt.="" 8.="" endocrine="" disruption.="" acibenzolar-s-methyl="" does="" not="" belong="" to="" a="" class="" of="" chemicals="" known="" or="" suspected="" of="" having="" adverse="" effects="" on="" the="" endocrine="" system.="" developmental="" toxicity="" studies="" in="" rats="" and="" rabbits="" and="" a="" reproduction="" study="" in="" rats="" gave="" no="" indication="" that="" acibenzolar-s-="" methyl="" might="" have="" any="" effects="" on="" endocrine="" function="" related="" to="" [[page="" 8105]]="" development="" and="" reproduction.="" acibenzolar-s-methyl="" is="" not="" a="" teratogenic="" hazard="" except="" at,="" or="" close="" to,="" the="" maximum="" tolerated="" dose.="" the="" chronic="" studies="" also="" showed="" no="" evidence="" of="" a="" long-term="" effect="" related="" to="" the="" endocrine="" system.="" c.="" aggregate="" exposure="" 1.="" dietary="" exposure--i.="" food.="" for="" the="" purposes="" of="" assessing="" the="" potential="" dietary="" exposure="" under="" the="" proposed="" tolerances,="" novartis="" has="" estimated="" aggregate="" exposure="" based="" upon="" the="" theoretical="" maximum="" residue="" concentration="" (tmrc)="" from="" the="" requested="" tolerances="" for="" the="" raw="" agricultural="" commodities:="" leafy="" vegetables="" (excluding="" spinach)="" at="" 0.25="" ppm;="" spinach="" at="" 1.0="" ppm;="" and="" fruiting="" vegetables="" at="" 1.0="" ppm.="" the="" tmrc="" is="" a="" ``worst="" case''="" estimate="" of="" dietary="" exposure="" since="" it="" assumes="" 100%="" of="" all="" crops="" for="" which="" tolerances="" are="" established="" are="" treated="" and="" that="" pesticide="" residues="" are="" at="" the="" tolerance="" levels.="" in="" conducting="" this="" exposure="" assessment,="" novartis="" has="" made="" very="" conservative="" assumptions="" --="" 100%="" of="" all="" leafy="" vegetable="" and="" spinach,="" and="" fruiting="" vegetable="" commodities="" will="" contain="" acibenzolar-s-methyl="" residues="" at="" tolerance="" levels="" --="" which="" result="" in="" an="" overestimate="" of="" human="" exposure.="" the="" rfd="" of="" 0.05="" mg/kg/day="" is="" based="" on="" a="" 1-year="" feeding="" study="" in="" dogs="" with="" a="" noael="" of="" 5="" mg/kg/day="" and="" an="" uncertainty="" factor="" of="" 100.="" no="" additional="" modifying="" factor="" for="" the="" nature="" of="" effects="" was="" judged="" to="" be="" necessary="" as="" weight="" changes="" were="" the="" most="" sensitive="" indicators="" of="" toxicity="" in="" that="" study.="" ii.="" drinking="" water.="" acibenzolar-s-methyl="" is="" rapidly="" degraded="" in="" the="" environment="" via="" photolysis="" and="" microbial="" degradation;="" aqueous="" and="" soil="" photolysis="" irradiated="" half-lives="" for="" acibenzolar-s-methyl="" are="" 0.6="" hours="" and="" 24="" hours,="" respectively.="" the="" aerobic="" metabolism="" half-life="" is="" 5.3="" hours.="" anaerobic="" aquatic="" metabolism="" half-lives="" are="" 4="" days="" and="" 96="" days="" for="" primary="" and="" secondary="" half-life,="" respectively.="" the="" leaching="" potential="" for="" acibenzolar-s-methyl="" is="" low="" (koc="492-3288)." dietary="" exposure="" to="" acibenzolar-s-methyl="" from="" water="" intake="" for="" the="" most="" sensitive="" subpopulation="" of="" children="" (1-6="" years="" old),="" was="" calculated="" to="" be="">< 0.01%="" of="" the="" rfd,="" based="" on="" the="" geneec="" model.="" based="" on="" these="" data,="" novartis="" does="" not="" anticipate="" exposure="" to="" residue="" of="" acibenzolar-s-="" methyl="" in="" drinking="" water.="" 2.="" non-dietary="" exposure.="" novartis="" believes="" that="" the="" potential="" for="" non-occupational="" exposure="" to="" the="" general="" public="" is="" unlikely="" except="" for="" potential="" residues="" in="" food="" crops="" discussed="" above.="" the="" proposed="" uses="" for="" acibenzolar-s-methyl="" are="" for="" agricultural="" crops="" and="" the="" product="" is="" not="" used="" residentially="" in="" or="" around="" the="" home.="" d.="" cumulative="" effects="" novartis="" believes="" that="" consideration="" of="" a="" common="" mechanism="" of="" toxicity="" is="" not="" appropriate="" at="" this="" time="" since="" there="" is="" no="" information="" to="" indicate="" that="" toxic="" effects="" produced="" by="" acibenzolar-s-methyl="" would="" be="" cumulative="" with="" those="" of="" any="" other="" chemicals.="" acibenzolar-s-methyl="" is="" a="" plant="" activator="" and="" no="" other="" compounds="" in="" this="" class="" are="" registered="" in="" the="" united="" states.="" consequently,="" novartis="" is="" considering="" only="" the="" potential="" exposure="" to="" acibenzolar-s-methyl="" in="" its="" aggregate="" risk="" assessment.="" e.="" safety="" determination="" 1.="" u.s.="" population.="" using="" the="" conservative="" exposure="" assumptions="" described="" above="" and="" based="" on="" the="" completeness="" and="" reliability="" of="" the="" toxicity="" data="" base="" for="" acibenzolar-s-methyl,="" novartis="" has="" calculated="" aggregate="" exposure="" levels="" for="" this="" chemical.="" based="" on="" chronic="" toxicity="" endpoints,="" only="" 1.8%="" of="" the="" rfd="" will="" be="" utilized="" for="" the="" u.s.="" general="" population.="" dietary="" exposure="" to="" acibenzolar-s-methyl="" from="" water="" intake="" for="" the="" most="" sensitive="" subpopulation="" of="" children="" (1-6="" years="" old),="" was="" calculated="" to="" be="">< 0.01%="" of="" the="" rfd,="" based="" on="" the="" geneec="" model.="" epa="" usually="" 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.="" novartis="" concludes="" that="" there="" is="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" from="" aggregate="" exposure="" to="" acibenzolar-s-methyl="" residues.="" 2.="" infants="" and="" children.="" embryotoxicity="" and="" fetotoxicity="" were="" apparent="" at="" maternally="" toxic="" doses="" of="" cga-245704="" technical="" in="" rats="" and="" rabbits.="" the="" lowest="" noael="" for="" this="" effect="" was="" established="" in="" the="" 2-="" generation="" reproduction="" study="" at="" 25="" mg/kg="" (200="" ppm).="" using="" the="" same="" conservative="" exposure="" assumptions="" as="" employed="" for="" the="" determination="" in="" the="" general="" population,="" novartis="" has="" calculated="" the="" utilization="" of="" rfd="" by="" aggregate="" exposure="" to="" residues="" of="" acibenzolar-s-methyl="" to="" be="" 0.4%="" for="" nursing="" infants="" less="" than="" 1="" year="" old,="" 1.5%="" for="" non-nursing="" infants="" less="" than="" 1="" year="" old,="" 3.2%="" for="" children="" 1-6="" years="" old,="" and="" 2.5%="" for="" children="" 7-12="" years="" old.="" dietary="" exposure="" to="" acibenzolar-s-methyl="" from="" water="" intake="" for="" the="" most="" sensitive="" subpopulation="" of="" children="" (1-6="" years="" old),="" was="" calculated="" to="" be="">< 0.01%="" of="" the="" rfd,="" based="" on="" the="" geneec="" model.="" novartis="" believes="" that="" under="" the="" worst="" case="" assumptions="" which="" overestimate="" exposure="" to="" infants="" and="" children,="" there="" is="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" to="" infants="" and="" children="" from="" aggregate="" exposure="" to="" acibenzolar-="" s-methyl="" residues.="" additionally,="" cga-245704="" is="" not="" a="" reproductive="" toxin.="" some="" signs="" of="" teratogenicity="" were="" found="" at,="" or="" close="" to,="" maternally="" toxic="" doses.="" no="" neurotoxic="" effects="" or="" oncogenic="" activity="" has="" been="" observed="" with="" cga-="" 245704.="" from="" these="" available="" toxicology="" data,="" no="" special="" susceptibility="" of="" infants="" or="" children="" is="" anticipated.="" f.="" international="" tolerances="" codex="" maximum="" residue="" levels="" (mrl's)="" have="" not="" been="" established="" for="" residues="" of="" cga-245704="" in="" or="" on="" raw="" agricultural="" commodities="" from="" the="" fruiting="" vegetable="" and="" leafy="" vegetable="" crop="" groups.="" maximum="" residue="" levels="" of="" 0.1="" ppm="" have="" been="" established="" for="" cga-245704="" on="" wheat="" in="" switzerland="" and="" hungary.="" proposed="" codex="" mrls="" of="" 1.0="" ppm="" on="" tomatoes="" and="" 0.1="" ppm="" on="" bananas,="" cereals,="" wheat,="" spring="" barley,="" and="" rice="" have="" been="" proposed.="" [fr="" doc.="" 99-4024="" filed="" 2-17-99;="" 8:45="" am]="" billing="" code="" 6560-50-f="">