[Federal Register Volume 62, Number 71 (Monday, April 14, 1997)]
[Notices]
[Pages 18116-18122]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-9582]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-730; FRL-5599-7]
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 agricultural commodities.
DATES: Comments, identified by the docket control number PF-730, must
be received on or before May 14, 1997.
ADDRESSES: By mail submit written comments to: Public Response and
Program Resources Branch, Field Operations Divison (7505C), Office of
Pesticides Programs, Environmental Protection Agency, 401 M St., SW.,
Washington, DC 20460. In person bring comments to: Rm. 1132, CM #2,
1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically by following
the instructions under ``SUPPLEMENTARY INFORMATION.'' No confidential
business information should be submitted through e-mail.
Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment that does not contain CBI must be submitted
for inclusion in the public record. Information not marked confidential
may be disclosed publicly by EPA without prior notice. All written
comments will be available for public inspection in Rm. 1132 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: By mail: Joanne Miller, PM-23,
Registration Division (7505C), Office of Pesticide Programs,
Environmental Protection Agency, 401 M St., SW., Washington, DC 20460.
Office location and telephone number: Rm. 237, Crystal Mall #2, 1921
Jefferson Davis Highway, Arlington, VA 22202, (703) 305-6224; e-mail:
miller.joanne@epamail.epa.gov.
SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as
follows proposing the establishment and/or amendment of regulations for
residues
[[Page 18117]]
of certain pesticide chemicals in or on various raw agricultural
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 grantinig of
the petition. Additional data may be needed before EPA rules on the
petition.
The official record for this notice, as well as the public version,
has been established for this notice of filing under docket control
number PF-730 (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 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket control number (PF-730) and appropriate
petition number. Electronic comments on this notice may be filed online
at many Federal Depository Libraries.
Authority: 21 U.S.C. 346a.
List of Subjects
Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: April 2, 1997.
Stephen L. Johnson,
Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Below summaries of the pesticide petitions are printed. The
summaries of the petitions were prepared by the petitioners. 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. K-I Chemical, U.S.A. Inc.
PP 7F4821
EPA has received a pesticide petition (PP 7F4821) from K-I
Chemical, U.S.A. Inc., 11 Martine Avenue, 9th Floor, White Plains, New
York 10606, proposing pursuant to section 408(d) of the Federal Food,
Drug and Cosmetic Act (FFDCA), 21 U.S.C 346a, 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 commodites field corn grain and
sweet corn grain (K + CWHR) at 0.02 ppm and corn forage and fodder at
0.05 ppm. The proposed analytical method is gas chromatography using a
nitrogen phosphorus detector and a large-bore fused silica column.
A. Fluthiacet-methyl uses:
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, is a new herbicide active
ingredient in the imide chemistry class. A petition for tolerance for
fluthiacet-methyl in soybeans (Pesticide Petition Number 6F04614)
submitted by Novartis Crop Protection, Inc. is pending EPA review. K-I,
Chemical, U.S.A. has submitted a petition for tolerance in corn.
Fluthiacet-methyl will be formulated as a 4.75% wettable powder,
packaged in water-soluble bags, and sold under the trade name Action
herbicide. Action is a highly selective herbicide for use in soybeans
and corn postemergence, and is particularly effective in controlling
velvetleaf. Control of other broadleaf weeds in corn and soybeans is
enhanced and the spectrum of control is broadened when Action is tank
mixed with other postemergence herbicides registered for use in these
crops.
Action offers effective weed control at extremely low use rates.
The maximum use rate per season is 0.0089 lb. active ingredient (3 oz.
of formulated product) per acre consisting of a maximum of two
applications. There is a wide application window extending in corn from
the 2-leaf stage (leaves fully expanded with collars exposed) to 48
inches tall or prior to tasseling, whichever comes first, and the
amount of Action to apply depends on the weed species and weed height.
Tank mixing Action with other postemergence herbicides further reduces
the amount required to control target weeds.
The purpose of this petition is to establish a tolerance for
fluthiacet-methyl in field and sweet corn. The tolerance proposed in
section 408(d)(2)(A)(vii) is:
------------------------------------------------------------------------
Comodity Part per million (ppm)
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corn, sweet - grain (k + CWHR) 0.02 ppm
corn, field - grain 0.02 ppm
corn - forage and fodder 0.05 ppm
------------------------------------------------------------------------
B. Fluthiacet-methyl Safety
In support of the pending petition for tolerance in soybeans, and
hereby referenced by K-I Chemical, Novartis Crop Protection (Ciba)
submitted a full battery of toxicology studies including, acute
effects, chronic feeding, oncogenicity, teratogenicity, mutagenicity,
and reproductive toxicity tests. The studies indicate that fluthiacet-
methyl has a low order of acute toxicity with acute effects in
catgegory III and IV, is not neurotoxic, does not pose a genotoxicity
hazard, and is not a reproductive toxicant or a teratogen.
Potential exposure to fluthiacet-methyl via the diet or drinking
water and through handling is very limited. Because of rapid
environmental degradation, extremely low residues in food crops, and
water-soluble packaging, considerable margins of safety exist for
dietary exposure for all subgroups of the population and for worker
exposure as well.
The following mammalian toxicity studies have been conducted to
support the proposed tolerance for fluthiacet-methyl:
A rat acute oral study with an LD50 > 5,000 mg/kg.
A rabbit acute dermal study with an LD50 > 2,000 mg/kg.
A rat inhalation study with an LC50 > 5.05 mg/liter.
A primary eye irritation study in the rabbit showing moderate eye
irritation.
A primary dermal irritation study in the rabbit showing no skin
irritation.
A primary dermal sensitization study in the Guinea pig showing no
sensitization.
28-day dermal toxicity study in rats with a NOEL equal to or higher
than the limit dose of 1,000 mg/kg.
6-Week dietary toxicity study in dogs with a NOEL of 162 mg/kg/day
in males
[[Page 18118]]
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 NOEL of 6.2
mg/kg/day based on liver changes and hematological effects.
24-month combined chronic toxicity/carcinogenicity study in rats
with a NOEL of 2.1 mg/kg/day. Based on reduced body weight 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 NOEL 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.
Teratology study in rats with a maternal and developmental NOEL
equal to or greater than 1,000 mg/kg/day.
Teratology study in rabbits with a maternal NOEL greater than or
equal to 1,000 mg/kg/day and a fetal NOEL of 300 mg/kg based on a
slight delay in fetal maturation.
2-generation reproduction study in rats with a NOEL 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.
Acute neurotoxicity study in rats. Neurotoxic effects were not
observed. The NOEL was 2,000 mg/kg.
90-day subchronic neurotoxicity study in rats. The NOEL was 0.5 mg/
kg/day based on reduced body weight gain. No clinical or morphological
signs of neurotoxicity were detected at any dose level.
In vitro gene mutation tests: Ames test - negative; Chinese hamster
V79 test - negative; rat hepatocyte DNA repair test - negative; E. Coli
letal DNA damage test - negative.
In vitro chromosomal aberration tests: Chinese hamster ovary -
positive at cytotoxic doses; Chinese hamster lung - positive at
cytotoxic doses; human lymphocyes - positive at cytotoxic doses.
In vivo chromosome aberration tests: Micronucleus assays in rat
liver - negative; mouse bone marrow test - negative.
1. Threshold effects. Using the Guidelines for Carcinogenic Risk
Assessment published September 24, 1986 (51 FR 33992), K-I Chemical
believes the Agency will classify fluthiacet-methyl as a Group ``C''
carcinogen (possible human carcinogen) based on findings of benign and
malignant liver tumors in male mice. These tumors most likely resulted
from a chronic regenerative and proliferative response of the affected
epithelial cells. This response is a non-genotoxic, threshold effect
which is due to the accumulation of cytotoxic porphyrins. A positive
trend of proliferative pancreatic changes in male rats is likely
attributable to the increased survival of the rats in the high dose
groups. The lesions observed are not uncommon in the rat strain used.
Because the effects observed are threshold effects, K-I Chemical
believes that exposure to fluthiacet-methyl should be regulated using a
margin of exposure approach. The RfD for fluthiacet-methyl can be
defined at 0.0014 milligrams (mg)/kilogram(kg)/day based on an 18-month
feeding study in mice with a No-Observed Effect Level (NOEL) of 0.14
mg/kg/day and an uncertainty factor of 100.
2. Non-threshold effects. Based on the results of an extensive
program of genotoxicity studies, fluthiacet-methyl is not mutagenic in
vivo. As outlined above, effects observed in toxicology studies are
attributable to an epigenetic, cytotoxic mechanism, resulting in
degenerative and inflammatory changes in the target organs. It is
therefore justified that exposure to fluthiacet-methyl should be
regulated using a margin of exposure approach.
3. Aggregate exposure. In this assessment, K-I 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 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 RfD.
Other potential sources of exposure of the general population to
residues of pesticides are residues in 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 riskof exposure to fluthiacet-
methyl does not include drinking water.
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.
K-I Chemical also considered the potential for cumulative effects
of fluthiacet-methyl and other substances. However, 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.
Thus K-I Chemical is considering only the potential risk of fluthiacet-
methyl in its aggregate exposure assessment.
4. Safety to the U.S. population. Using the very conservative
exposure assumptions described above coupled with toxicity data for
fluthiacet-methyl, K-I Chemical calculated that aggregate, chronic
exposure to fluthiacet-methyl will utilize no more than 2.3% of the RfD
for the U.S. population. Because the actual anticipated residues are
well below tolerance levels and the percent crop treated with
fluthiacet-methyl is expected to be less than 25% of planted corn or
soybeans, a more realistic estimate is that dietary exposure will
likely be at least 20 times less than the conservative estimate
previously noted (the margins of exposure will be accordingly higher).
Exposures below 100 percent of the RfD are generally not of concern
because the RfD represents the level at or below which daily aggregate
dietary exposure over a
[[Page 18119]]
lifetime will not pose appreciable risks to human health.
Also the acute dietary risk to consumers will be far below any
significant level; the lowest NOEL from a short term exposure scenario
comes from the teratology study in rabbits with a NOEL of 300 mg/kg.
This NOEL is 2,000-fold higher than the chronic NOEL 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 margins
of exposure of at least one million for 99.9% of the general population
and for women of child bearing age. Margins of exposure of 100 or more
are generally considered satisfactory.
Therefore, K-I Chemical concludes that there is a reasonable
certainty that no harm will result from aggregate exposure to
fluthiacet-methyl residues.
5. Safety to infants and children. In assessing the potential for
additional sensitivity of infants and children to residues of
fluthiacet-methyl, K-I 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 NOEL was 500 ppm for maternal animals and
their offspring, which is 50,000 fold higher than the RfD.
Reference dose. Using the same conservative exposure assumptions as
was used for the general population, the percent of the RfD that will
be utilized by aggregate exposure to residues of fluthiacet-methyl is
as follows: 1.5% for nursing infants less than 1 year old, 5.9% for
non-nursing infants, and 5.2% for children 1-6 years old. K-I Chemical
concludes that there is a reasonable certainty that no harm will result
to infants and children from aggregate exposure to residues of
fluthiacet-methyl.
6. Estrogenic effects. 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.
7. Chemical residue. There are no Codex maximum residue levels
established for residues of fluthiacet-methyl on corn. The nature of
the residues in corn and animals (goat and hen) is adequately
understood following application of fluthiacet-methyl. Residues do not
concentrate in processed commodities. 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 and corn
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 and corn 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 HPLC with 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. EPA can provide information on
these methods to FDA. The methods will be available to anyone who is
interested in pesticide residue enforcement from the Field Operations
Division, EPA Office of Pesticide Programs.
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. Residues of fluthiacet-methyl in treated corn grain and ears were
less than the method LOQ (<0.01 ppm).="" residues="" in="" forage="" after="" the="" day="" of="" application="" were="" less="" than="" the="" proposed="" tolerance="" of="" 0.05="" ppm.="" the="" proposed="" tolerances="" of="" 0.02="" ppm="" in="" grain="" and="" 0.05="" ppm="" in="" forage="" and="" fodder="" are="" adequate="" to="" cover="" residues="" likely="" to="" occur="" when="" action="" herbicide="" is="" applied="" to="" corn="" as="" directed.="" a="" feeding="" study="" in="" cattle="" has="" been="" submitted="" and="" tolerances="" for="" residues="" of="" fluthiacet-methyl="" in="" meat="" and="" milk="" will="" not="" be="" requested.="" 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.="" in="" studies="" with="" processed="" corn="" fractions,="" no="" concentration="" of="" fluthiacet-methyl="" was="" observed="" and="" tolerances="" in="" processed="" commodities="" will="" not="" be="" required.="" in="" addition,="" confined="" rotational="" crop="" studies="" indicated="" that="" fluthiacet-methyl="" will="" not="" be="" taken="" up="" by="" rotational="" crops.="" analytical="" method="" ag-603b="" has="" been="" submitted="" for="" analysis="" of="" residues="" of="" fluthiacet-methyl="" in="" soybeans="" and="" in="" corn="" and="" its="" processed="" fractions.="" this="" method="" can="" be="" provided="" to="" the="" fda.="" residue="" levels="" of="" fluthiacet-methyl="" are="" determined="" by="" gas="" chromatography="" and="" the="" limit="" of="" detection="" for="" the="" method="" is="" 0.01="" ppm.="" 8.="" environmental="" fate.="" action="" degraded="" rapidly="" under="" laboratory="" and="" field="" conditions.="" laboratory="" hydrolysis="" under="" basic="" conditions="" was="" t1/2="" 5="" hours="" at="" ph="" 9="" and="" stable="" under="" acidic="" conditions="" (t1/2="" 485="" days="" at="" ph="" 5).="" the="" soil="" metabolism="" half-life="" was="" extremely="" short,="" ranging="" from="" 1.1="" days="" under="" aerobic="" conditions="" to="" 1.6="" days="" under="" anaerobic="" conditions.="" photodegradation="" was="" rapid="" in="" soil="" (t1/2="" 0.5="" days)="" and="" moderate="" in="" solution="" at="" ph="" 5="" (5="" days).="" because="" of="" the="" extremely="" low="" use="" rate="" and="" very="" short="" half-life="" in="" the="" field,="" field="" dissipation="" experiments="" were="" conducted="" with="" radiolabeled="" chemical.="" after="" bare-ground="" application,="" the="" half-life="" of="" action="" was="" 1="" day="" in="" sandy="" loam="" and="" 1.8="" days="" in="" clay="" loam.="" all="" degradates="" identified="" in="" the="" field="" were="" also="" identified="" in="" the="" laboratory="" studies.="" parent="" and="" aged="" leaching="" laboratory="" experiments="" showed="" that="" the="" mobility="" of="" action="" ranged="" from="" slight="" to="" medium="" by="" soil="" type.="" based="" on="" estimates="" of="" relative="" mobility="" (koc),="" action="" was="" classified="" as="" having="" medium="" mobility="" in="" sand="" and="" low="" mobility="" in="" loam,="" silt="" loam="" and="" clay.="" the="" major="" degradation="" products="" of="" action="" were="" found="" to="" have="" high="" to="" low="" mobility="" classifications="" based="" on="" koc="" estimations.="" although="" the="" data="" suggest="" that="" some="" of="" the="" degradates="" are="" highly="" mobile="" a="" high="" degree="" of="" soil="" binding="" is="" expected="" based="" on="" results="" of="" the="" laboratory="" and="" the="" field="" experiments.="" since="" weeds="" and="" crop="" will="" intercept="" the="" majority="" of="" this="" product="" when="" it="" is="" applied,="" and="" given="" the="" extremely="" low="" use="" rate="" and="" high="" degree="" of="" soil="" binding,="" action="" herbicide="" is="" not="" expected="" to="" leach="" into="" groundwater.="" [[page="" 18120]]="" 2.="" novartis="" crop="" protection="" pp="" 6f4751="" epa="" has="" received="" a="" pesticide="" petition="" (pp="" 6f4751)="" from="" novartis="" crop="" protection,="" inc.,="" p.="" o.="" box="" 18300,="" greensboro,="" north="" carolina="" 27419,="" proposing="" pursuant="" to="" section="" 408(d)="" of="" the="" federal="" food,="" drug="" and="" cosmetic="" act,="" 21="" u.s.c.="" 346a(d),="" to="" amend="" 40="" cfr="" 180.368="" by="" establishing="" a="" tolerance="" for="" residues="" of="" the="" herbicide="" metolachlor="" in="" or="" on="" the="" raw="" agricultural="" commodity="" tomatoes="" at="" 0.1="" ppm.="" the="" proposed="" analytical="" method="" is="" available="" for="" enforcement="" purposes.="" pursuant="" to="" section="" 408(d)(2)(a)(i)="" of="" the="" ffdca,="" as="" amended,="" novartis="" crop="" protection="" has="" submitted="" the="" following="" summary="" of="" information,="" data="" and="" arguments="" in="" support="" of="" their="" pesticide="" petition.="" this="" summary="" was="" prepared="" by="" novartis="" crop="" protection="" and="" epa="" has="" not="" fully="" evaluated="" the="" merits="" of="" the="" petition.="" epa="" edited="" the="" summary="" to="" clarify="" that="" the="" conclusions="" and="" arguments="" were="" the="" petitioners="" and="" not="" necessarily="" epa's="" and="" to="" remove="" certain="" extraneous="" material.="" a.="" metolachlor="" uses="" metolachlor="" is="" a="" chloroacetanilide="" herbicide="" registered="" primarily="" for="" grass="" control="" on="" a="" wide="" variety="" of="" crops.="" it="" is="" proposed="" for="" use="" on="" tomatoes="" at="" a="" maximum="" rate="" of="" 3="" lbs.="" active="" ingredient="" per="" acre="" depending="" on="" soil="" texture="" and="" organic="" matter="" content.="" one="" application="" may="" be="" made="" preplant="" incorporated,="" preplant="" before="" transplanting,="" post-="" directed="" or="" post-over-the-top.="" a="" 90-day="" preharvest="" interval="" is="" to="" be="" observed.="" b.="" metabolism="" and="" analytical="" method="" 1.="" metabolism.="" the="" qualitative="" nature="" of="" the="" metabolism="" of="" metolachlor="" in="" plants="" and="" animals="" is="" well="" understood.="" metabolism="" in="" plants="" involves="" conjugation="" of="" the="" chloroacetyl="" side="" chain="" with="" glutathione,="" with="" subsequent="" conversion="" to="" the="" cysteine="" and="" thiolactic="" acid="" conjugates.="" oxidation="" to="" the="" corresponding="" sulfoxide="" derivatives="" occurs="" and="" cleavage="" of="" the="" side="" chain="" ether="" group,="" followed="" by="" conjugation="" with="" glucose.="" in="" animals,="" metolachlor="" is="" rapidly="" metabolized="" and="" almost="" totally="" eliminated="" in="" the="" excreta="" of="" rats,="" goats,="" and="" poultry.="" metabolism="" in="" plants="" and="" animals="" proceeds="" through="" common="" phase="" 1="" intermediates="" and="" glutathione="" conjugation.="" 2.="" analytical="" methodology.="" novartis="" crop="" protection="" has="" submitted="" a="" practical="" analytical="" method="" involving="" extraction="" by="" acid="" reflux,="" filtration,="" partition="" and="" cleanup="" with="" analysis="" by="" gas="" chromatography="" using="" nitrogen/phosphorous="" (n/p)="" detection.="" the="" methodology="" converts="" residues="" of="" metolachlor="" into="" a="" mixture="" of="" cga-37913="" and="" cga-49751.="" the="" limit="" of="" quantitation="" (loq)="" for="" the="" method="" is="" 0.03="" ppm="" for="" cga-37913="" and="" 0.05="" ppm="" for="" cga-49751.="" c.="" magnitude="" of="" residue="" thirteen="" field="" trials="" were="" conducted="" in="" major="" tomato="" production="" areas="" across="" the="" united="" states.="" both="" tomato="" and="" its="" processed="" fractions="" were="" analyzed="" for="" residues="" of="" metolachlor,="" measured="" as="" cga-37913="" and="" cga-49751.="" one="" application="" of="" metolachlor="" at="" 3.0="" lbs.="" ai/a="" (1x)="" was="" made="" post-foliar="" to="" tomato="" transplants.="" exaggerated="" rate="" applications="" (2x,="" 3x="" and="" 5x)="" were="" also="" made.="" two="" of="" the="" 13="" trials="" were="" used="" for="" processing="" into="" tomato="" commodity="" products.="" no="" residues="" (loq="" of="" 0.08="" ppm)="" were="" found="" at="" the="" 1x="" rate="" in="" the="" rac="" tomatoes.="" in="" processed="" commodities="" at="" the="" 1x="" rate="" of="" 3.0="" lbs="" ai/a,="" residues="" of="" metolachlor="" were="" found="" below="" the="" method="" loq="" in="" tomato="" puree="" (0.4="" ppm)="" and="" above="" the="" method="" loq="" in="" dry="" pomace="" and="" tomato="" paste="" (0.16="" and="" 0.13="" ppm,="" respectively).="" because="" residues="" in="" tomato="" puree="" and="" paste="" (commodities="" listed="" in="" table="" 1="" of="" oppts="" 860.1000="" as="" processed="" commodities="" of="" tomatoes)="" are="" less="" than="" 2x="" the="" loq="" of="" 0.08="" ppm,="" tolerances="" are="" not="" required="" according="" to="" oppts="" 860.1520="" (f)(3).="" no="" transfer="" of="" residues="" to="" beef="" and="" dairy="" cattle="" or="" poultry="" is="" expected="" from="" the="" use="" of="" metolachlor="" on="" tomatoes.="" d.="" codex="" alimentarius="" commission="" (codex)="" there="" are="" no="" maximum="" residue="" levels="" (mrl's)="" established="" for="" residues="" of="" metolachlor="" in="" or="" on="" raw="" agricultural="" commodities.="" e.="" toxicological="" profile="" of="" metolachlor="" 1.="" acute="" toxicity.="" metolachlor="" has="" a="" low="" order="" of="" acute="" toxicity.="" the="" combined="" rat="" oral="">50 is 2,877 mg/kg. The acute rabbit dermal
LD50 is > 2,000 mg/kg and the rat inhalation LD50 is > 4.33
mg/L. Metolachlor is not irritating to the skin and eye. It has been
shown to be positive in guinea pigs for skin sensitization. End use
formulations of metolachlor also have a low order of acute toxicity and
cause slight skin and eye irritation.
2. Subchronic toxicity. Metolachlor was evaluated in a 21-day
dermal toxicity study in the rabbit and a 6-month dietary study in
dogs; NOELs of 100 mg/kg/day and 7.5 mg/kg/day were established in the
rabbit and dog, respectively. The liver was identified as the main
target organ.
3. Chronic toxicity. A 1-year dog study was conducted at dose
levels of 0, 3.3, 9.7, or 32.7 mg/kg/day. The Agency-determined RfD for
metolachlor is based on the 1 year dog study with a NOEL of 9.7 mg/kg/
day. The RfD for metolachlor is established at 0.1 mg/kg/day using a
100-fold uncertainty factor. A combined chronic toxicity/oncogenicity
study was also conducted in rats at dose levels of 0. 1.5, 15 or 150
mg/kg/day. The NOEL for systemic toxicity was 15 mg/kg/day.
4. Developmental/Reproduction. The developmental and teratogenic
potential of metolachlor was investigated in rats and rabbits. The
results indicate that metolachlor is not embyrotoxic or teratogenic in
either species at maternally toxic doses. The NOEL for developmental
toxicity for metolachlor was 360 mg/kg/day for both the rat and rabbit
while the NOEL for maternal toxicity was established at 120 mg/kg/day
in the rabbit and 360 mg/kg/day in the rat. A 2-generation reproduction
study was conducted with metolachlor in rats at feeding levels of 0,
30, 300 and 1,000 ppm. The reproductive NOEL of 300 ppm (equivalent to
23.5 to 26 mg/kg/day) was based upon reduced pup weights in the F1a and
F2a litters at the 1,000 ppm dose level(equivalent to 75.8 to 85.7 mg/
kg/day). The NOEL for parental toxicity was equal to or greater than
the 1,000 ppm dose level.
5. Carcinogenicity. An evaluation of the carcinogenic potential of
metolachlor was made from two sets of oncogenicity studies conducted
with metolachlor in rats and mice. Using the Guidelines for
Carcinogenic Risk Assessment published September 24, 1986 (51 FR 33992)
and the results of the November, 1994 Carcinogenic Peer Review, EPA has
classified metolachlor as a Group C carcinogen and recommended using a
Margin of Exposure (MOE) approach to quantify risk. This classification
is based upon the marginal tumor response observed in livers of female
rats treated with a high (cytotoxic) dose of metolachlor (3,000 ppm).
The two studies conducted in mice were negative for oncogenicity.
6. Genotoxicity. Assays for genotoxicity were comprised of tests
evaluating metolachlor's potential to induce point mutations
(Salmonella assay and an L5178/TK+/- mouse lymphoma assay), chromosome
aberrations (mouse micronucleus and a dominant lethal assay) and the
ability to induce either unscheduled or scheduled DNA synthesis in rat
hepatocytes or DNA damage or repair in human fibroblasts. The results
indicate that metolachlor is not mutagenic or clastogenic and does not
provoke unscheduled DNA synthesis.
[[Page 18121]]
F. Threshold Effects
1. Chronic effects. Based on the available chronic toxicity data,
EPA has established the RfD for metolachlor at 0.1 mg/kg/day. The RfD
for metolachlor is based on a 1-year feeding study in dogs with a No-
Observed Effect Level (NOEL) of 9.7 mg/kg/day and an uncertainty factor
of 100.
2. Acute toxicity. Based on the available acute toxicity data, it
is believed metolachlor does not pose any acute dietary risks.
G. Non-threshold Effects
Carcinogenicity. Using its Guidelines for Carcinogenic Risk
Assessment published September 24, 1986 (51 FR 33992), EPA has
classified metolachlor as Group `C' for carcinogenicity (possible human
carcinogen) based on findings of a carcinogenic effect in the liver of
the female rat. Because this carcinogenic response was only observed at
the high dose of 3,000 ppm, a dose associated with evidence of liver
damage, it is likely that this response occurred via a non-genotoxic,
threshold-based mechanism. Therefore, EPA is regulating exposure to
metolachlor using a margin of exposure approach. A NOEL of 15 mg/kg/day
from the 2 year rat feeding study was determined to be appropriate for
use in the Margin of Exposure carcinogenic risk assessment. However,
because the chronic reference dose is lower (9.7 mg/kg/day) than the
oncogenic NOEL (15 mg/kg/day), the EPA is using the Reference Dose for
quantification of human risk.
H. Aggregate Exposure
1. Dietary exposure. For purposes of assessing the potential
dietary exposure to metolachlor, aggregate exposure has been estimated
based on the TMRC from the use of metolachlor in or on raw agricultural
commodities for which tolerances have been previously established (40
CFR 180.368). The incremental effect on dietary risk resulting from the
addition of tomatoes to the label was assessed by conservatively
assuming that exposure would occur at the proposed tolerance level of
0.1 ppm with 100% of the crop treated. The TMRC is obtained by
multiplying the tolerance level residue for all these raw agricultural
commodities by the consumption data which estimates the amount of these
products consumed by various population subgroups. Some of these raw
agricultural commodities (e.g. corn forage and fodder, peanut hay) are
fed to animals; thus exposure of humans to residues in these fed
commodities might result if such residues are transferred to meat,
milk, poultry, or eggs. Therefore, tolerances of 0.02 ppm for milk,
meat and eggs and 0.2 ppm for kidney and 0.05 ppm for liver have been
established for metolachlor. In conducting this exposure assessment, it
has been conservatively assumed that 100% of all raw agricultural
commodities for which tolerances have been established for metolachlor
will contain metolachlor residues and those residues would be at the
level of the tolerance--which results in an overestimation of human
exposure.
2. Drinking water. Another potential source of exposure of the
general population to residues of pesticides are residues in drinking
water. Based on the available studies used by EPA to assess
environmental exposure, it is not anticipated that exposure to residues
of metolachlor in drinking water will exceed 20% of the RfD (0.02 mg/
kg/day), a value upon which the Health Advisory Level of 70 ppb for
metolachlor is based. In fact, based on experience with metolachlor, it
is believed that metolachlor will be infrequently found in groundwater
(less than 5% of the samples analyzed), and when found, it will be in
the low ppb range.
3. Non-dietary exposure. Although metolachlor may be used on turf
and ornamentals in a residential setting, that use represents less than
0.1 percent of the total herbicide market for residential turf and
landscape uses. Currently, there are no acceptable, reliable exposure
data available to assess any potential risks. However, given the small
amount of material that is used, it is concluded that the potential for
non-occupational exposure to the general population is unlikely.
I. Cumulative Effects
The potential for cumulative effects of metolachlor and other
substances that have a common mechanism of toxicity has also been
considered. It is concluded that consideration of a common mechanism of
toxicity with other registered pesticides in this chemical class
(chloroacetamides) is not appropriate. Since EPA itself has concluded
that the carcinogenic potential of metolachlor is not the same as other
registered chloroacetamide herbicides, based on differences in rodent
metabolism (EPA Peer Review of metolachlor, 1994), it is believed that
only metolachlor should be considered in an aggregate exposure
assessment.
J. Safety Determinations
1. U.S. population in general. Using the conservative exposure
assumptions described above, based on the completeness and reliability
of the toxicity data, it is concluded that aggregate exposure to
metolachlor will utilize 1.4 percent of the RfD for the U.S.
population. EPA generally has no concern for exposures below 100
percent 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. Therefore, it is concluded that
there is a reasonable certainty that no harm will result from aggregate
exposure to metolachlor or metolachlor residues.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of metolachlor, data
from developmental toxicity studies in the rat and rabbit and a 2-
generation reproduction study in the rat have been considered. The
developmental toxicity studies are designed to evaluate adverse effects
on the developing organism resulting from chemical exposure during
prenatal development to one or both parents. Reproduction studies
provide information relating to effects from exposure to a chemical on
the reproductive capability of mating animals and data on systemic
toxicity.
Developmental toxicity (reduced mean fetal body weight, reduced
number of implantations/dam with resulting decreased litter size, and a
slight increase in resorptions/dam with a resulting increase in post-
implantation loss) was observed in studies conducted with metolachlor
in rats and rabbits. The NOEL's for developmental effects in both rats
and rabbits were established at 360 mg/kg/day. The developmental effect
observed in the metolachlor rat study is believed to be a secondary
effect resulting from maternal stress (lacrimation, salivation,
decreased body weight gain and food consumption and death) observed at
the limit dose of 1,000 mg/kg/day.
A 2-generation reproduction study was conducted with metolachlor at
feeding levels of 0, 30, 300 and 1,000 ppm. The reproductive NOEL of
300 ppm (equivalent to 23.5 to 26 mg/kg/day) was based upon reduced pup
weights in the F1a and F2a litters at the 1,000 ppm dose level
(equivalent to 75.8 to 85.7 mg/kg/day). The NOEL for parental toxicity
was equal to or greater than the 1,000 ppm dose level. FFDCA section
408 provides that EPA may apply an additional safety factor for infants
and children in the case of threshold effects to account for pre- and
post-natal toxicity and the completeness of the database. Based on the
current toxicological data requirements, the database relative to pre-
and post-natal
[[Page 18122]]
effects for children is complete. Further, for the chemical
metolachlor, the NOEL of 9.7 mg/kg/day from the metolachlor chronic dog
study, which was used to calculate the RfD (discussed above), is
already lower than the developmental NOEL's of 360 mg/kg/day from the
metolachlor teratogenicity studies in rats and rabbits. In the
metolachlor reproduction study, the lack of severity of the pup effects
observed (decreased body weight) at the systemic LOEL (equivalent to
75.8 to 85.7 mg/kg/day) and the fact that the effects were observed at
a dose that is nearly 10 times greater than the NOEL in the chronic dog
study (9.7 mg/kg/day) suggest there is no additional sensitivity for
infants and children. Therefore, it is concluded that an additional
uncertainty factor is not warranted to protect the health of infants
and children and that the RfD at 0.1 mg/kg/day based on the chronic dog
study is appropriate for assessing aggregate risk to infants and
children from use of metolachlor.
Using the conservative exposure assumptions described above, the
percent of the RfD that will be utilized by aggregate exposure to
residues of metolachlor including the proposed use on tomatoes is 1.1
percent for nursing infants less than 1 year old, 3.5 percent for non-
nursing infants, 3.0 percent for children 1 to 6 years old and 2.2
percent for children 7 to 12 years old. Therefore, based on the
completeness and reliability of the toxicity data and the conservative
exposure assessment, it is concluded that there is a reasonable
certainty that no harm will result to infants and children from
aggregate exposure to metolachlor residues.
K. Estrogenic Effects
Metolachlor does not belong to a class of chemicals known or
suspected of having adverse effects on the endocrine system. There is
no evidence that metolachlor has any effect on endocrine function in
developmental or reproduction studies. Furthermore, histological
investigation of endocrine organs in the chronic dog, rat and mouse
studies conducted with metolachlor did not indicate that the endocrine
system is targeted by metolachlor, even at maximally tolerated doses
administered for a lifetime. Although residues of metolachlor have been
found in raw agricultural commodities, there is no evidence that
metolachlor bioaccumulates in the environment.
[FR Doc. 97-9582 Filed 4-11-97; 8:45 am]
BILLING CODE 6560-50-F
