[Federal Register Volume 62, Number 143 (Friday, July 25, 1997)]
[Notices]
[Pages 40075-40086]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-19669]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-744; FRL-5726-4]
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-744, must
be received on or before August 25, 1997.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources andServices Division
(7506C), Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 1132, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically by following
the instructions under ``SUPPLEMENTARY INFORMATION.'' No confidential
business information should be submitted through e-mail.
Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment that does not contain CBI must be submitted
for inclusion in the public record. Information not marked confidential
may be disclosed publicly by EPA without prior notice. All written
comments will be available for public inspection in Rm. 1132 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: The product manager listed in the
table below:
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Office location/
Product Manager telephone number Address
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Mary Waller (PM 21)........... Rm. 265, CM #2, 703- 1921 Jefferson
308-9354, e- Davis Hwy,
mail:[email protected] Arlington, VA
ail.epa.gov.
Cynthia Giles-Parker (PM 22).. Rm. 247, CM #2, 703- Do.
305-7740, e-
mail:parker.cynthia@epamai.
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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 raw 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 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-744
[[Page 40076]]
(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''.
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 (insert docket number) 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: July 11, 1997.
James Jones,
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. Bayer
PP 3E2938
EPA has received a pesticide petition (PP) 3E2938 from Bayer
Corporation, 8400 Hawthorn Rd., P.O. Box 4913, Kansas City, MO 64120-
0013 proposing to amend 40 CFR 180.410 by establishing tolerances for
residues of the fungicide triadimefon, 1-(4-Chlorophenoxy)-3,3-
dimethyl-1-(1H-1,2,4-triazol-1-yl)-2-butanone, and its metabolites
containing chlorophenoxy and triazole moieties expressed as the
fungicide in or on the raw agricultural commodities coffee beans at 0.1
ppm. The nature of the residue in plants and livestock is adequately
understood. The analytical method for determining residues uses gas-
liquid chromatography coupled with a thermionic detector.
A. Residue Chemistry
1. Plant and livestock metabolism. The nature of the residue in
plants and animals is adequately understood. The residue of concern is
triadimefon and its triazole and chlorophenoxy metabolites. Since there
are no livestock feedstuffs derived from coffee, the nature of the
residue in poultry and ruminants is not of concern here.
2. Analytical method. Adequate analytical methods are available for
analysis of triadimefon and its triazole and chlorophenoxy metabolites
in or on coffee. These methods are available in PAM II as Method I.
3. Magnitude of residue. Fifteen separate residue trials have been
conducted and submitted to the EPA with triadimefon on coffee. These
trials were conducted in Brazil (4 trials), Mexico (4 trials), Costa
Rica (2 trials), El Salvador (2 trials), Guatemala (1 trial) and
Columbia (2 trials). The EPA has determined that these data show that
residues of triadimefon and its metabolites containing chlorophenoxy
and triazole moieties (expressed as the fungicide) in the raw
agricultural commodity coffee beans will not exceed the proposed
tolerance of 0.1 ppm. Although no data on roasted beans or instant
coffee were submitted, the EPA has concluded that food additive
tolerances are not required. There are no livestock feed stuffs from
coffee and therefore, secondary residues in meat, milk, poultry and
eggs are not expected. Since this is an import tolerance petition and
since coffee is not normally rotated, the nature of residue in
rotational crops is not of concern.
B. Toxicological Profile
1. Acute toxicity. Rat acute oral study with an LD50 of
568 + 61 mg/kg (male) and 363 + 41 mg/kg (female). Rabbit acute dermal
study with a LD50 of >2000 mg/kg. Rat acute inhalation study
with a LC50 of > 3.570 mg/l. Primary eye irritation study in
the rabbit which showed practically no irritation. Primary dermal
irritation study which showed practically no irritation. Primary dermal
sensitization study which indicated that triadimefon is a skin
sensitizer.
2. Genotoxicity. Triadimefon has been found to be negative in the
Ames reverse mutation test and in the Structural Chromosome Aberration
Test
3. Reproductive and developmental toxicity. A rat developmental
toxicity study showed a maternal systemic NOEL of 30 mg/kg/day and the
LOEL 90 mg/kg/day. The NOEL for developmental toxicity was 30 mg/kg/day
and the LOEL was 90 mg/kg/day. In the developmental toxicity study in
rabbits, the maternal systemic NOEL was 50 mg/kg/day and the LOEL 120
mg/kg/day. The NOEL for developmental toxicity was 20 mg/kg/day and the
LOEL was 50 mg/kg/day. Effects seen at the developmental LEL in the
rabbit study were irregular spinous process and ossification of various
bones. A 3-generation rat reproduction study showed decreases in
maternal body weight gain, fertility, and in litter size, pups survival
during the lactation phase, and pups weights. The maternal NOEL was 300
ppm and the reproductive NOEL was 50 ppm. A 2-generation rat
reproductive study showed reductions in litter size, pups viability,
birth and lactational weights. The reproductive NOEL was 50 ppm.
4. Subchronic toxicity. A 3-month feeding study in the rat with a
NOEL of 2,000 ppm based on decreased body weight gain and food
consumption attributed to palatability. A rat 30-day feeding study with
a NOEL of 10 mg/kg. A thirteen-week dog-feeding study with a NOEL of
2,400 ppm based on decreased body weight gain and food consumption due
to palatability. There was also a decreased hematocrit, RBC count,
hemoglobin volume and microsomal induction. A 28-day rabbit dermal
study with a NOEL >250 mg/kg. A rat 21-day inhalation study with a NOEL
= 78.7 mg/m3/6 hrs. per day/ 15 exposures.
5. Chronic toxicity. A 2-year rat chronic feeding study defined a
NOEL for systemic effect as 300 ppm (males = 16.4 mg/kg/day; females =
22.5 mg/kg/day). The systemic LOEL was 1,800 ppm (males = 114.0 mg/kg/
day; females = 199.0 mg/kg/day) based on neoplastic and systemic
effects. A dog feeding study showed only minimal toxic effects
(decrease in body weight, increase in liver weight and in hepatic N-
demethylase activity, and an increase in serum alkaline phosphatase
activity. The NOEL was established at 100 ppm. A mouse oncogenicity
study showed hepatocellular adenomas in both sexes of NMRI mice. The
NOEL was established for males at 50 ppm. No NOEL was reached for
females. A mouse oncogenicity study using CF1-W74 mice was negative for
oncogenicity.
6. Animal metabolism. In a general rat metabolism study triadimefon
was initially converted to triadimefon. This conversion was more rapid
in males.
[[Page 40077]]
The major metabolites were the acid and alcohol of triadimefon. In
males radioactivity was found mainly in feces, whereas, in females,
radioactivity was equally distributed between urine and feces. No
radioactivity was recovered in the expired air. Peak tissue levels were
found in 2 to 4 hours and were highest in fat, liver and kidney.
7. Endocrine effects. No special studies investigating potential
estrogenic or endocrine effects of triadimefon have been conducted.
However, the standard battery of required studies has been completed.
These studies include an evaluation of the potential effects on
reproduction and development, and an evaluation of the pathology of the
endocrine organs following repeated or long-term exposure. These
studies are generally considered to be sufficient to detect any
endocrine effects, but no such effects were noted in any of the studies
with either triadimefon or its metabolites.
8. Carcinogenicity. Using its Guidelines for Carcinogen Risk
Assessment published in the Federal Register of September 24, 1986 (51
FR 33992), EPA has classified triadimefon as Group ``C'' for
carcinogenicity (possible human carcinogen) based on the results of
carcinogenicity studies in 2 species. The classification as Group C was
based on borderline statistically significant increases in thyroid
adenomas in male rats, and increases in liver adenomas in both sexes of
mice. Because the tumors were benign, and there were no apparent
genotoxicity concerns, the Cancer Peer Review Committee recommended the
RfD approach for quantitation of human risk.
C. Aggregate Exposure
1. Dietary (food) exposure--a. Chronic. For purposes of assessing
the potential dietary exposure from food under the proposed tolerances,
Bayer has estimated exposure based on the Theoretical Maximum Residue
Contribution (TMRC) derived from the previously established tolerances
for triadimefon as well as the proposed tolerance for triadimefon on
coffee beans at 0.1 ppm. The TMRC is obtained by using a model which
multiplies the tolerance level residue for each commodity by
consumption data which estimate the amount of each commodity and
products derived from the commodities that are eaten by the U.S.
population and various population subgroups. In conducting this
exposure assessment, very conservative assumptions--100% of all
commodities will contain triadimefon residues, and those residues would
be at the level of the tolerance--which result in a large overestimate
of human exposure. Thus, in making a safety determination for these
tolerances, Bayer took into account this very conservative exposure
assessment.
b. Acute. EPA has not estimated non-occupational exposures other
than dietary for triadimefon. Acceptable, reliable data are not
currently available with which to assess acute risk. Triadimefon is
registered for outdoor residential use (lawn use). While dietary and
residential scenarios could possibly occur in a single day, triadimefon
would rarely be present on both the food eaten and the lawn on that
single day. Even assuming this were the case, it is yet more unlikely
that residues would be present at tolerance level on all food eaten
that day for which triadimefon tolerances exist, as is assumed in the
acute dietary risk analysis, and on the lawn that same day. Because the
acute dietary exposure estimate assumes tolerance level residues and
100% crop treated for all crops evaluated, it is a large over-estimate
of exposure and is considered to be protective of any acute exposure
scenario.
2. Drinking water exposure. Based on the available studies used in
EPA's assessment of environmental risk, triadimefon and its metabolites
are mobile and persistent and have the potential to leach into
groundwater. There is no established Maximum Concentration Level for
residues of triadimefon in drinking water. No drinking water health
advisory levels have been issued for triadimefon or its metabolite
triadimenol. The ``Pesticides in Groundwater Database'' (EPA 734-12-92-
001, September 1992) indicated that triadimefon was monitored for in 14
wells in California from 1984 to 1989. There were no detectable
residues (limit of detection was not stated). Although the Agency does
not have available data to perform a quantitative drinking water risk
assessment for triadimefon at this time, Bayer is currently conducting
2 prospective groundwater monitoring studies. Previous experience with
more persistent and mobile pesticides for which there have been
available data to perform quantitative risk assessments have
demonstrated that drinking water exposure is typically a small
percentage of the total exposure when compared to the total dietary
exposure. This observation holds even for pesticides detected in wells
and drinking water at levels nearing or exceeding established MCLs.
Based on this experience and the Agency's best scientific judgement,
EPA concludes that it is not likely that the potential exposure from
residues of triadimefon in drinking water added to the current dietary
exposure will result in an exposure which exceeds the RfD.
3. Non-occupational exposure. Triadimefon is currently registered
for use on turf and ornamentals. Bayer has conducted and submitted to
the EPA an exposure study designed to measure the upper bound acute
exposure potential of adults and children from contact with triadimefon
treated turf. The population considered to have the greatest potential
exposure from contact with pesticide treated turf soon after pesticides
are applied are young children. The estimated safe residue levels for
triadimefon on treated turf for 10-year-old children ranged from 1.3 -
6.4 g/cm2 and for 5-year-old children from 1.1 -
5.6 g/cm2. This compares with the average
triadimefon transferable residue level of 1.0 g/cm2
present immediately after the sprays have dried. These data indicate
that children can safely contact triadimefon-treated turf as soon after
application as the spray has dried.
D. Cumulative Effects
At this time, the Agency has not made a determination that
triadimefon and other substances that may have a common mode of
toxicity would have cumulative effects. For purposes of this tolerance,
only the potential risks of triadimefon in its aggregate exposure are
being considered.
E. Safety Determination
1. U.S. population.--a. Chronic risk. Based on the available
chronic toxicity data, EPA has established the RfD for triadimefon at
0.04 milligrams(mg)/kilogram(kg)/day. This RfD is based on a 2-year dog
feeding study with a NOEL of 11.4 mg/kg/day and an uncertainty factor
of 300. An uncertainty factor of 300 was applied to account for inter-
species extrapolation (10), intra-species variability (10), and the
lack of an adequate reproduction study (3). Decreased food intake,
depression in weight gain, and significantly (p <0.05) increased="" alkaline="" phosphatase="" activity="" in="" both="" sexes="" were="" the="" effects="" observed="" at="" the="" lowest="" effect="" level="" (lel).="" using="" the="" conservative="" exposure="" assumptions="" described="" above,="" bayer="" has="" determined="" that="" aggregate="" dietary="" exposure="" to="" triadimefon="" from="" the="" previously="" established="" and="" the="" proposed="" tolerance="" on="" coffee="" will="" utilize="" 12.32%="" of="" the="" rfd="" for="" the="" u.s.="" population="" (48="" states).="" there="" is="" generally="" no="" concern="" for="" exposures="" below="" 100="" percent="" of="" the="" rfd="" because="" the="" rfd="" represents="" the="" level="" at="" or="" below="" which="" daily="" aggregate="" exposure="" over="" a="" lifetime="" will="" not="" pose="" appreciable="" risks="" to="" human="" health.="" acceptable,="" reliable="" data="" are="" not="" available="" to="" quantitatively="" assess="" risk="" from="" drinking="" water="" or="" from="" [[page="" 40078]]="" residential="" uses.="" however,="" there="" is="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" from="" aggregate="" exposure="" to="" triadimefon="" residues.="" b.="" acute="" risk.="" the="" epa="" has="" recommended="" that="" the="" developmental="" noel="" from="" the="" rabbit="" developmental="" toxicity="" study="" (20="" mg/kg/day)="" be="" used="" for="" acute="" dietary="" risk="" calculations.="" based="" on="" the="" nfcs="" 1989-92="" data="" base,="" the="" population="" of="" concern="" for="" this="" risk="" assessment="" is="" children="" 1-6="" years="" old.="" the="" calculated="" margin="" of="" exposure="" (moe)="" value="" is="" 531.="" this="" moe="" does="" not="" exceed="" the="" agency's="" level="" of="" concern="" for="" acute="" dietary="" exposure.="" 2.="" infants="" and="" children.="" in="" assessing="" the="" potential="" for="" additional="" sensitivity="" of="" infants="" and="" children="" to="" residues="" of="" triadimefon,="" the="" data="" from="" developmental="" studies="" in="" both="" rat="" and="" rabbit="" and="" a="" 2-="" generation="" reproduction="" study="" in="" the="" rat="" should="" be="" considered.="" the="" developmental="" toxicity="" studies="" evaluate="" any="" potential="" adverse="" effects="" on="" the="" developing="" animal="" resulting="" from="" pesticide="" exposure="" of="" the="" mother="" during="" prenatal="" development.="" the="" reproduction="" study="" evaluates="" any="" effects="" from="" exposure="" to="" the="" pesticide="" on="" the="" reproductive="" capability="" of="" mating="" animals="" through="" 2-generations,="" as="" well="" as="" any="" observed="" systemic="" toxicity.="" a="" rat="" and="" rabbit="" developmental="" toxicity="" studies="" and="" a="" 2-generation="" and="" 3-generation="" rat="" reproduction="" studies="" have="" been="" conducted="" with="" triadimefon="" as="" described="" above="" under="" toxicology="" profile.="" maternal="" and="" developmental="" toxicity="" noels="" of="" 30="" mg/="" kg/day="" were="" determined="" in="" the="" rat="" developmental="" toxicity="" studies.="" in="" the="" rabbit="" developmental="" toxicity="" study,="" the="" maternal="" noel="" was="" 50="" mg/kg="" bwt/day="" and="" the="" developmental="" noel="" was="" 20="" mg/kg="" bwt/day.="" although="" epa="" has="" accepted="" the="" rat="" and="" rabbit="" developmental="" toxicity="" studies,="" they="" have="" determined="" that="" the="" rat="" reproduction="" studies="" are="" not="" acceptable="" and="" question="" whether="" another="" study="" would="" adequately="" answer="" the="" question="" about="" the="" potential="" reproductive="" toxicity="" of="" triadimefon.="" the="" epa="" believes="" that="" the="" additional="" information="" my="" be="" collected="" from="" the="" 90-="" day="" neurotoxicity="" study="" which="" was="" submitted="" to="" the="" epa="" on="" october="" 30,="" 1996.="" a.="" chronic="" risk.="" 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="" effects="" and="" the="" completeness="" of="" the="" toxicity="" database.="" therefore,="" epa="" has="" incorporated="" an="" additional="" 3-fold="" uncertainty="" factor="" into="" the="" calculation="" of="" the="" rfd="" because="" of="" the="" absence="" of="" an="" acceptable="" reproduction="" study.="" the="" agency="" notes="" that="" there="" is="" approximately="" a="" 2-fold="" difference="" between="" the="" developmental="" noel="" of="" 20="" mg/kg/day="" from="" the="" rabbit="" developmental="" toxicity="" study="" and="" the="" noel="" of="" 11.4="" mg/kg/day="" from="" the="" 2-year="" dog="" feeding="" study="" which="" was="" the="" basis="" of="" the="" rfd.="" it="" is="" further="" noted="" that="" in="" the="" rabbit="" developmental="" toxicity="" study,="" the="" developmental="" noel="" of="" 20="" mg/kg/day="" is="" lower="" than="" the="" maternal="" systemic="" noel="" of="" 50="" mg/kg/day,="" suggesting="" the="" possibility="" of="" increased="" sensitivity="" for="" the="" pre-natal="" child.="" the="" tmrc="" value="" for="" the="" most="" highly="" exposed="" infant="" and="" children="" subgroup="" (non-nursing="" infants=""><1 year="" old)="" occupies="" 35.1%="" of="" the="" rfd.="" however,="" this="" calculation="" also="" assumes="" 100%="" crop="" treated="" and="" uses="" tolerance="" level="" residues="" for="" all="" commodities.="" refinement="" of="" the="" dietary="" risk="" assessment="" by="" using="" percent="" of="" crop="" treated="" and="" anticipated="" residue="" data="" would="" likely="" greatly="" reduce="" the="" dietary="" exposure="" estimate="" and="" result="" in="" an="" anticipated="" residue="" contribution="" (arc)="" which="" would="" occupy="" a="" percent="" of="" the="" rfd="" that="" is="" substantially="" lower="" than="" the="" currently="" calculated="" tmrc="" value.="" should="" an="" additional="" uncertainty="" factor="" be="" deemed="" appropriate,="" when="" considered="" in="" conjunction="" with="" a="" refined="" exposure="" estimate,="" it="" is="" unlikely="" that="" the="" dietary="" risk="" will="" exceed="" 100="" percent="" of="" the="" rfd.="" therefore,="" taking="" into="" account="" the="" completeness="" and="" reliability="" of="" the="" toxicity="" data="" and="" the="" conservative="" exposure="" assessment,="" there="" is="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" to="" infants="" and="" children="" from="" aggregate="" exposure="" to="" triadimefon="" residues.="" b.="" acute="" risk.="" the="" epa="" has="" recommended="" that="" the="" developmental="" noel="" from="" the="" rabbit="" developmental="" toxicity="" study="" (20="" mg/kg/day)="" be="" used="" for="" acute="" dietary="" risk="" calculations.="" based="" on="" the="" nfcs="" 1989-92="" data="" base,="" the="" population="" of="" concern="" for="" this="" risk="" assessment="" is="" children="" 1-6="" years="" old.="" the="" calculated="" margin="" of="" exposure="" (moe)="" value="" is="" 531.="" this="" moe="" does="" not="" exceed="" the="" agency's="" level="" of="" concern="" for="" acute="" dietary="" exposure.="" f.="" international="" issues="" a="" codex="" maximum="" residue="" level="" (mrl)="" of="" 0.1="" ppm="" has="" been="" established="" for="" residues="" of="" triadimefon="" and="" triadimenol.="" g.="" mode="" of="" action="" triadimefon="" is="" a="" sterol="" demethylation="" inhibitor="" (dmi)="" fungicide.="" it="" is="" systemic="" and="" shows="" activity="" against="" rust="" infecting="" coffee.="" triadimefon="" provides="" protective="" activity="" by="" preventing="" completion="" of="" the="" infection="" process="" by="" direct="" inhibition="" of="" sterol="" synthesis.="" it="" is="" rapidly="" absorbed="" by="" plants="" and="" translocated="" systemically="" in="" the="" young="" growing="" tissues.="" (pm="" 22)="" 2.="" e.i.="" dupont="" de="" nemours="" &="" co.="" (dupont)="" pp="" 7f4805="" epa="" has="" received="" a="" pesticide="" petition="" (pp)="" 7f4805="" from="" e.i.="" dupont="" de="" nemours="" &="" co.="" (dupont),="" p.o.="" box="" 80038,="" wilmington,="" de="" 19880-0038="" proposing,="" pursuant="" to="" section="" 408(d)="" of="" the="" federal="" food,="" drug="" and="" cosmetic="" act="" (ffdca),="" 21="" u.s.c.="" section="" 346a,="" to="" amend="" 40="" cfr="" 180.474="" by="" establishing="" tolerances="" for="" residues="" of="" the="" fungicide="" cymoxanil:="" 2-="" cyano-n-[(ethylamino)carbonyl]-2-(methoxyimino)acetamide="" in="" or="" on="" the="" raw="" agricultural="" commodity="" potatoes="" at="" 0.1="" ppm.="" the="" proposed="" analytical="" method="" for="" determining="" residues="" is="" high="" performance="" liquid="" chromatography.="" a.="" residue="" chemistry="" 1.="" plant="" metabolism.="" the="" metabolism="" of="" cymoxanil="" in="" plants="" is="" adequately="" understood="" for="" the="" purposes="" of="" this="" tolerance.="" cymoxanil="" degrades="" rapidly="" and="" extensively="" in="" potatoes="" to="" natural="" products.="" the="" primary="" metabolite="" is="" glycine="" (a="" natural="" amino="" acid),="" which="" is="" reincorporated="" into="" other="" naturally="" occurring="" products.="" 2.="" animal="" metabolism.="" the="" metabolism="" of="" cymoxanil="" in="" animals="" is="" adequately="" understood.="" cymoxanil="" degrades="" rapidly="" and="" extensively="" in="" ruminants="" to="" natural="" products,="" including="" fatty="" acids,="" glycerol,="" glycine="" and="" other="" amino="" acids,="" lactose,="" and="" acid="" hydrolyzable="" formyl="" and="" acetyl="" groups.="" 3.="" analytical="" method.="" the="" proposed="" practical="" analytical="" method="" utilizes="" high="" performance="" liquid="" chromatography="" for="" detecting="" and="" measuring="" levels="" of="" cymoxanil="" in="" or="" on="" potatoes="" with="" a="" general="" limit="" of="" quantitation="" of="" 0.05="" ppm.="" this="" method="" allows="" monitoring="" of="" food="" with="" residues="" at="" or="" above="" the="" levels="" proposed="" in="" this="" tolerance.="" this="" method="" has="" been="" validated="" by="" an="" independent="" laboratory.="" 4.="" magnitude="" of="" the="" residue="" in="" plants.="" field="" residue="" trials="" were="" conducted="" with="" cymoxanil="" on="" potatoes="" at="" 19="" test="" sites="" in="" the="" u.s.="" at="" rates="" equal="" to="" or="" higher="" than="" (up="" to="" 5="" x="" )="" the="" proposed="" maximum="" use="" rate="" with="" pre-harvest="" intervals="" as="" short="" as="" 0="" days.="" no="" detectable="" cymoxanil="" residue="" (detection="" limit="0.02" ppm)="" was="" found="" in="" any="" sample="" at="" any="" of="" the="" tested="" sites="" or="" rates.="" 5.="" magnitude="" of="" the="" residue="" in="" processed="" commodities.="" because="" there="" were="" no="" detectable="" residues="" present="" in="" potato="" samples="" treated="" at="" highly="" exaggerated="" rates,="" no="" detectable="" residues="" are="" expected="" in="" processed="" potatoes="" at="" [[page="" 40079]]="" rates="" which="" would="" appear="" on="" the="" product="" label.="" 6.="" magnitude="" of="" the="" residue="" in="" animals.="" based="" on="" a="" ruminant="" metabolism="" study,="" no="" secondary="" tolerances="" in="" animal="" commodities="" are="" necessary.="" b.="" toxicological="" profile="" of="" cymoxanil="" 1.="" acute="" toxicity.="" technical="" cymoxanil="" has="" low="" acute="" toxicity.="" the="" acute="" oral="">50 is 960 mg/kg in rats. The acute dermal
LD50 is >2000 mg/kg in rabbits. The 4-hour rat inhalation
LC50 is >5.06 mg/L. Minimal transient irritation of the skin
and eyes was observed in rabbits. Cymoxanil did not cause skin
sensitization in guinea pigs. Cymoxanil should be classified as
Toxicity Category III for oral and dermal toxicity and Toxicity
Category IV for inhalation toxicity and skin and eye irritation
potential.
2. Genotoxicity. A battery of in vitro and in vivo tests were
conducted to determine the genotoxic potential of cymoxanil. Cymoxanil
was negative for mutagenicity in in vitro bacterial (Salmonella
typhimurium or Escherichia coli tester strains) and mammalian cell
assays (Chinese hamster ovary (CHO) cells) and is therefore considered
not mutagenic. Cymoxanil was positive for induction of chromosome
aberrations in in vitro assays (CHO cells and human lymphocytes), but
negative in 2 species of in vivo assays (rat clastogenicity and mouse
micronucleus). The weight-of-evidence indicates that cymoxanil is not
clastogenic. Cymoxanil was negative for induction of unscheduled DNA
synthesis (UDS) in 1 in vitro assay but positive in another; however,
it was negative for induction of UDS in both hepatocytes and
spermatocytes when evaluated in in vivo assays.
Therefore, Dupont believes that the weight-of-evidence indicates
that cymoxanil does not produce DNA damage. In summary, cymoxanil is
not considered genotoxic, nor does it have the potential to induce
heritable effects.
3. Reproductive and developmental toxicity. A 2-generation
reproduction study in rats fed diets containing 0, 100, 500, or 1,500
ppm resulted in no-observed-adverse-effects-level (NOAELs) of 100 ppm
for both parental rats (equivalent to 6.50 and 7.85 mg/kg/day for P1
males and females, respectively) and offspring (equivalent to 7.39 and
8.85 mg/kg/day for F1 males and females, respectively). The NOAELs were
based on alterations in body weight parameters, food consumption and
food efficiency in the parents at 500 ppm, and decreases in pup weights
and viability in the offspring at 500 ppm. Based on these results,
cymoxanil is not a reproductive toxin.
A developmental toxicity study was conducted with cymoxanil in rats
at 0, 10, 25, 75, or 150 mg/kg/day on days 7-16 of gestation. The no-
observable-effect levels (NOELs) for maternal and developmental effects
were considered to be 10 mg/kg/day for both maternal toxicity (based on
reduced weight gain and food consumption at 25 ppm and above) and
developmental toxicity (based on effects that included fetal variations
in ossification at 25 ppm and above).
A developmental toxicity study was conducted in rabbits at dose
levels of 0, 4, 8 and 16 mg/kg/day. Cymoxanil was not considered
maternally or fetally toxic at any dose level. A second rabbit study at
0, 8, 16 and 32 mg/kg/day demonstrated toxicity to the doe at 16 mg/kg/
day. Changes in axial skeleton of the fetus were observed at all dose
levels, but without direct relation to dosage. A third rabbit study was
conducted at 0, 1, 4, 8, and 32 mg/kg/day. Maternal toxicity was
observed at 8 mg/kg/day. Although skeletal variations were seen in some
fetal groups, they were not considered related to cymoxanil since they
were not statistically increased or dose related. A reevaluation of the
combined results of all three rabbit studies using current statistical
methods demonstrated NOAELs of 8 mg/kg/day for the doe and 4 mg/kg/day
for the fetus.
In the absence of significant differences between maternal and
fetal effect levels (revealed in both the rat and combined rabbit
studies), cymoxanil is not considered a developmental toxin.
4. Subchronic toxicity. A 90-day feeding study was conducted in
rats at dietary levels of 0, 100, 750, 1,500 or 3,000 ppm. Body weight
effects, increased food consumption, decreased food efficiency,
increased mean relative organ weights, and testicular (elongate
spermatid degeneration) and epididymal histopathologic effects were
observed at 1,500 and 3,000 ppm. The NOEL was 750 ppm (47.6 mg/kg/day
males; 59.9 mg/kg/day females).
The potential neurotoxicity of cymoxanil was evaluated in rats as
part of the 90-day feeding study at dietary levels of 0, 100, 750,
1,500 or 3,000 ppm. The NOEL for neurotoxicity was the highest dietary
level tested, 3,000 ppm for male (224 mg/kg/day) and female (333 mg/kg/
day) rats. Cymoxanil is judged not to be a neurotoxicant.
A 90-day feeding study was conducted in mice at dietary levels of
0, 50, 500 and 1,750, 3,500 or 7,000 ppm. The highest dietary level was
terminated by the third week of the study due to severe toxicity. The
NOEL was established at 50 ppm for female mice (11.3 mg/kg/day) based
on body weight effects at 500 ppm; no NOEL was established for male
mice due to body weight effects and increased liver weights at all
dietary levels. Liver weight increases were observed in female mice at
1,750 and 3,500 ppm. No histopathologic alterations were found in male
or female mice at levels up to 3,500 ppm.
A 90-day feeding study was conducted in dogs at dietary levels of
0, 100, 200 or 250/500 ppm (250 ppm for weeks 1 and 2; 500 ppm for the
remainder of the study). No NOEL was established for female dogs due to
lower body weight gain, food consumption and food efficiency at all
dietary levels. The NOEL in males was 100 ppm (3 mg/kg/day) based on
decreased body weight gain.
A 28-day repeated dose dermal study was conducted with rats at
dosages of 50, 500 or 1,000 mg/kg with daily 6-hour exposures. No
toxicologically significant effects were observed in any treatment
group. The NOEL is considered to be 1,000 mg/kg/day.
5. Chronic toxicity/oncogenicity. A 12-month chronic feeding study
was conducted in male dogs at dietary levels of 0, 50, 100 and 200 ppm
and in female dogs at 0, 25, 50 and 100 ppm. The NOAELs for chronic
toxicity were 100 ppm in male dogs (3.0 mg/kg/day) and 50 ppm in female
dogs (1.6 mg/kg/day), based on body weight and food consumption effects
in both sexes and decreased red cell parameters in males. No gross or
histopathological effects were observed.
An 18-month oncogenicity study was conducted in mice at dietary
levels of 0, 30, 300, 1,500 or 3,000 ppm. The NOEL was 30 ppm (4.19 and
5.83 mg/kg/day for males and females, respectively) based on
histopathological effects in testis and liver for males and the mucosal
lining of the gastrointestinal tract for females at 300 ppm. Cymoxanil
is not considered oncogenic.
A 2-year combined chronic toxicity/oncogenicity study was conducted
in rats at dietary levels of 0, 50, 100, 700 or 2,000 ppm. The NOEL for
chronic effects was 100 ppm (4.08 and 5.36 mg/kg/day for male and
female rats, respectively), based on decreased mean body weights, mean
body weight gains, food consumption, and food efficiency; and gross
and/or histopathological alterations of the retina, lymph nodes, lung,
intestine, testes, and sciatic nerve at 700 ppm. Cymoxanil is not
considered oncogenic.
[[Page 40080]]
6. Animal metabolism. An oral dose of radiolabelled cymoxanil was
extensively metabolized and rapidly eliminated in the rat. More than
85% of the dosed radioactivity is eliminated in the excreta, mostly in
the urine, within 48 hours. After 96 hours, less than 1% of the
administered dose remained in the tissues. The major excretory products
were polar metabolites such as 2-cyano-2-methoxyimino acetic acid,
glycine and other amino acid conjugates. These metabolites are rapidly
metabolized to other natural products. A minor metabolite, 1-ethyl-5,6-
di-2,4(1H,3H)pyridinedione, was also identified and is postulated as an
intermediate metabolite.
7. Metabolite toxicology. Cymoxanil breaks down rapidly in plants
and animals into naturally occurring compounds. Because of this, no
significant risk is expected from exposure to potatoes or other crops
treated with cymoxanil.
8. Endocrine effects. No evidence of endocrine effects were
observed upon comprehensive evaluation of data from the standard
battery of EPA required toxicology studies. These animal studies were
conducted at exposure levels that far exceed those likely to be
experienced by a human. Thus, adverse endocrine effects are not
expected to occur in humans (general population or sub-groups,
including nursing infants and children).
This battery of tests included, but is not limited to, the
following studies: reproductive, developmental, subchronic, chronic/
oncogenicity and metabolism. Most of these studies included gross and
histopathologic assessment of the endocrine organs (e.g., thyroid,
mammary glands, and testes).
C. Aggregate Exposure
Cymoxanil is a fungicide used on crops including potatoes,
tomatoes, and grapes. Cymoxanil is not registered for non-crop use in
any country. Although cymoxanil is not registered in the U.S., DuPont's
request for import tolerances on grapes and tomatoes is pending review
at EPA.
No aggregate exposure considerations are required for cymoxanil
because no residues are anticipated to occur in drinking water or from
other non-occupational exposures. Human exposure to residues in food is
the primary exposure consideration when calculating risk. Total chronic
dietary exposure to the most sensitive sub-population (children 1-6
yrs.) is determined to be less than 3% of the Reference Dose (RfD).
Details are given below:
1. Dietary (Food) Exposure. A complete and reliable database is
available for the assessment of threshold effects of cymoxanil.
Comparison of no effect levels (NOEL) for subchronic and chronic
studies found that the dog was the most sensitive species with a NOEL
of 1.6 mg/kg/day in the 1year study. The endpoint effects noted in this
study were reduced body weight gain, food consumption, and food
efficiency in females.
Applying a 100-fold safety factor, 0.016 mg/kg/day was selected as
the reference dose (RfD) in the dietary risk evaluation system (DRES)
analysis. No additional safety factor was used for infants or children
since they are not more sensitive to cymoxanil toxicity as discussed in
section E.2 of this document.
The ``worst-case'' DRES analysis included total potential dietary
intake of cymoxanil residues from potatoes, grapes, and tomatoes. It
was also assumed that 100% of these crops were treated with cymoxanil
and that all commodities contained residues at the proposed tolerance
levels (0.1 ppm). Analyses of actual field samples have detected no
residues of cymoxanil above the limit of detection (0.02 ppm). Potato
cells and processed potato waste may be fed to livestock. However, the
lack of detectable cymoxanil residues in any feed item and the lack of
transfer of cymoxanil to meat or milk in a ruminant metabolism study
indicate there is no reasonable expectation of cymoxanil residue in
meat and milk. Potatoes do not serve as a source of poultry feed, thus
no residues are expected in poultry or eggs.
Using this conservative exposure scenario, the DRES estimates a
theoretical maximum daily intake of 0.000216 mg/kg/day or 1.35% of the
RfD for the general U.S. population. Since cymoxanil is unlikely to
occur in drinking water, water was not included in this assessment (see
Section D.2 of this document). The most sensitive sub-population is
children (1-6 yrs.) with a predicted intake of 2.63% of the RfD. Using
the conservative exposure assumptions described above, it is estimated
that the cymoxanil exposure for infants and children ranges from 0.29%
of the RfD for nursing infants to 2.63% for children 1-6 years old.
An acute dietary risk exposure analysis for cymoxanil was not
performed. Since potatoes are the only commodity for which registration
of cymoxanil is being sought, significant dietary impact to any U.S.
population is not anticipated. Cymoxanil is not registered on grapes in
Chile or tomatoes in Mexico, the major countries that import these
commodities to the U.S. Therefore, exposure to cymoxanil from grapes
and tomatoes imported into the United States would not be expected to
contribute significantly to the U.S. diet. In addition, exposure to
cymoxanil through drinking water is unlikely since cymoxanil degrades
rapidly in soil and water as discussed in section D.2 of this document.
2. Dietary (Drinking Water) Exposure. It is unlikely that there
will be exposure to significant residues of cymoxanil through drinking
water supplies. Cymoxanil degrades rapidly in the environment. Studies
to satisfy the environmental fate data requirements are included with
this submission. Evaluation of these studies indicates the potential
for cymoxanil residues to be detected in drinking water supplies at
significant levels is minimal. Degradation from photolysis and both
anaerobic and aerobic metabolism in soils occur rapidly. Degradation
products also decline rapidly. The half-life of cymoxanil in soil under
field conditions was 1 to 9 days. Although cymoxanil and its degradates
are weakly adsorbed to the soil, they degrade so rapidly that movement
into groundwater is unlikely. Should movement into surface or ground
water occur, degradation will be very rapid. In water the photolytic
half-life of cymoxanil is less than 2-days at neutral and acidic
conditions, and its hydrolytic half-life at pH 9 is less than 1 hour.
3. Non-dietary exposure. Since cymoxanil is to be used on food
crops only there will be no non-dietary non-occupational exposure.
D. Cumulative Effects
Given cymoxanil's unique chemistry, low acute toxicity, the absence
of genotoxic, oncogenic, developmental, or reproductive effects, and
low exposure potential (see section C), the expression of cumulative
human health effects with cymoxanil and other natural or synthetic
pesticides is not anticipated. The potential for cumulative effects of
cymoxanil and other substances, that have a common mechanism of
toxicity, has been considered and is not applicable. Cymoxanil is a
unique cyanoacetamide and is chemically unrelated to any other
commercial plant disease control agents. Its biochemical mode of action
in fungi appears to be unique; it is theorized to act through
inhibition of multiple cellular processes, but a definitive mechanism
is not completely elucidated. Similarly, the mechanism of action
underlying observed toxicological effects in mammals is not fully
characterized and there is no reliable information to
[[Page 40081]]
suggest that cymoxanil has a mechanism of toxicity in common with any
other compound.
E. Safety Determination
1. U.S. population. Dupont believes that the chronic dietary risk
assessment demonstrates that an adequate margin of safety exists for
all U.S. sub-populations under DRES consideration.
A ``worst case'' DRES analysis was performed using proposed
tolerance levels for potatoes, tomatoes, and grapes and assuming 100%
of all crops are treated. Using these conservative assumptions, the
percentage of the RfD utilized by the general U.S. population is 1.35%.
The most sensitive sub-population, children 1-6 yrs., utilized 2.63% of
the RfD. These levels are well below those which would cause an
appreciable risk of harm from aggregate exposure to cymoxanil residues.
2. Infants and children. Based on the current toxicological
requirements, a complete and reliable database exists to assess the
potential for additional sensitivity of infants and children to the
residues of cymoxanil. Data from developmental and reproductive
toxicity studies (see section B.3) show that developing and young
animals are no more susceptible to prenatal and postnatal effects of
cymoxanil than the adult animals. In addition, the NOAEL from the dog
study proposed as the basis for the RfD is already more than 3-fold
lower than the lowest NOAEL observed in immature animals in the
developmental or reproductive studies. Therefore, Dupont concludes that
the safety factor used for protection of adults is fully appropriate
for the protection of infants and children; no additional safety factor
is necessary.
Thus toxicity of cymoxanil to developing and young animals is no
greater than to adults as demonstrated in the developmental and
reproductive toxicity studies.
Nonetheless, children 1-6 yrs. are identified as the most sensitive
sub-population in the chronic dietary risk analysis based on potential
for exposure (i.e., food consumption patterns). This sub-population
consumes more potatoes, grapes, and tomatoes than the general U.S.
population and other sub-populations. The chronic DRES found children
1-6 yrs. utilized 2.63% of the RfD. The general U.S. population
utilized 1.35% of the RfD and the exposure for infants and children
ranged from 0.29% of the RfD for nursing infants to 2.63% for children
1-6 yrs.
F. International Tolerances
Cymoxanil, a fungicide used to control potato late blight, is
currently registered for use on potatoes in 35 countries, including the
major European countries. The following Codex Alimentarius Commission
(Codex) Maximum Residue Levels (MRL's) for cymoxanil on potatoes have
been established: Belgium, Germany, Indonesia, Mexico, Netherlands,
Portugal, Spain, Switzerland - 0.05 ppm, Austria, Brazil, Japan, Italy
- 0.10 ppm, Hungary - 0.50 ppm, and Luxembourg - 2.0 ppm.
The U.S. Tolerance for potatoes being proposed is 0.10 ppm which is
twice the limit of quantitation of 0.05 ppm in the residue enforcement
method. Tolerances are not required for processed potatoes because no
residues were detected (detection limit = 0.02 ppm) in the magnitude of
residue study at highly exaggerated rates.
MRL's are also established internationally for cymoxanil on grapes,
tomatoes, hops, tobacco and various other vegetables. MRL's on grapes
range from 0.05-1.0 ppm and on tomatoes from 0.05-2.0 ppm. MRL's for
all other crops range from 0.05-2.0 ppm. (PM 21)
3. Novartis Crop Protection, Inc.
PP 5E4526
EPA has received a pesticide petition (PP 5E4526) from Novartis
Crop Protection, Inc. 410 Swing Road, Greensboro, NC 27401, proposing
to amend 40 CFR Part 180 by establishing a tolerance for residues of
the fungicide, difenoconazole, in or on the raw agricultural commodity
bananas at 0.2 ppm.
Analytical method AG-575B (MRID 42806504) is proposed as the
regulatory enforcement method. It is a revised version of AG-575A,
which was used to determine residues of difenoconazole in or on
bananas. The procedures in AG-575A remain unaltered in the revised
method, AG-575B, which incorporates specificity data and methodology
for megabore column gas chromatography. Procedural recoveries on banana
substrates (peel and pulp), fortified prior to extraction at levels
ranging from 0.02 ppm to 0.2 ppm, averaged 90.7+12% (n=42). Recoveries
ranged from 60 to 115%. Storage stability has been demonstrated under
frozen conditions for periods of up to 364 days.
A. Chemical Uses
Difenoconazole is the active ingredient in Sico 25EC, Sico 250EC,
Score 25EC, and Score 250EC, fungicides that offer broad-spectrum
control of several diseases in bananas and plantains. In the current
petition, Sico and Score are being developed as foliar treatments for
bananas. Difenoconazole is highly active at rates of 75 to 100 g a.i./
ha.
B. Difenoconazole Safety
Novartis has submitted over 20 toxicity studies in support of
tolerances for difenoconazole. Difenoconazole has a low order of acute
toxicity, minimal irritation potential, and no sensitization potential.
There was no evidence of genotoxicity, and it is not fetotoxic,
embryolethal, or teratogenic. It is not a reproductive toxin. The main
target organ of toxicity was the liver in the species tested. There was
an increase in liver tumors only in mice, and only, according to the
Carcinogenicity Peer Review Committee, at doses considered excessively
high for carcinogenicity testing. The EPA has concluded that for the
purpose of risk characterization, the Margin of Exposure (MOE) approach
(threshold model) should be used for quantification of human risk.
Margins of exposure are extremely high for the US population and all
population subgroups for both chronic effects and acute toxicity.
The following mammalian toxicity studies were conducted and
submitted in support of tolerances for difenoconazole. No-observable-
effect levels are consistent with those published in the Federal
Register of August 24, 1994 (FR 59 43491).
A rat acute oral study with an LD50 of 1,453 mg/kg.
A rabbit acute dermal study with an LD50 of >2010 mg/kg.
A rat acute inhalation study with an LC50 of >3.285 mg/
L.
A primary eye irritation study in the rabbit which showed slight
irritation.
A primary dermal irritation study in the rabbit which showed slight
irritation.
A dermal sensitization study in the guinea pig which showed no
irritation.
A 13-week rat feeding study identified liver as a target organ and
had a no-observable-effect level (NOEL) of 20 ppm.
A 13-week mouse feeding study identified liver as a target organ
and had a NOEL of 20 ppm.
A 26-week dog feeding study identified liver and eye as target
organs and had a NOEL of 100 ppm.
A 21-day dermal study in rabbits had a NOEL of 10 mg/mg/day based
on decreased body weight gain at 100 and 1,000 mg/kg/day.
A 24-month feeding study in rats had a NOEL of 20 ppm based on
liver toxicity at 500 and 2,500 ppm. There
[[Page 40082]]
was no evidence of an oncogenic response.
An 18-month mouse feeding study had an overall NOEL of 30 ppm based
on decreased body weight gain and liver toxicity at 300 ppm. There was
an increase in liver tumors only at dose levels that exceeded the
maximum tolerated dose (MTD). The oncogenic NOEL was 300 ppm.
A 12-month feeding study in dogs had a NOEL of 100 ppm based on
decreased food consumption and increased alkaline phosphatase levels at
500 ppm.
An oral teratology study in rats had a maternal NOEL of 16 mg/kg/
day based on excess salivation and decreased body weight gain and food
consumption. The developmental NOEL of 85 mg/kg/day was based on
effects seen secondary to maternal toxicity including slightly reduced
fetal body weight and minor changes in skeletal ossification.
An oral teratology study in rabbits had maternal NOEL of 25 mg/kg/
day based on decreased body weight gain, death, and abortion. The
developmental NOEL of 25 mg/kg/day was based on effects seen secondary
to maternal toxicity including slight increase in post-implantation
loss and resorptions, and decreased fetal weight.
A 2-generation reproduction study in rats had a parental and
reproductive NOEL of 25 ppm based on significantly reduced female body
weight gain, and reductions in male pup weights at 21 days.
There was no evidence of the induction of point mutations in an
Ames test.
There was no evidence of mutagenic effects in a mouse lymphoma
test.
There was no evidence of mutagenic effects in a nucleus anomaly
test with Chinese hamsters.
There was no evidence of induction of DNA damage in a rat
hepatocyte DNA repair test.
There was no evidence of induction of DNA damage in a human
fibroblast DNA repair test.
C. Threshold Effects
1. Chronic effects. Based on the data from chronic studies in rats,
mice, and dogs, the Reference Dose (RfD) for difenoconazole is 0.01 mg/
kg/day Federal Register of August 24, 1994 (FR 59 43492). The RfD for
difenoconazole is based on the chronic study in rats with a threshold
No-Observable-Effect Level of 1 mg/kg/day and an uncertainty factor of
100.
2. Acute toxicity. The EPA has concluded that the dietary acute
margin of exposure (MOE) for developmental toxicity was 25,000 for high
exposure in the females 13+ subgroup. The agency is generally not
concerned unless the MOE is below 100 for substances whose acute NOEL
is based on animals studies.
Novartis concurs, and has also considered that since the percentage
of the RfD utilized in the chronic exposure analysis for all population
subgroups is less than 10, it is highly unlikely that any acute dietary
exposure scenario would utilize a significant percentage of the RfD.
Since margins of exposure of 100 or more are considered
satisfactory, there is no concern for acute dietary exposure for the US
population, for various population subgroups, or for either gender.
3. Non-threshold effects (Carcinogenicity). The Health Effects
Division Carcinogenicity Peer Review Committee (CPRC) evaluated the
weight-of-the-evidence on difenoconazole with reference to its
carcinogenic potential. The CPRC concluded that difenoconazole should
be classified a Group C carcinogen, and for the purpose of risk
characterization the Margin of Exposure (MOE) approach should be used
for quantification of human risk.
In the 18-month study with CD-1 mice, there was a statistically
significant increase in hepatocellular adenomas, carcinomas, and
combined adenomas/carcinomas in both sexes, but only at dose levels
which were considered excessively high for carcinogenicity testing.
This is considered very weak evidence of carcinogenic potential.
Additionally, there was no evidence of carcinogenicity in either sex of
CD rat after 24 months, and there was no evidence of genotoxicity.
Therefore, a threshold model should be used for estimating risk. The
CPRC determined that a NOEL of 4.7 mg/kg/day, based on endpoints
related to hepatic tumor development, should be used for calculating
MOE's. The margin of exposure, calculated using worst case assumptions,
was 9,958 for the US population.
D. Aggregate Exposure
When the potential dietary exposure to difenoconazole is
calculated, the theoretical maximum residue concentration (TMRC) of
0.00041 mg/kg/day utilizes 4% of the RfD for the overall US population.
For the most exposed population subgroups, children and non-nursing
infants, the TMRC is 0.000946 mg/kg/day, utilizing 9% of the RfD
(Federal Register, August 24, 1994 FR 59 43492).
Novartis has conducted another exposure analysis using additional
crops and similar conservative assumptions. In this analysis, oats,
barley, and bananas (pending import tolerance) were included in
addition to wheat. Tolerances or proposed tolerances were 0.1 ppm each
for wheat, oats, and barley, and 0.2 ppm for bananas. Tolerances were
0.01 ppm for milk and 0.05 ppm for all other commodities: beef, goat,
horse, rabbit, sheep, pork, turkey, eggs, chicken, and other poultry.
Very conservative assumptions were used to estimate residues (i.e. 100%
of all wheat, oats, barley and imported bananas used for human
consumption or forage was treated and all RACs contained tolerance
level residues). These estimates result in a extreme overestimate of
human dietary exposure. Calculated TMRC values from these assumptions
utilize 4.7% of the RfD for the US population and 12.51% of the RfD for
non-nursing infants.
Although the import tolerance for bananas would not lead to the
exposure of the general population to residues of pesticides in
drinking water, this source of exposure was considered in the risk
assessment. Difenoconazole is currently used in the U.S. as a seed
treatment and residues are, therefore, incorporated into the soil at
very low rates (0.0125 to 0.025 lb a.i./100 lb of seed). The likelihood
of contamination of surface water from run-off is essentially
negligible. In addition, parent and aged leaching, soil adsorption/
desorption, and radiolabeled pipe studies indicated that difenoconazole
has a low potential to leach in the soil and would not be expected to
reach aquatic environments. For these reasons and because of the low
use rate, exposures to residues in ground water are not anticipated.
Non-occupational exposure for difenoconazole has not been estimated
since the current registration in the U.S. is limited to seed
treatment. Therefore, the potential for non-occupational exposure to
the general population is insignificant.
Novartis has considered the potential for cumulative effects of
difenoconazole and other substances of common mechanism of toxicity.
Novartis has concluded that consideration of a common mechanism of
toxicity in aggregate exposure assessment is not appropriate at this
time. Novartis has no information to indicate that the toxic effects
(generalized liver toxicity) seen at high doses of difenoconazole would
be cumulative with those of any other compound. Thus, Novartis is
considering only the potential risk of difenoconazole from dietary
exposure in its aggregate and cumulative exposure assessment.
[[Page 40083]]
E. Safety Determination
1.U.S. population. Reference Dose (RfD); using the very
conservative exposure assumptions described above, and based on the
completeness of the toxicity data base for difenoconazole, Novartis
calculates that aggregate exposure to difenoconazole utilizes <5% of="" the="" rfd="" for="" the="" us="" population="" based="" on="" chronic="" toxicity="" endpoints="" (noel="1" mg/kg/day).="" when="" using="" the="" carcinogenic="" noel="" of="" 4.7="" mg/kg/day="" and="" the="" margin="" of="" exposure="" approach="" recommended="" by="" the="" cprc,="" approximately="" 1%="" of="" the="" rfd="" is="" utilized.="" if="" more="" realistic="" assumptions="" were="" used="" to="" estimate="" anticipated="" residues="" and="" appropriate="" market="" share,="" this="" percentage="" would="" be="" considerably="" lower,="" and="" would="" be="" significantly="" lower="" than="" 100%,="" even="" for="" the="" highest="" exposed="" population="" subgroup.="" epa="" generally="" has="" no="" concern="" for="" exposures="" below="" 100%="" of="" the="" rfd.="" therefore,="" novartis="" concludes="" that="" there="" is="" reasonable="" certainty="" that="" no="" harm="" will="" result="" from="" daily="" aggregate="" exposure="" to="" residues="" of="" difenoconazole="" over="" a="" lifetime.="" 2.="" infants="" and="" children.="" developmental="" toxicity="" and="" 2-generation="" toxicity="" studies="" were="" evaluated="" to="" determine="" if="" there="" is="" a="" special="" concern="" for="" the="" safety="" of="" infants="" and="" children="" from="" exposure="" to="" residues="" of="" difenoconazole.="" there="" was="" no="" evidence="" of="" embryotoxicity="" or="" teratogenicity,="" and="" no="" effects="" on="" reproductive="" parameters,="" including="" number="" of="" live="" births,="" birth="" weights,="" and="" post-natal="" development,="" at="" dose="" levels="" which="" did="" not="" cause="" significant="" maternal="" toxicity.="" in="" addition,="" there="" were="" no="" effects="" in="" young="" post-weaning="" animals="" that="" were="" not="" seen="" in="" adult="" animals="" in="" the="" 2-generation="" reproduction="" study.="" therefore,="" novartis="" concludes="" that="" it="" is="" inappropriate="" to="" assume="" that="" infants="" and="" children="" are="" more="" sensitive="" than="" the="" general="" population="" to="" effects="" from="" exposure="" to="" residues="" of="" difenoconazole.="" f.="" estrogenic="" effects="" developmental="" toxicity="" studies="" in="" rats="" and="" rabbits="" and="" a="" 2-="" generation="" reproduction="" study="" in="" rats="" gave="" no="" specific="" indication="" that="" difenoconazole="" may="" have="" effects="" on="" the="" endocrine="" system="" with="" regard="" to="" development="" or="" reproduction.="" furthermore,="" histologic="" investigations="" were="" conducted="" on="" endocrine="" organs="" (thyroid,="" adrenal,="" and="" pituitary,="" as="" well="" as="" endocrine="" sex="" organs)="" from="" long-term="" studies="" in="" dogs,="" rats="" and="" mice.="" there="" was="" no="" indication="" that="" the="" endocrine="" system="" was="" targeted="" by="" difenoconazole,="" even="" when="" animals="" were="" treated="" with="" maximally="" tolerated="" doses="" over="" the="" majority="" of="" their="" lifetime.="" difenoconazole="" has="" not="" been="" found="" in="" raw="" agricultural="" commodities="" at="" the="" limit="" of="" quantification.="" based="" on="" the="" available="" toxicity="" information="" and="" the="" lack="" of="" detected="" residues,="" it="" is="" concluded="" that="" difenoconazole="" has="" no="" potential="" to="" interfere="" with="" the="" endocrine="" system,="" and="" there="" is="" no="" risk="" of="" endocrine="" disruption="" in="" humans.="" g.="" chemical="" residues="" the="" nature="" of="" the="" residue="" is="" adequately="" understood="" in="" plants="" and="" animals.="" the="" metabolism="" of="" difenoconazole="" has="" been="" studied="" in="" wheat,="" tomatoes,="" potatoes,="" and="" grapes.="" the="" metabolic="" pathway="" was="" the="" same="" in="" these="" 4="" separate="" and="" distinct="" crops.="" there="" are="" no="" codex="" maximum="" residue="" levels="" established="" for="" residues="" of="" difenoconazole="" in="" bananas.="" novartis="" has="" submitted="" a="" practical="" analytical="" method="" for="" detecting="" and="" measuring="" levels="" of="" difenoconazole="" in="" or="" on="" food="" with="" the="" limit="" of="" quantitation="" that="" allows="" monitoring="" of="" food="" with="" residues="" at="" or="" above="" the="" levels="" set="" in="" the="" proposed="" tolerances.="" epa="" will="" provide="" information="" on="" this="" method="" to="" fda.="" the="" method="" is="" available="" to="" anyone="" who="" is="" interested="" in="" pesticide="" residue="" enforcement="" from="" the="" field="" operations="" division,="" office="" of="" pesticide="" programs.="" confirmatory="" methods="" have="" also="" been="" supplied.="" eleven="" field="" residue="" studies="" were="" conducted="" in="" the="" major="" banana-="" producing="" regions="" of="" central="" america="" (belize,="" costa="" rica,="" guatemala),="" south="" america="" (ecuador),="" and="" mexico.="" up="" to="" 8="" applications="" were="" made="" at="" the="" label="" maximum="" of="" 100="" g="" a.i./ha.="" some="" applications="" were="" made="" at="" a="" 200="" g="" a.i./ha="" (2="" x="" )="" rate="" for="" comparison="" purposes.="" samples="" of="" bagged="" (standard="" commercial="" practice="" in="" many="" countries)="" and="" unbagged="" bananas="" were="" obtained="" 0,="" 1,="" and="" 2="" days="" after="" the="" last="" application.="" ten="" studies="" were="" conducted="" using="" ground="" equipment="" and="" one="" study="" was="" applied="" by="" air.="" six="" replicate="" bunches="" were="" collected="" in="" several="" studies="" to="" determine="" sample="" variation.="" selected="" samples="" were="" split;="" one-half="" was="" frozen="" immediately="" and="" the="" other="" half="" was="" stored="" under="" refrigerated="" or="" room="" temperature="" conditions="" to="" mimic="" typical="" transport="" to="" market.="" samples="" were="" separated="" into="" peel="" and="" pulp="" for="" analysis="" using="" analytical="" method="" ag-575a.="" difenoconazole="" was="" found="" in="" only="" 4="" of="" 76="" pulp="" samples="" at="" the="" 1="" x="" rate="" and="" 5="" of="" 36="" samples="" at="" the="" exaggerated="" (2="" x="" )="" rate.="" the="" maximum="" residues="" found="" in="" pulp="" were="" 0.03="" ppm="" and="" 0.05="" ppm="" for="" the="" 1="" x="" and="" 2="" x="" treatments,="" respectively.="" on="" a="" whole="" fruit="" basis,="" the="" maximum="" residues="" found="" for="" the="" 1="" x="" and="" 2="" x="" treatments="" were="" 0.16="" ppm="" and="" 0.24="" ppm,="" respectively.="" residues="" in="" bagged="" fruit="" were="" generally="" lower="" than="" unbagged="" fruit.="" residues="" were="" independent="" of="" the="" preharvest="" intervals="" (phis)="" used="" in="" these="" studies.="" the="" data="" support="" a="" 0.2="" ppm="" tolerance="" in="" bananas="" with="" no="" phi.="" there="" were="" no="" differences="" in="" residues="" between="" samples="" of="" green="" fruit="" frozen="" immediately="" and="" fruit="" allowed="" to="" ripen="" at="" temperatures="" normally="" encountered="" in="" transit="" to="" the="" us,="" indicating="" some="" residue="" stability="" even="" at="" temperatures="" above="" freezing.="" freezer="" storage="" stability="" has="" also="" been="" demonstrated.="" banana="" whole="" fruit="" samples="" were="" macerated,="" fortified="" at="" 0.2="" ppm="" with="" difenoconazole,="" and="" stored="" for="" one="" year="" in="" the="" freezer.="" samples="" analyzed="" at="" 0-,="" 28-,="" 84-,="" 168-,="" and="" 364-day="" intervals="" exhibited="" no="" degradation="" of="" the="" difenoconazole,="" demonstrating="" stability="" under="" these="" storage="" conditions.="" information="" on="" the="" transfer="" of="" residues="" to="" animals="" is="" not="" required="" or="" relevant="" to="" this="" petition.="" since="" there="" are="" no="" animal="" feedstuffs="" produced="" from="" this="" use="" on="" bananas,="" transfer="" of="" residues="" to="" livestock="" will="" not="" occur.="" there="" are="" no="" codex="" tolerances="" established="" for="" difenoconazole="" in="" bananas.="" h.="" environmental="" fate="" although="" the="" import="" tolerance="" for="" bananas="" would="" not="" lead="" to="" the="" exposure="" of="" the="" general="" population="" to="" residues="" of="" pesticides="" in="" the="" environment,="" these="" sources="" of="" exposure="" were="" considered="" in="" the="" risk="" assessment.="" difenoconazole="" is="" hydrolytically="" stable="" in="" solution="" at="" 25="" degrees="" celcius="" at="" ph="" 5,="" 7,="" and="" 9.="" the="" aerobic="" soil="" metabolism="" half-="" life="" ranges="" from="" 75="" to="" over="" 1,000="" days="" in="" various="" soils="" and="" environmental="" conditions.="" difenoconazole="" is="" considered="" to="" be="" immobile="" in="" soil.="" (pm="" 22)="" 4.="" novartis="" crop="" protection="" inc.="" pp="" 6f4723="" epa="" has="" received="" a="" pesticide="" petition="" (pp)="" 6f4723="" from="" novartis="" crop="" protection,="" inc.="" (novartis),="" 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.="" section="" 346a,="" to="" amend="" 40="" cfr="" 180.474="" by="" establishing="" revised="" tolerances="" for="" residues="" of="" the="" fungicide="" cga329351="" ([(r)-2-[(2,6-dimethylphenyl)-methoxyacetylamino]-propionic="" acid="" methyl="" ester).="" cga329351="" is="" the="" more="" active="" enantiomer="" contained="" in="" the="" racemic="" fungicide="" metalaxyl.="" novartis="" believes="" [[page="" 40084]]="" that="" because="" of="" its="" systemic="" and="" intrinsic="" activity,="" effective="" disease="" control="" can="" be="" obtained="" with="" mefenoxam="" at="" one-half="" the="" rate="" required="" for="" metalaxyl.="" this="" petition="" reflects="" the="" reduced="" dietary="" exposure="" associated="" with="" using="" cga329351.="" a.="" residue="" chemistry="" 1.="" cga329351="" uses.="" cga329351="" is="" highly="" efficacious="" against="" pythium="" spp.,="" phytophthora="" spp.,="" and="" fungi="" which="" cause="" downy="" mildews="" of="" turf,="" ornamental,="" and="" agricultural="" crops.="" application="" methods="" include="" seed="" treatment,="" in-furrow,="" soil="" drenches,="" and/or="" foliar.="" 2.="" metabolism.="" novartis="" believes="" the="" studies="" supporting="" this="" cga329351="" petition="" well="" characterize="" metabolism="" in="" plants="" and="" animals.="" the="" metabolism="" profile="" supports="" the="" use="" of="" an="" analytical="" enforcement="" method="" that="" accounts="" for="" combined="" residues="" of="" cga329351="" and="" its="" metabolites="" which="" contain="" the="" 2,6-dimethylaniline="" (dma)="" moiety.="" 3.="" analytical="" methodology.="" novartis="" has="" submitted="" a="" practical="" analytical="" method="" involving="" extraction,="" filtration,="" acid="" reflux,="" steam="" distillation,="" and="" solid="" phase="" cleanup="" with="" analysis="" by="" confirmatory="" gas="" chromatography="" using="" nitrogen/phosphorous="" (n/p)="" detection.="" a="" total="" residue="" method="" is="" used="" for="" determination="" of="" the="" combined="" residues="" of="" cga329351="" and="" its="" metabolites="" which="" contain="" the="" 2,6-dimethylaniline="" (dma)="" moiety.="" the="" limit="" of="" quantitation="" (loq)="" for="" the="" method="" is="" 0.05="" ppm.="" 4.="" magnitude="" of="" residue.="" this="" petition="" is="" supported="" by="" field="" residue="" trials="" conducted="" at="" various="" rates,="" timing="" intervals,="" and="" applications="" methods="" to="" represent="" the="" use="" patterns="" which="" would="" most="" likely="" result="" in="" the="" highest="" residues.="" in="" comparative="" side-by-side="" residue="" tests="" where="" cga329351="" was="" applied="" at="" one-half="" the="" labeled="" use="" rate="" of="" metalaxyl,="" resultant="" cga329351="" residues="" averaged="" one-half="" of="" those="" produced="" from="" the="" use="" of="" metalaxyl.="" for="" all="" samples,="" the="" total="" residue="" method="" was="" used="" for="" determination="" of="" the="" combined="" residues="" of="" parent="" and="" its="" metabolites="" which="" contain="" the="" dma="" moiety.="" b.="" toxicological="" profile="" of="" cga329351="" rat="" acute="" oral="" study="" with="" a="">50 value of 490 mg/kg.
Rat acute dermal study with a LD50 > 2000 mg/kg.
Rat inhalation study with a LC50 > 2.29 mg/liter air.
Primary eye irritation study in rabbit showing CGA329351 as
severely irritating.
Primary dermal irritation study in rabbit showing CGA329351 as
slightly irritating.
Skin sensitization studies in guinea pigs (Maximization and Buehler
Test) showing CGA329351 is not a sensitizer.
A 28-days cumulative toxicity study in rats with a No Observed
Effect Level (NOEL) of 50 mg/kg based on liver changes.
A 90-day subchronic dietary toxicity study in rats with a NOEL of
250 ppm based on liver changes.
A 90-day subchronic dietary toxicity study in dogs with a NOEL of
250 ppm basedon changes in blood biochemistry and hematology indicative
of functional liver changes.
A 21-day dermal toxicity study in rats with a NOEL equal to or
higher than the limit dose of 1,000 mg/kg. No local or systemic signs
of toxicity were found.
A 6-month dietary toxicity study in dogs with a NOEL of 250 ppm
based on changes in blood biochemistry indicative of hepatocellular
damage.
A 24-month combined chronic toxicity / carcinogenicity study
conducted in rats with a NOEL of 250 ppm based on liver changes. No
evidence of oncogenicity was seen.
A 24-month oncogenicity study conducted in mice with a NOEL of 250
ppm based on liver changes. No evidence of oncogenicity was seen.
Teratology study in rats with a maternal NOEL of 10 mg/kg based on
reduced body weight gain. The fetuses remained entirely unaffected at
the highest dose tested, 250 mg/kg.
Teratology study in rabbits with a maternal NOEL of 150 mg/kg based
on body weight loss. The developmental NOEL was greater than or equal
to the highest dose tested, 300 mg/kg.
3-generation reproduction study in rats with a NOEL of 1,250 ppm,
which was the highest dose tested. The treatment had no effect on
reproduction or fertility.
In vitro gene mutation test: Ames test - negative.
In vitro chromosomal aberration test: Chinese hamster ovary (CHO)-
negative.
In vitro gene mutation tests: Ames tests (3 independent studies) -
negative; gene mutation in mouse lymphoma cells - negative; reverse
mutation in Saccharomyces cerevisiae - negative.
In vitro chromosomal aberration tests: Chinese hamster bone marrow
cytogenetic test - negative.
DNA repair study in rat hepatoctes - negative.
Dominant lethal study in mouse - negative.
C. Threshold Effects
1. Chronic effects. Based upon chronic toxicity data, Novartis
believes the Reference Dose (RfD) for CGA329351 is 0.08 mg/kg/day. This
RfD is based on a 6-months feeding study conducted in dogs using an
uncertainty factor of 100. The No-Observed Effect Level was 8 mg/kg/
day.
2. Acute toxicity. The risk from acute dietary exposure to
CGA329351 is considered to be very low. The NOEL in a 28-day study was
50 mg/kg, which is 6-fold higher than the chronic NOEL. Since chronic
exposure assessment did not result in any unacceptable exposure for
even the most impacted population subgroup, it is anticipated that also
the acute exposure will be in an acceptable range.
3. Non-threshold effects. From toxicity studies supporting the
registration of CGA329351, the active ingredient is classified as a
Group ``E'' compound (evidence of noncarcinogenicty for humans). There
was no evidence of carcinogenicity in a 24-month feeding trial in mice
nor in a 24-month feeding study in rats at the dosage levels tested.
The doses tested were adequate for identifying a cancer risk.
D. Aggregate Exposure
1. Dietary Exposure. 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). The TMRC is a ``worst case'' estimate of dietary
exposure since it assumes 100 percent of all crops for which tolerances
are established are treated. Residue studies indicate a significant
reduction in plant residue levels for CGA329351 relative to those for
metalaxyl. With use rates that are one-half that of metalaxyl,
CGA329351 plant residue levels are also 50% lower. Novartis has
requested the following tolerances for CGA329351:
------------------------------------------------------------------------
commodity parts per million (ppm)
------------------------------------------------------------------------
Alfalfa, forage........................... 3.0 ppm
Alfalfa, hay.............................. 10.0 ppm
Almonds................................... 0.3 ppm
Almond, hulls............................. 5.0 ppm
Apples.................................... 0.1 ppm
Asparagus................................. 3.5 ppm
Berries Group 1.0 ppm.....................
Brassica (Cole) Leafy Vegetable Crop 0.05 ppm
Grouping (Except Broccoli, Cabbage,
Cauliflower, Brussels Sprouts, Mustard
Greens).
Broccoli.................................. 1.0 ppm
Brussels Sprouts.......................... 1.0 ppm
[[Page 40085]]
Cabbage................................... 0.5 ppm
Cattle (fat, liver, and kidney)........... 0.2 ppm
Cattle, meat and meat by products (except 0.05 ppm
kidney and liver).
Cauliflower............................... 0.5 ppm
Cereal Grains (Except Barley, Oats, and 0.05 ppm
Wheat).
Citrus Fruits Group....................... 0.5 ppm
Clover, forage............................ 0.5 ppm
Clover, hay............................... 1.3 ppm
Cottonseed, undelinted seed............... 0.05 ppm
Cranberries............................... 2.0 ppm
Cucurbit Vegetables Group................. 0.5 ppm
Eggs...................................... 0.05 ppm
Fruiting Vegetables....................... 0.5 ppm
Ginseng................................... 1.5 ppm
Goats (fat, liver, and kidney)............ 0.2 ppm
Goat, meat and meat by products (except 0.05 ppm
kidney and liver).
Grapes.................................... 1.0 ppm
Grass, Forage............................. 5.0 ppm
Grass, Hay................................ 12.5 ppm
Hogs (fat, liver, and kidney)............. 0.2 ppm
Hogs, meat and meat by products (except 0.05 ppm
kidney and liver).
Hops cones, dried......................... 10.0 ppm
Horses (fat, liver, and kidney)........... 0.2 ppm
Horses, meat and meat by products (except 0.05 ppm
kidney and liver).
Leafy Vegetables Group (Except Brassica, 2.5 ppm
Except Spinach).
Leaves of Root and Tuber Vegetables (human 7.5 ppm
food or animal feed) Group.
Legume Vegetable Group, Foliage of........ 4.0 ppm
Legume Vegetables (succulent or dried) 0.1 ppm
Group, except Soybeans.
Milk...................................... 0.01 ppm
Mustard Greens............................ 2.5 ppm
Bulb Vegetables Group..................... 5.0 ppm
Peanut, hay............................... 10.0 ppm
Peanut, nutmeat........................... 0.1 ppm
Pineapples................................ 0.05 ppm
Poultry (fat, liver, and kidney).......... 0.2 ppm
Poultry, meat and meat by products (except 0.05 ppm
kidney and liver).
Root and Tuber Vegetables, Except Ginseng. 0.3 ppm
Sheep (fat, liver, and kidney)............ 0.2 ppm
Sheep, meat and meat by products (except 0.05 ppm
kidney and liver).
Soybeans.................................. 0.5 ppm
Spinach................................... 5.0 ppm
Stone Fruit Group......................... 0.5 ppm
Strawberries.............................. 5.0 ppm
Sunflower, seed........................... 0.05 ppm
Walnuts................................... 0.3 ppm
Papaya (Regional tolerance for Hawaii).... 0.05 ppm
Citrus Oil................................ 3.5 ppm
Potatoes, granules / flakes............... 1.0 ppm
Potatoes, chips........................... 1.0 ppm
Prunes.................................... 2.0 ppm
Raisins................................... 3.0 ppm
Tomatoes, puree........................... 1.5 ppm
Apples, pomace............................ 0.2 ppm
Citrus, dried pulp........................ 3.5 ppm
Peanut, meal.............................. 0.5 ppm
Pineapple, process residue................ 0.3 ppm
Potato, waste from processing............. 5.0 ppm
Soybeans, hulls........................... 1.0 ppm
Soybeans, meal............................ 1.0 ppm
Sugar beets, molasses..................... 2.5 ppm
Sunflower seeds, meal..................... 0.1 ppm
Wheat, milling byproducts................. 1.0 ppm
------------------------------------------------------------------------
The following indirect or inadvertent tolerances also have been
requested:
------------------------------------------------------------------------
commodity parts per million (ppm)
------------------------------------------------------------------------
Barley, forage............................ 2.0 ppm
Barley, grain............................. 0.2 ppm
Barley, hay............................... 6.0 ppm
Barley, straw............................. 2.0 ppm
Forage, Fodder, and Straw of Cereal Grains 1.0 ppm
Group (except wheat, barley, and oats)
Fodder, Forage and Straw.
Forage, Fodder, and Straw of Cereal Grains 3.0 ppm
Group (except wheat, barley, and oats)
Fodder, Forage and Hay.
Oat, forage............................... 2.0 ppm
Oat, hay.................................. 6.0 ppm
Oat, grain................................ 0.2 ppm
Oat, straw................................ 2.0 ppm
Wheat, forage............................. 2.0 ppm
Wheat, hay................................ 6.0 ppm
Wheat, grain.............................. 0.2 ppm
Wheat, straw.............................. 2.0 ppm
Barley, milling fractions................. 1.0 ppm
Oat, milling fractions.................... 1.0 ppm
Wheat, milling fractions.................. 1.0 ppm
------------------------------------------------------------------------
In conducting this exposure assessment, Novartis has made very
conservative assumptions -- 100% of all requested commodities will
contain CGA329351 at tolerance levels which result in an overestimate
of human exposure.
2. Drinking water exposure. Novartis anticipates the potential
exposure from residues of CGA329351 in drinking water to be relatively
low. Although the potential for groundwater contamination cannot be
completely excluded where soils are highly permeable and the water
table is shallow, the reduced use rate associated with CGA329351
reduces potential groundwater contamination relative to that for
metalaxyl. Based on historical groundwater monitoring data for
metalaxyl from 5 states, levels typically do not exceed 3 ppb. This
contamination level would lead to a potential uptake of 0.09 x 10-3 mg/
kg/day CGA329351 (for an adult person consuming 2 liters of water per
day), which is equivalent to 0.1% of the RfD. On the basis of this
worst case estimate for CGA329351, Novartis concludes that the
contribution of any potential groundwater contamination will be
negligible.
3. Non-dietary exposure. In addition to uses on agricultural crops,
CGA329351 is registered for use against soil-borne disease in turf and
ornamentals. The product, however, is not used residentially by
homeowners and potential exposure to the general public is extremely
low. Novartis believes the non-occupational exposure to the general
public from turf andornamentals uses of CGA329351 to be negligible.
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 CGA329351 would be
cumulative with those of any other chemicals. Consequently, Novartis is
considering only the potential exposure to CGA329351 in its aggregate
risk assessment.
E. Safety Determination
1. U.S. population. Under the conservative exposure assumptions of
100 percent of all crops for which tolerances are established are
treated, and CGA329351 residue levels are at tolerance level (i.e.,
TMRC), less than 9% of the RfD will be utilized by the U.S. general
population. EPA generally has no concern for exposures below 100
percent of the RfD. Therefore, based on the completeness and
reliability of the toxicity data supporting this petition, Novartis
believes that there is a reasonable certainty that no harm will result
from aggregate exposure to residues of CGA329351, including anticipated
dietary exposure and all other types of non-occupational exposures.
2. Infants and children. There is no indication that CGA329351
interferes with the pre-or neonatal development, even when experimental
animals were exposed to very high doses leading to maternal toxicity.
Infants and children are not expected to show any particular
sensitivity to CGA329351. Calculated on the basis of the TMRC,
utilization of RfD from dietary exposure of children is estimated as:
6% for nursing infants less than 1 year old, 16% for non-nursing
infants less than 1 year old, 18% for 1 to 6 year old and 13% for
children 7-12 years old.
Novartis believes that under the worst case assumptions which
overestimate exposure to infants and children, there is a reasonable
certainty that no harm
[[Page 40086]]
will result to infants and children form aggregate exposure to
CGA329351.
F. Estrogenic Effects
CGA329351 does not belong to a class of chemicals known or
suspected of having adverse effects on the endocrine system.
Furthermore, supporting developmental toxicity studies in rats and
rabbits and a reproduction study in rats gave no indication of any
effects on endocrine function related to development and reproduction.
Subchronic and chronic treatment did not induce any morphological
changes in endocrine organs and tissues.
G. International Tolerances
There are no Codex Alimentarius Commission (CODEX) maximum residue
levels (MRL's) established for residues of CGA329351 in or on raw
agricultural commodities. (PM 21)
[FR Doc. 97-19669 Filed 7-24-97; 8:45 am]
BILLING CODE 6560-50-F
