[Federal Register Volume 62, Number 195 (Wednesday, October 8, 1997)]
[Notices]
[Pages 52552-52558]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-26535]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-765; FRL-5745-9]
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-765, must
be received on or before November 7, 1997.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Division
(7506C), Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 1132, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically to: docket@epamail.epa.gov. Follow the instructions under ``SUPPLEMENTARY
INFORMATION.'' No confidential business information should be submitted
through e-mail.
Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
Confidential Business Information (CBI). CBI should not be submitted
through e-mail. Information marked as CBI will not be disclosed except
in accordance with procedures set forth in 40 CFR part 2. A copy of the
comment that does not contain CBI must be submitted for inclusion in
the public record. Information not marked confidential may be disclosed
publicly by EPA without prior notice. All written comments will be
available for public inspection in Rm. 1132 at the address given above,
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal
holidays.
FOR FURTHER INFORMATION CONTACT: The product manager listed in the
table below:
[[Page 52553]]
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Office location/
Product Manager telephone number Address
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Joe Tavano.................... Rm. 214, CM #2, 703- 1921 Jefferson
305-6411, e-mail: Davis Hwy,
[email protected] Arlington, VA
a.gov.
Bipin Gandhi,................. Rm. 4W53, CS #1, 703- 2800 Crystal
308-8380, e-mail: Drive,
[email protected] Arlington, VA
epa.gov.
Eugene Wilson................. Rm. 245, CM #2, 703- 1921 Jefferson
305-6103, e-mail: Davis Hwy,
[email protected] Arlington, VA
.epa.gov.
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SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as
follows proposing the establishment and/or amendment of regulations for
residues of certain pesticide chemicals in or on various food
commodities under section 408 of the Federal Food, Drug, and Comestic
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these petitions
contain data or information regarding the elements set forth in section
408(d)(2); however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data supports granting of
the petition. Additional data may be needed before EPA rules on the
petition.
The official record for this notice of filing, as well as the
public version, has been established for this notice of filing under
docket control number [PF-765] (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 number PF-765 and appropriate petition number.
Electronic comments on notice may be filed online at many Federal
Depository Libraries.
List of Subjects
Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: September 25, 1997.
James Jones,
Actinig Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Petitioner summaries of the pesticide petitions are printed below
as required by section 408(d)(3) of the FFDCA. The summaries of the
petitions were prepared by the petitioners and represent the views of
the petitioners. EPA is publishing the petition summaries verbatim
without editing them in any way. The petition summary announces the
availability of a description of the analytical methods available to
EPA for the detection and measurement of the pesticide chemical
residues or an explanation of why no such method is needed.
1. B2E Corporation
PP 7E4907
EPA has received a pesticide petition (PP 7E4907) from B2E
Corporation, 16 School Street, Rye, NY 10580 proposing pursuant to
section 408(d) of the Federal Food, Drug and Cosmetic Act,(FFDCA) 21
U.S.C. 346a(d), to amend 40 CFR part 180 to establish an exemption from
the requirement of a tolerance for 2-Hydroxyacetophenone (2-HAP) in or
on the raw agricultural commodity. The proposed analytical method
involves homogenization, filtration, partition and cleanup with
analysis by high performance liquid chromatography using UV detection.
EPA has determined that the petition contains data or information
regarding the elements set forth in section 408(d)(2) of the FFDCA;
however, EPA has not fully evaluated the sufficiency of the submitted
data at this time or whether the data supports granting of the
petition. Additional data may be needed before EPA rules on the
petition.
A. Toxicological Profile
1. Acute toxicity. A rat acute oral study with an LD50 >
500 milligrams/kilogram (mg)/(kg), a rabbit acute dermal toxicity study
with an LD50 > 2,000 mg/kg, a primary eye irritation study
in the rabbit showing no irritation, a rabbit primary dermal irritation
study showing 2-HAP is not an irritant, a skin sensitization study in
guinea pigs showing 2-HAP is a slight skin sensitizer, and a 28 day rat
inhalation study with a no observed-effect-level (NOEL) of 160
milligrams/cubic meter (mg)/(m3).
2. Genotoxicty. 2-HAP was tested in the Ames Salmonella/microsome
plate incorporation assay both in the presence and the absence of a
metabolic activation system. Under the conditions of the assay, 2-HAP
did not exhibit genetic activity according to the assay criteria. It
can therefore be considered non-mutagenic.
3. Ecotoxicity. A study of acute toxicity to Bluegill Sunfish was
conducted at five nominal concentrations, selected on the basis of
preliminary toxicity screening, as well as a control and the solvent
(acetone). The fish (10 in each replicate) were observed at 24, 48, 72
and 96 hour intervals for signs of toxic effects and mortality. 2-HAP
was determined to have an LC50 (96 hours) of 115 milligrams/
liter (mg)/(L) and a no observed effect-concentration (NOEC) of 31.3
mg/L.
A study of acute toxicity to Daphnids was conducted at five nominal
concentrations as well as a control and solvent (acetone) over 48 hours
(hrs). They were observed at 24 and 48 hours for signs of toxic effects
and mortality. 2-HAP was calculated to have an EC50 (48 hr)
of 57 mg/L under these conditions. The NOEC was found to be 25 mg/L.
B. Environmental Fate
Aerobic soil metabolism was evaluated by a Ready Biodegradation by
CO2 Production study. The test liquid was added to test
medium at 10 and 20 mg/L. Unacclimated diluted inoculum (20 ml, 1.3
million CFU. ml) was added to 2 liters of diluted test material,
positive control material (glucose at 20 milligrams/milliter (mg)/(ml)
or control medium. Carbon dioxide free air was bubbled through the
stirred 22.6-23.2 deg. C. incubation mixtures and carbon dioxide
collected for 28 days. Carbon dioxide was measured by titration of
barium hydroxide traps at regular intervals of the study. Percent
biodegradation was estimated by percent of theoretical carbon dioxide
[[Page 52554]]
(TCO2) production achieved based on the empirical formula,
assuming that all organic carbon in the test material is converted to
carbon dioxide, and by measurement of total organic carbon (TOC)
remaining after the 28 day incubation.
After a lag of about 1 day, test material carbon dioxide production
achieved 93.2% (at 10 mg/L) and 86.7% (at 20 mg/l) TCO2 28
days after study start. The soluble organic carbon content at study
termination was < 0.5="" mg/l="" and="" 0.7="" mg/l="" initial="" concentrations="" of="" test="" material="" respectively.="" this="" corresponds="" to="" 100%="" (at="" 10="" mg/l)="" and="" 98.6%="" (at="" 20="" mg/l)="" removal="" of="" test="" material="" also="" indication="" effective="" mineralization.="" the="" 2-hap="" produced="" greater="" than="" 60%="" of="" the="">2 within
28 days of incubation and can be considered readily biodegradable.
Anaerobic degradation is not expected to be a factor given the
application of the product.
C. Aggregate Exposure
1. Dietary exposure. Dietary exposure for 2-HAP is expected to be
negligible for the application of 2-HAP in non-food use pesticides. If
2-HAP were to be incorporated in pesticides used for food crops, the
level of 2-HAP would be at most, a small fraction of the acceptable
tolerances of the pesticides. The use level within the pesticide is
only a maximum of 0.1% by weight. The rapid biodegradability make
significant uptake into plant tissue unlikely. Human exposure may be
expected to be within acceptable (note: FDA classifies this as a GRAS
material for use in meat products, poultry, condiments, soups and
seasonings) limits.
2. Drinking water. Although 2-HAP is not considered to be
hydrolyzable, it is readily biodegradable. Use levels at a maximum of
0.1% within pesticides also make it unlikely that there will be a
presence in groundwater. Based on this data, exposure to residues in
drinking water in not anticipated. The EPA has not established a
Maximum Concentration Level for residues of 2-HAP in drinking water.
3. Non-dietary exposure. Evaluations by B2E Corporation of the
estimated non-occupational exposure to 2-HAP have concluded that the
potential exposure for the general population may be from residues in
food crops discussed above. Another possible exposure is from the use
on turf of pesticides containing 2-HAP as an inert. The route of
exposure would be dermal (assuming that people would be walking
barefoot on treated areas) and the material has been shown to have a
low order of acute dermal toxicity (rabbit - LD50 10,300 mg/
kg).
D. Cumulative Effects
B2E Corporation considered the potential for cumulative effects of
2-HAP and similar substances that may have a common mechanism of
toxicity. there is no information to indicate that toxic effects that
might be found at high levels of exposure to 2-HAP would be cumulative
with other chemical compounds. The potential risks of 2-HAP are judged
solely in its aggregate exposure.
E. Safety Determination
1. U.S. population. Based on the exposure assumptions and the
toxicity data described above, there is no appreciable risk to human
health. It can be concluded that there is a reasonable certainty that
no harm will result from aggregate exposure to 2-HAP residues.
2. Infants and children. Based on the use patterns of the material
and the levels of exposure, there is a reasonable certainty that no
harm will result to infants and children from aggregate exposure to 2-
HAP residue.
F. International Tolerances
No international tolerances have been established.
2. Novartis Crop Protection, Inc.
PP 6F4616, 6F4617, 6F4618, & 6F4633
EPA has received a pesticide petition (PP 6F4616, 6F4617, 6F4618, &
6F4633) from Novartis Crop Protection, Inc., P.O. Box 18300,
Greensboro, NC 27419-8300 proposing pursuant to section 408(d) of the
Federal Food, Drug and Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR
part 180 by establishing a tolerance for residues of Fenoxycarb,
ethyl[2-(4-phenoxyphenoxy)ethyl]carbamate in or on the raw agricultural
commodities: pome fruit at 0.02 parts per million (ppm); nutmeat at
0.05 ppm; almond hulls at 4.0 ppm; citrus fruit at 0.05 ppm; grass
Forage (except Bluegrass) at 0.6 ppm; grass hay (except Bluegrass) at
0.5 ppm; milk, meat and meat byproducts of cattle, goats, hogs, horses
and sheep at 0.01 ppm; and fat of cattle, goats, hogs, horses and sheep
at 0.05 ppm. The proposed analytical method involves Column switching
high performance liquid chromatography and UV detection. EPA has
determined that the petitions contain data or information regarding the
elements set forth in section 408(d)(2) of the FFDCA; however, EPA has
not fully evaluated the sufficiency of the submitted data at this time
or whether the data supports granting of the petition. Additional data
may be needed before EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The metabolism of fenoxycarb in plants
(apples, citrus and grass) is well understood. Identified metabolic
pathways are similar in plants and animals. It has been determined that
fenoxycarb, per se, is the residue of concern for tolerance setting
purposes.The metabolism of fenoxycarb in plants (apples, citrus and
grass) is well understood. Identified metabolic pathways are similar in
plants and animals. It has been determined that fenoxycarb, per se, is
the residue of concern for tolerance setting purposes.
2. Analytical method. Novartis Crop Protection Inc. has submitted
practical analytical methodology for detecting and measuring levels of
fenoxycarb in or on food. The limits of detection (2.5 ng) and
quantitation (0.01 ppm) allow monitoring of food with residues at or
above the levels in the proposed tolerances. All methods are based on
crop specific cleanup procedures and determination nce liquid
chromatography with column-switching and UV detection.
3. Magnitude of residues. Residue trials: 15 residue trials in 8
states on apples and pears; 16 field trials in 13 states on grasses; 13
residue trials in 4 states on citrus; 8 residue trials in 6 states on
tree nuts. No residues of fenoxycarb (0.01 ppm) were found in apples or
pears treated at the maximum labeled rate. The maximum residues found
in grasses were 0.056 ppm in forage and 0.041 in hay. Only one
detectable residue at 0.02 ppm was found on citrus. This grapefruit
sample was aerially treated with the maximum labeled rate. The maximum
residue found in nutmeats treated at the maximum labeled rate was 0.02
ppm.
B. Toxicological Profile
1. Acute toxicity. The following acute toxicity studies have been
conducted to support the proposed tolerance for fenoxycarb. The studies
indicate that fenoxycarb has a low order of acute toxicity with effects
in catgegory III and IV.
\ Rat acute oral study with an LD50 >10,000 mg/kg.
\ Rabbit acute dermal study with an LD50 > 2,000 mg/kg.
\ Rat inhalation study with an LC50 > 4.4 mg/L.
\ Primary eye irritation study in the rabbit showing slight eye
irritation.
\ Primary dermal irritation study in the rabbit showing fenoxycarb
is not a skin irritant.
[[Page 52555]]
\ Skin sensitization study showing fenoxycarb is not a skin
sensitizer in the Guinea pig.
\ Dermal absorption study showing a maximum of 30.2% of fenoxycarb
is absorbed by the rat following a 24 hour dermal exposure.
2. Genotoxicty. Results from the following assays indicate that
fenoxycarb is not genotoxic: Ames Assay - Negative; Mouse Micronucleus
Test - Negative; Saccharomyces cerevisiae D7 test - Negative.
3. Reproductive and developmental toxicity. Novartis conducted a
teratogenicity study in the rat at doses of 0, 50, 150, or 500 mg/kg/
day by gavage with maternal and developmental NOELs of 500
mg/kg/day.
Novartis also conducted a teratogenicity study in the rabbit at
doses of 0, 30, 100, 200 or 300 mg/kg/day. The maternal NOEL based on
reduced body weight gains was 100 mg/kg/day. The developmental NOEL was
300 mg/kg/day.
In a 2-generation reproduction study, rats were dosed of 0, 200,
600 or 1,800 ppm. The systemic NOEL was 200 ppm based on decreased body
weight gains and food consumption, increased gonad weights (without
effects on reproductive performance or a morphological correlate),
liver hypertrophy and focal necrosis and increased liver weights. There
were no effects on fertility or reproductive performance. Based on
decreased pup weights and slight delays in pinna unfolding and eye
opening, there was no clear developmental NOEL. A derived NOEL (DNOEL),
determined using analysis of variance and regression, was 40 ppm.
4. Subchronic toxicity. Novartis conducted a 21-day dermal study in
which fenoxycarb was applied to the shaved skin of 5 male and 5 female
New Zealand White rabbits at dose levels of 0, 20, 200, or 2,000 mg/kg
for 21 consecutive days. The only effect observed was a slight increase
in liver weights at the high dose. However, there was no
histopathological correlate to this finding and the change was
interpreted as representing an adaptive response. The NOEL was 200 mg/
kg.
In a 6-month oral (capsule) study of dogs dosed at 0, 50, 150 or
500 mg/kg/day, the NOEL was 150 mg/kg/day based on reduced weight gain
in females.
In a 90-day feeding study, Sprague Dawley rats were fed fenoxycarb
at dietary concentrations to result in doses of 0, 80, 250 or 800 mg/
kg/day. Based on slight liver weight increases at 80 mg/kg/day, the
NOEL was < 80="" mg/kg/day.="" novartis="" conducted="" a="" 90-day="" feeding="" study="" in="" mice="" in="" which="" mice="" were="" fed="" dietary="" concentrations="" of="" fenoxycarb="" to="" result="" in="" doses="" of="" 0,="" 100,="" 300="" or="" 900="" mg/kg/day.="" based="" on="" increased="" liver="" weight="" accompanied="" by="" fatty="" changes,="" glycogen="" depletion="" and="" increased="" multinucleated="" hepatocytes,="" the="" noel="" was="" 100="" mg/kg/day.="" rats="" in="" a="" 21-day="" inhalation="" study="" were="" exposed="" to="" 0,="" 0.01,="" 0.10="" or="" 1.13="" mg/l="" for="" 6="" hrs/day/5="" days/week.="" based="" on="" decreased="" body="" weight="" gain="" in="" males="" and="" increased="" liver="" weight="" in="" females="" the="" noel="" was="" 0.10="" mg/l.="" 5.="" chronic="" toxicity.="" in="" a="" 52="" week="" oral="" (capsule)="" study,="" dogs="" were="" dosed="" at="" levels="" of="" 0,="" 25,="" 80="" or="" 260="" mg/kg/day.="" based="" on="" decreased="" body="" weight="" gain="" and="" food="" consumption="" and="" decreases="" in="" adrenal="" weights="" and="" inorganic="" phosphorous="" the="" noel="" was="" 25="" mg/kg/day.="" in="" a="" 24-month="" chronic="" feeding="" and="" oncogenicity="" study,="" rats="" were="" dosed="" at="" levels="" of="" 0,="" 200,="" 600="" or="" 1,800="" ppm.="" based="" on="" liver="" toxicity="" (non-neoplastic="" histopathology="" and="" increased="" liver="" enzymes)="" the="" noel="" was="" 200="" ppm.="" there="" was="" no="" evidence="" of="" carcinogenic="" potential.="" in="" an="" 80-week="" chronic="" feeding="" and="" oncogenicity="" study,="" mice="" were="" dosed="" at="" 0,="" 30,="" 110="" or="" 420="" ppm="" for="" males="" and="" 0,="" 20,="" 80="" or="" 320="" ppm="" for="" females.="" systemic="" toxicity="" was="" not="" observed="" at="" any="" level.="" the="" noel="" for="" chronic="" toxicity="" was=""> 420 ppm and 320 ppm for males and
females, respectively. There was evidence of carcinogenic potential.
Lung adenomas and combined adenoma/carcinoma in addition to Harderian
gland tumor incidences were increased in males at 420 ppm.
In an 18-month oncogenicity study, mice were dosed at 0, 10, 50,
500 or 2,000 ppm with a NOEL of 50 ppm (5 - 6 mg/kg/day). A
carcinogenic response was noted in the lung in males and females at 500
and 2,000 ppm and in the liver of male mice at 500 and 2,000 ppm.
In a study investigating biochemical parameters in livers, mice
were treated at doses of 0, 50, 500 or 2,000 ppm showing that
fenoxycarb is a strong inducer of hepatic xenobiotic metabolizing
enzymes in the mouse and can be classified as a peroxisome
proliferator..
6. Animal metabolism. The metabolism of fenoxycarb in animals (goat
and rat) is well understood. It has been determined that fenoxycarb,
per se, is the residue of concern in animal commodities for tolerance
setting purposes.
C. Aggregate Exposure
1. Food. For purposes of assessing the potential dietary exposure
under the proposed tolerances, Novartis has estimated aggregate
exposure based on exposure from anticipated residues on pome fruit,
tree nuts, citrus, cattle meat and milk. Since there were no detections
of fenoxycarb in pome fruit, tree nuts or citrus treated according to
label directions, the anticipated residue of 0.005 ppm, one-half the
limit of quantitation, was used. Exposure via meat and milk comes from
the possible consumption by cattle of almond hulls, grass, citrus pulp
and apple pomace. Theoretical residues in milk make up greater than 50%
of the possible exposure to fenoxycarb. Almost all of the theoretical
residue in milk comes from almond hulls in the theoretical diet for
cattle. The anticipated residue in milk is greatly exaggerated since
almond hulls, in general, are not a significant portion of cattle diet.
Percent crop treated figures for food crops and cattle feed were also
used in the analysis.
2. Drinking water. The product chemistry data for fenoxycarb
indicate that movement of fenoxycarb into drinking water would be
unlikely and that fenoxycarb would be expected to have a strong
affinity for binding to the soil. Soil metabolism data further
demonstrate that fenoxycarb and its residues have an affinity for
binding to soil, and thus a low propensity to move from the soil
surface. Field studies in Washington, Georgia and in California showed
that fenoxycarb did not move below the top 6 inches of the soil. Based
on the available data, Novartis does not anticipate exposure to
residues of fenoxycarb in drinking water. There is no established
Maximum Contaminant Level for residues of fenoxycarb in drinking water
The product chemistry data for fenoxycarb indicate that movement of
fenoxycarb into drinking water would be unlikely and that fenoxycarb
would be expected to have a strong affinity for binding to the soil.
Soil metabolism data further demonstrate that fenoxycarb and its
residues have an affinity for binding to soil, and thus a low
propensity to move from the soil surface. Field studies in Washington,
Georgia and in California showed that fenoxycarb did not move below the
top 6 inches of the soil. Based on the available data, Novartis does
not anticipate exposure to residues of fenoxycarb in drinking water.
There is no established Maximum Contaminant Level for residues of
fenoxycarb in drinking water.
[[Page 52556]]
3. Non-dietary exposure. Other potential sources of exposure of the
general population to residues of pesticides are exposure from non-
occupational sources. Novartis has estimated non-occupational exposure
to fenoxycarb and concludes that the potential for exposure is
insignificant. The potential for non-occupational exposure to
fenoxycarb resulting from use of pet sprays or carpet sprays containing
fenoxycarb is not included in safety determinations for the U.S.
population and infants (shown below) since the registrations for these
uses have been canceled. Exposure through turf uses of fenoxycarb as a
fire ant bait is also considered not significant. Used as a fire ant
bait, fenoxycarb is only applied to turf with active fire ant
infestations and has no efficacy as a preventive treatment. Turf
infested with fire ants is not commonly used for recreational
activities because of the danger presented by fire ants. In addition,
studies demonstrate that > 95% of the bait applied to fire ant
infestations is removed by the ants within 24 hours. Therefore
opportunity for exposure to fenoxycarb as a fire ant bait through
treated turf is extremely small.
D. Cumulative Effects
Novartis also considered the potential for cumulative effects of
fenoxycarb and other substances that have a common mechanism of
toxicity. Novartis concluded that consideration of a common mechanism
of toxicity is not appropriate at this time. Novartis does not have
reliable information to indicate that toxic effects produced by
fenoxycarb would be cumulative with those of any other chemical
compounds; thus Novartis is considering only the potential risks from
dietary exposure of fenoxycarb in its aggregate exposure assessment.
E. Safety Determination
1. U.S. population. Using the exposure assumptions described above
and based on the completeness and reliability of the toxicity data base
for fenoxycarb, Novartis has calculated that aggregate exposure to
fenoxycarb will utilize 0.016% of the Reference Dose (RfD) for the U.S.
population - 48 states - all seasons, based on chronic toxicity
endpoints. Lifetime carcinogenic risk for dietary exposure based on
quantitative risk assessment and a Q1* of 5.6 x
10-2 (mg/kg/day)-1, is 7.31 x 10-7.
EPA generally has no concern for exposures below 100% of the RfD or
lifetime carcinogenic risks less than 1 x 10-6. Since
anticipated residues of fenoxycarb in food are extremely low and all
short term NOELs are at least an order of magnitude higher than the
chronic NOEL, no acute risk from exposure to residues of fenoxycarb is
anticipated. Therefore, Novartis concludes that there is a reasonable
certainty that no harm will result from aggregate exposure to
fenoxycarb residues.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of fenoxycarb, Novartis
considered data from developmental toxicity studies in the rat and
rabbit and a 2-generation reproduction study in the rat. No evidence of
developmental toxicity was observed in rats or rabbits. Fenoxycarb did
not impair any reproductive or postnatal development parameters and was
neither embryotoxic nor teratogenic. The NOELs for maternal and
developmental toxicity in the rat were determined to be 500
mg/kg/day. The NOEL for maternal toxicity in the rabbit, based on
reduced body weight gains, was 100 mg/kg/day and the NOEL for
developmental toxicity was 300 mg/kg/day. In a 2-generation
reproduction study in rats, the systemic NOEL for parental animals was
200 ppm based on decreased body weight gains and food consumption,
increased gonad weights (without effects on reproductive performance or
a morphological correlate), liver hypertrophy and focal necrosis and
increased liver weights. There were no effects on fertility or
reproductive performance. Based on decreased pup weights and slight
delays in pinna unfolding and eye opening, there was no clear
developmental NOEL. A NOEL of 40 ppm was derived using analysis of
variance and regression. The mild nature of the effects of fenoxycarb
on rat pups and the lack of effects in the developmental toxicity
studies suggest that there is no particular sensitivity to fenoxycarb
for infants and children.
Using the same exposure assumptions used for the determination in
the general population, Novartis has concluded that the percent of the
RfD that will be utilized by aggregate exposure to residues of
fenoxycarb is 0.038% for nursing infants less than 1 year old, 0.098%
for non-nursing infants, 0.048% for children 1-6 years old and 0.028%
for children 7-12 years old. Therefore, based on the completeness and
reliability of the toxicity data base, Novartis concludes that there is
a reasonable certainty that no harm will result to infants and children
from aggregate exposure to fenoxycarb residues.
F. International Tolerances
No Codex MRLs have been established for residues of fenoxycarb.
3. Novartis Crop Protection, Inc.
PP 7F4897
EPA has received a pesticide petition (PP 7F4897) from Novartis
Crop Protection, Inc., Greensboro, NC 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 metolachlor in or on the raw agricultural commodities
sunflower seed at 0.3 ppm and sunflower meal at 0.6 ppm. The proposed
analytical method involves extraction by acid reflux, filtration,
partition and cleanup with analysis by gas chromatography using
Nitrogen/Phosphorous (N/P) detection. EPA has determined that the
petition contains data or information regarding the elements set forth
in section 408(d)(2)of the FFDCA; however, EPA has not fully evaluated
the sufficiency of the submitted data at this time or whether the data
supports granting of the petition. Additional data may be needed before
EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The qualitative nature of the metabolism of
metolachlor in plants 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.
2. Analytical method. 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.
3. Magnitude of residues. Eight residue trials were conducted in
major sunflower growing areas of the United States [CA, KS, TX (2),
MN(2), ND, IL). Five tests were conducted with metolachlor alone and
three were conducted as a tank mix of metolachlor and another product.
Metolachlor residues were analyzed for in all trials. Applications were
made at the
[[Page 52557]]
maximum labeled rate of 3.0 lbs. active ingredient/Acre (ai/A) and at 2
times the maximum labeled rate (6.0 lbs. ai/A). A processing study was
also conducted with seeds processed into meal, hulls, crude oil,
refined oil and soapstock. According to the Revised Table II of
Subdivision O, only meal and refined oil are now required. Based on
these studies and an earlier EPA review of these data, tolerances are
proposed in sunflower seeds at 0.3 ppm and in sunflower meal at 0.6
ppm.
B. Toxicological Profile
1. Acute toxicity. Metolachlor has a low order of acute toxicity.
The combined rat oral LD50 is 2,877 mg/kg. The acute rabbit
dermal LD50 is > 2,000 mg/kg and the rat inhalation
LC50 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. Genotoxicty. 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.
3. Reproductive and developmental toxicity. 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.
4. 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.
5. 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. 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. Animal metabolism. The qualitative nature of the metabolism of
metolachlor in animals is well understood. 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.
7. Metabolite toxicology. The metabolism of metolachlor has been
well characterized in standard FIFRA rat metabolism studies. The
metabolites found are considered to be toxicologically similar to
parent. Metolachlor does not readily undergo dealkylation to form an
aniline or quinone amine as has been reported for other members of the
chloroacetanilide class of chemicals. Therefore, it is not appropriate
to include metolachlor with the group of chloroacetanilides that
readily undergo dealkylation, producing a common toxic metabolite
(quinone imine).
C. Aggregate Exposure
1. Dietary exposure. Dietary exposure consists of exposures from
food and drinking water.
2. Food. 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
sunflowers to the label was assessed by conservatively assuming that
exposure would occur at the proposed tolerance level of 0.3 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, sunflower meal) 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 an EPA review of sunflower residue data previously
submitted by Novartis, the EPA has indicated that any secondary
residues in meat, milk, poultry and eggs will be covered by existing
metolachlor tolerances.
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.
3. 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.
4. Non-dietary exposure. Although metolachlor may be used on turf
and ornamentals in a residential setting, that use represents less than
0.1% of the total herbicide market for residential turf and landscape
uses. Currently, there
[[Page 52558]]
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.
D. 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 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.
E. Safety Determination
1. U.S. population. 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 1.3% of the RfD for the U.S. population. EPA generally has
no concern for exposures below 100% of the RfD because the RfD
represents the level at or below which daily aggregate dietary exposure
over a lifetime will not pose appreciable risks to human health.
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 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 lowest observed-effect-level (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 sunflowers is
1.1% for nursing infants less than 1 year old, 3.3% for non-nursing
infants, 2.7% for children 1 to 6 years old and 2.0% 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.
F. International Tolerances
There are no Codex Alimentarius Commission (CODEX) maximum residue
levels (MRL's) established for residues of metolachlor in or on raw
agricultural commodities.
[FR Doc. 97-26535 Filed 10-7-97; 8:45 am]
BILLING CODE 6560-50-F
