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Diflufenzopyr (BASF). November 21, 1997. Pesticide Tolerance Petition for residues in or on the raw agricultural commodities CORN: grain, forage and fodder at 0.05 ppm. Federal Register.
http://www.epa.gov/fedrgstr/EPA-PEST/1997/November/Day-21/p30659.htm
[Federal Register: November 21, 1997 (Volume 62, Number 225)]
[Notices]
[Page 62304-62308]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr21no97-59]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-778; FRL-5755-4]
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-778, must
be received on or before December 22, 1997.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Division
(7502C), Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 1132, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically to: opp-
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:
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Office location/
Product Manager telephone number Address
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Joanne Miller (PM 23)......... Rm. 237, CM #2, 703- 1921 Jefferson
305-6224, e- Davis Hwy,
mail:miller.joanne@ep Arlington, VA
amail.epa.gov.
Kerry Leifer.................. Rm. 4W17, CS #1, 703- 2800 Crystal
308-8811, e-mail: Drive,
leifer.kerry@epamail. 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-778] 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
[[Page 62305]]
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-778 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: November 10, 1997
James Jones,
Acting 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. BASF Corporation
PP 7F4848
EPA has received a pesticide petition (PP 7F4848) from BASF
Corporation, P.O. Box 13528, Research Triangle Park, NC 27709-3528
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 tolerances for residues of diflufenzopyr, (2-[1-[[[(3,5-
difluorophenyl) amino]carbonyl]hydrazono] -ethyl]-3-pyridinecarboxylic
acid), and its metabolites M1 (8-methylpyrido(2,3-d)pyridazin-5(6H)-
one) and M5 (6-((3,5-Difluorophenyl-carbamoyl-8-methyl-pyrido (2,3-d)-
5-pyridazinone) all as the M1 component in or on the raw agricultural
commodities corn grain, corn forage and corn fodder at 0.05 parts per
million (ppm). EPA has determined that the petition contains data or
information regarding the elements set forth in section 408(d)(2) of
the FFDCA; however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data supports granting of
the petition. Additional data may be needed before EPA rules on the
petition.
A. Residue Chemistry
1. Analytical method. The proposed analytical method involves
extraction, partition, clean-up and detection of residues by gas
chromatography/nitrogen phosphorous detector (gc/npd).
2. Magnitude of residues. Over 20 residue trials were conducted in
16 states. Residues of diflufenzopyr, M5 and M1 were measured as M1 by
gc/npd. The method of detection had a limit of detection of 0.01 parts
per million (ppm). Residues ranged from non detectable (majority) to
0.02 ppm rt text.
B. Toxicological Profile
1. Acute toxicity. A battery of acute toxicity tests were conducted
which place diflufenzopyr in acute oral toxicity category IV, acute
dermal toxicity category IV, acute inhalation toxicity category IV,
primary eye irritation category III, and primary dermal irritation
category IV. Diflufenzopyr is not a dermal sensitizer. Diflufenzopyr is
not a neurotoxin in males and females at 2,000 mg/kg (limit test).
2. Genotoxicity. Diflufenzopyr was found to be negative for
mutagenicity in a battery of mutagenicity tests (Ames Testing, Mouse
Lymphoma testing In vivo micronucleus assay (mouse) and Unscheduled DNA
synthesis).
3. Reproductive and developmental toxicity--i. Developmental
toxicity (rat). Sprague-Dawley rats were dosed with 0, 100, 300 and
1,000 mg/kg/day diflufenzopyr in the diet from days 6 through 15 of
gestation. The maternal no observed adverse effect level (NOAEL) was
determined to be 300 mg/kg/day and the maternal lowest effect level
(LEL) was determined to be 1,000 mg/kg/day based on reduced body weight
gain, and reduced absolute and relative feed consumption during the
dosing period. The developmental NOAEL was determined to be 300 mg/kg/
day and the developmental LEL was determined to be 1,000 mg/kg/day
based on reduced fetal body weight and reversible delays in sternal and
caudal vertebral ossification.
ii. Developmental toxicity (rabbit). New Zealand white rabbits were
dosed with 0, 30, 100, and 300 mg/kg/day diflufenzopyr in the diet from
days 6 through 19 of gestation. The maternal NOEL was determined to be
30 mg/kg/day and the maternal LEL was determined to be 100 mg/kg/day
based on increased incidence of abnormal feces and weight loss for the
entire dosage period. The developmental NOEL was determined to be 100
mg/kg/day and the developmental LEL was determined to be 300 mg/kg/day
based on increased incidences of supernumerary thoracic ribs, a
variation in fetal ossification that commonly occurs at maternally
toxic dosages. Only at the 300 dose level deaths and abortions were
accompanied by gastric trichobezoars. Diflufenzopyr was not teratogenic
to rabbit fetuses even at the higher of two dosages (100 and 300 mg/kg/
day) that were toxic to the does.
iii. Reproductive toxicity testing. In a 2-Generation Reproduction
study, Wistar rats were dosed with 0, 500, 2,000 and 8,000 ppm
diflufenzopyr in the diet. The parental: systemic NOAEL/reproductive-
developmental NOEL was determined to be 2,000 ppm in both sexes
(averaging 600 mg/kg/day in females during gestation). The parental LEL
was determined to be 8,000 ppm (averaging 2,500 mg/kg/day in females
during gestation) based on weight gain deficits in males and females
during premating and pregnancy phases. The developmental NOEL was
determined to be 2,000 ppm (averaging 400 mg/kg/day in dams during
lactation) and the LEL determined to be 8,000 ppm (averaging 1,500 mg/
kg/day in dams during lactation) based on slightly lower live birth
(93%) and viability (90%) indices.
4. Subchronic toxicity-- i. 21-Day dermal (rabbit). Rabbits were
repeatedly dosed with diflufenzopyr at 0, 100, 300 and 1,000 mg/kg/day
for 21 days. The NOAEL for systemic toxicity and dermal irritation was
determined to be 1,000 mg/kg/day.
ii. 90-Day rodent (rat). Wistar rats were dosed with diflufenzopyr
at 0, 1,000, 5,000, 10,000 and 20,000 ppm in the diet for 90 days. The
NOEL was determined to be 5,000 ppm (350 mg/kg/day) for males and 430
mg/kg/day in females. The LEL was determined to be 10,000 ppm (720 mg/
kg/day) for males and 890 mg/kg/day in females based on reduced body
weight gains, impaired food utilization; disturbances in hematology
values in males, clinical chemistry values in both sexes, values for
urinalysis in females; with histopathology seen in both sexes as
increased foamy macrophages in the lungs.
iii. 90-Day mouse. CD-1 mice were dosed with diflufenzopyr at 0,
350, 1,750, 3,500 and 7,000 ppm in the diet for 13 weeks. The NOEL was
determined to be 7,000 ppm (1,225 mg/kg/day) in males and (1,605 mg/kg/
day) in females as no clear toxic effects were observed.
iv. 90-Day non-rodent (dog). Beagle dogs were dosed with
diflufenzopyr at
[[Page 62306]]
0, 1,500, 10,000, and 30,000 ppm in the diet for 13 weeks. The NOEL was
determined to be 1,500 ppm (58 mg/kg/day) in males and (59 mg/kg/day)
in females. The LEL was determined to be 10,000 ppm (403 mg/kg/day) in
males and (424 mg/kg/day) in females based on histopathological
disturbances seen as erythreoid hyperplasia in the bone marrow and
extramedullary hemopoiesis in the liver of a few dogs and hemosiderin
deposits in Kupffer cells in 1 female dog.
v. 90-Day neurotoxicity (rat). Rats were dosed with diflufenzopyr
at 0, 25, 75, and 1,000 mg/kg/day in the diet for 13 weeks. At the
1,000 mg/kg/day treatment there was associated weight gain and impaired
efficiency of food utilization. Therefore the no adverse effect level
was set at 75 mg/kg/day. The NOAEL for subchronic neurotoxicity was
determined to be 1,000 mg/kg/day based on the absence of changes
indicative of neurotoxicity.
5. Chronic toxicity--i. 1-Year non-rodent (dog). Beagle dogs were
dosed with diflufenzopyr at 0, 750, 7,500 and 15,000 ppm in the diet
for one year. The NOEL was determined to be 750 ppm (26 mg/kg/day) in
males and (28 mg/kg/day) in females. The LOAEL was 7,500 ppm (299 mg/
kg/day) in males and (301 mg/kg/day) in females. This is based on an
erythropoietic response in bone marrow and increased hemosiderin
deposits in spleen, liver and kidneys. Peripheral hematology
investigations revealed mild to moderate reticulocytosis at the 7,500
and 15,000 ppm dose levels, in the absence of any signs of anemia. The
erythropoietic response of bone marrow is thought to compensate
probable toxic effects to erythrocytes. Because of a similarity of NOEL
levels from this dog study and the rat chronic/oncogenicity study a
suggested risk assessment reference dose (Rfd) is calculated by using
25 as a Noel level with a 100 fold safety factor ending with 0.25 mg/
kg/day.
ii. Combined rodent chronic toxicity/oncogenicity (rat). Wistar
rats were fed 0, 500, 1,500, 5,000 and 10,000 ppm diflufenzopyr in the
diet for 104 weeks. The NOEL was determined to be 500 ppm (22 mg/kg/
day) in males and (29 mg/kg/day) in females. The NOAEL was determined
to be 1,500 ppm (69 mg/kg/day) in males and (93 mg/kg/day) in females
based on reduced body weight gains of 8 % in males and 7% in females.
The LEL was determined to be 5,000 ppm (235 mg/kg/day ) in males
and(323 mg/kg/day) in females based on 9% reduced weight gain in
females and 11% in males plus males showed lower triglyceride and
higher phosphate levels. Diflufenzopyr was not carcinogenic under the
conditions of the test.
iii. Oncogenicity in the rodent (mouse). CD-1 mice were fed 0,
700, 3,500 and 7,000 ppm diflufenzopyr in the diet for 78 weeks. The
NOAEL was determined to be 7,000 ppm (1037 mg/kg/day) in males and
(1,004 mg/kg/day) in females. There were no changes or
histopathological findings attributed to the dietary inclusion of test
material in the 52 (interim) or 78 (terminal) week animals.
Diflufenzopyr was not carcinogenic under the conditions of the test.
C. Aggregate Exposure
1. Dietary exposure. The potential aggregate dietary exposure is
based on the Theoretical Maximum Residue Contribution (TMRC) from the
tolerances for all crops on which diflufenzopyr is to be applied. The
TMRC from the proposed use of diflufenzopyr of corn at the tolerance
level of 0.05 ppm is 0.173168 ug/kg/day, and utilizes 0.069 percent of
the RfD for the overall U.S. population. The exposure of the most
highly exposed subgroup in the population, non-nursing infants, is
0.195424 ug/kg/day, and utilizes 0.078 percent of the RfD.
2. Drinking water. Based on the studies submitted to EPA for
assessment of environmental risk, BASF does not anticipate exposure to
residues of diflufenzopyr in drinking water. There is no established
maximum concentration level for residues of diflufenzopyr in drinking
water under the Safe Drinking Water Act.
3. Non-dietary exposure. BASF has not estimated non-occupational
exposure for diflufenzopyr since the only pending registration for
diflufenzopyr is limited to commercial crop production use.
Diflufenzopyr products are not labeled for any residential uses
therefore, eliminating the potential for residential exposure. The
potential for non-occupational exposure to the general population is
considered to be insignificant.
D. Cumulative Effects
BASF also considered the potential for cumulative effects of
diflufenzopyr and other substances that have a common mechanism of
toxicity. BASF has concluded that consideration of a common mechanism
of toxicity is not appropriate at this time since there is no
indication that toxic effects produced by diflufenzopyr would be
cumulative with those of any other chemical compounds. Semicarbazone
chemistry is new and diflufenzopyr has a novel mode of action compared
to currently registered active ingredients.
E. Safety Determination
1. U.S. population. Dietary and occupational exposure will be the
major routes of exposure to the U.S. population and ample margins of
safety have been demonstrated for both situations. The TMRC from the
proposed tolerance of 0.05 ppm is 0.173168 ug/kg/day and utilizes
0.0692 percent of the RfD for the overall U.S population. The MOEs for
occupational exposure are greater than 7,000. Based on the completeness
and reliability of the toxicity data and the conservative exposure
assessments, there is a reasonable certainty that no harm will result
from the aggregate exposure of residues of diflufenzopyr including all
anticipated dietary exposure and all other non-occupational exposures.
2. Infants and children. Dietary exposure of the most highly
exposed subgroup in the population, non-nursing infants, is 0.195424
ug/kg/day. This accounts for only 0.078 percent of the RfD. There are
no residential uses of diflufenzopyr and contamination of drinking
water is extremely unlikely. All chronic, lifespan and
multigenerational bioassays in mammals plus tests in aquatic organisms
and wildlife failed to reveal any endocrine effects. Based on 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 the aggregate exposure of residues
of diflufenzopyr including all anticipated dietary exposure and all
other non-occupational exposures.
F. International Tolerances
A maximum residue level has not been established for diflufenzopyr
by the Codex Alimentarius Commission.
2. Novartis Crop Protection, Inc.
PP 7E3489
EPA has received a pesticide petition (PP 7E3489) from Novartis
Crop Protection, Inc. (formerly Ciba Crop Protection), P.O. Box 18300,
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
part 180 by establishing a tolerance for combined residues of 4-
(dichloroacetyl)-3,4-dihydro-3-methyl-2H-1,4-benzoxazine (benoxacor)
when used as an inert ingredient (safener) in pesticide formulations
containing metolachlor in or on raw agricultural commodities for which
tolerances have been established for metolachlor. The proposed
analytical method is capillary gas
[[Page 62307]]
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/Animal metabolism. Novartis Crop Protection, Inc.
(Novartis) notes that the metabolism in plants and animals (goat, hen,
and rat) is well understood. Identified metabolic pathways are similar
in plants and animals.
2. Analytical method. Novartis Analytical Method AG536(C) is
available and involves extraction, filtering, dilution, partitioning,
and cleanup. Samples are then analyzed by capillary gas chromatography
using Nitrogen/Phosphorous (N/P) detection. The limit of quantitation
(LOQ) is 0.01 ppm.
3. Magnitude of residues. More than 30 residue trials were
conducted in 19 states on a variety of agricultural crops [corn (field
and sweet); soybeans, potatoes, green beans, radishes, sorghum,
peanuts, head lettuce, peas]. There were no detectable residues of
benoxacor at the limit of quantitation (LOQ) of 0.01 ppm (many samples
were analyzed at an LOQ of 0.005 ppm and no residues were detected) in
any raw agricultural commodity or processed commodity. No transfer of
residue to animals is expected through their diet. Benoxacor is stable
for a minimum of 12 months at temperatures down to -15 deg.C.
B. Toxicological Profile
1. Acute toxicity. A rat acute oral study with an LD50 >
5,000 mg/kg, a rabbit acute dermal study with an LD50 >
2,010 mg/kg, a rat inhalation study with an LC50 > 2,000 mg/
liter, a primary eye irritation study in the rabbit showing moderate
eye irritation, a primary dermal irritation study in the rabbit showing
benoxacor is not a skin irritant, and a skin sensitization study which
showed benoxacor to be a skin sensitizer in the Guinea pig. Results of
a dermal absorption study show a maximum of 55.7% of benoxacor is
absorbed by the rat following a 24 hour dermal exposure. Benoxacor was
applied to the shaved skin of 5 male and 5 female New Zealand white
rabbits at dose levels of 0, 1,500, or 1,010 mg/kg for at least 22
consecutive days. This study showed benoxacor is not dermally toxic at
doses greater than the limit dose of 1,000 mg/kg/day.
2. Genotoxicty. Benoxacor did not induce point mutations in vitro
at limit (cytotoxic) concentrations in a Salmonella/mammalian microsome
test or show any mutagenic activity in the Chinese hamster V79
mammalian point mutation test and is neither clastogenic nor aneugenic
in the Chinese hamster at doses up to the limit dose of 5,000 mg/kg.
Benoxacor did not induce unscheduled DNA synthesis in isolated rat
hepatocytes at cytotoxic concentrations up to 20 micrograms/ml.
3. Reproductive and developmental toxicity. A 2-generation
reproduction study in the rat at approximate doses of 0, 0.5, 2.5, 25
or 50 mg/kg/day. No effects on fertility, reproductive performance or
development were seen in the rat at a maximally-tolerated dose of 50
mg/kg/day. Treatment related effects on body weight at feeding levels
of > 25 mg/kg/day were accompanied by marginally reduced food intake
only in the high dose group. The parental NOEL ranged from 3.4 to 4.8
mg/kg/day while the developmental NOEL was approximately 10-fold
greater. A developmental toxicity study in the rat at doses of 0, 1,
100, or 400 mg/kg/day by gavage with maternal and developmental NOEL's
of 1 and 100 mg/kg/day, respectively. Maternal, embryo, and fetal
toxicity were observed at doses > 100 mg/kg/day. A developmental
toxicity study in the rabbit at doses of 0, 0.5, 2.5, 12.5 or 62.5 mg/
kg/day. Slight evidence of maternal and fetal toxicity was observed at
62.5 mg/kg/day. The maternal and developmental NOEL's were 12.5 mg/kg/
day.
4. Subchronic toxicity. Six groups of 15 male and 15 female Sprague
Dawley rats were fed benoxacor at dietary concentrations of
approximately 0, 0.5, 5, 15, 50 or 300 mg/kg/day for 13 weeks. The
liver (pigmentation, karyomegaly, cytomegaly, bile duct proliferation,
portal mononuclear cell infiltration) and stomach (pyloric gland
degeneration and necrosis) were identified as target organs in the 300
mg/kg/day group. Based on a significant depression of body weight gain
at 50 and 300 mg/kg/day as well as hematology, clinical chemistry and
pathology findings, the NOEL was determined to be 15 mg/kg/day.
A 90-day feeding study in the dog at approximate doses of 0, 0.25,
1, 5, 50, 150, or 400 mg/kg/day. Liver, kidney, stomach, and thymus
were identified as target organs. The NOEL was 50 mg/kg/day. The
maximum tolerated dose was exceeded at > 150 mg/kg/day.
A 90-day feeding study in CD-1 mice at dietary concentrations of
approximately 0, 6.25, 62.5, 250, or 750 mg/kg/day for 90 days. Effects
on survival, clinical signs, body weight, food consumption, the
hematological system, and liver and kidney were seen at 750 mg/kg/day
and to a lesser extent at 250 mg/kg/day. The NOEL was 62.5 mg/kg/day.
5. Chronic toxicity. A 52-week feeding study in the dog at doses of
0, 1, 5, 40, or 80 mg/kg. Liver and kidney were identified as target
organs and the NOEL was established at 5 mg/kg.
An 18-month oncogenicity study in the mouse at approximate doses of
0, 1.4, 4.2, 84, or 168 mg/kg/day with a NOEL of 4.2 mg/kg/day for both
chronic toxicity and tumors. Target organs were the liver and
forestomach. A carcinogenic response was noted in the forestomach and
is likely to be linked to a non-genotoxic mode of action involving
direct irritation to the epithelial lining of the forestomach and
limiting ridge between the non-glandular and glandular stomach.
A 24-month chronic feeding and oncogenicity study in the rat at
approximate doses of 0, 0.5, 2.5, 25, or 50 mg/kg/day. Liver and
forestomach were identified as target organs. A carcinogenic response
was seen in the forestomach and is likely linked to a non-genotoxic
mode of action involving direct irritation to the epithelial lining of
the forestomach and the limiting ridge. The NOEL for tumors was 25 mg/
kg/day and the NOEL for chronic toxicity was 0.5 mg/kg/day.
Based on the available chronic toxicity data, EPA has established
the RfD for benoxacor at 0.004 mg/kg/day. This RfD is based on the 2
year feeding study in rats with a NOEL of 0.4 mg/kg/day and an
uncertainty factor of 100. The uncertainty factor of 100 was applied to
account for inter-species extrapolation (10) and intra-species
variability (10).
Using the Guidelines for Carcinogenic Risk Assessment published
September 24, 1986 (51 FR 33992), Novartis believes the Agency will
classify benoxacor as a Group C carcinogen (possible human carcinogen)
based on findings of a carcinogenicity effect in the non-glandular
stomach of both rats and mice. Because this carcinogenic response was
only observed at high doses in the non-glandular stomach of the rodent,
an anatomical structure not found in humans, it is likely this response
occurred via a non-genotoxic, threshold based mechanism. Novartis
believes exposure to benoxacor should be regulated using a margin of
exposure approach where the carcinogenic NOEL established in the most
sensitive species, the mouse, was 4.2 mg/kg/day.
[[Page 62308]]
C. Aggregate Exposure
1. Dietary exposure-- Food. For purposes of assessing the potential
dietary exposure under the proposed tolerances, Novartis has estimated
aggregate exposure based on the theoretical maximum residue
contribution (TMRC) from the benoxacor tolerance of 0.01 ppm in or on
raw agricultural commodities for which tolerances have been established
for metolachlor. In conducting this exposure assessment, Novartis has
made very conservative assumptions--100% of all raw agricultural
products for which tolerances have been established for metolachlor
will contain benoxacor residues and those residues would be at the
level of the tolerance (0.01 ppm) which result in an overestimate of
human exposure.
2. Drinking water. Although benoxacor is mobile and hydrolyzes
slowly at low pHs, it rapidly degrades in the soil (half-life of 49
days under aerobic conditions and 70 days anaerobically). Based on this
data, Novartis does not anticipate exposure to residues of benoxacor in
drinking water. This is supported by extensive experience with
metolachlor, where in large scale ground water monitoring studies,
metolachlor has been detected in less than 4% of the samples with the
typical value being 1 ppb or less. Since benoxacor is formulated as a 1
to 30 ratio with metolachlor, (maximum of 0.2 pounds benoxacor per
acre) the presence of benoxacor in groundwater is highly unlikely. The
EPA has not established a Maximum Concentration Level for residues of
benoxacor in drinking water.
3. Non-dietary exposure. Novartis has evaluated the estimated non-
occupational exposure to benoxacor and based on its low use rate
concludes that the potential for non-occupational exposure to the
general population is unlikely except for the potential residues in
food crops discussed above. Benoxacor is used only on agricultural
crops and is not used in or around the home.
D. Cumulative Effects
Novartis also considered the potential for cumulative effects of
benoxacor 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 any
reliable information to indicate that toxic effects seen at high doses
of benoxacor (generalized liver toxicity, nephrotoxicity and the
occurrence of forestomach tumors in an organ not present in humans)
would be cumulative with those of any other chemical compounds; thus
Novartis is considering only the potential risks of benoxacor in its
aggregate exposure assessment.
E. Safety Determination
1. U.S. population. Using the conservative exposure assumptions
described above and based on the completeness and reliability of the
toxicity data base for benoxacor, Novartis has calculated that
aggregate exposure to benoxacor will utilize 4.7% of the RfD for the
U.S. population based on chronic toxicity endpoints and only 0.4% based
on a margin of exposure assessment and a carcinogenic NOEL of 4.2 mg/
kg/day. EPA generally has no concern for exposures below 100 percent of
the RfD because the RfD represents the level at or below which daily
aggregate dietary exposure over a lifetime will not pose appreciable
risks to human health. Novartis concludes that there is a reasonable
certainty that no harm will result from aggregate exposure to benoxacor
residues.
2. Infants and children. Using the same conservative 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 benoxacor is 5.3% for
nursing infants less than 1 year old, 20.2% for non-nursing infants,
11.9% for children 1-6 years old and 7.7% for children 7-12 years old.
These worst case estimates are likely at least 4 times greater than
actual values when considering that benoxacor residues have not been
detected at the limit of quantitation of 0.005 ppm (tolerance is 0.01
ppm) and using a more realistic market share of 50% rather than the
conservative 100%. Therefore, based on the completeness and reliability
of the toxicity data base and the conservative exposure assessment,
Novartis concludes that there is a reasonable certainty that no harm
will result to infants and children from aggregate exposure to
benoxacor residues.
F. International Tolerances
A maximum residue level has not been established for benoxacor by
the Codex Alimentarius Commission.
[FR Doc. 97-30659 Filed 11-20-97; 8:45 am]
BILLING CODE 6560-50-F