[Federal Register Volume 62, Number 225 (Friday, November 21, 1997)]
[Notices]
[Pages 62304-62308]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-30659]


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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: <a href="/cdn-cgi/l/email-protection#ec839c9cc1e688838f878998ac899c8d818d8580c2899c8dc28b839a">opp-
<span class="__cf_email__" data-cfemail="cbafa4a8a0aebf8baebbaaa6aaa2a7e5aebbaae5aca4bd">[email protected]</span></a>. 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:<a href="/cdn-cgi/l/email-protection" class="__cf_email__" data-cfemail="2d40444141485f0347424c4343486d485d">[email protected]</a>   Arlington, VA  
                                 amail.epa.gov.                         
Kerry Leifer..................  Rm. 4W17, CS #1, 703-   2800 Crystal    
                                 308-8811, e-mail:       Drive,         
                                 <a href="/cdn-cgi/l/email-protection" class="__cf_email__" data-cfemail="462a232f202334682d2334343f062336272b272f2a68">[email protected]</a>   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:
    <a href="/cdn-cgi/l/email-protection#a7c8d7d78ac3c8c4ccc2d3e7c2d7c6cac6cecb89c2d7c689c0c8d1"><span class="__cf_email__" data-cfemail="b1dec1c19cd5ded2dad4c5f1d4c1d0dcd0d8dd9fd4c1d09fd6dec7">[email protected]</span></a>


[[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 LD<INF>50</INF> > 
5,000 mg/kg, a rabbit acute dermal study with an LD<INF>50</INF> > 
2,010 mg/kg, a rat inhalation study with an LC<INF>50</INF> > 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


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