[Federal Register Volume 61, Number 215 (Tuesday, November 5, 1996)]
[Notices]
[Pages 56954-56956]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-28551]


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ENVIRONMENTAL PROTECTION AGENCY
[PF-672; FRL-5572-8]


Pesticide Tolerance Petition; Notice of Filing

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice of filing.

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SUMMARY: This notice is a summary of a pesticide petition proposing the 
extension of time-limited tolerances 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. This summary was 
prepared by the petitioner.

DATES: Comments, identified by the docket number [PF-672], must be 
received on or before December 5, 1996.

ADDRESSES: By mail, submit written comments to: Public Response and 
Program Resources Branch, Field Operations Division (7506C), Office of 
Pesticide 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 22202.
    Comments and data may also be submitted electronically by sending 
electronic mail (e-mail) to: [email protected]. Electronic 
comments must be submitted as an ASCII file avoiding the use of special 
characters and any form of encryption. Comments 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-672]. Electronic comments on this notice may be filed 
online at many Federal Depository Libraries. Additional information on 
electronic submissions can be found below in this document.
    Information submitted as comments concerning this notice may be 
claimed confidential by marking any part or all of that information as 
``Confidential Business Information'' (CBI). No 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 a.m. to 4:30 p.m., Monday through Friday, 
excluding legal holidays.

FOR FURTHER INFORMATION CONTACT: By mail, Kerry B. Leifer, Registration 
Division (7505W), Office of Pesticide Programs, Environmental 
Protection Agency, 401 M St. SW, Washington, DC 20460. Office location 
and telephone number: Rm. 6-F, Crystal Station #1, 2800 Jefferson Davis 
Highway, Arlington, VA 22202, (703) 308-8811; e-mail: 
[email protected].

SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition (PP) 
7E3489 from Ciba Crop Protection, Ciba-Geigy Corporation, P.O. Box 
18300, Greensboro, NC 27419, proposing pursuant to section 408(d) of 
the Federal Food, Drug and Cosmetic Act (FFDCA), 21 U.S.C section 346a 
(d), to amend 40 CFR part 180 by extending a time-limited 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 
from December 1, 1996 to December 1, 1998. The proposed analytical 
method is capillary gas chromatography using Nitrogen/Phosphorous (N/P) 
detection.
    Pursuant to section 408(d)(2)(A)(i) of the FFDCA, as amended, Ciba-
Geigy Corporation has submitted the following summary of information, 
data and arguments in support of their pesticide petition. This summary 
was prepared by Ciba-Geigy and EPA has not fully evaluated the merits 
of the petition. EPA edited the summary to clarify that the conclusions 
and arguments were the petitioner's and not necessarily EPA's and to 
remove certain extraneous material.

I. Ciba-Geigy Petition Summary:

1. Residue Chemistry

    A. Plant/Animal Metabolism
    Ciba Crop Protection (Ciba) notes that the metabolism in plants and 
animals (goat, hen, and rat) is well understood. Identified metabolic 
pathways are similar in plants and animals.
    B. Analytical Method
    Ciba 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.
    C. Magnitude of the 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 -15C.

2. Toxicological Profile

    The following studies were submitted in support of this petition:
    A. Acute toxicity
    A rat acute oral study with an LD50 > 5000 mg/kg, a rabbit acute 
dermal study with an LD50 > 2010 mg/kg, a rat inhalation study with an 
LC50 > 2000 mg/liter, a primary eye irritation study in the rabbit 
showing moderate eye

[[Page 56955]]

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 1010 mg/kg 
for at least 22 consecutive days. This study showed benoxacor is not 
dermally toxic at doses greater than the limit dose of 1000 mg/kg/
day.

    B. Genotoxicity
    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 5000 mg/kg. Benoxacor did not 
induce unscheduled DNA synthesis in isolated rat hepatocytes at 
cytotoxic concentrations up to 20  g/ml.
    C. Developmental and Reproductive Toxicity
    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 mg/
kg/day. 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 and 62.5 mg/kg/day, respectively.
    A two-generation reproduction study in the rat at doses of 0, 10, 
50, 500, or 1000 ppm with a NOEL of 50 ppm. No effects on fertility, 
reproductive performance or development were seen in the rat at a 
maximally-tolerated dose of 1000 ppm. Treatment related effects on body 
weight at feeding levels of > 500 ppm were accompanied by marginally 
reduced food intake only in the 1000 ppm group.
    D. Subchronic Toxicity
    Six groups of 15 male and 15 female Sprague Dawley rats were fed 
benoxacor at dietary concentrations of 0, 10, 100, 300, 1000, or 6000 
ppm 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 6000 ppm group. Based on a significant depression 
of body weight gain at 1000 and 6000 ppm as well as hematology, 
clinical chemistry and pathology findings, the NOEL was determined to 
be 300 ppm.
    A 90-day feeding study in the dog at 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 0, 
50, 500, 2000 or 6000 ppm for 90 days. Effects on survival, clinical 
signs, body weight, food consumption, the hematological system, and 
liver and kidney were seen at 6000 ppm and to a lesser extent at 2000 
ppm. The NOEL was 500 ppm.
    E. 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 doses of 0, 10, 30, 
600, or 1200 ppm with a NOEL of 30 ppm (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 
doses of 0, 10, 50, 500, or 1000 ppm. 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 500 ppm (25 mg/kg/day) 
and the NOEL for chronic toxicity was 10 ppm (0.5 mg/kg/day).
    Based on the available chronic toxicity data, Ciba Crop Protection 
believes the RfD for benoxacor is 0.002 milligrams (mg)/kilogram(kg)/
day based on a 2-year feeding study in rats with a No-Observed Adverse 
Effect Level (NOAEL) of 0.5 mg/kg/day and an uncertainty factor of 300. 
For this action, Ciba has used the NOAEL instead of a NOEL because of 
slight effects noted on target organs at the low dose of 0.5 mg/kg/day 
used in the chronic rat study. The use of a 300-fold safety factor 
takes into account these changes and the reference dose derived in this 
manner will provide an adequate safety margin for human exposure.
    Using the Guidelines for Carcinogenic Risk Assessment published 
September 24, 1986 (51 FR 33992), Ciba 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. Ciba 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.

3. Aggregate Exposure

    A. Dietary exposure
      1) Food
    For purposes of assessing the potential dietary exposure under the 
proposed tolerances, Ciba 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, Ciba 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, Ciba 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 or 1 to 20 
ratio with metolachlor and acetamide, respectively, (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.
    B. Non-Dietary Exposures

[[Page 56956]]

    Ciba 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.

4. Cumulative Effects

    Ciba also considered the potential for cumulative effects of 
benoxacor and other substances that have a common mechanism of 
toxicity. Ciba concluded that consideration of a common mechanism of 
toxicity is not appropriate at this time. Ciba 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 
Ciba is considering only the potential risks of benoxacor in its 
aggregate exposure assessment.

5. Safety Determination

    A. U.S. Population
    Using the conservative exposure assumptions described above and 
based on the completeness and reliability of the toxicity data base for 
benoxacor, Ciba has calculated that aggregate exposure to benoxacor 
will utilize 9.4% 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. Ciba 
concludes that there is a reasonable certainty that no harm will result 
from aggregate exposure to benoxacor residues.
    B. Infants and Children
    Using the same conservative exposure assumptions used for the 
determination in the general population, Ciba has concluded that the 
percent of the RfD that will be utilized by aggregate exposure to 
residues of benoxacor is 10.5% for nursing infants less than 1 year 
old, 40.4% for non-nursing infants, 23.8% for children 1-6 years old 
and 15.4% 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, Ciba concludes that 
there is a reasonable certainty that no harm will result to infants and 
children from aggregate exposure to benoxacor residues.

6. International Tolerances

    A maximum residue level has not been established for benoxacor by 
the Codex Alimentarius Commission.

II. Administrative Matters:

    Interested persons are invited to submit comments on this notice of 
filing. Comments must bear a notation indicating the document control 
number, [PF-672].
    A record has been established for this rulemaking under docket 
number [PF-672] (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 a.m. 
to 4:30 p.m., Monday through Friday, excluding legal holidays. The 
public record is located in Rm. 1132 of the Public Response and Program 
Resources Branch, Field Operations Division (7506C), Office of 
Pesticide Programs, Environmental Protection Agency, Crystal Mall #2, 
1921 Jefferson Davis Highway, Arlington, VA.
    Electronic comments may be sent directly to EPA at:
    [email protected].


    Electronic comments must be submitted as an ASCII file avoiding the 
use of special characters and any form of encryption.
    The official record for this notice, as well as the public version, 
as described above will be kept in paper form. Accordingly, EPA will 
transfer all comments received electronically into printed, paper form 
as they are received and will place the paper copies in the official 
notice record which will also include all comments submitted directly 
in writing. The official rulemaking record is the paper record 
maintained at the address in ``ADDRESSES'' at the beginning of this 
document.

List of Subjects

    Environmental protection, Administrative practice and procedure, 
Agricultural commodities, Pesticides and pests, Reporting and 
recordkeeping requirements.

    Dated: October 31, 1996.

Stephen L. Johnson,
Director, Registration Division, Office of Pesticide Programs.

[FR Doc. 96-28551 Filed 11-1-96; 1:38 pm]
BILLING CODE 6560-50-F