[Federal Register Volume 62, Number 58 (Wednesday, March 26, 1997)]
[Notices]
[Pages 14426-14429]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-7222]


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ENVIRONMENTAL PROTECTION AGENCY
[PF-727; FRL-5595-6]


Novartis Crop Protection, Inc.; Pesticide Tolerance Petition 
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 
establishment of a regulation for the residues of CGA-248757, acetic 
acid [[2-chloro-4-fluoro-5-[(tetrahydro-3-oxo-1H,3H-
[1,3,4]thiadiazolo[3,4-]pyridazin-1-ylidene) 
amino]phenyl]thio]-methyl ester in or on soybeans. This summary was 
prepared by the petitioner.
DATES: Comments, identified by the docket control number [PF-727], must 
be received on or before April 25, 1997.

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-727]. Electronic comments on this notice may be filed 
online at many Federal Depository Libraries. Additional information on 
electronic submissions can be found in Unit II. of 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 8:30 a.m. to 4 p.m., Monday through Friday, 
excluding legal holidays.

FOR FURTHER INFORMATION CONTACT: By mail: Joanne Miller, Product 
Manager (PM) 23, Registration Division (7505W), Office of Pesticide 
Programs, Environmental Protection Agency, 401 M St., SW., Washington, 
DC 20460. Office location, telephone number, and e-mail address: Rm. 
237, CM #2, 1921 Jefferson Davis Highway, Arlington, VA, (703) 305-
6224, e-mail: [email protected].
SUPPLEMENTARY INFORMATION: A notice of filing of pesticide petition 
6F4614 was published in the Federal Register of June 12, l996 (61 FR 
29752) (FRL-5354-7). The Notice stated that Ciba Crop Protection, Ciba-
Geigy Corporation had proposed to amend 40 CFR part 180 by establishing 
a tolerance for residues of the herbicide, acetic acid [[2-chloro-4-
fluoro-5-[(tetrahydro-3-oxo-1H,3H-[1,3,4]thiadiazolo[3,4-
]pyridazin-1-ylidene) amino]phenyl]thio]-methyl ester in or on 
the raw agricultural commodity soybeans at 0.02 part per million (ppm). 
The proposed analytic method for determining residues was gas 
chromatographic. On January 1, l997, Ciba Crop Protection merged with 
Sandoz, Inc. to form a new corporation, Novartis Crop Protection, Inc.
    EPA has received a second notice of filing of (PP) 6F4614, from 
Novartis Crop Protection, Inc., 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 establishing a tolerance for residues of the herbicide CGA-
248757, acetic acid [[2-chloro-4-fluoro-5-[(tetrahydro-3-oxo-1H,3H-
[1,3,4]thiadiazolo[3,4-]pyridazin-1-ylidene) 
amino]phenyl]thio]-methyl ester in or on the raw agricultural commodity 
soybeans at 0.01 ppm. The proposed analytical method is gas 
chromatography using a nitrogen phosphorus detector and a large-bore 
fused silica column.
    Pursuant to section 408(d)(2)(A)(i) of the FFDCA, as amended, 
Novartis Crop Protection, Inc. has submitted the following summary of 
information, data and arguments in support of their pesticide petition. 
This summary was prepared by Novartis and EPA has not fully evaluated 
the merits of the

[[Page 14427]]

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. Novartis Petition Summary

    1. CGA-248757 uses. CGA-248757, acetic acid [(2-chloro-4-fluoro-5-
[(tetrahydro-3-oxo-1H,3H-[1,3,4]thiadiazolo [3,4-]pyridazin-1-
ylidene)amino]phenyl]thio]-methyl ester, is a new herbicide active 
ingredient in the imide chemistry class. It will be formulated as a 
4.75% wettable powder, packaged in water-soluble bags, and sold under 
the trade name Action Herbicide. Action is a highly selective 
herbicide for use in soybeans postemergence, and is particularly 
effective in controlling velvetleaf. Control of other broadleaf weeds 
in soybeans is enhanced and the spectrum of control is broadened when 
Action is tank mixed with other postemergence herbicides registered for 
use in soybeans.
    Action offers effective weed control at extremely low use rates. 
The maximum use rate per season is 0.0089 lb. active ingredient (3 
ounces (oz). of formulated product) per acre consisting of a maximum of 
two applications. There is a wide application window extending from the 
first trifoliate stage of soybean development through the full 
flowering stage, and the amount of Action to apply depends on the weed 
species and weed height. Tank mixing Action with other postemergence 
herbicides further reduces the amount required to control target weeds.
    The purpose of this petition is to establish a tolerance for CGA-
248757 in soybeans. The tolerance proposed is: Soybeans--0.01 ppm.
    2.  CGA-248757 safety. In support of the petition for tolerance in 
soybeans, Novartis submitted a full battery of toxicology studies 
including, acute effects, chronic feeding, oncogenicity, 
teratogenicity, mutagenicity, and reproductive toxicity tests. The 
studies indicate that CGA-248757 has a low order of acute toxicity with 
acute effects in catgegory III and IV, is not neurotoxic, does not pose 
a genotoxicity hazard, and is not a reproductive toxicant or a 
teratogen.
    Potential exposure to CGA-248757 via the diet or drinking water and 
through handling is very limited. Because of rapid environmental 
degradation, extremely low residues in food crops, and water-soluble 
packaging, considerable margins of safety exist for dietary exposure 
for all subgroups of the population and for worker exposure as well.
    The following mammalian toxicity studies have been conducted to 
support the proposed tolerance for CGA-248757:
     A rat acute oral study with an LD50 > 5,000 
milligram/kilogram (mg/kg).
     A rabbit acute dermal study with an LD50 2,000 mg/kg.
     A rat inhalation study with an LC50 5.05 mg/liter.
     A primary eye irritation study in the rabbit showing 
moderate eye irritation.
     A primary dermal irritation study in the rabbit showing no 
skin irritation.
     A primary dermal sensitization study in the Guinea pig 
showing no sensitization.
     Twenty-eight day dermal toxicity study in rats with a no-
observed effect level (NOEL) equal to or higher than the limit dose of 
1,000 mg/kg.
     Six-week dietary toxicity study in dogs with a NOEL of 
6,500 ppm in males and 2,000 ppm in females based on decreased body 
weight gain and modest hematological changes.
     Ninety-day subchronic dietary toxicity study in rats with 
a NOEL of 100 ppm based on liver changes and hematological effects.
     Twenty-four-month combined chronic toxicity/
carcinogenicity study in rats with a NOEL of 50 ppm. Based on reduced 
body weight development and changes in bone marrow, liver, pancreas and 
uterus the MTD was exceeded at 3,000 ppm.
     A positive trend of adenomas of the pancreas in male rats 
treated at 3,000 ppm and above may be attributable to the increased 
survival of the rats treated at high doses.
     Eighteen-month oncogenicity study in mice with a NOEL of 1 
ppm. Based on liver changes, the MTD was reached at 10 ppm. The 
incidence of hepatocellular tumors was increased in males treated at 
100 ppm and 300 ppm.
     Teratology study in rats with a maternal and developmental 
NOEL equal to or greater than 1,000 mg/kg/day.
     Teratology study in rabbits with a maternal NOEL greater 
than or equal to 1,000 mg/kg/day and a fetal NOEL of 300 mg/kg based on 
a slight delay in fetal maturation.
     Two-generation reproduction study in rats with a NOEL of 
500 ppm, based on liver lesions in parental animals and slightly 
reduced body weight development in parental animals and pups. The 
treatment had no effect on reproduction or fertility.
     Acute neurotoxicity study in rats.
     Neurotoxic effects were not observed. The NOEL was 2,000 
mg/kg.
     Ninety-day subchronic neurotoxicity study in rats. The 
NOEL was 10 ppm based on reduced body weight gain. No clinical or 
morphological signs of neurotoxicity were detected at any dose level.
     In vitro gene mutation tests: Ames test--negative; Chinese 
hamster V79 test--negative; rat hepatocyte DNA repair test--negative; 
E. Coli letal DNA damage test--negative.
     In vitro chromosomal aberration tests: Chinese hamster 
ovary--positive at cytotoxic doses; Chinese hamster lung--positive at 
cytotoxic doses; human lymphocyes--positive at cytotoxic doses.
     In vivo chromosome aberration tests: Micronucleus assays 
in rat liver--negative; mouse bone marrow test--negative.
    3. Threshold effects. Using the Guidelines for Carcinogenic Risk 
Assessment published September 24, 1986 (51 FR 33992), Novartis 
believes the Agency will classify CGA-248757 as a Group ``C'' 
carcinogen (possible human carcinogen) based on findings of benign and 
malignant liver tumors in male mice. These tumors most likely resulted 
from a chronic regenerative and proliferative response of the affected 
epithelial cells. This response is a non-genotoxic, threshold effect 
which is due to the accumulation of cytotoxic porphyrins. A positive 
trend of proliferative pancreatic changes in male rats is likely 
attributable to the increased survival of the rats in the high dose 
groups. The lesions observed are not uncommon in the rat strain used.
    Because the effects observed are threshold effects, Novartis 
believes that exposure to CGA-248757 should be regulated using a margin 
of exposure approach. The reference dose (RfD) for CGA-248757 can be 
defined at 0.0014 milligram/kilogram/day (mg/kg) based on an 18-month 
feeding study in mice with a NOEL of 0.14 mg/kg/day and an uncertainty 
factor of 100.
    4. Non-threshold effects. Based on the results of an extensive 
program of genotoxicity studies, CGA-248757 is not mutagenic in vivo. 
As outlined above, effects observed in toxicology studies are 
attributable to an epigenetic, cytotoxic mechanism, resulting in 
degenerative and inflammatory changes in the target organs. It is 
therefore justified that exposure to CGA-248757 should be regulated 
using a margin of exposure approach.
    5. Aggregate exposure. In this assessment, Novartis has 
conservatively assumed that 100% of all soybeans used for human 
consumption would contain residues of CGA-248757 and all residues would 
be at the level of the tolerance. The potential dietary exposure to 
CGA-248757 was calculated on the basis of the proposed

[[Page 14428]]

tolerance of the LOQ, 0.01 ppm, in soybeans. The proposed tolerances is 
set at the limit of detection in the respective commodity because, with 
the available methodology, there are no detectable residues of CGA-
248757 in soybeans. Residues in milk, meat, and eggs due to the feeding 
of soybean commodities are not expected and tolerances for milk, meat, 
and eggs are not required. Calculated on the basis of the proposed 
tolerance, the dietary exposure of the U.S. population to CGA-248757 
would correspond to 0.24% of its RfD.
    Other potential sources of exposure of the general population to 
residues of pesticides are residues in drinking water. Although CGA-
248757 has a slight to medium leaching potential; the risk of the 
parent compound to leach to deeper soil layers is negligible under 
practical conditions in view of the fast degradation of the product. 
For example, the soil metabolism half-life was extremely short, ranging 
from 1.1 days under aerobic conditions to 1.6 days under anaerobic 
conditions. Even in the event of very heavy rainfalls immediately after 
application, which could lead to a certain downward movement of the 
parent compound, parent CGA-248757 continues to be degraded during the 
transport into deeper soil zones. Considering the low application rate 
of CGA-248757, the strong soil binding characteristics of CGA-248757 
and its degradates, and the rapid degradation of CGA-248757 in the 
soil, there is no risk of ground water contamination with CGA-248757 or 
its metabolites. Thus, aggregate risk of exposure to CGA-248757 does 
not include drinking water. CGA-248757 is not registered for any other 
use and is proposed for use only on agricultural crops. Thus, there is 
no potential for non-occupational exposure other than consumption of 
treated commodities containing CGA-248757 residue.
    Novartis also considered the potential for cumulative effects of 
CGA-248757 and other substances. However, a cumulative exposure 
assessment is not appropriate at this time because there is no 
information available to indicate that effects of CGA-248757 in mammals 
would be cumulative with those of another chemical compound. Thus 
Novartis is considering only the potential risk of CGA-248757 in its 
aggregate exposure assessment.
    6. Safety to the U.S. population. Using the very conservative 
exposure assumptions described above and based on the completeness and 
reliability of the toxicity data for CGA-248757, Novartis has 
calculated that aggregate exposure to CGA-248757 will utilize 0.24% of 
the RfD for the U.S. population. Thus, even a worst case exposure 
estimate results in human exposure to CGA-248757 which is 40,000-fold 
below the NOEL in the most sensitive species. As anticipated residues 
are below tolerance levels and the market share of CGA-248757 will not 
approach 25% of planted soybeans, the safety margin is likely to be at 
least 20 times greater. Exposures below 100 percent of the RfD are 
generally not of concern 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.
    Also the acute dietary risk to consumers will be far below any 
significant level: The lowest NOEL from a short-term exposure scenario 
comes from the teratology study in rabbits with a NOEL of 300 mg/kg. 
This NOEL is 2,000-fold higher than the chronic NOEL which provides the 
basis for the RfD (see above). Because chronic exposure estimates did 
not result in any significant exposure, it is anticipated that the 
acute dietary risk will also be negligible with margins of acute 
exposure in the hundred thousands (margins of exposure of 100 or more 
are generally considered satisfactory). Therefore, Novartis concludes 
that there is a reasonable certainty that no harm will result from 
aggregate exposure to CGA-248757 residues.
    7. Safety to infants and children. In assessing the potential for 
additional sensitivity of infants and children to residues of CGA-
248757, Novartis considered data from developmental toxicity studies in 
the rat and rabbit and a 2-generation reproduction study in the rat. A 
slight delay in fetal maturation was observed in a teratology study in 
rabbits at a daily dose of 1,000 mg/kg. In a 2-generation reproduction 
study, CGA-248757 did not affect the reproductive performance of the 
parental animals or the physiological development of the pups. The NOEL 
was 500 ppm for maternal animals and their offspring, which is 50,000 
fold higher than the RfD.
    Using the same conservative exposure assumptions as for the 
determination in the general population, the percent of the RfD that 
will be utilized by aggregate exposure to residues of CGA-248757 is 
0.28% for nursing infants less than 1 year old, 1.16% for non-nursing 
infants, 0.45% for children 1 to 6 years old and 0.35% for children 7 
to 12 years old. Novartis concludes that there is a reasonable 
certainty that no harm will result to infants and children from 
aggregate exposure to residues of CGA-248757.
    8. Estrogenic effects. Based on the results of short-term, chronic, 
and reproductive toxicity studies there is no indication that CGA-
248757 might interfere with the endocrine system. Considering further 
the low environmental concentrations and the lack of bioaccumulation, 
there is no risk of endocrine disruption in humans or wildlife.
    9. Chemical residue. The nature of the residues in soybeans and 
animals (goat and hen) is adequately understood following application 
of CGA-248757. Residues do not concentrate in processed commodities. 
There are no Codex maximum residue levels established for residues of 
CGA-248757 on soybeans. Ciba has submitted a practical analytical 
method for detecting and measuring the level of CGA-248757 in or on 
food with a limit of detection that allows monitoring of food with 
residues at or above the levels set for the proposed tolerance. The 
limit of quantification of the method is 0.01 ppm. The analytical 
method involves extraction, filtration, and solid phase clean up. 
Residue levels of CGA-248757 are determined by gas chromatographic 
analysis utilizing a nitrogen phosphorus detector and a fused-silica 
column. EPA can provide information on this method to FDA. The method 
will be available to anyone who is interested in pesticide residue 
enforcement from the Field Operations Division, EPA's Office of 
Pesticide Programs.
    The residue of concern in soybeans is CGA-248757 per se. Twenty 
field residue studies were conducted with soybeans grown in 18 states. 
Residues of CGA-248757 in treated soybeans were less than the method 
LOQ (0.01 ppm) which is the proposed tolerance. The proposed tolerance 
level is adequate to cover residues likely to occur when Action 
herbicide is applied as directed.
    Livestock feeding studies have not been submitted and tolerances 
for residues of CGA-248757 in livestock commodities have not been 
requested. Results of hen and goat metabolism studies wherein CGA-
248757 was fed at exaggerated rates indicated that CGA-248757 is poorly 
absorbed. Based upon the exaggerated feeding levels in the goat and hen 
metabolism studies, the results of soybean metabolism studies, the 
requested tolerance level of 0.01 ppm for soybeans, and the maximum 
dietary exposure of beef and dairy cattle and poultry to CGA-248757, 
detectable residues of CGA-248757 or its metabolite, CGA-300403 (> 0.01 
ppm) are unlikely to occur in meat, milk, poultry, or eggs.
    In studies with processed soybean fractions, concentration of CGA-
248757 was not found and tolerances in processed commodities will not 
be

[[Page 14429]]

required. In addition, confined rotational crop studies indicated that 
CGA-248757 will not be taken up by rotational crops.
    Novartis analytical Method AG-603A has been independently validated 
for collection of residues of CGA-248757 in soybeans and processed 
fractions and this method has been provided to the FDA. Residue levels 
of CGA-248757 are determined by gas chromatography and the limit of 
detection for the method is 0.01 ppm.
    10. Environmental fate. Action degraded rapidly under laboratory 
and field conditions. Laboratory hydrolysis under basic conditions was 
T1/2  5 hours at pH 9 and stable under acidic conditions 
(T1/2  485 days at pH 5).The soil metabolism half-life was 
extremely short, ranging from 1.1 days under aerobic conditions to 1.6 
days under anaerobic conditions. Photodegradation was rapid in soil 
(T1/2  0.5 days) and moderate in solution at pH 5 (5 days). 
Because of the extremely low use rate and very short half-life in the 
field, field dissipation experiments were conducted with radiolabeled 
chemical. After bare-ground application, the half-life of Action was 1 
day in sandy loam and 1.8 days in clay loam. All degradates identified 
in the field were also identified in the laboratory studies. Parent and 
aged leaching laboratory experiments showed that the mobility of Action 
ranged from slight to medium by soil type. Based on estimates of 
relative mobility (Koc), Action was classified as having medium 
mobility in sand and low mobility in loam, silt loam and clay. The 
major degradation products of Action were found to have high to low 
mobility classifications based on Koc estimations. Although the 
data suggest that some of the degradates are highly mobile, a high 
degree of soil binding is expected based on results of the laboratory 
and the field experiments. Because weeds and crop will intercept the 
majority of this product when it is applied, and given the extremely 
low use rate and high degree of soil binding, Action herbicide is not 
expected to leach into groundwater.

II. Public Record

    Interested persons are invited to submit comments on this notice of 
filing. Comments must bear a notation indicating the docket control 
number, [PF-727]. A record has been established for this document under 
docket control number [PF-727] (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 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 
Virginia 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: March 12, 1997.
Stephen L. Johnson,

Director, Registration Division, Office of Pesticide Programs.

[FR Doc. 97-7222 Filed 3-25-97; 8:45 am]
BILLING CODE 6560-50-F