[Federal Register Volume 64, Number 32 (Thursday, February 18, 1999)]
[Notices]
[Pages 8102-8105]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-4024]


-----------------------------------------------------------------------

ENVIRONMENTAL PROTECTION AGENCY

[PF-861; FRL-6061-4]


Novartis Crop Protection; Pesticide Tolerance Petition Filing

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: This notice announces the initial filing of a pesticide 
petition proposing the establishment of regulations for residues of a 
certain pesticide chemical in or on various food commodities.


[[Page 8103]]


DATES: Comments, identified by the docket control number PF-861, must 
be received on or before March 22, 1999.

ADDRESSES: By mail submit written comments to: Information and Records 
Integrity Branch, Public Information and Services Divison (7502C), 
Office of Pesticides Programs, Environmental Protection Agency, 401 M 
St., SW., Washington, DC 20460. In person bring comments to: Rm. 119, 
CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
    Comments and data may also be submitted electronically by following 
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. 119 at the 
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday, 
excluding legal holidays.

FOR FURTHER INFORMATION CONTACT: Cynthia Giles-Parker, Registration 
Support Branch, 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. 
247, Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA 
22202, (703) 305-7740; e-mail: [email protected].
SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition as 
follows proposing the establishment and/or amendment of regulations for 
residues of certain pesticide chemical 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 this petition 
contains 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-861] (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:
    [email protected]


    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 5.1/6.1 file format or 
ASCII file format. All comments and data in electronic form must be 
identified by the docket control number (PF-861) and appropriate 
petition number. Electronic comments on this 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: February 9, 1999.

James Jones,

Director, Registration Division, Office of Pesticide Programs.

Summary of Petition

    The petitioner summary of the pesticide petition is printed below 
as required by section 408(d)(3) of the FFDCA. The summary of the 
petition was prepared by the petitioner and represents the views of the 
petitioner. 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.

 Novartis Crop Protection

 8F4974

    EPA has received a pesticide petition (8F4974) from Novartis Crop 
Protection, 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. 346a(d), to amend 40 CFR part 180 by establishing a tolerance 
for residues of 1,2,3-Benzothiadiazole-7-carbothioic acid S-methyl 
ester in or on the raw agricultural commodities leafy vegetables crop 
group (excluding spinach), spinach, and fruiting vegetables at 0.25, 
1.0, and 1.0 parts per million (ppm), respectively. EPA has determined 
that the petition contains data or information regarding the elements 
set forth in section 408(d)(2) of the FFDCA; however, EPA has not fully 
evaluated the sufficiency of the submitted data at this time or whether 
the data supports granting of the petition. Additional data may be 
needed before EPA rules on the petition.

A. Residue Chemistry

    1. Plant metabolism. Novartis believes the metabolism of 
acibenzolar-S-methyl has been well characterized. Only 4.6% and 14.9% 
of the total radioactive residue (TRR) was non-extractable in lettuce 
at the recommended application rate and three times the recommended 
application rate, respectively. Non-extractables were also low in a 
tomato metabolism study; 3.4% and 7.4% in tomatoes and foliage, 
respectively. The metabolism in these crops proceeded via hydrolysis of 
benzo [1,2,3] thiadiazole-7-carbothioic acid S-methyl ester to benzo 
[1,2,3] thiadiazole-7-carboxylic acid (BTCA), followed by conjugation 
as ester, glycoside and/or other plant constituents. The metabolism 
profile supports the use of an analytical enforcement method that 
accounts for acibenzolar-S-methyl and metabolites containing the benzo 
[1,2,3] thiadiazole-7-carboxylic acid (BTCA) moiety.
    2. Analytical method. Novartis Analytical Method AG-671A is a 
practical and valid method for the determination and confirmation of 
CGA-245704 in raw agricultural commodities (RAC) and processing 
substrates from the tobacco, leafy and fruiting vegetable crop groups 
at a limit of quantitation (LOQ) of 0.02 ppm. The method involves 
extraction, solid phase cleanup of samples with analysis by high 
performance liquid chromotography (HPLC) with ultraviolet (UV) 
detection or confirmatory LC/MS. The validity is demonstrated by the 
acceptable accuracy and precision obtained on numerous procedural 
recovery samples (radiovalidation and field trial sample sets), and by 
the extractability and accountability obtained by the analysis

[[Page 8104]]

of weathered radioactive substrates using Analytical Method AG-671A.
    3. Magnitude of residues. This petition is supported by forty-four 
field trials conducted on representative members of the Fruiting 
Vegetable and the Leafy Vegetable Crop Groupings. All samples were 
analyzed for by the total residue method (AG-671A) to determine the 
combined residues of acibenzolar-S-methyl and metabolites which contain 
the benzo [1,2,3] thiadiazole-7-carboxylic acid (BTCA) moiety. In 
fruiting vegetables, the residues found for tomatoes, bell peppers, and 
non-bell peppers ranged from 0.06 ppm to 0.61 ppm, from 0.16 ppm to 
0.74 ppm, and from 0.26 ppm 0.68 ppm, respectively. Residues did not 
concentrate in tomato puree (0.55 ppm). Residues did not concentrate 
significantly in tomato paste (1.33 ppm); dilution-corrected residue 
does not exceed the assumed tolerance for the RAC. A tolerance of 1.0 
ppm for the fruiting vegetable crop group has been requested. In leafy 
vegetables, the maximum residues found on representative commodities 
were 0.09 ppm, 0.11 ppm, 0.20 ppm, and 0.69 ppm for celery, head 
lettuce, leaf lettuce, and spinach, respectively. A tolerance of 0.25 
ppm has been proposed for the Leafy Vegetable Crop Grouping (excluding 
spinach). A tolerance of 1.0 ppm has been proposed for spinach.

B. Toxicological Profile

    1. Acute toxicity. The risk from acute dietary exposure to 
acibenzolar-S-methyl is considered to be very low. CGA-245704 and the 
formulated 50 WG product have low orders of acute toxicity by the oral, 
dermal and inhalation exposure routes. Results from acute studies all 
fall within toxicity rating categories of III or IV. CGA-245704 
technical has a low order of acute toxicity, is only slightly 
irritating to skin and eyes, but may cause sensitization by skin 
contact. An LD50 of greater than 5,000 milligram/kilogram 
(mg/kg) was observed for the acute oral toxicity study in rats. The 
lowest no-observed-adverse-effect level (NOAEL) in a short term 
exposure scenario, identified as 50 mg/kg in the rabbit and rat 
teratology studies, is 10-fold higher than the chronic NOAEL. Based on 
worst case assumptions, the chronic exposure assessments (see below) 
did not result in any margin of exposure (MOE) less than 3,330 for even 
the most impacted population subgroup, Novartis believes the MOE is 
greater than 100 for any population subgroups; EPA considers MOEs of 
100 or more as satisfactory. The following are results from the acute 
toxicity tests conducted on the technical material:
    i. Rat oral LD50: > 5,000 mg/kg/bwt. (M/F) Tox. Category 
IV
    ii. Rat dermal LD50: > 2,000 mg/kg/bwt. (M/F) Tox. 
Category III
    iii. Acute Inhalation LC50: > 5,000 mg/L (M/F) Tox. 
Category IV
    iv. Rabbit Eye Irritation: Minimally irritating -- Tox. Category 
III
    v. Rabbit dermal irritation: Slightly irritating -- Tox. Category 
IV
    vi. Dermal Sensitization: Sensitizer
    2. Genotoxicty. CGA-245704 technical was not mutagenic or 
clastogenic and did not provoke unscheduled DNA synthesis when tested 
thoroughly in a battery of standard in vivo, and in vitro independent 
assays, using both eukaryotes and prokaryotes, and with or without 
metabolic activation. These tests are summarized below:
    i. Microbial/Microsome Mutagenicity Assay: Non-mutagenic
    ii. Mammalian Cell CHO Mutagenicity Assay: Non-mutagenic; Non-
clastogenic
    iii. CH Bone marrow: Non-clastogenic; negative for chromosome 
aberrations
    iv. Mouse Micronucleus Test: Non-clastogenic ; negative for 
chromosome aberrations
    v. DNA Damage and Repair Rat hepatocyte: Negative]
    3. Reproductive and developmental toxicity. Acibenzolar-S-methyl is 
not a teratogenic hazard except at, or close to, the maximum tolerated 
dose. In the rat multigeneration study, CGA-245704 (acibenzolar-S-
methyl) technical had no effect on rat reproductive parameters 
including gonadal function, estrus cycles, mating behavior, conception, 
parturition, lactation, weaning, and sex organ histopathology. At 4,000 
ppm, parental body weights (bwt) were reduced. This demonstrated by the 
results of the following studies:
    i. Rat oral teratology - Maternal NOAEL of 200 mg/kg based on 
embryotoxicity and teratogenic effects; Fetal NOAEL of 50 mg/kg.
    ii. Rabbit oral teratology study - Maternal NOAEL of 50 mg/kg based 
on maternal toxicity and slightly delayed ossification; Fetal NOAEL of 
300 mg/kg based on changes in bwt.
    iii. Rat 2-generation reproduction study - NOAEL of 25 mg/kg based 
on weight development in adults at 4,000 ppm and pups during lactation 
at 2,000 ppm and above. No adverse effects on reproduction or 
fertility.
    4. Subchronic toxicity. No signs of neurotoxicity were noted with 
CGA-245704 in both acute and subchronic studies even at the highest 
dose levels of 800 mg/kg and 8,000 ppm, respectively. The evaluated 
parameters included functional observation battery, motor activity 
measurement and neurohistopathologic assessment. These tests are 
summarized below:
    i. Rat 28-day dermal study - NOAEL of 1,000 mg/kg/day
    ii. Dog 90-day feeding study - NOAEL of 10 mg based on reduced bwt 
gain at 50 mg/kg/day
    iii. Mouse 90-day feeding - NOAEL of < 30 mg/kg based on reduced 
bwt development at 1,000 ppm and above
    iv. Rat 90-day feeding study - NOAEL of 25 mg/kg based on 
inappetence and reduced bwt development at higher dose levels (4,000, 
and 8,000 ppm).
    5. Chronic toxicity. Based on the available chronic toxicity data, 
Novartis Crop Protection, Inc. believes the Reference dose (RfD) for 
acibenzolar-S-methyl is 0.05 mg/kg/day. Acibenzolar-S-methyl is not 
oncogenic in rats or mice and is not likely to be carcinogenic in 
humans. No carcinogenic activity was detected in mice and rats at the 
Maximum Tolerated Dose (MTD). There was no evidence of carcinogenicity 
in an 18-month feeding study in mice and a 24 month feeding study in 
rats. Dosage levels in both the mouse and the rat studies were adequate 
for identifying a cancer risk. Novartis believes acibenzolar-S-methyl 
should be classified as a ``Not Likely'' carcinogen based on the lack 
of carcinogenicity in rats and mice.
    6. Animal metabolism. Metabolism proceeded primarily via hydrolysis 
to form the corresponding carboxylic acid (BTCA) which was subsequently 
conjugated with several amino acids including glycine, lysine and 
ornithine. Elimination was rapid in all cases. Oxidation of the 
aromatic ring of the acid was a very minor pathway observed in goats. 
The metabolic fate of CGA-245704 in plants paralleled that observed in 
animals. The major metabolite in all test systems was the same 
hydrolysis product BTCA. Thus, the metabolism profile supports the use 
of an analytical enforcement method that accounts principally for 
parent and BTCA.
    7. Metabolite toxicology. In short-term toxicity studies in rats, 
CGA-210007 was found to be of, at most, equal or less toxicity than the 
parent compound. As with parent CGA-245704, the subchronic NOAEL for 
CGA-210007 was 100 mg/kg bwt.
    8. Endocrine disruption. Acibenzolar-S-methyl does not belong to a 
class of chemicals known or suspected of having adverse effects on the 
endocrine system. Developmental toxicity studies in rats and rabbits 
and a reproduction study in rats gave no indication that acibenzolar-S-
methyl might have any effects on endocrine function related to

[[Page 8105]]

development and reproduction. Acibenzolar-S-methyl is not a teratogenic 
hazard except at, or close to, the maximum tolerated dose. The chronic 
studies also showed no evidence of a long-term effect related to the 
endocrine system.

C. Aggregate Exposure

    1. Dietary exposure--i. Food. For the purposes of assessing the 
potential dietary exposure under the proposed tolerances, Novartis has 
estimated aggregate exposure based upon the Theoretical Maximum Residue 
Concentration (TMRC) from the requested tolerances for the raw 
agricultural commodities: Leafy Vegetables (excluding spinach) at 0.25 
ppm; Spinach at 1.0 ppm; and Fruiting Vegetables at 1.0 ppm. The TMRC 
is a ``worst case'' estimate of dietary exposure since it assumes 100% 
of all crops for which tolerances are established are treated and that 
pesticide residues are at the tolerance levels. In conducting this 
exposure assessment, Novartis has made very conservative assumptions -- 
100% of all leafy vegetable and spinach, and fruiting vegetable 
commodities will contain acibenzolar-S-methyl residues at tolerance 
levels -- which result in an overestimate of human exposure. The RfD of 
0.05 mg/kg/day is based on a 1-year feeding study in dogs with a NOAEL 
of 5 mg/kg/day and an uncertainty factor of 100. No additional 
modifying factor for the nature of effects was judged to be necessary 
as weight changes were the most sensitive indicators of toxicity in 
that study.
    ii. Drinking water. Acibenzolar-S-methyl is rapidly degraded in the 
environment via photolysis and microbial degradation; aqueous and soil 
photolysis irradiated half-lives for acibenzolar-S-methyl are 0.6 hours 
and 24 hours, respectively. The aerobic metabolism half-life is 5.3 
hours. Anaerobic aquatic metabolism half-lives are 4 days and 96 days 
for primary and secondary half-life, respectively. The leaching 
potential for acibenzolar-S-methyl is low (Koc = 492-3288). Dietary 
exposure to acibenzolar-S-methyl from water intake for the most 
sensitive subpopulation of children (1-6 years old), was calculated to 
be < 0.01% of the RfD, based on the GENEEC model. Based on these data, 
Novartis does not anticipate exposure to residue of acibenzolar-S-
methyl in drinking water.
    2. Non-dietary exposure. Novartis believes that the potential for 
non-occupational exposure to the general public is unlikely except for 
potential residues in food crops discussed above. The proposed uses for 
acibenzolar-S-methyl are for agricultural crops and the product is not 
used residentially in or around the home.

D. Cumulative Effects

    Novartis believes that consideration of a common mechanism of 
toxicity is not appropriate at this time since there is no information 
to indicate that toxic effects produced by acibenzolar-S-methyl would 
be cumulative with those of any other chemicals. Acibenzolar-S-methyl 
is a plant activator and no other compounds in this class are 
registered in the United States. Consequently, Novartis is considering 
only the potential exposure to acibenzolar-S-methyl in its aggregate 
risk 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 acibenzolar-S-methyl, Novartis has calculated 
aggregate exposure levels for this chemical. Based on chronic toxicity 
endpoints, only 1.8% of the RfD will be utilized for the U.S. general 
population. Dietary exposure to acibenzolar-S-methyl from water intake 
for the most sensitive subpopulation of children (1-6 years old), was 
calculated to be < 0.01% of the RfD, based on the GENEEC model. EPA 
usually has no concern for exposures below 100% of the RfD because the 
RfD represents the level at or below which daily aggregate dietary 
exposure over a lifetime will not pose appreciable risks to human 
health. Novartis concludes that there is a reasonable certainty that no 
harm will result from aggregate exposure to acibenzolar-S-methyl 
residues.
    2. Infants and children. Embryotoxicity and fetotoxicity were 
apparent at maternally toxic doses of CGA-245704 technical in rats and 
rabbits. The lowest NOAEL for this effect was established in the 2-
generation reproduction study at 25 mg/kg (200 ppm).
    Using the same conservative exposure assumptions as employed for 
the determination in the general population, Novartis has calculated 
the utilization of RfD by aggregate exposure to residues of 
acibenzolar-S-methyl to be 0.4% for nursing infants less than 1 year 
old, 1.5% for non-nursing infants less than 1 year old, 3.2% for 
children 1-6 years old, and 2.5% for children 7-12 years old. Dietary 
exposure to acibenzolar-S-methyl from water intake for the most 
sensitive subpopulation of children (1-6 years old), was calculated to 
be < 0.01% of the RfD, based on the GENEEC model. Novartis believes 
that under the worst case assumptions which overestimate exposure to 
infants and children, there is a reasonable certainty that no harm will 
result to infants and children from aggregate exposure to acibenzolar-
S-methyl residues.
    Additionally, CGA-245704 is not a reproductive toxin. Some signs of 
teratogenicity were found at, or close to, maternally toxic doses. No 
neurotoxic effects or oncogenic activity has been observed with CGA-
245704. From these available toxicology data, no special susceptibility 
of infants or children is anticipated.

F. International Tolerances

    Codex maximum residue levels (MRL's) have not been established for 
residues of CGA-245704 in or on raw agricultural commodities from the 
fruiting vegetable and leafy vegetable crop groups. Maximum residue 
levels of 0.1 ppm have been established for CGA-245704 on wheat in 
Switzerland and Hungary. Proposed CODEX MRLs of 1.0 ppm on tomatoes and 
0.1 ppm on bananas, cereals, wheat, spring barley, and rice have been 
proposed.
[FR Doc. 99-4024 Filed 2-17-99; 8:45 am]
BILLING CODE 6560-50-F