Notice of Filing of Pesticide Petition

ENVIRONMENTAL PROTECTION AGENCY

[PF-793; FRL-5773-2]

Notice of Filing of Pesticide Petition

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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SUMMARY: This notice announces the initial filing of a pesticide

petition proposing the establishment of regulations for residues of the

pesticide chemical pymetrozine, in or on various food commodities.

DATES: Comments, identified by the docket control number PF-793, must

be received on or before June 19, 1998.

ADDRESSES: By mail submit written comments to: Public Information and

Records Integrity Branch, Information Resources and Services Division

(7506C), 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 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. 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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Leonard Cole.................. Rm. 211, CM #2, 703- 1921 Jefferson

305-5412, e- Davis Hwy,

mail:cole.l[email protected] Arlington, VA

mail.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

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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-793] (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 number (insert docket number) 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: May 6, 1998.

James Jones,

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.

Norvartis Crop Protection, Inc.

PP 8F4929

EPA has received a pesticide petition (PP 8F4929) from Norvartis

Crop Protection, Inc., P.O. Box 18300, Greensboro, NC 27419-8300

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 residues of Pymetrozine in or on the raw

agricultural commodity cucumbers, fruiting vegetables, potatoes, hops

at 0.02, 0.05 parts per million. 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. The metabolism of CGA-215944 in plants is

understood for the purposes of the proposed tolerance. Studies in rice,

tomatoes, cotton and potatoes gave similar results. Identified

metabolic pathways have demonstrated that pymetrozine is the residue of

concern for tolerance setting purposes.

2. Analytical method-- i. Crops. Novartis has submitted two

analytical methods for the determination of pymetrozine and its major

crop metabolite, in crop substrates. For both methods, the limit of

detection (LOD) is 1.0 ng and the limit of quantitation (LOQ) is 0.02

ppm. Samples are extracted using acetonitrile: 0.05M sodium borate and

an aliquot is taken for each method. The aliquots were cleaned up with

solid-phase and/or liquid-liquid partitions and analyzed by HPLC with

column-switching and UV detection. Both methods have undergone

independent laboratory validation. The pymetrozine Analytical Method is

proposed as the tolerance enforcement method.

ii. Livestock. Novartis has also submitted analytical methods for

the determination of pymetrozine in eggs, milk and poultry, dairy and

goat tissues, and for its major livestock metabolite in dairy and goat

tissues and milk. This method also accounts for a phosphate conjugate,

which is a significant metabolite found only in milk. The LOD for the

analytical method is 1.0 ng and the LOQ is 0.01 ppm. Samples are

extracted using acetonitrile: Water, cleaned up with solid-phase and

liquid-liquid partitions, and analyzed for pymetrozine by HPLC with

column switching and UV detection. The LOD for the metabolite method is

1.5 ng and the is LOQ of 0.01 ppm. Samples are extracted using

methanol: Water. Milk samples are heated to hydrolyze the phosphate

conjugate, and all samples are cleaned up with solid-phase partitions

and analyzed by HPLC with UV detection. The parent Analytical Method

has successfully undergone independent laboratory validation.

3. Magnitude of residues--i. Cucurbits. Twenty-two field trials

were conducted in 13 states representing typical fruiting vegetables

growing areas in the United States, including Arizona, California,

Florida, Georgia, Indiana, Michigan, New York, North Carolina, Ohio,

Oregon, South Carolina, and Texas. Cantaloupes, summer squash, and

cucumbers were treated with two post foliar applications of pymetrozine

50WG at 21 and 14 days prior to harvest of mature fruit using a 1X rate

of 80 g a.i./A per application (160 g a.i. or 0.35 lb a.i.per a).

Samples of summer squash and cucumbers from early harvest harvest

intervals (pre-harvest interval (PHI) 50 in rats is > 5,820 milligrams per kilogram (mg/kg) for

males and females, combined. The rat dermal LD50 is > 2,000

mg/kg and the rat inhalation LC50 is > 1.8 mg/L air.

Pymetrozine is not a skin sensitizer in guinea pigs and does not

produce dermal irritation in rabbits. It produces minimal eye

irritation in rabbits. End-use water-dispersible granule formulations

of pymetrozine have similar low acute toxicity profiles.

2. Genotoxicty. Pymetrozine did not induce point mutations in

bacteria (Ames assay in Salmonella typhimurium and Escherichia coli) or

in cultured mammalian cells (Chinese hamster V79) and was not genotoxic

in an in vitro unscheduled DNA synthesis assay in rat hepatocytes.

Chromosome aberrations were not observed in an in vitro test using

Chinese hamster ovary cells and there were no clastogenic or aneugenic

effects on mouse bone marrow cells in an in vivo mouse micronucleus

test. These studies show that pymetrozine is not genotoxic.

3. Reproductive and developmental toxicity. In a teratology study

in rats, pymetrozine caused decreased body weights and food consumption

in females given 100 and 300 mg/kg/day during gestation. This maternal

toxicity was accompanied by fetal skeletal

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anomalies and variations consistent with delayed ossification. The no-

observed-effect level (NOEL) for maternal and fetal effects in rats was

30 mg/kg/day. A teratology in rabbits showed that pymetrozine caused

maternal death and reduced body weight gain and food consumption at 125

mg/kg/day (highest dose tested). Maternal toxicity was accompanied by

embryo- and feto-toxicity (abortion in one female and total resorptions

in two females). Body weight and food consumption decreases, early

resorptions and postimplantation losses were also observed in maternal

rabbits given 75 mg/kg/day. There was an increased incidence of fetal

skeletal anomalies and variations at these maternally toxic doses. The

NOEL for maternal and fetal effects in rabbits was 10 mg/kg/day.

Pymetrozine is not teratogenic in rats or rabbits. In a two generation

reproduction study in rats, parental body weights and food consumption

were decreased, liver and spleen weights were reduced and

histopathological changes in liver, spleen and pituitary were observed

at 2,000 ppm (highest dose tested). Liver hypertrophy was observed in

parental males at 200 ppm (approximately 10-40 mg/kg/day). Reproductive

parameters were not affected by treatment with pymetrozine. The NOEL

for reproductive toxicity is 2,000 ppm (approximately 110-440 mg/kg/

day). Offspring body weights were slightly reduced at 2,000 and 200 ppm

and eye opening was slightly delayed in pups at 2,000 ppm. Effects on

offspring were secondary to parental toxicity. The NOEL for toxicity to

adults and pups is 20 ppm (approximately 1-4 mg/kg/day).

4. Subchronic toxicity. Pymetrozine was evaluated in 13-week

subchronic toxicity studies in rats, dogs and mice. Liver, kidneys,

thymus and spleen were identified as target organs. The NOEL was 500

ppm (33 mg/kg/day) in rats and 100 ppm (3 mg/kg/day) in dogs. In mice,

increased liver weights and microscopical changes in the liver were

observed at all doses tested. The NOEL in mice was < 1,000 ppm (198 mg/

kg/day). No dermal irritation or systemic toxicity occurred in a 28-day

repeated dose dermal toxicity study with pymetrozine in rats given

1,000 mg/kg/day. Minimum direct dermal absorption (1.1%) of pymetrozine

was detected in rats over a 21 hour period of dermal exposure. Maximum

radioactivity left on or in the skin at the application site and

considered for potential absorption was 11.9%.

5. Chronic toxicity. Based on chronic toxicity studies in the dog

and rat, a reference dose (RfD) of 0.0057 mg/kg/day is proposed for

pymetrozine. This RfD is based on a NOEL of 0.57 mg/kg/day established

in the chronic dog study and an uncertainty factor of 100 to account

for interspecies extrapolation and interspecies variability. Minor

changes in blood chemistry parameters, including higher plasma

cholesterol and phospholipid levels, were observed in the dog at the

lowest-observed-effect level (LOEL) of 5.3 mg/kg/day. The NOEL

established in the rat chronic toxicity study was 3.7 mg/kg/day, based

on reduced body weight gain and food consumption, hematology and blood

chemistry changes, liver pathology and biliary cysts.

6. Animal metabolism. The metabolism of pymetrozine (CGA-215944) in

the rat is well understood. Metabolism involves oxidation of the 5-

methylene group of the triazine ring yielding 4,5-dihydro-5-hydroxy-6-

methyl-4-[(3-pyridinylmethylene)amino]-1,2,4-triazin-3(2H)-one (CGA-

359009). Oxidation of the methyl substituent of the triazine ring led

to 4,5-dihydro-6-(hydroxymethyl)-4-[(3-pyridinylmethylene)amino]-1,2,4-

triazin-3(2H)-one (CGA-313124) which was further oxidized to the

corresponding carboxylic acid, 4,5-dihydro-6-carboxy-4-[(3-

pyridinylmethylene)amino]-1,2,4-triazin-3(2H)-one. Hydrolysis of the

enamino bridge yielded 4-amino-6-methyl-1,2,4-triazin-3,5(2H,4H)-dione

(CGA-294849). This was further degraded to 6-methyl-1,2,4-triazin-

3,5(2H,4H)-dione (METABOLITE). Hydrolysis of the enamino bridge of CGA-

215944 produced CGA-215525 which undergoes either acylation (CGA-

259168) or deamination yielding 4,5-dihydro-6-methyl-1,2,4-triazin-

3(2H)-one (CGA-249257). Hydrolysis of the enamino bridge also formed 3-

pyridinecarboxaldehyde (CGA-300407), nicotinic acid (CGA-180777),

nicotinamide (CGA-180778), 3-pyridinemethanol (CGA-128632) and 1,6-

dihydro-1-methyl-6-oxo-3-pyridinecarboxamide. Identified metabolic

pathways in animals and plants are similar.

7. Metabolite toxicology. The residue of concern for tolerance

setting purposes is the parent compound. Metabolites of pymetrozine are

considered to be of equal or lesser toxicity than the parent.

8. Endocrine disruption. Pymetrozine does not belong to a class of

chemicals known or suspected of having adverse effects on the endocrine

system. There is no evidence that pymetrozine has any effect on

endocrine function in developmental and reproduction studies.

Furthermore, histological investigation of endocrine organs in chronic

dog, rat and mouse studies did not indicate that the endocrine system

is targeted by pymetrozine.

C. Aggregate Exposure

1. Food. For purposes of assessing the potential dietary exposure

under the proposed tolerances, Novartis has estimated aggregate

exposure based on exposure from residues of 0.05 ppm on fruiting

vegetables, 0.02 ppm on cucurbits, 0.02 ppm on potatoes and 5 ppm on

hops. A 100% market share was assumed.

2. Drinking water. Another potential source of exposure of the

general population to pymetrozine is via residues in drinking water.

Pymetrozine is not expected to contaminate drinking water based on its

environmental attributes and the low application rates applied.

Pymetrozine breaks down relatively quickly in the environment by a wide

variety of mechanisms and degradation pathways. Leaching studies showed

that pymetrozine is tightly bound to soil and is unlikely to leach in

the field. Field dissipation studies show little movement beyond the

uppermost soil horizon.

3. Non-dietary exposure. There are no other uses currently

registered for pymetrozine. The proposed uses involve application of

pymetrozine to crops grown in an agricultural environment. There are no

proposed uses which would be expected to result in residential exposure

of pymetrozine. Therefore, there is no potential for non-occupational

exposure to the general population. is not expected to be significant.

D. Cumulative Effects

The potential for cumulative effects of pymetrozine and other

substances that have a common mechanism of toxicity has also been

considered. Pymetrozine belongs to a new chemical class known as

pyridine azomethines. It exhibits a unique mode of action which can be

characterized as nervous system inhibition of feeding behavior. It does

not have a general toxic or paralyzing effect on insects, but

selectively interferes with normal feeding activities by affecting

nervous system regulation of fluid intake. There is no reliable

information to indicate that toxic effects produced by pymetrozine

would be cumulative with those of any other chemical including another

pesticide. Therefore, Novartis believes it is appropriate to consider

only the potential risks of pymetrozine in an aggregate risk

assessment.

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E. Safety Determination

1. U.S. population. Using the conservative exposure assumptions and

the proposed RfD described above, the aggregate exposure to pymetrozine

will utilize 3.78% of the RfD for the U.S. population. EPA generally

has no concern for exposures below 100% of the RfD because the RfD

represents the level at or below which daily aggregate exposure over a

lifetime will not pose appreciable risks to human health. Therefore,

Novartis concludes that there is a reasonable certainty that no harm

will result from aggregate exposure to pymetrozine residues.

2. Infants and children. In assessing the potential for additional

sensitivity of infants and children to residues of pymetrozine, data

from developmental toxicity studies in the rat and rabbit and a two-

generation reproduction study in the rat have been considered.

In a teratology study in rats, developmental toxicity anomalies and

variations associated was observed only at maternally toxic doses.

Similarly, in a rabbit teratology study, was observed only at

maternally toxic doses. The NOELs in the rat and rabbit teratology

studies were 30 and 10 mg/kg/day, respectively. In the two-generation

reproduction study, there were no effects on reproductive parameters.

Offspring body weights were slightly reduced and eye opening was

slightly delayed at dose levels producing parental toxicity. The NOEL

for parental and offspring toxicity was 20 ppm (approximately 1-4 mg/

kg/day).

FFDCA section 408 provides that EPA may apply an additional safety

factor for infants and children in the case of threshold effects to

account for pre- and post-natal toxicity and the completeness of the

database. Based on the current toxicological requirements, the database

relative to pre- and post-natal effects for children is complete.

Further, for pymetrozine, the NOEL of 0.57 from the chronic feeding

study in dogs, which was used to calculate the RfD (0.0057 mg/kg/day),

is already lower than the developmental NOELs (30 and 10 mg/kg/day)

from the teratogenicity studies in rats and rabbits by a factor of more

than tenfold. In the pymetrozine rat reproduction study, the mild

nature of the effects observed (decreased body weight) at the systemic

LOEL (10-40 mg/kg/day) and the fact that the effects were observed at a

dose that is more than 10 times greater than the NOEL in the chronic

dog study (0.57 mg/kg/day) suggest that there is no additional

sensitivity for infants and children. Therefore, it is concluded that

an additional uncertainty factor is not warranted to protect the health

of infants and children and that an RfD of 0.0057 mg/kg/day based on

the chronic dog study is appropriate for assessing aggregate risk to

infants and children from pymetrozine.

Using the exposure assumptions described above, the percent of the

RfD that will be utilized by aggregate exposure to residues of

pymetrozine is 0.43% for nursing infants less than 1 year old, 1.49%

for non-nursing infants, 3.44% for children 1-6 years old and 2.72% for

children 7-12 years old. Therefore, based on the completeness and

reliability of the toxicity database, Novartis concludes that there is

a reasonable certainty that no harm will result to infants and children

from aggregate exposure to pymetrozine residues.

F. International Tolerances

There are no Codex maximum levels established for residues of

pymetrozine.

[FR Doc. 98-13447 Filed 5-19-98; 8:45 am]

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