Notice of Filing Pesticide Petitions to Establish a Tolerance for Certain Pesticide Chemicals in or on Food

Note: EPA no longer updates this information, but it may be useful as a reference or resource.

[Federal Register: September 1, 1999 (Volume 64, Number 169)]
[Notices]
[Page 47795-47806]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr01se99-97]

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ENVIRONMENTAL PROTECTION AGENCY

[PF-885; FRL-6096-8]

Notice of Filing Pesticide Petitions to Establish a Tolerance for
Certain Pesticide Chemicals in or on Food

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 docket control number [PF-885], must be
received on or before October 1, 1999.

ADDRESSES: Comments may be submitted by mail, electronically, or in
person. Please follow the detailed instructions for each method as
provided in Unit I.C. of the SUPPLEMENTARY INFORMATION section. To
ensure proper receipt by EPA, it is imperative that you identify docket
control number PF-885 in the subject line on the first page of your
response.

[[Page 47796]]

FOR FURTHER INFORMATION CONTACT: By mail: Shaja Brothers, Registration
Support Branch, Registration Division (7505C), Office of Pesticide
Programs, Environmental Protection Agency, 401 M St., SW., Washington,
DC 20460; telephone number: (703) 308-3194; and e-mail address:
brothers.shaja@epa.gov.
For technical questions, contact the appropriate Product Manager:
Joseph Tavano, telephone number: (703) 305-6411 and e-mail address:
tavano.joseph@epa.gov.; or Cynthia Giles-Parker (PM 22), telephone
number: (703) 305-7740 and e-mail address: giles-
parker.cynthia@epa.gov.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

You may be affected by this action if you are an agricultural
producer, food manufacturer or pesticide manufacturer. Potentially
affected categories and entities may include, but are not limited to:

------------------------------------------------------------------------
Examples of
Categories NAICS potentially
affected entities
------------------------------------------------------------------------
Industry 111 Crop production

112 Animal production

311 Food manufacturing
32532 Pesticide
manufacturing
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This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in the table could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether or not this action might apply to certain entities. If you have
questions regarding the applicability of this action to a particular
entity, consult the person listed in the ``FOR FURTHER INFORMATION
CONTACT'' section.

B. How Can I Get Additional Information, Including Copies of this
Document and Other Related Documents?

1. Electronically. You may obtain electronic copies of this
document, and certain other related documents that might be available
electronically, from the EPA Internet Home Page at http://www.epa.gov/.
To access this document, on the Home Page select ``Laws and
Regulations'' and then look up the entry for this document under the
``Federal Register--Environmental Documents.'' You can also go directly
to the Federal Register listings at http://www.epa.gov/fedrgstr/.
2. In person. The Agency has established an official record for
this action under docket control number PF-885. The official record
consists of the documents specifically referenced in this action, any
public comments received during an applicable comment period, and other
information related to this action, including any information claimed
as confidential business information (CBI). This official record
includes the documents that are physically located in the docket, as
well as the documents that are referenced in those documents. The
public version of the official record does not include any information
claimed as CBI. The public version of the official record, which
includes printed, paper versions of any electronic comments submitted
during an applicable comment period, is available for inspection in the
Public Information and Records Integrity Branch (PIRIB), Rm. 119,
Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA, from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
PIRIB telephone number is (703) 305-5805.

C. How and to Whom Do I Submit Comments?

You may submit comments through the mail, in person, or
electronically. To ensure proper receipt by EPA, it is imperative that
you identify docket control number PF-885 in the subject line on the
first page of your response.
1. By mail. Submit your comments to: Public Information and Records
Integrity Branch (PIRIB), Information Resources and Services Division
(7502C), Office of Pesticide Programs (OPP), Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460.
2. In person or by courier. Deliver your comments to: Public
Information and Records Integrity Branch (PIRIB), Information Resources
and Services Division (7502C), Office of Pesticide Programs (OPP),
Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921
Jefferson Davis Highway, Arlington, VA. The PIRIB is open from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
PIRIB telephone number is (703) 305-5805.
3. Electronically. You may submit your comments electronically by
E-mail to: ``opp-docket@epa.gov ,'' or you can submit a computer disk
as described above. Do not submit any information electronically that
you consider to be CBI. Avoid the use of special characters and any
form of encryption. Electronic submissions will be accepted in
Wordperfect 5.1/6.1 or ASCII file format. All comments in electronic
form must be identified by docket control number PF-885. Electronic
comments may also be filed online at many Federal Depository Libraries.

D. How Should I Handle CBI That I Want to Submit to the Agency?

Do not submit any information electronically that you consider to
be CBI. You may claim information that you submit to EPA in response to
this document as CBI by marking any part or all of that information as
CBI. Information so marked will not be disclosed except in accordance
with procedures set forth in 40 CFR part 2. In addition to one complete
version of the comment that includes any information claimed as CBI, a
copy of the comment that does not contain the information claimed as
CBI must be submitted for inclusion in the public version of the
official record. Information not marked confidential will be included
in the public version of the official record without prior notice. If
you have any questions about CBI or the procedures for claiming CBI,
please consult the person identified in the ``FOR FURTHER INFORMATION
CONTACT'' section.

E. What Should I Consider as I Prepare My Comments for EPA?

You may find the following suggestions helpful for preparing your
comments:
1. Explain your views as clearly as possible
2. Describe any assumptions that you used.
3. Provide copies of any technical information and/or data you
used that support your views.
4. If you estimate potential burden or costs, explain how you
arrived at the estimate that you provide.
5. Provide specific examples to illustrate your concerns.
6. Make sure to submit your comments by the deadline in this
notice.
7. To ensure proper receipt by EPA, be sure to identify the docket
control number assigned to this action in the subject line on the first
page of your response. You may also provide the name, date, and Federal
Register citation.

II. What Action is the Agency Taking?

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

[[Page 47797]]

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.

List of Subjects

Environmental protection, Agricultural commodities, Feed additives,
Food additives, Pesticides and pests, Reporting and recordkeeping
requirements.

Dated: August 19, 1999.

James Jones,

Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

Petitioner summaries of the pesticide petitions are printed below
as required bysection 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. IR-4 Project

PP 6E4603, 6E4787, and 7E4878

EPA has received pesticide petitions [PP 6E4603, 6E4787, and
7E4878] from the Interregional Research Project Number 4 (IR-4), New
Jersey Agricultural Experiment Station, P. O. Box 231 Rutgers
University, New Brunswick, NJ 08903 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 tolerances for
combined residues of the herbicide, pendimethalin [N-(1-ethylpropyl)-
3,4-dimethyl-2,6-dinitrobenzenamine, and its 3, 5-dinitrobenzyl alcohol
metabolite (CL 202347) in or on the food commodities as follows:
1 PP 6E4603. Proposes the establishment of a tolerance for carrots
at 0.5 parts per million (ppm).
2 PP 6E4787. Proposes the establishment of a tolerance for citrus
fruit crop group at 0.1 ppm.
3. PP 7E4878. Proposes the establishment of tolerances, with
regional registration for peppermint and spearmint tops at 0.2 ppm, and
peppermint and spearmint oil at 1.0 ppm. Registration will be limited
to Idaho, Oregon, and Washington based on the geographical
representation of the residue data submitted to EPA.
EPA has determined that the petitions contain 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 support granting of the
petitions. Additional data may be needed before EPA rules on the
petitions.

A. Residue Chemistry

1. Plant metabolism. The qualitative nature of the residues of
pendimethalin in plants is understood based on adequate studies
conducted with [14 C]-pendimethalin on various crops.
Pendimethalin and its 3,5-dinitrobenzyl alcohol metabolite (CL202347)
are the only residues of concern.
2. Analytical method. Section 408 (b)(3) of the amended FFDCA
requires EPA to determine that there is a practical method for
detecting and measuring levels of the pesticide chemical residue in or
on food and that the tolerance be set at a level at or above limit of
detection of the designated method. The Gas Chromatography (GC) of
pendimethalin and (CL202347) analytical methods, M691 and M692, are
proposed as the enforcement methods for the residues in carrots; M1999
is the proposed method for citrus fruit crop group, and processed
citrus commodities; and M1930.01 has been proposed for mint and mint
oil. All methods utilize electron capture detectors and have a limit of
quantitation (LOQ) of 0.05 ppm for the respective residues of concern.
3. Magnitude of residues--i. Residue field trials were conducted in
seven major carrot producing states in the United States at both the 1x
rate of 2 pounds (lbs) active ingredient/acre (ai/A) and an exaggerated
rate of 4 lbs ai/A (2x the typical application rate). Maximum
pendimethalin residues recovered from carrot samples treated with these
applications were 0.10 ppm from the 1x treatment and 0.16 ppm from the
2x treatment. For the alcohol metabolite, CL202347, the maximum
recovered residues ranged from 0.29 ppm from the 1x treatment to 0.44
ppm from the 2x treatment. The registrant believes that the results
from these studies support the proposed tolerance of 0.5 ppm
pendimethalin in or on carrots.
ii. Residue field trials were conducted on oranges, grapefruits,
and lemons in major citrus fruit crop group producing states in the
United States at a 1.5x rate of 6 lbs ai/A and an exaggerated 3x rate
of 12 lbs ai/A. The plots were treated with pendimethalin at a variety
of different intervals prior to harvest. The raw agricultural commodity
(RAC) samples were also processed into wet and dried pulp, molasses,
oil and juice. RAC samples taken from plots treated one day prior to
harvest, a worst case residue situation, resulted in residues of 0.008
ppm (in grapefruit) or less. No residues were recovered from wet pulp
and juice samples at the 0.005 ppm level. Residues of pendimethalin
were recovered at 0.005 ppm in dried pulp, 0.009 ppm in molasses and
0.026 ppm in orange oil. It should be noted that data for wet pulp and
molasses are no longer required as per Table I of the Residue Chemistry
Test Guidelines EPA OPPTS 860.1000. The registrant believes that the
results from these studies are adequate to support the proposed
tolerance of 0.1 ppm pendimethalin in or on citrus fruit crop group,
and in processed citrus commodities.
iii. Residue field trials were conducted in two major mint
producing states in the United States at both the 1x rate of 2 lbs ai/A
and an exaggerated rate of 10 lbs ai/A (5x the typical application
rate). Fresh mint foliage samples were either harvested and directly
analyzed or processed into mint oil before analyses. The registrant
believes that the results from these studies support the proposed
tolerances of 0.2 ppm pendimethalin in mint foliage (leaves and stems)
and 1.0 ppm pendimethalin in mint oil.

B. Toxicological Profile

1. Acute toxicity. The acute oral lethal dose (LD<INF>50</INF>)
values for pendimethalin technical in the Wistar rat are 1,250
milligrams/kilograms/body weight (mg/kg/bwt) (males) and 1,050 mg/kg/
bwt (females). The acute dermal LD<INF>50</INF> was greater than 5,000
mg/kg in New Zealand white rabbits. The 4-hour rat inhalation lethal
concentration (LC<INF>50</INF>) was > 320 milligram per liter (mg/L)
(nominal concentration). Pendimethalin was shown to be slightly
irritating to rabbit eyes and non-irritating to rabbit skin.
Pendimethalin did not cause skin sensitization in guinea pigs.
2. Genotoxicity. Extensive mutagenicity studies conducted to
investigate point and gene mutations, DNA damage and chromosomal
aberration, using in vitro and in vivo test systems show pendimethalin
to be non-genotoxic.

[[Page 47798]]

3. Reproductive and developmental toxicity. Results from a 2-
generation rat reproduction study showed the no-observed adverse effect
level (NOAEL) for parental and reproductive toxicity to be 2,500 ppm
(172 mg/kg bwt/day) and the lowest-observed adverse effect level
(LOAEL) to be 5,000 ppm (346 mg/kg/bwt/day). No developmental toxicity
was observed in either the rat or rabbit developmental toxicity
studies, nor was there any evidence in the 2-generation rat
reproduction study that there was developmental or reproductive
toxicity at dose levels below those in which parental toxicity was
observed. For rabbits, the developmental toxicity NOAEL was > 60 mg/kg/
day, the highest dose tested (HDT). The maternal NOAEL was > 60 mg/kg/
day, based on mortality observed at 125 mg/kg/day in a pilot study. For
rats, there were no maternal or developmental effects at any dose level
and the NOAELs for both maternal and developmental effects were
<gr-thn-eq> 500 mg/kg/day, the HDT.
4. Subchronic toxicity. A 90-day feeding study was conducted in
rats and dogs. The NOAELs for these studies were 500 ppm (50 mg/kg/bwt/
day) and 2,500 ppm (62.5 mg/kg/bwt/day) for the rat and dog studies,
respectively.
5. Chronic toxicity. The chronic toxicity of pendimethalin has been
extensively investigated in three species (i. e., the rat, mouse, and
dog). The results are as follows:
i. Rats. In an initial 2-year feeding study in Sprague-Dawley rats,
conducted at dose levels of 0, 100, 500, and 5,000 ppm (corresponding
to dietary intakes of 0, 5, 25, and 250 mg/kg/bwt/day, respectively), a
clear NOAEL was established at 500 ppm (25 mg/kg/bwt/day). The LOAEL
was set at 5,000 ppm (250 mg/kg/bwt/day) based on decreased survival,
body weight gain and food consumption, increased gamma glutamyl
transferase and cholesterol, an increase in absolute and/or relative
liver weight, generalized icterus, dark adipose tissue in females,
diffusely dark thyroids and follicular cell hyperplasia of the thyroid.
In a second 2-year feeding study in rats, conducted at dose levels of
0, 1,250, 2,500, 3,750, and 5,000 ppm (corresponding to dietary intakes
of 0, 51, 103, 154, and 213 mg/kg/bwt/day, respectively), a NOAEL was
not determined. The LOAEL of less than or equal to 1,250 ppm
(<gr-thn-eq> 51 mg/kg/bwt/day) was based on non-neoplastic thyroid
follicular cell changes and increased liver weight.
ii. Mouse. Pendimethalin technical was administered at dietary
concentrations of 100, 500, and 5,000 ppm (corresponding to dose levels
of 12.3, 62.3 and 622.1 mg/kg/bwt/day in males and 15.6, 78.3, and
806.9 mg/kg/ bwt/day in females) to CD-1 mice for 18-months. In this
study, the NOAEL was 500 ppm (62.3 mg/kg/bwt/day) and the LOAEL, based
on mortality, body weight decrease, organ weight changes and
amyloidosis, was 5,000 ppm (622.1 mg/kg/ bwt/day).
iii. Dog. In a 2-year oral (capsule) study, conducted at dose
levels of 0, 12.5, 50 and 200 mg/kg/bwt/day, the NOAEL was equal to or
greater than the maximum dose tested <gr-thn-eq> 200 mg/kg/bwt/day with
no LOAEL established.
Pendimethalin has been classified as a Group C, ``possible human
carcinogen,'' chemical by EPA based on a statistically significant
increased trend and pairwise comparison between the high dose group and
controls for thyroid follicular cell adenomas in male and female rats.
EPA recommended using the chronic population adjusted dose (cPAD)
approach for quantification of human risk. Therefore, the cPAD is
deemed protective of all chronic human health effects, including
cancer.
6. Animal metabolism. Adequate goat and poultry metabolism studies
are available for pendimethalin. As no poultry feed items are
associated with carrots, citrus fruit crop group processed citrus
commodities, or mint, poultry metabolism studies are not relevant to
this petition. In addition, the registrant has determined that there is
no reasonable expectation of finite pendimethalin residues of concern
in animal commodities as a result of use on multiple crops and no
tolerances for pendimethalin residues of concern in livestock
commodities are needed.
7. Endocrine disruption. Collective results from several
mechanistic studies provide support that pendimethalin disrupts
thyroid-pituitary hormonal balance. An analysis of the data obtained
from these studies supports fluctuations in thyroid hormones (T3 and/or
T4) at dietary concentrations of 500 ppm (31 mg/kg/bwt/day) and
greater. However, no fluctuations in thyroid hormones were observed at
100 ppm (10 mg/kg/bwt/day) in either of the 14-day special feeding
studies, supporting a NOAEL for thyroid effects of 100 ppm or 10 mg/kg/
bwt/day. As the cPAD is based on the NOAEL of 10 mg/kg/bwt/day obtained
from these studies, thyroid hormonal changes are already accounted for
in the characterization of the potential risks to humans. Moreover,
because of species differences in thyroid gland physiology, slight
fluctuations in thyroid hormone levels noted in rats may not be
applicable to humans. In addition, collective organ weights and
histopathological findings from the 2-generation rat reproduction
study, as well as from the subchronic and chronic toxicity studies in 3
different animal species demonstrate no apparent estrogenic effects or
treatment-related effects on any other component of the endocrine
system.

C. Aggregate Exposure

Pendimethalin is widely used as a pre-emergent herbicide to control
broad-leaf weeds in both food and non-food crops, as well as non-
agricultural use sites including residential lawns. In examining
aggregate exposure, FQPA directs EPA to consider available information
concerning exposures from the pesticide residue in food and water
(dietary) and all other non-occupational exposures. The primary non-
food sources of exposure the Agency evaluates include drinking water
(whether from groundwater or surface water), and exposure through
pesticide use in gardens, lawns, or buildings (residential and other
indoor uses). The potential for aggregate exposure from all registered
and proposed uses is discussed below:
1. Dietary (food) exposure. Tolerances have been established (40
CFR 180.361) for the combined residues of pendimethalin and its 3,5-
dinitrobenzyl alcohol metabolite (CL 202347) in or on a variety of food
commodities at levels ranging from 0.05 ppm in rice grain to 0.1 ppm in
corn, peanuts, soybeans and other commodities. Based on conservative
assumptions of tolerance level residues and 100% crop treatment with
pendimethalin, the EPA's Dietary Exposure Evaluation Model (DEEM)
estimates chronic dietary exposure to pendimethalin from all currently
registered uses to be only 0.00042 mg/kg/day (< 1% cPAD) for the
overall U. S. population. The estimated most highly exposed DEEM
subgroup for pendimethalin is non-nursing infants at a level of 0.00140
mg/kg/day (< 2%).
Additional maximum dietary contributions, (of up to 0.000498 mg/kg/
bwt/day and 0.001294 mg/kg/bwt/day for the general U.S. population and
for non-nursing infants less than 1-year old, respectively) anticipated
from use on carrots and citrus fruit crop group will still utilize < 1%
(actual 0.5%) and < 2% (actual 1.3%) of the cPAD for the respective
population subgroups. The additional dietary burden that will result
from the pendimethalin tolerances in mint and mint oil will also be
insignificant. Thus, the American Cyanamid Company believes that there
should be no reason for concern from the additional dietary burden that
will result from the proposed tolerances of pendimethalin in carrots,
citrus fruit

[[Page 47799]]

crop group, and mint because the contribution to the cPAD will be
insignificant.
i. Drinking water. Pendimethalin has low water solubility and a
strong absorption to soil, which makes it essentially immobile in all
soil types. Therefore, American Cyanamid Company concludes that there
is no concern for the potential for pendimethalin to runoff to surface
water or leach to ground water. No Maximum Concentration Level and no
Health Advisory Level has been established for residues of
pendimethalin in drinking water. A pendimethalin drinking water
exposure analysis for a 10 kg child shows that a chronic exposure from
a worst case dietary intake (drinking water only) of 0.0018 mg/kg/day
would utilize < 2% of the cPAD. Thus, the American Cyanamid Company
believes that contributions to the dietary burden from residues of
pendimethalin in water, alone, would be inconsequential.
2. Non-dietary exposure. Pendimethalin is currently registered for
use on the following residential and non-food sites: ornamental lawns,
grasses, ground covers, turf, and ornamental plantings, which are
short- and intermediate-term non-occupational exposure scenarios. Thus,
the American Cyanamid Company believes that the estimates margins of
exposure (MOEs) for residential applicators (MOE = 833) and residential
post-application exposures to children (MOE = 111) are more than
adequate.

D. Cumulative Effects

The Agency has not yet published guidelines to determine whether
pendimethalin has a common mechanism of toxicity with other substances
or how to include this pesticide in a cumulative risk assessment.
Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, pendimethalin does
not appear to produce a toxic metabolite produced by other substances.
For the purposes of this tolerance action, the American Cyanamid
Company assumes that pendimethalin does not have a common mechanism of
toxicity with other substances.

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, the American Cyanamid Company concludes that the total
aggregate exposure to pendimethalin from food will utilizes less than
1% of the cPAD for the overall U.S. population. EPA generally has no
concern for exposures below 100% of the cPAD because the cPAD
represents the level at or below which daily aggregate dietary exposure
over a lifetime will not pose appreciable risks to human health.
Despite the potential for exposure to pendimethalin in drinking water
and from non-dietary non-occupational exposures, the American Cyanamid
Company does not expect the aggregate exposure to exceed 100% of the
cPAD. The registrant concludes that the aggregate risks estimated from
the following three scenarios: (i) < 4% of the cPAD for chronic dietary
exposures (food plus water), (ii) MOE = 680 for chronic dietary
exposures (food plus water) plus residential applicator exposures, and
(iii) MOE = 107 for chronic dietary exposures (food plus water) plus
residential post-application exposures to children, do not exceed the
Agency's levels of concern. Thus, the American Cyanamid Company
concludes that there is a reasonable certainty that no harm will result
from aggregate exposure to pendimethalin residues as a result of the
establishment of the proposed tolerance in carrots, citrus fruit crop
group, and processed citrus commodities, mint and mint oil.
2. Infants and children. The major identifiable subgroup with the
highest aggregate exposure is non-nursing infants less than 1-year old.
In assessing the potential for additional sensitivity of infants and
children to residues of pendimethalin, the data from developmental
toxicity studies in the rat and rabbit, and a 2-generation reproduction
study in the rat has been considered. The developmental toxicity
studies are designed to evaluate adverse effects on the developing
organism resulting from maternal pesticide exposure during prenatal
development. Reproduction studies provide information relating to
effects on the reproductive capabilities of parental animals from
exposure to the pesticide as well as additional data on systemic
toxicity.
The prenatal and postnatal toxicology data base for pendimethalin
is complete with respect to current toxicological data requirements.
The data base does not indicate a potential for increased sensitivity
from prenatal or postnatal exposure. As mentioned in item B.3. above,
no developmental toxicity was observed in either the rat or rabbit
developmental toxicity studies, nor was there any evidence in the 2-
generation rat reproduction study that there was developmental or
reproductive toxicity at dose levels below those in which parental
toxicity was observed. For rabbits, the developmental toxicity NOAEL
was > 60 mg/kg/day, the HDT. The maternal NOAEL was > 60 mg/kg/day,
based mortality observed at 125 mg/kg/day in a pilot study. For rats,
there were no maternal or developmental effects at any dose level and
the NOAELs for both maternal and developmental effects were <gr-thn-eq>
500 mg/kg/day, the HDT. In the 2-generation reproductive toxicity study
in rats, the parental and reproductive NOAELs were 172 mg/kg/day. The
reproductive LOAEL of 346 mg/kg/day was based on decreased pup weight,
which occurred in the presence of parental (systemic) toxicity at 346
mg/kg/day.
FFDCA section 408 provides that EPA may apply an additional tenfold
margin of safety for infants and children in the case of threshold
effects to account for prenatal and postnatal toxicity and the
completeness of the data base. Based on current toxicological data
requirements, the toxicology data base for pendimethalin is complete.
Furthermore, the reproductive NOAEL of 172 mg/kg/day is seventeen-fold
higher than the NOAEL of 10 mg/kg/day used for the cPAD. Additionally,
the reproductive LOAEL occurred in the presence of parental (systemic)
toxicity, and there was no evidence of developmental toxicity in either
the rat or the rabbit studies. Therefore, the American Cyanamid Company
believes that these proposed tolerances do not represent any
unacceptable prenatal or postnatal risk to infants and children.
Using the conservative exposure assumptions described above, and
based on previous EPA reports, the American Cyanamid Company has
concluded that aggregate exposure to pendimethalin from food will
utilize less than 2% of the cPAD for infants and children. EPA
generally has no concern for exposures below 100% of the cPAD because
the cPAD represents the level at or below which daily aggregate dietary
exposure over a lifetime will not pose appreciable risks to human
health. Despite the potential for exposure to pendimethalin in drinking
water and from non-dietary, non-occupational exposure, the American
Cyanamid Company does not expect the aggregate exposure to exceed 100%
of the cPAD. Thus, the registrant concludes that there is a reasonable
certainty that no harm will result to infants and children from
aggregate exposure to pendimethalin residues.

F. International Tolerances

There are no Codex, Canadian or Mexican International Maximum
Residue Levels established for residues of pendimethalin in carrots,
citrus fruit

[[Page 47800]]

crop group and processed citrus commodities, or mint at this time.

2. Rohm and Haas Company

PP 7F4824

EPA has received a pesticide petition (PP 7F4824) from Rohm and
Haas Company, 100 Independence Mall West, Phila., PA 19106-2399
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 indirect or inadvertent residues of
tebufenozide [benzoic acid, 3,5-dimethyl-, 1-(1,1-dimethylethyl)-2-(4-
ethylbenzoyl) hydrazide] and its metabolite [Benzoic acid, 3,5-
dimethyl-1-(1,1-dimethylethyl)-2-[4-(1-hydroxyethyl) benzoyl]
hydrazide] in or on the RAC grass forage, fodder and hay at 0.5 parts
per million (ppm) and forage, fodder, straw and hay of nongrass animal
feeds at 0.5 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. Plant metabolism. The metabolism of tebufenozide in plants
(grapes, apples, rice and sugar beets) is adequately understood for the
purpose of this tolerance. The metabolism of tebufenozide in all crops
was similar and involves oxidation of the alkyl substituents of the
aromatic rings primarily at the benzylic positions. The extent of
metabolism and degree of oxidation are a function of time from
application to harvest. In all crops, parent compound comprised the
majority of the total dosage. None of the metabolites were in excess of
10% of the total dosage. Tebufenozide, the metabolite, benzoic acid,
3,5-dimethyl-1-(1,1-dimethylethyl)-2-[4-(1-hydroxyethyl) benzoyl, and
sugar conjugates of the metabolite were detected in a confined rotation
crop study.
2. Analytical method. Validated high performance liquid
chromatographic (HPLC) analytical methods using ultraviolet (UV) or
mass selective (MS) detection are employed for measuring residues of
tebufenozide and its metabolite in grains, forage, fodder, stover, hay,
and straw. The methods involve extraction by blending with solvents,
purification of the extracts by liquid-liquid partitions and final
purification of the residues using solid phase extraction column
chromatography. The limit of quantitation (LOQ) of the method for all
matrices is 0.02 ppm for tebufenozide and its metabolite.
3. Magnitude of residues. Field rotation crop residue trials were
conducted and residues of tebufenozide and its metabolite were
measured. Results of analyses showed that residues of tebufenozide and
its metabolite will not exceed 0.1 ppm in forage of legumes and 0.5 ppm
in forage, hay or straw of cereal grains.

B. Toxicological Profile

1. Acute toxicity--Acute toxicity studies with technical grade.
Oral LD<INF>50</INF> in the rat is > 5 grams for males and females -
Toxicity Category IV; dermal LD<INF>50</INF> in the rat is = 5,000 mg/
kg for males and females - Toxicity Category III; inhalation
LD<INF>50</INF> in the rat is > 4.5 mg/l - Toxicity Category III;
primary eye irritation study in the rabbit is a non-irritant; primary
skin irritation in the rabbit > 5 mg - Toxicity Category IV.
Tebufenozide is not a sensitizer.
2. Genotoxicty. Several mutagenicity tests which were all negative.
These include an Ames assay with and without metabolic activation, an
in vivo cytogenetic assay in rat bone marrow cells, and in vitro
chromosome aberration assay in CHO cells, a CHO/HGPRT assay, a reverse
mutation assay with E. Coli, and an unscheduled DNA synthesis (UDS)
assay in rat hepatocytes.
3. Reproductive and developmental toxicity--i. In a prenatal
developmental toxicity study in Sprague-Dawley rats 25/group
Tebufenozide was administered on gestation days 6-15 by gavage in
aqueous methyl cellulose at dose levels of 50, 250, or 1,000 mg/kg/day
and a dose volume of 10 ml/kg. There was no evidence of maternal or
developmental toxicity; the maternal and developmental toxicity NOAEL
was 1,000 mg/kg/day.
ii. In a prenatal developmental toxicity study conducted in New
Zealand white rabbits 20/group Tebufenozide was administered in 5 ml/kg
of aqueous methyl cellulose at gavage doses of 50, 250, or 1,000 mg/kg/
day on gestation days 7-19. No evidence of maternal or developmental
toxicity was observed; the maternal and developmental toxicity NOAEL
was 1,000 mg/kg/day.
iii. In a 1993 2-generation reproduction study in Sprague-Dawley
rats Tebufenozide was administered at dietary concentrations of 0, 10,
150, or 1,000 ppm (0, 0.8, 11.5, or 154.8 mg/kg/day for males and 0,
0.9, 12.8, or 171.1 mg/kg/day for females). The parental systemic NOAEL
was 10 ppm (0.8/0.9 mg/kg/day for males and females, respectively) and
the lowest observed adverse effect level (LOAEL) was 150 ppm (11.5/12.8
mg/kg/day for males and females, respectively) based on decreased body
weight, body weight gain, and food consumption in males, and increased
incidence and/or severity of splenic pigmentation. In addition, there
was an increased incidence and severity of extramedullary hematopoiesis
at 2,000 ppm. The reproductive NOAEL was 150 ppm. (11.5/12.8 mg/kg/day
for males and females, respectively) and the LOAEL was 2,000 ppm
(154.8/171.1 mg/kg/day for males and females, respectively) based on an
increase in the number of pregnant females with increased gestation
duration and dystocia. Effects in the offspring consisted of decreased
number of pups per litter on postnatal days 0 and/or 4 at 2,000 ppm
(154.8/171.1 mg/kg/day for males and females, respectively) with a NOEL
of 150 ppm (11.5/12.8 mg/kg/day for males and females, respectively).
In a 1995 2-generation reproduction study in rats Tebufenozide was
administered at dietary concentrations of 0, 25, 200, or 2,000 ppm (0,
1.6, 12.6, or 126.0 mg/kg/day for males and 0, 1.8, 14.6, or 143.2 mg/
kg/day for females). For parental systemic toxicity, the NOAEL was 25
ppm (1.6/1.8 mg/kg/day in males and females, respectively), and the
LOAEL was 200 ppm (12.6/14.6 mg/kg/day in males and females), based on
histopathological findings (congestion and extramedullary
hematopoiesis) in the spleen. Additionally, at 2,000 ppm (126.0/143.2
mg/kg/day in M/F), treatment-related findings included reduced parental
body weight gain and increased incidence of hemosiderin-laden cells in
the spleen. Columnar changes in the vaginal squamous epithelium and
reduced uterine and ovarian weights were also observed at 2,000 ppm,
but the toxicological significance was unknown. For offspring, the
systemic NOAEL was 200 ppm. (12.6/14.6 mg/kg/day in males and females),
and the LOAEL was 2,000 ppm (126.0/143.2 mg/kg/day in M/F) based on
decreased body weight on postnatal days 14 and 21.
4. Subchronic toxicity. In a 21-day dermal toxicity study, Crl: CD
rats (6/sex/dose) received repeated dermal administration of either the
technical 96.1% product RH-75,992 at 1,000 mg/kg/day limit-dose or the
formulation 23.1% a.i. product RH-755,992 2F at 0, 62.5, 250, or 1,000
mg/kg/day, 6 hours/day, 5 days/week for 21 days. Under conditions of
this study, RH-75,992

[[Page 47801]]

Technical or RH-75,992 2F demonstrated no systemic toxicity or dermal
irritation at the HDT 1,000 mg/kg/ during the 21-day study. Based on
these results, the NOAEL for systemic toxicity and dermal irritation in
both sexes is 1,000 mg/kg/day HDT. A LOAEL for systemic toxicity and
dermal irritation was not established.
5. Chronic toxicity-- i. A 1-year dog feeding study with a (LOAEL)
of 250 ppm, 9 mg/kg/day for male and female dogs based on decreases in
red blood cells (RBC), HCT, and HGB, increases in Heinz bodies,
methemoglobin, MCV, MCH, reticulocytes, platelets, plasma total
bilirubin, spleen weight, and spleen/body weight ratio, and liver/body
weight ratio. Hematopoiesis and sinusoidal engorgement occurred in the
spleen, and hyperplasia occurred in the marrow of the femur and
sternum. The liver showed an increased pigment in the Kupffer cells.
The NOAEL for systemic toxicity in both sexes is 50 ppm (1.9 mg/kg/
day).
ii. An 18-month mouse carcinogenicity study with no carcinogenicity
observed at dosage levels up to and including 1,000 ppm.
iii. A 2-year rat carcinogenicity with no carcinogenicity observed
at dosage levels up to and including 2,000 ppm (97 mg/kg/day and 125
mg/kg/day for males and females, respectively).
6. Animal metabolism. The pharmacokinetics and metabolism of
tebufenozide were studied in female Sprague-Dawley rats (3-6/sex/group)
receiving a single oral dose of 3 or 250 mg/kg of RH-5992
14C labeled in one of three positions (A-ring, B-ring or N-
butylcarbon). The extent of absorption was not established. The
majority of the radiolabeled material was eliminated or excreted in the
feces within 48 hours within 48 hours; small amounts (1 to 7% of the
administered dose) were excreted in the urine and only traces were
excreted in expired air or remained in the tissues. There was no
tendency for bioaccumulation. Absorption and excretion were rapid. A
total of 11 metabolites, in addition to the parent compound, were
identified in the feces; the parent compound accounted for 96 to 99% of
the administered radioactivity in the high dose group and 35 to 43% in
the low dose group. No parent compound was found in the urine; urinary
metabolites were not characterized. The identity of several fecal
metabolites was confirmed by mass spectral analysis and other fecal
metabolites were tentatively identified by cochromatography with
synthetic standards. A pathway of metabolism was proposed based on
these data. Metabolism proceeded primarily by oxidation of the three
benzyl carbons, two methyl groups on the B-ring and an ethyl group on
the A-ring to alcohols, aldehydes or acids. The type of metabolite
produced varies depending on the position oxidized and extent of
oxidation. The butyl group on the quaternary nitrogen also can be
cleaved (minor), but there was no fragmentation of the molecule between
the benzyl rings.
No qualitative differences in metabolism were observed between
sexes, when high or low dose groups were compared or when different
labeled versions of the molecule were compared.
7. Metabolite toxicology. The absorption and metabolism of
tebufenozide were studied in a group of male and female bile-duct
cannulated rats. Over a 72 hour period, biliary excretion accounted for
30% male to 34% female of the administered dose while urinary excretion
accounted for about 5% of the administered dose and the carcass
accounted for < 0.5% of the administered dose for both males and
females. Thus systemic absorption (percent of dose recovered in the
bile, urine and carcass) was 35% male to 39% female. The majority of
the radioactivity in the bile (20% male to 24% female of the
administered dose) was excreted within the first 6 hours post-dosing
indicating rapid absorption. Furthermore, urinary excretion of the
metabolites was essentially complete within 24 hours post-dosing. A
large amount [67% (female) to 70% (male) of the administered dose was
unabsorbed and excreted in the feces by 72 hours. Total recovery of
radioactivity was 105% of the administered dose.
A total of 13 metabolites were identified in the bile; the parent
compound was not identified, i.e., unabsorbed compound, nor were the
primary oxidation products seen in the feces in the pharmacokinetics
study. The proposed metabolic pathway proceeded primarily by oxidation
of the benzylic carbons to alcohols, aldehydes or acids. Bile contained
most of the other highly oxidizedproducts found in the feces. The most
significant individual bile metabolites accounted for 5% to 18% of the
total radioactivity (female and/or male). Bile also contained the
previously undetected (in the pharmacokinetics study] ``A'' Ring ketone
and the ``B'' Ring diol. The other major components were characterized
as high molecular weight conjugates. No individual bile metabolite
accounted for > 5% of the total administered dose. Total bile
radioactivity accounted for about 17% of the total administered dose.
No major qualitative differences in biliary metabolites were
observed between sexes. The metabolic profile in the bile was similar
to the metabolic profile in the feces and urine.

C. Aggregate Exposure

1. Dietary exposure-- From food and feed uses. Tolerances have been
established (40 CFR 180.482) for the residues of tebufenozide, in or on
walnuts at 0.1 ppm, pome fruit at 1.5 ppm, pecans at 0.01, kiwifruit at
0.5ppm, leafy and cole crop vegetables at 10 ppm and wine grapes at 0.5
ppm. Numerous section 18 tolerances have been established at levels
ranging from 0.3 ppm in sugar beet roots to 5.0 ppm in turnip tops. The
current petition requests establishment of tolerances due to indirect
or inadvertent residues of tebufenozide and its metabolite in or on
grass forage, fodder and hay and forage, fodder, straw and hay of
nongrass animal feeds Risk assessments were conducted by Rohm and Haas
to assess dietary exposures and risks from tebufenozide, benzoic acid,
3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl) hydrazide and are
presented in the followingdiscussion:
i. Food--Acute exposure and risk. Acute dietary risk assessments
are performed for a food-use pesticide if a toxicological study has
indicated the possibility of an effect of concern occurring as a result
of a one day or single exposure. Toxicity observed in oral toxicity
studies were not attributable to a single dose (exposure). No neuro- or
systemic toxicity was observed in rats given a single oral
administration of tebufenozide at 0, 500, 1,000 or 2,000 mg/kg. No
maternal or developmental toxicity was observed following oral
administration of tebufenozide at 1,000 mg/kg/day (limit-dose) during
gestation to pregnant rats or rabbits. This risk is considered to be
negligible.
ii. Chronic exposure and risk. The RfD used for the chronic dietary
analysis is 0.018 mg/kg/day. In conducting this chronic dietary (food)
exposure assessment, Rohm and Haas used (a) tolerance level residues
for pecans, walnuts, wine and sherry, imported apples and all other
commodities with established or pending tebufenozide tolerances; and
(b) percent crop-treated (%CT) information on some of these crops.
Further refinement using anticipated residue values and additional %CT
information would result in a lower estimate of chronic dietary
exposure. The Novigen DEEM system was used for this chronic dietary
exposure analysis. The subgroups listed below are (c) the U.S.
Population (48

[[Page 47802]]

States); (d) those for infants and children; and (e) the other
subgroups (adult) for which the percentage of the reference dose (RfD)
occupied is greater than that occupied by the subgroup U.S. population
(48 States). The results are summarized below:

------------------------------------------------------------------------
Groups %RfD (percentage)
------------------------------------------------------------------------
U.S. Population..................... 10.0%
All Infants (< 1-year).............. 12.2%
Nursing Infants (< 1-year old)...... 5.7%
Non-Nursing Infants (< 1-year old).. 15.0%
Children (1-6 years old)............ 22.5%
Children (7-12 years old)........... 14.1%
Females (13 + years old, nursing)... 10.1%
U.S. Population autumn season....... 10.3%
U.S. Population winter season....... 10.1%
Non-Hispanic Blacks................. 10.4%
Non-Hispanic Other than Black or 11.0%
White..............................
Northeast Region.................... 10.3%
Southern Region..................... 10.1%
Western Region...................... 10.5%
Pacific Region...................... 10.7%
------------------------------------------------------------------------

iii. Drinking water-- i. Acute exposure and risk. Because no acute
dietary endpoint was determined, Rohm and Haas concludes that there is
a reasonable certainty of no harm from acute exposure from drinking
water.
iv. Chronic exposure and risk. Submitted environmental fate studies
suggest that tebufenozide is moderately persistent to persistent and
mobile. Under certain conditions tebufenozide appears to have the
potential to contaminate ground and surface water through runoff and
leaching; subsequently potentially contaminating drinking water. There
are no established Maximum Contaminant Levels (MCL) for residues of
tebufenozide in drinking water and no Health Advisories (HA) have been
issued for tebufenozide therefore these could not be used as
comparative values for risk assessment. Therefore, potential residue
levels for drinking water exposure were calculated previously by EPA
using GENEEC (surface water) and SCIGROW (ground water) for human
health risk assessment. Because of the wide range of half-life values
(66-729 days) reported for the aerobic soil metabolism input parameter
a range of potential exposure values were calculated. In each case the
worst case upper bound exposure limits were then compared to
appropriate chronic drinking water level of concern (DWLOC). In each
case the calculated exposures based on model data were below the DWLOC.
2. Non-dietary exposure. Tebufenozide is not currently registered
for use on any residential non-food sites. Therefore , there is no
chronic, short- or intermediate-term exposure scenario.

D. Cumulative Effects

Section 408(b)(2)(D)(v) requires that, when considering whether to
establish, modify, or revoke a tolerance, the Agency consider
``available information'' concerning the cumulative effects of a
particular pesticide's residues and ``other substances that have a
common mechanism of toxicity.'' The Agency believes that ``available
information'' in this context might include not only toxicity,
chemistry, and exposure data, but also scientific policies and
methodologies for understanding common mechanisms of toxicity and
conducting cumulative risk assessments. For most pesticides, although
the Agency has some information in its files that may turn out to be
helpful in eventually determining whether a pesticide shares a common
mechanism of toxicity with any other substances, EPA does not at this
time have the methodologies to resolve the complex scientific issues
concerning common mechanism of toxicity in a meaningful way. EPA has
begun a pilot process to study this issue further through the
examination of particular classes of pesticides. The Agency hopes that
the results of this pilot process will increase the Agency's scientific
understanding of this question such that EPA will be able to develop
and apply scientific principles for better determining which chemicals
have a common mechanism of toxicity and evaluating the cumulative
effects of such chemicals. The Agency anticipates, however, that even
as its understanding of the science of common mechanisms increases,
decisions on specific classes of chemicals will be heavily dependent on
chemical specific data, much of which may not be presently available.
Although at present the Agency does not know how to apply the
information in its files concerning common mechanism issues to most
risk assessments, there are pesticides as to which the common mechanism
issues can be resolved. These pesticides include pesticides that are
toxicologically dissimilar to existing chemical substances (in which
case the Agency can conclude that it is unlikely that a pesticide
shares a common mechanism of activity with other substances) and
pesticides that produce a common toxic metabolite (in which case common
mechanism of activity will be assumed).
EPA does not have, at this time, available data to determine
whether tebufenozide, benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-
2-(4-ethylbenzoyl) hydrazide has a common mechanism of toxicity with
other substances or how to include this pesticide in a cumulative risk
assessment. Unlike other pesticides for which EPA has followed a
cumulative risk approach based on a common mechanism of toxicity,
tebufenozide, benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-
ethylbenzoyl) hydrazide does not appear to produce a toxic metabolite
produced by other substances. For the purposes of this tolerance
action, therefore, Rohm and Haas has not assumed that tebufenozide,
benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl)
hydrazide has a common mechanism of toxicity with other substances.

E. Safety Determination

1. U.S. population-- i. Acute risk. Since no acute toxicological
endpoints were established, no acute aggregate risk exists.

[[Page 47803]]

ii. Chronic risk. Using the conservative exposure assumptions
described above, and taking into account the completeness and
reliability of the toxicity data, Rohm and Haas has concluded that
dietary (food only) exposure to tebufenozide will utilize 10.0% of the
RfD for the U.S. population. Submitted environmental fate studies
suggest that tebufenozide is moderately persistent to persistent and
mobile; thus, tebufenozide could potentially leach to groundwater and
runoff to surface water under certain environmental conditions. The
modeling data for tebufenozide indicate levels less than OPP's drinking
water levels concern (DWLOC). EPA generally 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. There are no registered
residential uses of tebufenozide. Since there is no potential for
exposure to tebufenozide from residential uses, Rohm and Haas does not
expect the aggregate exposure to exceed 100% of the RfD.
iii. Short- and intermediate-term risk. Short- and intermediate-
term aggregate exposure takes into account chronic dietary food and
water (considered to be a background exposure level) plus indoor and
outdoor residential exposure. Since there are currently no registered
indoor or outdoor residential non-dietary uses of tebufenozide and no
short- or intermediate-term toxic endpoints, short- or intermediate-
term aggregate risk does not exist.
2. Infants and children-- i. In general. In assessing the potential
for additional sensitivity of infants and children to residues of
tebufenozide, benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-
ethylbenzoyl) hydrazide, EPA previously considered data from
developmental toxicity studies in the rat and rabbit and a 2-generation
reproduction study in the rat. The developmental toxicity studies are
designed to evaluate adverse effects on the developing organism
resulting from maternal pesticide exposure gestation. Reproduction
studies provide information relating to effects from exposure to the
pesticide on the reproductive capability of mating animals and data on
systemic toxicity.
FFDCA section 408 provides that EPA shall apply an additional
tenfold margin of safety for infants and children in the case of
threshold effects to account for prenatal and postnatal toxicity and
the completeness of the data base unless EPA determines that a
different margin of safety will be safe for infants and children.
Margins of safety are incorporated into EPA risk assessments either
directly through use of a MOE analysis or through using uncertainty
(safety) factors in calculating a dose level that poses no appreciable
risk to humans. EPA believes that reliable data support using the
standard uncertainty factor (usually 100 for combined inter- and intra-
species variability)) and not the additional tenfold MOE/uncertainty
factor when EPA has a complete data base under existing guidelines and
when the severity of the effect in infants or children or the potency
or unusual toxic properties of a compound do not raise concerns
regarding the adequacy of the standard MOE/safety factor.
The toxicology data base for tebufenozide is complete and includes
acceptable developmental toxicity studies in both rats and rabbits as
well as a 2-generation reproductive toxicity studies in rats.
The EPA determined that the data provided no indication of
increased sensitivity of rats or rabbits to in utero and/or postnatal
exposure to tebufenozide. No maternal or developmental findings were
observed in the prenatal developmental toxicity studies at doses up to
1,000 mg/kg/day in rats and rabbits. In the 2-generation reproduction
studies in rats, effects occurred at the same or lower treatment levels
in the adults as in the offspring.
Rohm and Haas concludes that there is a reasonable certainty that
no harm will result to infants and children from aggregate exposure to
tebufenozide, benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-
ethylbenzoyl) hydrazide residues.

F. International Tolerances

There are currently no CODEX, Canadian or Mexican maximum residue
levels (MRLs) established for tebufenozide in rotation crops so no
harmonization issues are required for this action.

3. Rohm and Haas Company

PP 9F5058

EPA has received a pesticide petition (PP 9F5058) from Rohm and
Haas Company, 100 Independence Mall West, Philadelphia, PA 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 combined residues of RH-117281 Technical Benzamide-3,5-
dichloro-N-(3-chloro-1-ethyl-1-methyl-2oxopropyl)-4-methyl and
metabolites 3,5-dichloro-4-hydroxy methyl-benzoic acid and 3,5-
dichloro-1,4-benzene dicarboxylic (RH-141452 and RH-141455) in or on
the raw agricultural commodity (RAC) potatoes at 0.1 parts per million
(ppm), grapes at 5 ppm, and raisins at 15 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. Plant metabolism. The metabolism of RH-117281 Technical in
plants (grapes and potatoes) is adequately understood for the purposes
of these tolerances. There were no significant metabolites other than
the parent compound in grapes. Residues in grapes were surface residues
of parent RH-117281 and minor amounts of hydrolysis and photolysis
degradates. In potatoes, two minor rat metabolites, RH-141452 and RH-
141455, comprised the majority of the residue. No other metabolites
were present in excess of 10% of the total dosage. It is most likely
that the source of these residues is extremely low level uptake of
highly degraded metabolites from the soil, rather than metabolism
within the plant, since these compounds are highly metabolized, but
there are no intermediate products found in the potato.
2. Animal metabolism. The metabolism of RH-117281 Technical in
food-producing animals (dairy goats) is adequately understood. Hen
metabolism is not required for the current submission because no
components of grape or potato are fed to poultry. Metabolism in
laboratory and food-producing animals was similar and extensive,
occurring through multiple pathways involving primary hydrolysis,
glutathione-mediated reactions, and reductive dehalogenation; secondary
oxidation; and terminal glucuronic and amino acid conjugation. RH-
117281 Technical and its residues are rapidly excreted in animals. No
significant residues in these food commodities.
3. Analytical method. Tolerance enforcement methods using gas
chromatography/electron capture detection (GC/ECD) or gas
chromatography/mass selective detection (GC/MSD), have been developed
for RH-117281 in grapes, grape juice and raisins. The limit of
quantification (LOQ) is 0.01 ppm for all matrices. Average recoveries
are 95.8-106% for grapes, 84.2-101% for juice, and 85.9-108% for
raisins, over the range of fortifications.

[[Page 47804]]

A tolerance enforcement method using GCECD or GC/MSD detection has
also been developed for RH-117281 in potatoes and for the metabolites
RH-141452 and RH-141455 in potatoes, potato chips and potato flakes.
The LOQ for all analytes is 0.02 ppm for all matrices.
The methods involve extraction with solvent, filtration, liquid-
liquid partition, and final purification of the residues using solid
phase column chromatography. An independent validation of the methods
has been completed.
4. Magnitude of residues--i. Grape. Twelve field residue trials
were conducted over two seasons in four States at either 1.25 lb active
ingredient (a.i)/acre and 2.50 lb a.i./acre (1.40 kiligram/hectare Kg/
ha and 2.81 Kg/ha) or 2.0 lbs a.i/acre and 4.0 lbs a.i acre (2.25 Kg/ha
and 4.49 Kg/ha). Ten applications were made in each trial. In two of
the trials, fruit was harvested at 0, 7, 14, and 21 days after the
final application. In the remaining trials, samples were taken at 13 or
14 days after the final application. The proposed seasonal use rate is
1.6 lb a.i/acre (1.8 Kg/ha) with a 14- day pre-harvest interval (PHI).
Samples were analyzed for residues of RH-117281. Residue levels in
the 34 samples from the 2.0 or 2.5 lb/acre (2.25 and 2.81 kg/ha) rates
and 13 or 14 day PHI ranged from 0.218 to 4.52 ppm. The average residue
was 0.88 ppm.
These data support a permanent tolerance of 5.0 ppm on grapes.
Grape juice (clarified and unclarified) and raisins were generated from
two RAC samples from one residue trial. Residues in grape juice were
much lower than in the whole fruit, roughly 10% of the levels in the
RAC. Residues concentrated in the raisins. The data support a permanent
tolerance of 15 ppm on raisins.
ii. Potatoes. Sixteen field residue trials were conducted over two
seasons in 10 States at either 1.25 lb a.i./acre and 2.50 lb a.i/a
(1.40 kg/ha and 2.81 kg/ha) or 2.0 lbs a.i./acre and 4.0 lbs a.i./acre
(2.25 kg/ha and 4.49 kg/ha). Ten applications were made in each trial.
In two of the trials, tubers were harvested at 0, 3, 7, and 14 days
after the final application. In the remaining trials, samples were
taken at 3 days after the final application. The proposed maximum
seasonal use rate is 1.6 lb a.i./acre (1.8 kg/ha) with a 3-day PHI.
Samples were analyzed for parent RH-117281 and the two metabolites RH-
141452 and RH-141455.
Samples were below the LOQ in nearly all cases. These residues
support the establishment of a permanent tolerance of 0.1 ppm on
potatoes.
Twelve residue trials were conducted in 7 regions in Canada during
1998 at 2.0 kg/ha and a PHI of 3-days. There were no residues of any
analyte above the LOQ of 0.02 ppm in any sample.
A potato process study was conducted. Residues of two metabolites
concentrated in flakes, consistent with loss of water from the potato.

B. Toxicological Profile

1. Acute toxicity. RH-117281 Technical was practically non-toxic by
ingestion of a singe oral dose in rats and mice lethal dose
(LD<INF>50</INF>) > 5,000 milligram/kilogram (mg/kg), practically non-
toxic by dermal application to rats (LD<INF>50</INF> > 2,000 mg/kg),
and practically non-toxic to rats after a 4-hour inhalation exposure
with an LC<INF>50</INF> value of > 5.3 milligrams per liter (mg/L)
(highest attainable concentration ), is not considered to be a primary
eye irritant or a skin irritant and is not a dermal sensitizer. The
technical material was non irritating to skin after single applications
and moderately irritating to eyes. RH-117281 Technical produced delayed
contact hypersensitivity in the guinea pig at concentrations of 2,500
ppm and higher. An acute neurotoxicity study in rats did not produce
any neurotoxic or neuropathologic effects with a NOAEL > 2,000 mg/kg.
2. Genotoxicity. RH-117281 was nonmutagenic in a standard battery
of tests. In in vitro assays, RH-117281 showed no evidence of mutagenic
activity in an Ames and CHO/HGPRT assays for gene mutation, and no
evidence of structural chromosomal aberrations in the CHO in vitro
cytogenetic study. As predicted by its antitubulin mode of action,
mitotic accumulation and polyploidy were noted at cytotoxic doses in
the in vitro chromosomal assay. However, there was no evidence of
structural or numerical chromosomal aberrations when RH-117281
Technical was tested in vivo in the mouse micronucleus test.
3. Reproductive and developmental toxicity. NOAELs for
developmental and maternal toxicity to RH-117281 Technical were
established at 1,000 mg/kg/day, highest dose tested (HDT) in both the
rat and rabbit. No signs of developmental toxicity were exhibited.
In a 2-generation reproduction study in the rat, RH-117281
Technical had no adverse effects on reproductive performance or pup
development at doses up to and exceeding 1474 mg/kg/day, the limit dose
tested (LDT). This NOAEL was 20-fold higher than the NOAEL for adult
toxicity of 71 mg/kg/day. A delay in periweaning weight gain and
associated spleen effects in the F1 and F2a litters were shown in the
F2b litters to be a secondary effect related to feed refusal due to
palatability of the treated diets, and not to a systemic toxic effect.
The consequences of feed refusal due to palatability do not constitute
an adverse effect relevant to human health risk assessment.
4. Subchronic toxicity. The NOAEL in a 90-day rat subchronic
feeding study was 1,509 mg/kg/day in males and 1,622 mg/kg/day in
females (HDT). RH-117281 Technical did not produce neurotoxic or
neuropathologic effects.
In a 90-day feeding study with mice, the NOAEL was 436 mg/kg/day in
males and 574 mg/kg/day in females based on a slight decrease in weight
gain among the females only at the LOAEL of 1,666 mg/kg/day.
A 90-day dog feeding study gave a NOAEL of 55 mg/kg/day in males
and 62 mg/kg/day in females based on increased liver weights without a
corresponding clinical or histopathologic change in females only at 322
mg/kg/day.
No signs of systemic toxicity were observed when RH-117281
Technical was administered dermally to rats for 28 days at a limit dose
of 1,000 mg/kg/day. This occurred despite skin irritation at all doses
tested (150, 400, and 1,000 mg/kg/day). Similarly, in vivo dermal
absorption was shown to be low regardless of concentration or
formulation type (i.e. < 1-6% of theadministered dose was systemically
absorbed after 24 hours).
5. Chronic toxicity. In a combined rat chronic/oncogenicity study,
the NOAEL for chronic toxicity was 51 mg/kg/day in males and 65 mg/kg/
day based on an equivocal increase in relative liver weight at a LOAEL
of 328 mg/kg/day in females at the interim sacrifice only. The NOAEL
was considered to be 1,058 mg/kg/day in males and 1,331 mg/kg/day in
females (HDT, limit dose). No carcinogenicity was observed.
An 18-month mouse carcinogenicity study showed no signs of
carcinogenicity or of any other compound-related effect at dosage
levels up to 1,021 mg/kg/day in males and 1,289 mg/kg/day in females
HDT, limit dose).
The NOAEL in a 1-year feeding study in dogs was 255 mg/kg/day in
males and 48 mg/kg/day in females based on minimal effects on body
weight (bwt) and body weight gain and increased liver weights in
females only at a LOAEL of 278 mg/kg/day.
6. Animal metabolism. In pharmacokinetic and metabolism studies in
the rat, RH-117281 Technical

[[Page 47805]]

was rapidly and extensively absorbed, metabolized and excreted
following oral exposure. A total of approximately 60% of the
administered dose was systemically absorbed. Plasma levels peaked
within 8 hours of dosing, and declined with a half-life of 12-14 hours,
consistent with the nearly complete excretion within 48 hours. No
evidence of accumulation of the parent compound or its metabolites was
observed. The predominant route of excretion was hepatobiliary.
Metabolism was found to occur through multiple pathways involving
primary hydrolysis, glutathione-mediated reactions, and reductive
dehalogenation; secondary oxidation on both the aromatic methyl and the
aliphatic side-chain; and terminal glucuronic acid and amino acid
conjugation. Altogether, 32 separate metabolites were identified; no
single metabolite other than parent RH-117281 accounted for more than
10% of the administered dose. The rapid metabolism and excretion of RH-
117281 Technical was a major factor explaining the compound's overall
remarkably low toxicity profile in animals.
7. Metabolite toxicology. Of these multiple pathways, all three are
common to both laboratory (rat) and food-producing animals (goat).
Extensive degradation and elimination occurs in animals such that
residues are unlikely to accumulate in humans or animals exposed to
these residues through the diet. There were no significant metabolites
other than the parent RH-117281 in grapes. Two minor metabolites in the
rat constituted a major portion of the residue in potato tubers in the
14 C-metabolism study. RH-141452 and RH-141455 are not
considered toxicologically significant as they were practically non-
toxic after acute oral administration in mice, non mutagenic in the
Ames test, and rapidly excreted essentially unchanged in rats. Actual
residues in field trials never exceeded trace levels approximating the
LOQ.
8. Endocrine disruption. Based on structure-activity and mode of
action information as well as the lack of developmental and
reproductive toxicity, RH-117281 Technical is unlikely to exhibit
endocrine activity. There was no evidence of a functional or
histopathologic change in the male or female reproductive tract, and no
indicators of an endocrine effect of any kind below limit doses in
mammalian subchronic or chronic studies or in mammalian and avian
reproduction studies. A slight thyroid effect at the limit dose (994-
1139 mg/kg/day) in the subchronic dog studies was secondary to liver
hypertrophy and enlargement at that dose. Collectively, the weight of
evidence provides no indication of an endocrine effect of RH-117281
Technical.
9. Toxicological endpoints-- i. Acute and short term dietary. No
endpoint of concern was identified for acute or short term (1-7 day)
dietary exposure to RH-117281 Technical, and no acute or short term
risk assessment is required.
ii. Chronic dietary. The proposed RfD for RH-117281 Technical is
0.5 mg/kg/day, based on application of a 100-fold uncertainty factor to
the chronic NOAELs in the rat and dog of 51 and 48 mg/kg/day,
respectively.
iii. Carcinogen classification. There was no evidence of oncogenic
potential in two well-conducted lifetime feeding studies in rats and
mice, at doses up to and including the limit dose. Thus, RH-117281
Technical should be classified as ``unlikely'' to have carcinogenic
potential.

C. Aggregate Exposure

1. Dietary (food) exposure. Tolerances are proposed for the
residues of RH-117281 Technical in or on potatoes (0.1 ppm), grapes (5
ppm), and raisins (15 ppm). The goat metabolism study demonstrated that
there is no reasonable expectation of transfer of residues of RH-117281
Technical into meat or milk from potatoes. There are no grape feed
commodities fed to livestock, and no potato or grape feed commodities
fed to poultry. There are no other established or proposed United
States tolerances for RH-117281 Technical, and no currently registered
uses in the United States. Risk assessments were conducted by Rohm and
Haas to assess dietary exposures and risks from RH-117281 Technical as
follows:
i. Acute exposure and risk. No acute endpoint was identified for
RH-117281 Technical and no acute risk assessment is required.
ii. Chronic exposure and risk. For chronic dietary risk assessment,
the proposed tolerance values, as well as anticipated (average)
residues and processing factors, were used and the assumption that 100%
of all potatoes and grapes will contain residues of RH-117281 Technical
at the tolerance or anticipated residue levels. Potential chronic
exposures were estimated using USDA food consumption data from the
1989-1992 survey. With the proposed tolerances and anticipated residue
levels for RH-117281 Technical, the percentage of the 0.5 mg/kg/day
reference dose (RfD) utilized as follows:

----------------------------------------------------------------------------------------------------------------
Group AnticipatedResidues Total % RfD Tolerance Levels Total % RfD
----------------------------------------------------------------------------------------------------------------
U.S. Population 48 States............... 0.5 0.1
Nursing Infants < 1 year old............ 1.0 0.2
Non-Nursing Infants < 1-year old........ 1.2 < 0.1
Children 1-6 years old.................. 1.7 .1
Children 7-12 years old 0.5 0.1
----------------------------------------------------------------------------------------------------------------

The chronic dietary risks from these uses do not exceed EPA's level
of concern.
2. Drinking water. No direct information is available on potential
for exposure to RH-117281 Technical from drinking water. However,
exposure from drinking water is unlikely to occur as a result of the
uses on potatoes or grapes. Submitted environmental fate studies
indicat0e that Rh-117281 Technical dissipates rapidly from the
environment under all conditions tested, and that is not mobile and
poses no threat to groundwater. Furthermore, its environmental
metabolites are very snort-lived and also have no potential to leach.
There is no established Maximum Concentration Level (MCL) for
residues of RH-117281 Technical in drinking water, and no drinking
water health advisory levels have been established. There is no entry
for RH-117281 Technical in the ``Pesticides in Groundwater Database''
(EPA 734-12-001, September 1992).
i. Chronic exposure and risk. Nevertheless, to assess an upper
bound on the potential for exposure from drinking water, chronic
exposure to RH-117281 Technical in drinking water was estimated using
the generic expected environmental concentration (GENEEC) V1.2 and SCI-
GROW models, as directed in the Office of Pesticide Program's Interim
Approach for Addressing Drinking Water Exposure. GENEEC is a highly
conservative model used to estimate residue concentrations in surface
water. SCI=GROW is an equally

[[Page 47806]]

conservative model used to estimate residue concentrations in shallow,
highly vulnerable groundwater (i.e., sites with sandy soils and depth
to groundwater of 10 to 20 feet). As indicated in EPA's drinking water
exposure guidance, a very small percentage of people in the United
States would derive their drinking water from such sources. GENEEC (56-
Day average) and SCI-GROW water exposure values utilizes substantially
less than 1% of the RfD for adults and children.
3. Non-dietary exposure. RH-117281 Technical is not currently
registered for any indoor or outdoor residential or structural uses,
and no application is pending; therefore, no non-dietary non-
occupational exposure is anticipated.
4. Aggregate exposure and risk. The anticipated exposure from food
and drinking water combined is < 2% of the RfD, and there is no
expectation of other non-occupational exposure. Thus, aggregate
exposure of RH-117281 Technical does not exceed EPA's level of concern,
and is essentially negligible.

D. Cumulative Effects

At this time, no data are available to determine whether RH-117281
Technical has a common mechanism of toxicity with other substances.
Thus, it is not appropriate to include this fungicide in a cumulative
risk assessment. Unlike other pesticides for which EPA has followed a
cumulative risk approach based on a common mechanism of toxicity, RH-
117281 Technical does not appear to produce a toxic metabolite produced
by other substances. In addition, the toxicity studies submitted to
support this petition indicate that RH-117281 has only limited toxic
potential. No toxic endpoints of potential concern were identified. For
the purposes of this tolerance action, therefore, RH-117281 Technical
[Benzamide-3,5-dichloro-N-(3-Clair-1-ethyl-1-methyl-2-oxopropyl)-4-
methyl] is assumed not to have a common mechanism of toxicity with
other substances.

E. Safety Determination

1. U.S. population-- i. Acute exposure and risk. Since no acute
endpoint was identified for RH-117281 Technical, no acute risk
assessment is required.
ii. Chronic exposure and risk. Using the conservative exposure
assumptions described above and taking into account the completeness
and reliability of the toxicity data, the percentage of the RfD that
will be utilized by the dietary (food only) exposure to residues of RH-
117281 Technical from the proposed tolerances is 0.5% (tolerance
levels) and 0.1% (anticipated residues) for the U.S. population.
Aggregate exposure (food and water) are expected to be < 1% RfD. EPA
generally 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. Rohm and Haas concludes there is a reasonable certainty that no
harm will result from aggregate exposure to RH-117281 Technical
residues to the U.S. population.
2. Infants and children--i. General. The potential for additional
sensitivity of infants and children to residues of RH-117281 Technical
is assessed using data from developmental toxicity studies in the rat
and rabbit and 2-generation reproduction studies in the rat. The
developmental toxicity studies are designed to evaluate adverse effects
on the developing organism resulting from maternal pesticide exposure
during gestation. Reproduction studies provide information relating to
effects from exposure to the pesticide on the reproductive capability
of mating animals and data on systemic toxicity.
ii. Developmental toxicity studies--Rats. In a developmental
toxicity study in rats, the maternal NOAEL was 1,000 mg/kg/day, HDT,
and the developmental (pup) NOAEL was 1,000 mg/kg/day HDT.
Rabbits. In a developmental toxicity study in rats, the maternal
NOAEL was 1,000 mg/kg/day HDT, and the developmental (pup) NOAEL was
1,000 mg/kg/day HDT.
iii. Reproductive toxicity study--Rats. In a multigeneration
reproductive toxicity study in rats, theparental (systemic) NOAEL was
71 mg/kg/day, based on an equivocal liver effect at the lowest observed
adverse effect levels (LOAEL) of 360 mg/kg/day. The NOAEL for
reproductive and developmental effects was 1,471 mg/kg/day HDT. No
adverse reproductive or developmental effects were observed.
iv. Prenatal and postnatal sensitivity. No developmental or
reproductive effects were demonstrated for RH-117281 Technical as a
result of systemic exposure at up to limit doses of 1,000 and 1,471 mg/
kg/day. Additionally, these NOAELs are greater than 20-fold higher than
the NOAELs of 48-51 mg/kg/day from the dog and rat chronic studies
which are the basis of the RfD. These developmental and reproductive
studies indicate that developing and maturing animals are not more
sensitive either pre or postnatally than other age groups to RH-117281
Technical; i.e., RH-117281 Technical does not exhibit additional pre or
postnatal sensitivity. Thus, reliable data indicate that an additional
FQPA uncertainty factor is not necessary to insure an adequate margin
of safety for protection of infants and children.
a. Acute exposure and risk. No acute endpoint was identified for
RH-117281 Technical, and therefore no acute risk assessment is
required.
b. Chronic exposure and risk. Using the conservative exposure
assumptions described above and taking into account the completeness
and reliability of the toxicity data, the percentage of the RfD that
will be utilized by dietary (food only) exposure to residues of RH-
117281 Technical from the proposed tolerances is 1.0% (tolerance
levels) and 0.2% (anticipated residues) for children, 1-infants (< 1-
year) and 1.7% (tolerance levels) and 0.1% (anticipated residues) for
children, 1-6 years old, the most highly exposed subgroups. Aggregate
exposure (food and water) are expected to be < 2% RfD. EPA generally
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.

F. International Tolerances

There are currently no CODEX, Canadian or Mexican maximum residue
levels (MRLs) established for RH-117281 Technical in potatoes, potato
chips or flakes, grapes or raisins. Thus, no harmonization issues are
required to be resolved for this action.

G. Rotation Crop Restrictions

An outdoor <INF></INF> C rotation crop study was conducted, in
which leafy, root, and grain crops and soybeans were planted back 30,
137, 210, and 365 days following four applications. No individual
metabolite comprised greater than or equal to 0.01 ppm in any matrix.
[FR Doc. 99-22455 Filed 8-31-99; 8:45 am]
BILLING CODE 6560-50-F

Notice of Filing Pesticide Petitions to Establish a Tolerance for Certain Pesticide Chemicals in or on Food

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