[Federal Register Volume 64, Number 169 (Wednesday, September 1, 1999)]
[Notices]
[Pages 47795-47806]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-22455]


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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: 
[email protected].
    For technical questions, contact the appropriate Product Manager: 
Joseph Tavano, telephone number: (703) 305-6411 and e-mail address: 
[email protected].; or Cynthia Giles-Parker (PM 22), telephone 
number: (703) 305-7740 and e-mail address: giles-
[email protected].

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

    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: ``[email protected] ,'' 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 (LD50) 
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 LD50 was greater than 5,000 
mg/kg in New Zealand white rabbits. The 4-hour rat inhalation lethal 
concentration (LC50) 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 
 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 
( 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  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  
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 LD50 in the rat is > 5 grams for males and females - 
Toxicity Category IV; dermal LD50 in the rat is = 5,000 mg/
kg for males and females - Toxicity Category III; inhalation 
LD50 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 
(LD50) > 5,000 milligram/kilogram (mg/kg), practically non-
toxic by dermal application to rats (LD50 > 2,000 mg/kg), 
and practically non-toxic to rats after a 4-hour inhalation exposure 
with an LC50 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  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