[Federal Register Volume 66, Number 4 (Friday, January 5, 2001)]
[Notices]
[Pages 1129-1135]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-369]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-989; FRL-6761-4]


Notice of Filing a Pesticide Petition to Establish a Tolerance 
for a Certain Pesticide Chemical in or on Food

AGENCY:  Environmental Protection Agency (EPA).

ACTION:  Notice.

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

[[Page 1130]]


DATES:  Comments, identified by docket control number PF-989, must be 
received on or before February 5, 2001.

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. To ensure 
proper receipt by EPA, it is imperative that you identify docket 
control number PF-989 in the subject line on the first page of your 
response.

FOR FURTHER INFORMATION CONTACT:  By mail: Indira Gairola, Registration 
Division (7505C), Office of Pesticide Programs, Environmental 
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; 
telephone number: (703) 308-8375; e-mail address: 
<a href="/cdn-cgi/l/email-protection#4e292f273c21222f6027202a273c2f0e2b3e2f60292138"><span class="__cf_email__" data-cfemail="dfb8beb6adb0b3bef1b6b1bbb6adbe9fbaafbef1b8b0a9">[email protected]</span></a>.

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 codes         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 under FOR FURTHER INFORMATION 
CONTACT.

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,'' ``Regulations and Proposed Rules,'' 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-989. 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-989 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, 1200 Pennsylvania Ave., NW., 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: <a href="/cdn-cgi/l/email-protection#8ee1fefea3eae1ede5ebfaceebfeefa0e9e1f8"><span class="__cf_email__" data-cfemail="d0bfa0a0fdb4bfb3bbb5a490b5a0b1feb7bfa6">[email protected]</span></a>, 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 6.1/
8.0 or ASCII file format. All comments in electronic form must be 
identified by docket control number PF-989. 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 under FOR FURTHER INFORMATION 
CONTACT.

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

[[Page 1131]]

name, date, and Federal Register citation.

II. What Action is the Agency Taking?

    EPA has received a pesticide petition as follows proposing the 
establishment and/or amendment of regulations for residues of a certain 
pesticide chemical in or on various food commodities under section 408 
of the Federal Food, Drug, and Comestic Act (FFDCA), 21 U.S.C. 346a. 
EPA has determined that this petition contains data or information 
regarding the elements set forth in section 408(d)(2); however, EPA has 
not fully evaluated the sufficiency of the submitted data at this time 
or whether the data support 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: December 21, 2000.
  James Jones,
Director, Registration Division, Office of Pesticide Programs.

Summary of Petition

    The petitioner summary of the pesticide petition is printed below 
as required by section 408(d)(3) of the FFDCA. The summary of the 
petition was prepared by the petitioner and represents the view of the 
petitioner. EPA is publishing the petition summary verbatim without 
editing it 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.

Morflex Inc.

PP 8E4966, PP 8E4967

    EPA has received two pesticide petitions (PP 8E4966, PP 8E4967) 
from Morflex, Inc., 2110 High Point Road, Greensboro, North Carolina 
27403. proposing, pursuant to section 408(d) of the (FFDCA), 21 U.S.C. 
346a(d), to amend 40 CFR part 180 to establish an exemption from the 
requirement of a tolerance for acetyl tributyl citrate 
(Citroflex<Register> A4) and triethyl citrate (Citroflex<Register>) 
when used as inert ingredients in or on growing crops, when applied to 
raw agricultural commodities (RAC) after harvest or when applied to 
animals (40 CFR 180.1001(c), and (e)). 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

    Residue chemistry data are generally not required by EPA regarding 
decisions relevant to exemptions from the requirement of a tolerance 
for inert ingredient. However, applicable dietary modeling data and 
environmental fate data have been completed and is used for the 
assessments included in these petitions. Since Morflex is requesting an 
exemption from the requirement of a tolerance, an analytical method is 
not required.

B. Toxicological Profile

    1. Acute toxicity--i. Oral LD<INF>50</INF> in rats. Acetyl tributyl 
citrate (ATBC). The acute oral LD<INF>50</INF> for ATBC is 31.5 grams/
kilograms body weight (g/kg bwt). Rising doses of ATBC were 
administered to groups consisting of 5 rats per group of from 10.5 to 
31.5 g/kg bwt. Some animals appeared sluggish, however, they recovered 
during the 21-day post dosing observation period. There were no 
mortalities at any dose.
    ii. Triethyl citrate (TEC). The acute oral LD<INF>50</INF> of TEC 
in rats was determined to be 7 milligrams/Liters (mL)/kg bwt. The 
technical material triethyl citrate was administered to groups of 5 
rats by stomach tube at doses ranging from 5 to 15 mL/kg bwt. Signs of 
toxicity occurred within 1-hour and included weakness, depression, 
ataxia, hyperexcitability, unrest, urinary incontinence, irregular, and 
labored respiration, convulsions preceeding death in some animals. 
Mortalities occurred in 2 hours to 3 days, while survivors recovered 
within 15 hours to 4 days.
    iii. Oral LD<INF>50</INF> in cats--ATBC. The acute oral 
LD<INF>50</INF> of ATBC was determined to be greater than 50 mL/kg bwt. 
The animals showed signs of slight nausea, and within a few hours they 
developed a diarrhea with oozing of the oily material from the rectum. 
The diarrhea subsided in less than 24 hours. There were no systemic 
toxicity signs as judged by the general appearance and behavior of the 
animals for periods up to 2 months.
    iv. TEC. The acute oral LD<INF>50</INF> of TEC was determined to be 
approximately 4 g/kg bwt in cats. TEC was administered by stomach tube 
to cats fasted for 24 hours in doses ranging from 1.1 to 10.8 g/kg bwt. 
Signs of toxicity consisted of nausea, vomiting, ataxia, weakness, 
muscle twitching, tremors, lowered body temperature, gasping, and 
shallow respiration, prostration, convulsions, respiratory failure and 
death. Mortalities occurred in about 2 hours to 2 days. Animals 
surviving recovered within 4 hours to 3 days depending upon the dose 
administered. Postmortem examinations showed no abnormalities of the 
thoracic abdominal organs related to the toxic signs.
    v. Intraperitoneal LD<INF>50</INF> in mice--ATBC. The acute 
intraperitoneal LD<INF>50</INF> of ATBC was determined to be greater 
than 4g/kg bwt in Swiss Albino mice. The animals were observed for 
gross effects on appearance and behavior for 72 hours after dosing.
    vi. TEC. The intraperitoneal LD<INF>50</INF> of TEC was determined 
to be 1.75 g/kg bwt in Swiss Albino mice. Signs of toxicity included 
rapid loss of righting reflex without loss of consciousness, increased 
respiration rate, and clonic convulsions. Mortalities occurred during 
the first hour post dosing.
    vii. Intraperitoneal LD<INF>50</INF> in rats. The acute 
intraperitoneal LD<INF>50</INF> of TEC in rats is 4.2 mL/kg bwt for 
females and 4.0 mL/kg bwt for males. Most deaths occurred within one 
hour post dosing following a depression of respiration and clonic 
convulsions. Pathological examinations of the animals that died 
indicated hemorrhage of the lung, pancreas and thymus, and marked 
congestion in the kidneys and liver.
    viii. Acute subcutaneous LD<INF>50</INF> in rats. The subcutaneous 
administration of TEC to rats resulted in LD<INF>50</INF> of 6.7 mL/kg 
bwt in females and 6.6 mL/kg bwt in males. Mortalities typically 
occurred within 24 hours of dosing. Pathological examinations showed 
extensive hemorrhage in the lungs, and thymus, loss of hair, edema, and 
crust formation at injection sites. In surviving animals, at the end of 
the 14-day observation period, necrotic ulcers were noted at injection 
sites.
    ix. Acute dermal LD<INF>50</INF> in guinea pig and rabbit. The 
dermal LD<INF>50</INF> of TEC was determined to be greater than 11.4 g/
kg bwt in guinea pigs and greater than 5.7 mg/kg bwt in rabbits.
    x. Acute inhalation LC<INF>50</INF> in rats. The 6-hour inhalation 
LC<INF>50</INF> of TEC in rats was determined to be approximately 1,300 
ppm. In this study, groups of rats were exposed to vaporized TEC for 6 
hours at concentrations between 1,300 and 3,500 ppm.
    xi. Skin irritation in rabbits--ATBC. ATBC was found to be non-
irritating to rabbit skin when applied as the undiluted technical 
material. The abdomens of 3 male Albino rabbits were clipped and 1 mL 
of ATBC was applied

[[Page 1132]]

to the intact skin daily for 4 days. The animals were observed for a 
period of 36 hours after the last application. There was no evidence of 
irritation.
    xii. TEC--TEC was determined to be non-irritating to rabbit skin. 
Undiluted TEC was applied to intact or abraded rabbit skin for 24 hours 
under occlusion before scoring for irritation.
    xiii. Guinea pig sensitization--ATBC. ATBC was found to be non 
sensitizing to the skin of Guinea pigs following the method Magnusson 
and Kligman's Guinea pig maximumization test. Sensitization was induced 
in guinea pigs by intradermal injections of the test substance and 
complete Freunds Adjuvant. The induction process was supplemented 7 
days later by application of ATBC to the shoulder injection sites under 
occlusion. Fourteen days later the animals were challenged by occluded 
patches. Challenges were repeated after 1-week. Evaluations for contact 
sensitization were performed at 24 and 48 hours after patch removal.
    xiv. TEC. TEC was found to be a strong sensitizer in 9 of 10 Guinea 
pigs after the first challenge and in all 10 Guinea pigs after the 
second challenge. TEC was tested for the potential to induce contact 
dermatitis according to the Magnusson-Kligman's Guinea pig maximization 
test method. Sensitization was induced by intradermal injections of 
both test substance and Freunds Adjuvant and the induction process 
supplemented 7 days later by the test substance applied to the shoulder 
injections sites under occlusion. The animals were challenged by 
occluded patch 14 days later.
    xv. Human repeated insult patch test--ATBC. ATBC was evaluated in 
59 human subject panelists (males and females) in the repeated insult 
patch test of Draize. The test substance was found not to induce dermal 
irritation or contact sensitization. For this test, each of the 59 
panelists received a test patch (20x20 cm) moistened with 0.4 mL of 
ATBC to the upper arms 3 times a week for 3 weeks. Patches were secured 
in place for 24 hours before removal. Duplicate challenges were made 2 
weeks after the final serial applications, 1 set of patches to original 
sites and 1 set to adjacent sites. Patch sites were scored prior to 
patch applications and scored at 48 and 96 hours after applications.
    xvi. TEC. Triethyl citrate was tested in an adaptation of the 
repeat insult patch test of Draize in 59 human subject panelists (males 
and females). A quantity of 0.4 mL of undiluted TEC was applied to each 
test patch prior to application. Patches were applied to each panelist 
3 times a week for 3 consecutive weeks. Instructions were given to each 
panelist to keep the patches dry and to remove them 24 hours after 
application. Duplicate challenge applications were made 2 weeks after 
the final serial applications; 1 at the original site and 1 at an 
adjacent site. The patch sites were evaluated at 48 and 96 hours after 
application. There was no evidence of dermal irritation and no 
reactions suggestive of contact sensitization in any of the panelists.
    2. Genotoxicty--i. ATBC. Ames Salmonella/microsome reverse mutation 
assay. ATBC did not exhibit mutagenic activity in the Ames assay with 
or with metabolic activation. ATBC was tested in a preincubation 
modification of the Ames assay with Salmonella typhimurium tester 
strains TA98, TA100, TA1535, and TA1537. Tests were performed in all 
strains, both with and without metabolic activation using S-9 rat liver 
systems. Assays were repeated twice in all strains. Another test was 
performed with ATBC using Salmonella typhimurium strains TA98, TA100, 
TA1535, TA1537 and TA1538, with and without metabolic activation using 
rat liver S-9 mix or hamster liver S-9 mix. Results were negative for 
mutagenicity in all 5 strains in the presence of both rat and hamster 
liver S-9 mix and in the absence of metabolic activation.
    ii. Mouse lymphoma mutagenesis assay. ATBC produced a negative 
response in cultures with and without metabolic activation using 
Arochlor induced rat liver S-9 mix. The test article was assayed for 
mutagenic potential using thymidine kinase locus of L51784 TK+/-mouse 
lymphoma cells.
    iii. In vitro chromosomal aberration assay in rat lymphocytes. ATBC 
did not exhibit clastogenic activity (increases in chromosomal 
aberrations) in cultured rat lymphocytes as compared with negative 
controls, either in the presence or absence of metabolic activation. 
ATBC was evaluated in a cytogenic assay using rat lymphocyte cells with 
and without rat liver S-9 mix metabolic activation. Frequencies of 
chromosomal aberrations, based upon mitotic indicies were determined 
from ATBC treated cultures and were found not to be significantly 
different than negative controls. Based upon the results of this study, 
ATBC did not exhibit clastogenic activity in cultured rat lymphocytes.
    iv. Chinese hamster ovary cell/hypoxanthine-guanine-phosphoribosyl 
transferase (CHO/HGPRT) forward mutation assay. In this forward 
mutation assay, ATBC in 2 independent tests, did not induce a mutagenic 
response. ATBC was evaluated both in the absence and presence of rat 
liver S-9 mix metabolic activation. The forward mutation frequencies of 
ATBC treated cultures were not significantly different from those of 
negative controls, indicating no mutagenic response.
    v. Unscheduled DNA synthesis in rats. ATBC did not induce 
unscheduled DNA systhesis (UDS) in livers from rats treated with 
commercial material at a dose of 10 mL/kg.
    3. Genotoxicity--TEC. Microbial assays, Salmonella typhimurium and 
Saccaromyces cerevisiae. TEC was not mutagenic in Salmonella 
typhimurium strains TA1535, TA1537, and TA1538 and in Saccharomyces 
cerevisiae strain D4, without metabolic activation, and with metabolic 
activation using S-9 mix from male mouse, rat and monkey livers. Plate 
tests and suspension tests were performed with the indicator strains of 
both test organisms. Based upon cell toxicity studies, concentrations 
from 0.4 to 1.7% were employed as the dose levels in the mutagenicity 
assays. Results were negative for mutagenicity with both bacteria and 
yeast organisms, with both the plate and suspension tests, with and 
without metabolic activation.
    4. Reproductive and developmental toxicity--i. ATBC. A 2-generation 
reproduction study in rats. A 2-generation reproduction study conducted 
with ATBC in Sprague Dawley rats resulted in a no observed effect level 
(NOEL) of 100 milligrams/kilogram body weight mg/kg bwt/day based upon 
the lowest observed effect level (LOEL) of 300 mg/kg bwt/day for 
decreased maternal bwts gains and water consumption and reduced bwts 
and slightly higher mortalities among their offspring. This 2-
generation reproduction study was conducted in Sprague Dawley rats with 
ATBC at dietary levels of 100, 300, or 1,000 mg/kg bwt/day to evaluate 
the potential effects on reproductive performance and on the survival 
and growth of offspring through 2-generations. In this study, 4 groups 
of male and female rats received control or 1 of the 3 dietary levels 
of ATBC continuously. Prior to mating, males were treated for 77 days 
and females for 21 days. After mating, males of the F<INF>0</INF> 
generation were removed and pregnant females were continued on diet 
through gestation, delivery and lactation. Subsequent F<INF>1</INF> 
offspring were maintained on the same diets as their parents for at 
least 10 weeks prior to mating within groups. The resulting 
F<INF>2</INF> generation litters were also maintained on the same diets 
as their parents for at least 14 days.
    ii. TEC. Developmental toxicity in the developing chicken embryo. 
Treatment

[[Page 1133]]

of chicken embryos with TEC resulted in a negative teratogenic 
response. In this study, TEC was dissolved in ethanol to deliver a 
maximum of 10 mg per egg. The test substance in solution was 
administered by 2 routes, into the yolk and through the air sac. For 
each route, eggs were treated at 2 stages of incubation: preincubation 
(0-hour), and at the fourth day (96- hour).
    5. Subchronic toxicity--i. ATBC. Fourteen-day range finding dietary 
toxicity in rats. In a 14-day range finding feeding study with ATBC, 
the NOEL was determined to 1,000 mg/kg bwt/day. In this study ATBC was 
administered in the diet at concentrations of 1%, 2.5% and 5% 
equivalent to doses of 1,000, 2,700 and 5,000 mg/kg bwt/day. 
Observations included clinical signs of toxicity, bwts, food intake, 
test substance intake, complete gross pathology including organ 
weights, and histopathologic examinations of livers. Food intake was 
initially decreased in all test groups, however, differences persisted 
in only among males of the 5,000 mg/kg bwt/day group. The initial 
differences are likely related to the unpalatability of the diet. Body 
weights were significantly lower among animals of the 2,700 mg/kg bwt/
day and 5,000 mg/kg bwt/day treatment groups throughout the study. 
Organ weight determinations resulted in significantly increased 
relative liver weights among high dose females. Upon microscopic 
examinations of the livers there were increased cytoplasmic 
eosinophilia and a concomitant reduction of glycogen content of 
hepatocytes in periportal areas from animals of the 2,700 mg/kg bwt/day 
and 5,000 mg/kg bwt/day dose groups.
    ii. Ninety-day dietary toxicity in rats. The results of a 90-day 
feeding study with ATBC resulted in a NOEL of 300 mg/kg bwt/day based 
upon the LOEL of 1,000 mg/kg bwt/day for minor changes is relative 
liver weights, liver enzymes and bilirubin levels. This study was 
conducted Sprague Dawley rats receiving dietary levels of ATBC of 0, 
100, 300, or 1,000 mg/kg bwt/day for 90 days. All animals were observed 
daily for clinical signs of toxicity. Ophthalmoscopic observations were 
conducted in all animals of the highest dose group at pretest, and just 
prior to the treatment period. Body weights were recorded daily for all 
animals on day 1 of treatment and weekly thereafter. Food consumption 
was measured over 1 week periods, while water consumption was measured 
in each animal during the first and eleventh week of dosing. The 
results of clinical chemistries, hematology and urinalysis were 
recorded and complete necropsies with histological examinations were 
performed. A few statistically significant differences were noted 
between animals of the high dose group (1,000 mg/kg bwt/day) and 
controls including increased relative liver weights, liver enzymes, and 
bilirubin levels. However, there were no histopathological findings 
indicative of treatment related effects.
    iii. TEC. Subchronic oral toxicity in mice. TEC was evaluated for 
subchronic toxicity in a group of 20 mice receiving 350 mg/kg bwt/day 
of commercial grade test substance (purity >99%) in 3% acacia 
intraperitoneally, daily for 14 consecutive days. A control group 
consisting of the same number of mice received 3% acacia daily under 
the same schedule. Body weight gains of TEC treated mice were 
significantly lower as compared with controls by day 7. There were no 
significant differences in red and white blood cell counts, clotting 
times, and hemoglobin levels between treated and control mice. Under 
the conditions of the study, the LOEL was established at 350 mg/kg bwt/
day, when given intraperitoneally for 14 days.
    iv. Subchronic dietary toxicity in rats. In an 8 week dietary 
feeding study in rats with TEC, the NOEL was established at 4 g/kg bwt/
day. Groups of approximately 4 males and 4 females were administered 
TEC in the diet at concentrations of 0, 0.5, 1.0, or 2.0%. These 
dietary concentrations were estimated to be equivalent to 0, 1, 2, or 4 
g/kg bwt/day TEC. TEC administered daily in the diet at doses up to 
approximately 1/2 of the rat oral LD<INF>50</INF> had no significant 
effect on growth. Blood counts including red and white blood cell 
counts, differential cell counts were not significantly among treatment 
and control groups. There were no, gross findings in thoracic or 
abdominal organs at necropsy. Histological sections of organs, 
including the heart, lungs, gastrointestinal tract, liver, pancreas, 
spleen, and kidneys, revealed no differences between treatment and 
control animals.
    v. Subchronic toxicity in dogs. In this study, 4 dogs were given 
daily doses of 2.5 to 3.5 mL/kg bwt/day (2,840 to 3,975 mg/kg bwt/day) 
as rising doses for 7 to 12 weeks. The study report indicates bwt gains 
were normal as were results of urinalysis and serum chemistries. 
Hematology results suggested a tendency to anemia. Organ weights were 
normal except for one abnormally heavy liver. At these doses severe and 
widespread liver pathology was evident. Other organs were reportedly 
normal. As the purpose of the study was to determine the toxic dose for 
repeated administrations of TEC, the NOEL was not established.
    6. Chronic toxicity--i. ATBC. 2-year chronic toxicity in rats. A 2-
year chronic toxicity study conducted with ATBC in Sherman rats at 
dietary concentrations of 0, 200, 2,000, or 20,000 ppm (equivalent to 
0, 10, 100, or 1,000 mg/kg bwt/day) resulted in a NOEL of 1,000 mg/kg 
bwt/day. Animals were observed for physical appearance and behavior 
throughout the study as were individual bwts. All animals that died and 
those sacrificed at the end of the study were examined for gross and 
histological changes. No differences in behavior or physical appearance 
was noted among treated and control animals. There were no 
statistically significant differences between the growth of animals 
treated with ATBC and controls. There were no statistical differences 
in mortalities among treatment and control animals. Inflammatory 
disease of the lungs was the most common finding at autopsy, however, 
there was no treatment related differences. There were no differences 
in tumor frequencies among treatment and control animals. There was no 
reported evidence of effects on the endocrine system.
    ii. TEC. 2-year chronic dietary toxicity in rats. In this study, 
TEC administered to rats for 2 years via dietary administration 
resulted in no significant effects at the highest dose tested, 
equivalent to 1,500 mg/kg bwt/day. Sprague Dawely rats (15 per sex per 
dose group) were fed diets containing TEC at concentrations of 0, 0.33, 
1.0, or 3.0% for 2 years. These dietary concentrations are estimated to 
be equivalent to 0, 165, 500, or 1,500 mg/kg bwt/day. Clinical 
observations were made daily and individual bwts were measured weekly. 
Blood and urine evaluations were conducted at specified intervals. 
Scheduled interim sacrifices of animals included macroscopic 
examinations of thoracic and abdominal organs and microscopic 
examinations of the kidney and liver tissues. All animals that died 
spontaneously during the study, as well as all animals remaining at the 
termination of study (1 or 2 years), were examined by a pathologist. At 
terminal sacrifice, microscopic examinations were made of kidney, 
liver, heart, lungs, spleen, stomach, small intestine, adrenals, 
ovaries, uterus, testes, and seminal vesicles. There were transiently 
lower bwts among males of the high dose group animals, possibly related 
to the unpaletibility of the diet. There were no significant 
differences observed between treated and control groups for the

[[Page 1134]]

following blood examinations: hemoglobin, erythrocyte count, non-
protein nitrogen, and sugar determination. Urine tests for reaction, 
albumin, reducing substances, and microscopic evaluation were all 
considered to be normal. Terminal and interim autopsies disclosed no 
findings that were significant or attributable to TEC treatment. Size 
and weight of organs of the principal tissues at the time of autopsy 
were unremarkable. There were no significant differences between 
treated and control animals in comparison to the pathological findings.
    iii. Six months dietary toxicity in dogs. In a 6 month dietary 
toxicity study in dogs, TEC did not exhibit any toxic effects and the 
NOEL is greater than 280 mg/kg bwt/day the highest dose tested (HDT). 
Groups of 4 Beagle or Beagle type dogs (males and females) were 
administered 6 days per week for 6 months at dietary levels of TEC 
equivalent to 55 or 280 mg/kg bwt/day. The dogs were observed daily, 
weighed weekly and urinalysis were conducted at 3 and 6 months after 
initiation of the study. Blood samples were taken at 2, 4, and 6 months 
after initiation of dosing for hematological examinations. Dogs were 
sacrificed at the end of the in-life dosing phase and necropsied. Body 
weight gain and clinical observations were normal throughout the study. 
No significant changes or abnormalities were reported in hematology, 
serum chemistry or urinalysis during the course of the study. Gross 
examinations of major organs and organ weights at necropsy were normal. 
Histopathologic examinations of the major organs did not show any 
abnormalities.
    7.  Animal metabolism--i. ATBC. Metabolism and disposition of 
acetyl tributyl citrate in male Sprague Dawley rats. The metabolism of 
ATBC using \14\C-ATBC in rats receiving single oral doses of 70 mg/kg. 
ATBC was determined to be rapidly absorbed and excreted with an 
elimination half-life of 3.4 hours. Greater than 98% of administered 
\14\C was achieved via urine, feces and in expired air 48 hours after 
dosing. Urinary metabolites identified in this study include acetyl 
citrate, monobutyl citrate, acetyl monobutyl citrate, dibutyl citrate, 
and acetyl dibutyl citrate.
    ii. Metabolism of acetyltributylcitrate (ATBC) and tributylcitrate 
(TBC) in human serum and rat liver homogenates. The metabolism of ATBC 
and the intermediate deacetylated metabolite tributylcitrate (TEC), was 
studied in vitro using human serum and rat liver homogenates. At a 
concentration of 100 <greek-m>g/mL in human serum, ATBC was found to 
undergo extensive metabolism with a half-life of approximately 32 
hours. Also, at a concentration of 100 <greek-m>g/mL in rat liver 
homogenate, ATBC was found to undergo extensive and complete metabolism 
with a half-life of approximately 10 minutes. There is very little or 
no emonstrable TBC in the 2 test systems because of the rapid further 
metabolism of this intermediate metabolite. The metabolic half-life of 
TBC in human serum and rat liver homogenate was approximately 4 hours 
and a few seconds, respectively. These studies confirm the ready and 
complete conversion of ATBC and TBC via ester hydrolysis to acetic 
acid, citric acid and butanol. Butanol would be expected to undergo 
oxidation to butyric acid and further metabolism by b-oxidation.
    iii. TEC. Absorption, distribution, metabolism and excretion of 
tiethyl citrate in the rat. Following a single oral 2 mg/kg dose of 
\14\C-TEC in rats, a peak blood concentration of about 1.48 <greek-m>g 
eq./g blood was achieved at 15 minutes post-administration, blood 
concentration rapidly decreased to about 0.05 <greek-m>g eq./gm blood 
after 1 hour and was barely detectable after 24 hours. Tissue 
distribution was examined after single oral administration of a 2 mg/kg 
dose of \14\C-TEC to rats. At 15 minutes post-administration, 
relatively high \14\C concentrations were found in the didney (37.81+ 
5.02 <greek-m>g eq./g tissue), stomach (10.00+ 3.53 <greek-m>g eq./g 
tissue), small intestines including contents (10.65 + 3.15 <greek-m>g 
eq./g tissue) and liver (4.40 + 0.77 <greek-m>g eq./g tissue). By 24 
hours after dosing, the \14\C concentrations detected in most tissues 
had decreased to near the detection limit (0.01 <greek-m>g eq./g 
tissue), with the exception of the large intestine including contents. 
Cumulative urinary, fecal and expiratory excretions of \14\C-TEC were 
93, 0.2 and 1%, respectively, 8 hours after administration of a single 
2 mg/kg dose of \14\C-TEC. At 120 hours after dosing, the total \14\C 
excretion of urine, feces and expiration had reached 99%. Metabolism of 
\14\C-TEC was investigated using the 24-hour urine of rats after a 
single oral administration of a 2 mg/kg dose. Three major metabolites 
were separated by thin-layer chromatography and identified using gas 
chromatography (GC/MS). Two of the metabolites were isomers of diethyl 
citrate and 1 was found to be monoethyl citrate.
    8. Endocrine disruption. Chronic and reproductive toxicity data 
conducted with ATBC and chronic toxicity data conducted with TEC are 
without adverse effects to reproductive or the endocrine system. Also, 
the compounds do not share structural similarities with currently known 
or chemicals suspected to have endocrine disruptive properties.

C. Aggregate Exposure

    1. Dietary exposure--i. Food. ATBC and TEC are currently classified 
as generally recognized as safe (GRAS) for use in foods and food 
packaging, cosmetics, pharmaceuticals, and as plasticizers for consumer 
and packaging products. The current petition, requests the exemption 
from tolerances for these compounds when used as inert ingredients in 
agricultural formulations for use on growing crops for post harvest 
applications to food crops and applications to animals. Although 
residue data are generally not required for inert ingredient exemptions 
from tolerances, Morflex, Inc. has developed worst case assumptions 
using Novigen Sciences Dietary Exposure Evaluation Model (DEEM) with 
data inputs based upon the model of Kenaga and Hoergers: Maximum 
Expected Residues on Vegetation. The Kenega nomogram is used to predict 
maximum residue levels present on day 0 following different application 
rates of a chemical to 1 of 6 different categories of plants or plant 
parts. The 3 basic features of the Kenaga nomogram-catagories of plants 
and plant parts, maximum predicted residue levels, and a linear dose-
residue relationship. Crops and crop groups selected for this analysis 
include the following: leafy vegetables (succulent or dried), fruiting 
vegetables, cucurbit vegetables, citrus fruits, pome fruits, stone 
fruits, berries, cereal grains, grapes, and bananas. The reference dose 
chosen for this analysis, was derived from the NOEL resulting from a 
chronic rat (2-year) study conducted with ATBC. This study was 
conducted at dietary concentrations of 0, 200, 2,000, and 20,000 ppm 
equivelant to 0, 10, 100, and 1,000 mg/kg bwt/day of ATBC. No effects 
were reported up to the HDT. Therefore, for the purposes of this 
assessment, a chronic reference dose (RfD) of 10 mg/kg bwt/day was 
used. The chronic RfD includes an uncertainty factor of 100 to account 
for intra-species and inter-species variations. Food consumption data 
from the United States Department of Agriculture (USDA) CSFII conducted 
in 1994 through 1996, were used to estimate dietary exposure. The 
levels of ATBC and TEC can vary depending upon the percent of ATBC and 
TEC in the formulation and/or the application rate of the product. For 
purposes of this screening level assessment, an application rate of 3 
pounds per acre of ATBC or TEC was assumed. Also, no adjustment was 
made for percent crop

[[Page 1135]]

treated and all commodities contain residues at predicted day zero 
levels. For this screening level assessment with an application rate of 
3 pounds ATBC or TEC per acre, the following 0-time level residues are 
predicted from the nomogram: leafy vegetables-375 ppm, legume 
vegetables-36 ppm, fruiting vegetables, cucurbit vegetables, citrus 
fruits, pome fruits, stone fruits, berries, cereal grains, grapes, and 
bananas-21 ppm.. Using the above modeling parameters, chronic exposure 
was estimated for the overall U.S. population and 25 population 
subgroups. Chronic exposure for the overall U.S. population was 
estimated to be 0.492873 mg/kg bwt/day, representing 4.9% of the RfD. 
The exposure estimate for the most highly exposed population subgroup, 
children 1-6 years of age, was 0.984312 mg/kg bwt/day, or 9.8%.
    ii. Drinking water. Based upon the chemical and physical 
properties, and the environmental fate characteristics, ATBC and TEC 
are not expected to persist environmentally, nor result in significant 
concentrations in drinking water sources.
    2. Non-dietary exposure. ATBC and TEC are currently used in non-
food use pesticide formulations, as well as in food, food packaging, 
cosmetics, medical devices and pharmaceuticals, and as plasticizers.

D. Cumulative Effects

    Cumulative effects are not expected since ATBC and TEC are rapidly 
degraded to natural substances.

E. Safety Determination

    1. U.S. population. Based upon the dietary residue exposure 
analysis using the Kenega nomogram, the most sensitive population, 
children 1-6 years, was 0.984312 mg/kg bwt/day or 9.8% of the RfD for 
the crops and crop groups used in this assessment. Results of a 2-
generation reproduction study with ATBC did not reveal developmental or 
reproduction effects at doses up to 100 mg/kg bwt/day. Also, based on 
the absence of pup toxicity up to the dose level (1,000 mg/kg bwt/day) 
producing maternal effects, there is no evidence of special post-natal 
sensitivity to infants and children. It is concluded that there is 
reasonable certainty that no harm will result to infants and children 
from aggregate exposure to acetyl tributyl citrate (ATBC) or triethyl 
citrate (TEC) when used as inert ingredients in agricultural 
formulations of pesticides.
    2. Infants and children. No embryotoxic, developmental, or 
teratogenic effects have been associated with acetyltributyl citrate 
(ATBC) or triethyl citrate (TEC).

F. International Tolerances

    Morflex Inc. is unaware of any International tolerances or CODEX 
maximum residue limits (MRL's) for acetyltributyl citrate (ATBC) or 
triethyl citrate (TEC) on any crop or livestock commodities.
[FR Doc. 01-369 Filed 1-4-01; 8:45 am]
BILLING CODE 6560-50-S


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