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clodinafop-propargyl Pesticide Petition Filing 4/00


[Federal Register: April 26, 2000 (Volume 65, Number 81)]
[Notices]               
[Page 24471-24477]
>From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr26ap00-56]                         

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ENVIRONMENTAL PROTECTION AGENCY

[PF-938; FRL-6554-2]

 
Notice of Filing a Pesticide Petition 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 amended filing of a pesticide 
petition 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-938, must be 
received on or before May 26, 2000.

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-938 in the subject line on the first page of your 
response.

FOR FURTHER INFORMATION CONTACT:  By mail: Susan Stanton, Registration 
Division (7505C), Office of Pesticide Programs, Environmental 
Protection Agency, Ariel Rios Bldg., 1200 Pennsylvania Ave., NW., 
Washington, DC 20460; telephone number: (703) 305-5218; e-mail address: 
stanton.susan@epa.gov.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

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


------------------------------------------------------------------------
                                                          Examples of
           Categories                    NAICS            potentially
                                                       affected entities
------------------------------------------------------------------------
Industry                          111                 Crop production
                                  112                 Animal production
                                  311                 Food manufacturing
                                  32532               Pesticide
                                                       manufacturing
------------------------------------------------------------------------

    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'' 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-938. 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-938 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

[[Page 24472]]

(7502C), Office of Pesticide Programs (OPP), Environmental Protection 
Agency, Ariel Rios Bldg., 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: ``opp-docket@epa.gov,'' or you can submit a computer disk as 
described above. Do not submit any information electronically that you 
consider to be CBI. Avoid the use of special characters and any form of 
encryption. Electronic submissions will be accepted in Wordperfect 6.1/
8.0 or ASCII file format. All comments in electronic form must be 
identified by docket control number PF-938. 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 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 certain 
pesticide chemical in or on various food commodities under section 408 
of the Federal Food, Drug, and Comestic Act (FFDCA), 21 U.S.C. 346a. 
EPA has determined that this petition contains data or information 
regarding the elements set forth in section 408(d)(2); however, EPA has 
not fully evaluated the sufficiency of the submitted data at this time 
or whether the data supports granting of the petition. Additional data 
may be needed before EPA rules on the petition.

List of Subjects

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

    Dated: April 14, 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 
petitioners. 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.

Novartis Crop Protection, Inc.

PP 7F4924

Amended Pesticide Petition

    On June 5, 1998, EPA published a notice that it had received a 
pesticide petition (PP 7F4924) from Novartis Crop Protection, Inc., 
P.O. Box 18300, Greensboro, NC 27419 proposing tolerances for the 
herbicide clodinafop-propargyl (propanoic acid, 2-[4-[(5-chloro-3-
fluoro-2-pyridinyl)oxy]phenoxy]-2-propynyl ester; CGA-184927) in or on 
the raw agricultural commodities of wheat. EPA has received an 
amendment to PP 7F4924 from Novartis Crop Protection, Inc., P.O. Box 
18300, Greensboro, NC 27419 proposing, pursuant to section 408(d) of 
the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to 
amend 40 CFR part 180 to increase, as requested by EPA, the original 
proposed tolerances; thereby establishing tolerances for the combined 
residues of clodinafop-propargyl and its acid metabolite, CGA-193469 
((R)-2-[4-[(5-chloro-3-fluoro-2-pyridinyl)oxy]phenoxy]-propanoic acid), 
in or on the raw agricultural commodities wheat, grain at 0.1 ppm; 
wheat, forage at 0.1 ppm; wheat, hay at 0.1 ppm and wheat, straw 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 clodinafop-propargyl in 
wheat is understood for the purposes of the proposed tolerances. Two 
studies, one with the racemic mixture of the R (+) and S (-) forms and 
the other with the pure R (+) form (CGA-184927 pyridyloxy labeled), 
gave similar results. Metabolism involves hydrolysis of the parent to 
the resulting acid followed by conjugation, arylhydroxylation at the 6 
position of the pyridyl ring followed by sugar conjugation, and 
cleavage of the pyridinyloxy-phenoxy ether bridge which forms the 
breakdown products 2-(4-hydroxyphenoxy) propanoic acid and 2-hydroxy-3-
fluoro-5-chloropyridine.
    2. Analytical method. Novartis has submitted practical analytical 
methods for the determination of clodinafop-propargyl and its major 
plant metabolite CGA-193469 in wheat raw agricultural commodities 
(RACs). Clodinafop-

[[Page 24473]]

propargyl is extracted from crops with acetonitrile, cleaned up by 
solvent partition and solid phase extraction and determined by column 
switching high performance liquid chromotography (HPLC) with ultra 
violet (UV) detection. CGA-193469 is extracted from crops with an 
acetone-buffer (pH=3) solution, cleaned up by solvent partition and 
solid phase extraction, and determined by HPLC with UV detection. The 
limits of quantitation (LOQ) for the methods are 0.02 ppm for 
clodinafop-propargyl in grain and forage, 0.05 ppm for clodinafop-
propargyl in straw, and 0.05 ppm for CGA-193469 in forage, straw and 
grain.
    3. Magnitude of residues. Both Canadian and U.S. spring wheat 
residue trials were conducted. Twelve residue trials were conducted 
from 1989-1992 in the major spring wheat growing areas of Manitoba, 
Alberta and Saskatchewan, which share compatible crop zones with the 
major spring wheat growing areas of the United States (MT, ND, SD, MN). 
Nine trials were conducted in 1989-91 with a tank mix of clodinafop-
propargyl and a safener as separate EC formulations, and three trials 
in 1992 were conducted with clodinafop-propargyl and the safener as a 
pre-pack EC formulation. All trials had a single post-emergence 
application of clodinafop-propargyl at a rate of 80 gram active 
ingredient/hectacre (g a.i./ha).
    In 1998, an additional six spring wheat trials were conducted in 
the major growing areas of the United States. In these trials, 
clodinafop-propargyl was applied as a single application of a 240EC 
formulation at a rate of 70 g a.i./ha. Samples of 30-day forage and 
hay, and mature straw and grain treated 60 days prior to harvest were 
taken for analysis. Grain treated at an exaggerated rate in one trial 
was processed under simulated commercial processing conditions.
    At pre-harvest intervals (PHIs) of 30 days for forage and hay in 
the U.S. trials, and 60-97 days for mature straw and grain in all 
trials, no detectable residues of clodinafop-propargyl were found. 
Residues of the metabolite CGA-193469 were detected in mature straw 
from four trials, with a maximum Highest Average Field Trail (HAFT) 
residue of 0.35 ppm. Separate decline studies on green forage in both 
the United States and Canada showed no detectable residues of 
clodinafop-propargyl or the metabolite CGA-193469 beyond the 7 days 
after application interval. No residues of clodinafop-propargyl or the 
metabolite CGA-193469 were found in mature grain or grain processed 
fractions in any trial.
    A freezer storage stability study indicated reasonable stability of 
both analytes for a period of 1 year, with clodinafop-propargyl showing 
a decline to 56% in grain and 47% in straw after 2 years. CGA-193469 
remained stable for at least 2 years.

B. Toxicological Profile

    1. Acute toxicity. The acute oral and dermal LD50 values 
for clodinafop-propargyl are 1,829 milligrams/kilograms (mg/kg) and 
greater than 2,000 mg/kg for rats of both sexes, respectively. Its 
acute inhalation LC50 in the rat is greater than 2.33 
milligram/liter (mg/L), the highest attainable concentration. 
Clodinafop-propargyl is slightly irritating to the eyes, minimally 
irritating to the skin of rabbits, but was found to be sensitizing to 
the skin of the guinea pig. This technical will carry the EPA signal 
word ``Caution.''
    2. Genotoxicity. The mutagenic potential of clodinafop-propargyl 
was investigated in six independent studies covering different end 
points in eukaryotes and prokaryotes in vivo and in vitro. These tests 
included: Ames reverse mutation with Salmonella typhimurium and Chinese 
hamster V79 cells in vitro; chromosomal aberrations using human 
lymphocytes in vitro and the mouse micronucleus test in vivo; and DNA 
repair using rat hepatocytes and human fibroblasts in vitro. 
Clodinafop-propargyl was found to be negative in all these tests and, 
therefore, is considered devoid of any genotoxic potential at the 
levels of specific genes, chromosomes, or DNA primary structure.
    3. Reproductive and developmental toxicity. Dietary administration 
of clodinafop-propargyl over 2-generations at levels as high as 1,000 
ppm did not affect mating performance, fertility, or litter sizes. Body 
weight was reduced in parental animals at 500 and 1,000 ppm. The 
physiological developmental and the survival of the pups during the 
last week of the lactation period were slightly reduced at levels equal 
to or greater than 500 ppm during the first generation only. Target 
organs were liver (adults) and kidney (adults and pups). The treatment 
had no effect on reproductive organs. The NOAEL for toxicity to the 
parental rats and offspring was 50 ppm, corresponding to a mean daily 
intake of 3.2 mg/kg clodinafop-propargyl. The NOAEL for reproductive 
toxicity was 1,000 ppm (64.2 milligram/kilogram body weight/day (mg/kg 
bw/day)).
    In a developmental toxicity study in rats, the highest dose level 
of 160 mg/kg resulted in reduced body weight gain of the dams and signs 
of retarded fetal body weight and incomplete ossification of vertebrae 
and sternebrae. No teratogenic activity of the test article was 
detected. Novartis concluded that the NOAEL for dams and fetuses was 40 
mg/kg/day. The EPA's Hazard Identification Assessment Review Committee 
(HIARC) concluded that based on an increase in bilateral distension and 
torsion of the ureters and delayed ossification in the fetuses, the 
developmental LOAEL was 40 mg/kg/day and the NOAEL was 5 mg/kg/day.
    In a developmental toxicity study in rabbits, mortality was 
observed in dams at dose levels of 125 and 175 mg/kg. No teratogenic or 
fetotoxic effects were noted. Novartis concluded that the maternal 
NOAEL was 25 mg/kg/day and the fetal NOAEL was 175 mg/kg/day. The HIARC 
considered that the developmental NOAEL was 125 mg/kg/day due to 
significant mortality at 175 mg/kg/day.
    4. Subchronic toxicity. A 90-day feeding study in rats at 1,000 ppm 
resulted in reduced body weight gain, increased liver weights, 
hematological changes, and increased serum activities of the alkaline 
phosphatase. Target organs were liver (increased weight), thymus 
(atrophy) and spleen (reduced weight). The changes were reversible 
during 4 weeks of recovery. The NOAEL was 15 ppm (0.92 mg/kg in males 
and 0.94 mg/kg in females). The EPA HIARC suggested the NOAEL in female 
rats was 8.24 mg/kg bw/day.
    In a 90-day feeding study in mice, 400 ppm resulted in reduced 
activity, one death, markedly increased activities of 
aminotransferases, alkaline phosphatase, and albumin concentration, 
increased liver weights, hepatocellular hypertrophy, and single cell 
necroses in all mice. Other findings included intrahepatic bile duct 
proliferation, Kupffer cell hyperplasia, and higher incidence of 
inflammatory cell infiltration. These findings were considered to be 
secondary to the hepatocyte necrosis. The NOAEL of 6 ppm was equivalent 
to a daily dose of 0.9 mg/kg in males and 1.05 mg/kg in females.
    In a 90-day study in beagle dogs, levels of 500 and 1,000 ppm fed 
over 2 weeks clearly exceeded a maximum tolerated dose and led to 
mortality and severe toxicity. Effects at 50 and 200 ppm were limited 
to dermatitis and clinical chemistry changes, which were generally mild 
and transient. The NOAEL of 10 ppm was equivalent to a mean daily 
intake of 0.36 mg/kg in males. The HIARC concluded that in

[[Page 24474]]

females the NOAEL was 50 ppm (1.9 mg/kg bw/day).
    5. Chronic toxicity. In a 12-month feeding study in dogs, 500 ppm 
resulted in transient dermatitis and reduced body weight gain. Two 
females were more severely affected and showed inappetence, body weight 
loss, tremors, and severe dermatitis, and necessitated an interruption 
of the treatment in order to avoid mortality. Histopathology revealed 
slight hepatocellular hypertrophy in one male and one female. The NOAEL 
of 100 ppm was equivalent to a mean daily intake of 3.38 mg/kg in males 
and 3.37 mg/kg in female.
    Lifetime dietary administration of clodinafop-propargyl to mice 
resulted in reduced body weights and reduced survival in males treated 
at 250 ppm. Severe hepatotoxicity was noted at 100 and 250 ppm in both 
sexes. Based on markedly increased liver weights, enhanced serum 
activities of hepatic enzymes and hepatocellular necroses, dietary 
levels of 100 ppm and 250 ppm clearly exceeded maximum tolerated doses 
in males and females, respectively. The increased incidence of benign 
liver tumors that occurred in males treated at 250 ppm was, therefore, 
considered a toxicologically irrelevant response as the livers of these 
animals were damaged significantly and this finding was not 
interpretable. The toxicity to liver can be associated with the 
peroxisomal proliferating activity of clodinafop-propargyl in the 
mouse. Despite this mode of action, the incidence of hepatocellular 
carcinoma, in these clearly compromised mice, remained within the 
historical control range, although the incidence was slightly increased 
in comparison to the concomitant controls. Tumor incidences in females 
were generally low and well within the range of the historical 
controls. The NOAEL of 10 ppm was equivalent to a mean daily dose of 
1.10 mg/kg in males and 1.25 mg/kg in females.
    Dietary treatment of rats with concentrations over 2 years resulted 
in initial inappetence in males and reduced body weight development in 
both sexes treated at 750 ppm. The main target organ of toxicity was 
the liver. Changes in plasma protein and lipid levels, strongly 
enhanced serum activities of liver enzymes, increased liver weights, 
and severe liver necroses were observed at dietary doses of 300 and 750 
ppm in males and at 750 ppm in females. The degenerative lesions 
provide strong evidence that these dose levels exceeded a maximum 
tolerated dose (MTD). Top dose group males showed a higher incidence of 
prostate adenoma, while prostate hyperplasia was reduced. However, the 
total incidence of proliferative changes in the prostate remained 
unchanged indicating a progression from prostate hyperplasia to 
adenoma. Females treated at the same high dose had higher incidences of 
ovary tubular adenoma. The slightly enhanced incidences of these 
lesions are likely a consequence of the severe disturbance of the 
general metabolic balance due to excessive liver toxicity. In fact, 
male rats fed 750 ppm exhibited a marked increase in 
peroxisomal oxidation, and an increase in cytochrome P450 4A1/ 
A3 and 4A2 in their livers. Further, a decrease in cytochrome P450 
isoenzymes including CYP 2A, CYP 3A, and male-specific CYP 2C11 was 
observed. The total oxidation rate of testosterone, aromatase (CYP 
19A1) activity plasma estradiol concentration and plasma--
dihydrotestosterone are altered at this level of treatment. Clodinafop-
propargyl is a potent peroxisome proliferator in the rat liver and this 
peroxisomal prolifering activity manifests itself by altering 
Cytochrome P450-dependent monooxygenses which are involved in steroid 
hormone homeostasis. The NOAEL of 10 ppm was equivalent to a mean daily 
dose of 0.32 mg/kg in males and 0.37 mg/kg in females. The EPA HIARC 
concluded that based on hepatocellular hypertrophy and kidney findings, 
the NOAEL was 1 ppm (0.031 in males and 0.034 in females.
    Carcinogenicity. The EPA HIARC recommended, based on the increased 
incidence of prostate and ovarian tumors in rats and hepatocellular 
tumors in mice, that the Cancer Assessment Review Committee review 
clodinafop-propargyl. A Q1* value based on the combined incidence of 
liver tumors in male mice has been calculated by the EPA Science 
Analysis Branch. The Q1* value estimate is 1.29  x  
E-1 (mg/kg/day)-1 in human equivalents.
    6. Animal metabolism. In rats, clodinafop-propargyl was rapidly 
absorbed through the gastrointestinal tract. Absorption through the 
skin of rats is considerably slower with 15% of a dermally applied dose 
being absorbed within 8 hours. The EPA HIARC estimated the dermal 
absorption rate for clodinafop-propargyl to be 2.5% derived by taking 
the ratio of the LOAEL from the 28-day oral toxicity study in rats (5 
mg/kg/day) and 28-day dermal toxicity study in rats (200 mg/kg/day). 
Female rats excreted single doses more rapidly than males. Most likely 
due to enzyme induction, differences were much less pronounced after 
repeated treatment. Both sexes excreted clodinafop-propargyl with urine 
and feces mainly in the form of its propionic acid derivative, CGA-
193469. Simultaneous administration of the safener, cloquintocet-mexyl, 
did not alter the rate of excretion of clodinafop-propargyl or its 
metabolite pattern.
    7. Metabolite toxicology. Clodinafop-propargyl acts as a typical 
peroxisome proliferator in the rodent liver, which is most likely 
induced by its propionic acid derivative metabolite, CGA-193469. Like 
other known well-characterized substances with this property, CGA-
193469 caused peroxisome proliferation in vitro in hepatocytes of the 
mouse and rat, but not of the Guinea pig, marmoset, or human. In 
addition, clodinafop-propargyl was unable to activate the PPAR 
-dependent human ACYL CoA oxidase promoter which further 
supports the evidence that humans are refractory to peroxisome 
proliferation and related changes. The scientific evidence available 
amply demonstrates that exposure to substances that produce tumors by a 
peroxisome proliferator mode of action does not represent a risk of 
tumor development in man. Novartis, therefore, has concluded that 
clodinafop-propargyl is not a carcinogen of relevance to humans.
    8. Endocrine disruption. No special studies investigating potential 
estrogenic or endocrine effects of clodinafop-propargyl have been 
conducted. However, the standard battery of required studies has been 
completed. These studies include an evaluation of the potential effects 
on reproduction and development and an evaluation of the pathology of 
the endocrine organs following repeated or long-term exposure. Although 
prostate adenomas and ovarian adenomas were observed to be 
statistically increased in rats at the highest feeding level with 
clodinafop-propargyl, this feeding level clearly exceeded the MTD and 
the livers in these rats were severely compromised. These findings in 
the endocrine organs were considered to be secondary to the severe 
liver effects.

C. Aggregate Exposure

    1. Dietary exposure. Chronic and acute dietary exposure were 
calculated for the use of clodinafop-propargyl and the corresponding 
hydrolysis product, CGA-193469 on wheat. Analyses were conducted using 
the Dietary Exposure Evaluation Model (DEEMTM) by Novigen 
Sciences and the 1994-96 Continuing Survey of Food Intake (CSFII). 
Chronic and acute tier three assessments were conducted to account for 
the consumption of commodities containing

[[Page 24475]]

wheat grain and residues were adjusted with a projected percent of crop 
treated value of 4%. Residues of parent clodinafop-propargyl were below 
the limit of quantitation (LOQ) of 0.02 ppm in all grain samples. 
Residues of the acid (CGA-193469) were also below the LOQ (LOQ = 0.05 
ppm) in grain. Since no residues were observed in any of the samples, a 
statistical limit of detection (sLOD) was calculated for parent and the 
corresponding acid metabolite and one-half of the sLOD of each were 
summed and entered into the chronic and the acute assessments. Although 
wheat fractions may be fed to livestock and poultry, calculation of 
dietary burden with subsequent transfer to animal commodities shows 
secondary residues are extremely negligible and do not impact risk. 
Tolerances of 0.1 ppm are being proposed for clodinafop-propargyl and 
the acid metabolite, CGA-193469, for wheat grain, forage, and hay and 
0.5 ppm for straw. Tolerances for meat, milk and eggs are not required.
    i. Food--a. Chronic. Chronic exposure was compared to a chronic 
reference dose (RfD) of 0.00003 mg/kg/day based on a no-effect level of 
0.03 mg/kg/day from a 2-year chronic toxicity/carcinogenicity study in 
rats and a 1,000X uncertainty factor. Exposure results are compared 
against the aforementioned reference dose as well as the Agency's 
Q1* value of 0.129. Since all residues in grain were below 
the LOQ, an sLOD was calculated for parent and CGA-193469. One-half 
sLOD values for parent clodinafop-propargyl and the corresponding acid 
were 0.0049 ppm and 0.0147 ppm, respectively. These values were summed 
and adjusted with a market share value of 4% for the calculation of 
exposure. The exposure results show that the U.S. population utilizes 
4.3% of the chronic RfD. The most sensitive subpopulation is children 
(1-6 years old) with an exposure of 9.9% of the chronic RfD. Using the 
Agency's Q1* value of 0.129, a lifetime risk of 1.35 x 
10-7 was calculated. These results indicate there is more 
than a reasonable certainty that exposure to residues of clodinafop-
propargyl and its corresponding acid metabolite (CGA-193469) will 
result in no harm.
    b. Acute. Acute exposure to females greater than 13 years old was 
compared to an acute reference dose (aRfD) of 0.005 mg/kg/day based on 
a NOAEL of 5 mg/kg/day from a developmental study in rats and a 1,000x 
uncertainty factor. As in the chronic assessment, one-half sLOD was 
used for parent clodinafop-propargyl and the corresponding acid (0.0049 
ppm and 0.0147 ppm for parent and acid, respectively). These values 
were summed and zeroes were added to the residue distribution file 
corresponding to the percent of crop not treated (96% not treated). For 
all female populations in the DEEMTM, exposure ranged from 
3.0% - 4.2% of the aRfD at the 99.9th percentile of exposure. The most 
sensitive female population was nursing females (13+ years old) with an 
exposure of 4.2% of the aRfD (99.9th percentile). Acute exposure for 
the general population excluding females (> 13 years old), was compared 
to an aRfD of 0.025 mg/kg/day based on a NOAEL of 25 mg/kg/day from a 
developmental study in rabbits and a 1,000x uncertainty factor (UF). 
Acute exposure at the 99.9th percentile for the general population, 
children and males (all populations excluding females) ranged from 
0.18% (seniors, 55+) to 0.62% of the aRfD for children (1-6 years old). 
These results demonstrate that there is a high degree of certainty of 
no harm resulting from acute exposure to dietary residues of 
clodinafop-propargyl.
    ii. Drinking water. Another potential route of exposure to residues 
of pesticides includes drinking water. Field and laboratory study 
results have demonstrated that clodinafop-propargyl and its degradation 
products have slight to medium mobility in soil. However, due to rapid 
degradation of the product under field conditions and its low 
application rate, the potential for it to reach surface and ground 
water is considered to be negligible. Thus, drinking water exposure to 
clodinafop-propargyl and its degradation products was not included in 
the aggregate risk assessment. Also, since clodinafop-propargyl is not 
intended for uses other than the agricultural use on wheat, there is no 
potential for nonoccupational exposure.
    The estimated exposures of clodinafop-propargyl and its main 
environmental degradate were combined and the hazards for both 
compounds were based on the RfD values determined for clodinafop-
propargyl alone. The estimated water concentrations for clodinafop-
propargyl and the degradate were estimated, weighted and combined based 
on applications rates adjusted for the maximum concentration of the 
degradate present in the aerobic soil metabolism studies.
    The Screening Concentration in Ground Water (SCI-GROW) model was 
used to provide the estimated ground water concentration of the 
combined clodinafop-propargyl and degradate residues, 0.006688 ppb. The 
Pesticide Root Zone Model/Exposure Analysis Modeling Systems (PRZM/
EXAMS) model using the Index Reservoir scenario and the Percent Cropped 
Area provided the estimated surface water concentrations of the 
combined clodinafop-propargyl and degradate residues for a wheat 
application in North Dakota. The estimated 90th percentile acute peak 
concentration for the combined residues was 0.792 part per billion 
(ppb). The estimated 36-year mean-yearly chronic concentration for the 
combined residues was 0.0519 ppb.
    Concerning the acute and chronic exposures to clodinafop-propargyl 
and the degradate, an additional 10 x -safety factor has been proposed 
by the EPA HIARC for the protection of infants and children. This 
additional safety factor was applied to the acute and chronic non-
cancer RfD values for all sub-populations as a worse case estimate of 
exposure. This resulted in an acute RfD for females 13+ years of 0.005 
mg/kg/day and 0.025 mg/kg/day for all other subgroups. This also 
resulted in a chronic RfD for infants and children of 0.00003 mg/kg/
day. A chronic lifetime cancer risk exposure of 0.129 mg/kg/day has 
also been proposed by the EPA. This was applied to the adult population 
exposures only.
    For ground water, the acute dietary assessment provided drinking 
water levels of comparison (DWLOC) ranging from 140 to 873 ppb. The 
estimated ground water concentration, 0.006688 ppb, represented from 
0.0008% to 0.0048% of the acute RfD for all sub-populations. The 
chronic dietary exposures provided DWLOC values of 0.16 ppb (infants), 
0.31 ppb (children), and 0.2026 to 0.2363 ppb (lifetime cancer risk for 
adults). The estimated ground water concentration represented 3.98%, 
1.93% and 2.5 to 2.9% of the chronic risk, respectively.
    For surface water, the acute dietary assessment provided DWLOC 
values ranging from 140 to 873 ppb. The estimated acute surface water 
concentration, 0.792 ppb, represented from 0.09% to 0.57% of the acute 
RfD for all sub-populations. The chronic dietary exposures provided 
DWLOC values of 0.16 ppb (infants), 0.31 ppb (children), and 0.2026 to 
0.2363 ppb (lifetime cancer risk for adults). The estimated surface 
water concentration, 0.0519 ppb, represented 31%, 15% and 19.1-to-22.3% 
of the chronic risk, respectively. Therefore, the acute and chronic 
drinking water exposures for clodinafop-propargyl and its main 
environmental degradate did not exceed the exposures allowed by the 
risk cup.
    2. Non-dietary exposure. Exposure to clodinafop-propargyl for the 
mixer/loader/ground-boom/aerial applicator

[[Page 24476]]

and flagger was calculated using the Pesticide Handlers Exposure 
Database (PHED). It was assumed that the product would be applied 6 
days per year by ground-boom application to a maximum of 80 acres per 
day by the grower, 15 days per year by ground-boom application to a 
maximum of 80 acres per day by the commercial ground-boom applicator 
and 15 days per year to a maximum of 350 acres per day by the aerial 
applicator, at a maximum use rate of 28.3 grams active ingredient per 
acre. For purposes of this assessment, it was assumed that an 
applicator would be wearing a long sleeved shirt and long pants and the 
mixer/loader would, in addition, wear gloves. Daily doses were 
calculated for a person weighting 70 kg assuming 100% dermal 
penetration. Short-term and intermediate-term dermal and inhalation 
risk assessments were performed. Doses and endpoints used for risk 
assessments were based on Agency determined toxicological endpoints 
recommended by the HIARC. The NOAEL of 50 mg/kg/day from the 28-day rat 
dermal study was used for short- and intermediate-term dermal risk 
assessments. The NOAEL of 5 mg/kg/day from the developmental toxicity 
study in rats was used for short-term inhalation risk assessments. The 
NOAEL of 0.9 mg/kg/day based on a subchronic oral toxicity study in 
rats was used for intermediate-term inhalation risk assessments. Based 
on the use pattern of clodinafop-propargyl, no long-term dermal or 
inhalation exposure is expected to occur and long-term risk assessments 
are not required.
    Large margins of exposure (MOEs) exist for all occupational 
exposure scenarios. Short-term dermal exposure MOEs ranged from 4.0E+03 
for the commercial open mixer-loader to 1.8E+05 for the commercial or 
grower ground-boom enclosed-cab applicator. Intermediate-term dermal 
exposure MOEs ranged from 9.7E+04 for the commerical open mixer-loader 
to 1.1E+07 for the grower ground-boom enclosed-cab applicator. Short-
term inhalation exposure MOEs ranged from 3.6E+04 for the commercial 
open mixer-loader to 1.7E+06 for the commercial or grower ground-boom 
enclosed-cab applicator. Intermediate-term inhalation exposure MOEs 
ranged from 1.6E+05 for the commercial open mixer-loader to 1.8E+07 for 
the grower ground-boom enclosed-cab applicator.
    Although there are no residential uses of clodinafop-propargyl, 
there is potential for residential exposure to spray drift resulting 
from aerial application. No standard operating procedure exists for 
performing this risk assessment; however, a very conservative risk 
assessment was performed assuming dermal exposure equal to total 
deposition to outside clothing for a flagger as well as inhalation 
exposure equivalent to a pesticide flagger, as reflected in PHED. A 
dermal absorption factor of 2.5%, as estimated by HIARC, was assumed. 
Offsite drift was assumed to be 15% and the area assumed to be adjacent 
to the sensitive area was one acre. Large MOEs exist for this potential 
exposure scenario. Dermal exposure MOEs were 6.0E+07 for a 15 kg child 
and 2.8E+08 for a 70 kg adult. Inhalation MOEs were 2.3E+07 for a 15 kg 
child and 1.1E+8 for a 70 kg adult.

D. Cumulative Effects

    A cumulative exposure assessment for effects of clodinafop-
propargyl and other substances with the same mechanism of action is not 
appropriate because there is ample evidence to indicate that humans are 
not sensitive to the effects of clodinafop-propargyl and other 
peroxisome proliferators. Thus, the calculations outlined below were 
done for clodinafop-propargyl alone.

E. Safety Determination

    1. U.S. population. Acute and chronic dietary exposure is minimal 
for clodinafop-propargyl and the corresponding acid metabolite. Both 
chronic and acute exposure estimates showed that less than 10% of the 
RfD is utilized in all populations.
    Exposure through the consumption of drinking water is minimal from 
both surface water and ground water model estimates and in all cases 
less than 35% of the risk cup is utilized. The estimated water 
concentrations are very conservative since conservative model 
parameters were assumed.
    There are no residential uses of clodinafop-propargyl that would 
result in non-dietary exposure. However, there is a remote possibility 
that spray drift resulting from aerial application could lead to 
residential exposure. Since exposure from spray drift would be an 
unlikely event, it is not appropriate to include non-dietary exposure 
into the aggregate assessment. Therefore, it is concluded that there is 
more than a reasonable certainty that no harm will result from 
aggregate exposure to residues of clodinafop-propargyl.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of clodinafop-
propargyl, data from developmental toxicity studies in the rat and 
rabbit and a 2-generation reproduction study in the rat have been 
considered. The developmental toxicity studies are designed to evaluate 
adverse effects on the developing organism resulting from chemical 
exposure during prenatal development to one or both parents. 
Reproduction studies provide information relating to effects from 
exposure to a chemical on the reproductive capability of mating animals 
and data on systemic toxicity.
    Retarded fetal body weight and incomplete ossification of vertebrae 
and sternebrae were observed at a maternally toxic dose of 160 mg/kg/
day in rats; however, no developmental toxicity of the test article was 
detected. Novartis believes that the NOAEL for dams and fetuses was 40 
mg/kg/day. The EPA's HIARC concluded that based on an increase in 
bilateral distension and torsion of the ureters and delayed 
ossification in the fetuses, the developmental LOAEL was 40 mg/kg/day 
and the NOAEL was 5 mg/kg/day. Although mortality was observed in 
rabbit dams at dose levels of 125 and 175 mg/kg, no teratogenic or 
fetotoxic effects were noted. The maternal NOAEL was 25 mg/kg/day and 
the fetal NOAEL was 175 mg/kg/day.
    Clodinafop-propargyl fed over 2-generations to rats at levels as 
high as 1,000 ppm did not affect mating performance, fertility, or 
litter sizes. Body weight was reduced in parental animals at 500 and 
1,000 ppm. Physiological developmental and the survival of the pups 
during the last week of the lactation period were slightly reduced at 
levels equal to or greater than 500 ppm during the first generation 
only. Target organs were liver (adults) and kidney (adults and pups). 
The NOAEL for toxicity to the parental animals and offspring was 50 
ppm, corresponding to a mean daily intake of 3.2 mg/kg bw/day of 
clodinafop-propargyl. The NOAEL for reproductive toxicity was 1,000 ppm 
(64.2 mg/kg bw/day).
    FFDCA section 408 provides that EPA may apply an additional safety 
factor for infants and children in the case of threshold effects to 
account for prenatal and postnatal toxicity and the completeness of the 
database. Based on the current toxicological data requirements, the 
database relative to prenatal and postnatal effects for children is 
complete. The results from the 2-generation reproduction study and the 
rabbit developmental toxicity study would indicate there is no 
additional sensitivity of infants and children to clodinafop-propargyl. 
The HIARC selected the developmental NOAEL of 5 mg/kg/day from the rat 
developmental toxicity as opposed to the maternal NOAEL of 40 mg/kg bw/
day. Therefore, the HIARC recommended the 10x safety

[[Page 24477]]

factor should be retained based on this increased susceptibility.
    Using conservative exposure assumptions, dietary exposure to the 
most sensitive subpopulation, children (1-6 years old) utilizes 9.9% of 
the chronic reference dose. Chronic dietary exposure to infants (non-
nursing, 1-6 years old) is 2.0% of the chronic RfD. Acute exposure for 
all infants and children is less than 1.0% of the acute RfD (0.62% of 
the RfD for the most sensitive subpopulation, children 1-6 years old). 
Exposure to drinking water for children (1-6 years old) utilizes 31% of 
the chronic RfD (surface water estimate). Children (1-6 years old) 
utilize 15% of the chronic RfD (surface water estimate). For acute 
exposure to drinking water, the worst case estimates (surface water) 
for infants show that only 0.57% of the aRfD is utilized and children 
(1-6 years old) utilize 0.27% of the aRfD. These results show that 
aggregate exposure to residues of clodinafop-propargyl in the diet and 
drinking water is negligible. Based on the completeness and reliability 
of the toxicity data and the conservative nature of the exposure 
assumptions, it is concluded that there is a more than reasonable 
certainty that no harm will result to infants and children from 
exposure to residues of clodinafop-propargyl.

F. International Tolerances

    There are no Codex Alimentarius Commission (CODEX) maximum residue 
levels (MRLs) established for residues of clodinafop-propargyl in or on 
raw agricultural commodities.
[FR Doc. 00-10432 Filed 4-25-00; 8:45 am]
BILLING CODE 6560-50-F