[Federal Register Volume 67, Number 152 (Wednesday, August 7, 2002)]
[Notices]
[Pages 51262-51267]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-19803]


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ENVIRONMENTAL PROTECTION AGENCY

[OPP-2002-0151; FRL-7188-6]


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.

DATES: Comments, identified by docket ID number OPP-2002-0151, must be 
received on or before September 6, 2002.

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 ID 
number OPP-2002-0151 in the subject line on the first page of your 
response.

FOR FURTHER INFORMATION CONTACT: By mail: Sidney Jackson, Registration 
Division (7505C), Office of Pesticide Programs, Environmental 
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; 
telephone number: (703) 305-7610; e-mail address: 
[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 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.

[[Page 51263]]

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 actionunder docket ID number OPP-2002-0151. 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 ID number OPP-2002-0151 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: [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 6.1/
8.0 or ASCII file format. All comments in electronic form must be 
identified by docket ID number OPP-2002-0151. 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 
ID 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 a certain 
pesticide chemical in or on various food commodities under section 408 
of the Federal Food, Drug, and Cosmetic 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: July 25, 2002.
Peter Caulkins,
Acting 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 Federal Food, Drug, and 
Cosmetic Act (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.

Interregional Reseaarch Project Number 4

PP 0E6205

Summary of Petitions

    EPA has received a pesticide petition (PP 0E6205) from the 
Interregional Research Project Number 4 (IR-4), Technology Centre of 
New Jersey, Rutgers, the State University, 681 U. S. Highway #1 South, 
North Brunswick, NJ 08902 proposing, pursuant to section

[[Page 51264]]

408(d) of the FFDCA, 21 U.S.C. 346a(d), to amend 40 CFR 180.300 by 
establishing a tolerance for residues of ethephon, (2-
chloroethyl)phosphonic acid in or on the raw agricultural commodity 
coffee, bean at 0.5 parts per million (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 support granting of the petition. Additional data may be 
needed before EPA rules on the petition.
    This Notice was prepared by Aventis CropScience USA LP, Research 
Triangle Park, NC 27709.

A. Residue Chemistry

    1. Plant metabolism. The qualitative nature of the residue in 
plants is adequately understood based on tomato, cantaloupe, apple, 
fig, pineapple, tobacco, grape, walnut, filbert, cherry, tangerine and 
lemon metabolism data. Ethephon degrades to ethylene, phosphate and 
chloride. Data indicate that proximal and distal translocation of 
ethephon to fruits may occur following application to leaves. The 
residue of concern in plants is ethephon.
    2. Analytical method. Adequate methods for purposes of enforcement 
of ethephon tolerances in plant commodities, ruminant tissues, and milk 
are available. The Amchem-Plant Method (PAM, Vol. II, Method I) is the 
recommended method for enforcement purposes for plant commodities and 
processed products other than wheat and barley straw. The Amchem-Cereal 
Method (forwarded to the Food and Drug Administration (FDA) for 
inclusion in the PAM, Vol. II, Method I) is the recommended method for 
enforcement purposes for wheat and barley straw. The Union Carbide-
Animal Method (forwarded to the FDA for inclusion in the PAM, Vol. II, 
Method III) is the recommended method for enforcement purposes for milk 
and animal tissues. These methods employ diazomethane as a methylating 
agent. A new plant and animal method has been submitted for enforcement 
purposes that does not employ diazomethane. The method principally 
involves the decomposition of ethephon to ethylene to determine the 
residues of ethephon. An independent lab validation of this method has 
been completed and accepted by EPA.
    3. Magnitude of residues. Residue studies have been conducted to 
support ethephon registrations on: cotton, apple, cherry, tomato, 
wheat, barley, pepper, grape, tobacco, walnut, almond, blackberry, 
cantaloupe, pineapple, sugarcane and macadamia nuts. In addition, IR-4 
has conducted residue studies to support use on coffee. All residue 
data requirements cited in the ethephon Reregistration Eligibility 
Document (RED) have been submitted to EPA. As a result of this work, 
increased tolerances have been proposed for cottonseed (6 ppm, PP 
6F4743) and cotton gin by-products (180 ppm, amendment to PP 1H5603). 
As part of the reregistration process, the following tolerances will be 
revoked: cucumber, filbert, lemon, pineapple forage and fodder, 
pumpkin, tangerine, tangerine hybrids and sugarcane molasses. The 
tolerances for residues of ethephon in or on food and feed commodities 
are currently based in terms of ethephon per se. Processing studies 
have been conducted on apple, barley, cottonseed, grape, pineapple, 
tomato, and wheat and are deemed adequate to determine the extent to 
which residues of ethephon concentrate in food/feed items upon 
processing of the raw agricultural commodity. Data indicate that 
ethephon residues concentrate in apple juice, dried apple pomace, 
barley hulls, cottonseed meal, grape juice, raisin, raisin waste, dried 
grape pomace, pineapple bran and pulp, dried tomato pomace, wheat bran, 
wheat shorts and germ and red dog. Available apple processing data 
indicate that residues of ethephon do not concentrate in wet apple 
pomace. Therefore, a feed additive tolerance on apple pomace is not 
required. Available tomato processing data indicate that residues of 
ethephon do not concentrate in tomato paste and, therefore, no 
tolerance is needed. Pineapple processing data indicate that residues 
of ethephon concentrate in dried pineapple bran (5.3X; no longer a 
processed commodity) and wet pulp (1.2X), but do not concentrate in 
juice, syrup, and slices. No feed additive tolerance for residues of 
ethephon in processed pineapple is required. As a result of a recent 
cow feeding study, new animal tolerances have been proposed. The 
following tolerances have been proposed for cattle, goat, hog, horse, 
and sheep: meat - 0.02 ppm; meat byproducts (except kidney) - 0.20 ppm; 
kidney - 1.0 ppm; fat 0.02 ppm, and milk (cow and goat) - 0.01 ppm. 
Following a hen feeding study, new tolerances were proposed for 
poultry: poultry meat - 0.01 ppm; poultry meat byproducts (except 
liver) - 0.01 ppm; poultry fat - 0.02 ppm; poultry liver - 0.05 ppm; 
and eggs - 0.002 ppm.

B. Toxicological Profile

    1. Acute toxicity. A complete battery of acute toxicity studies for 
ethephon technical was completed. The acute oral toxicity study 
resulted in a lethal dose LD50 of 1,600 milligram/kilogram 
(mg/kg) for both sexes. The acute dermal toxicity in rabbits resulted 
in an LD50 in either sex of greater than 5,000 mg/kg. The 
acute inhalation study in rats resulted in a lethal concentration 
LC50 of 4.52 milligram/liter (mg/l). Ethephon was corrosive 
to the skin of rabbits in the primary dermal irritation study. 
Therefore, the primary eye irritation study in rabbits was not 
required. The dermal sensitization study in guinea pigs indicated that 
ethephon is not a sensitizer. Based on the results of the dermal 
irritation study, and the anticipated results in an eye irritation 
study, ethephon technical is placed in toxicity Category I. Based on 
the acute toxicity data cited above, the registrant concluded that 
ethephon technical does not pose any acute dietary risks.
    2. Genotoxicty. The potential for genetic toxicity of ethephon was 
evaluated in several assays. The compound was found to be mutagenic in 
strain TA-1535 with and without S9 activation in the Ames assay. In the 
in vitro chromosomal aberrations study with Chinese hamster ovary 
cells, ethephon was negative. Ethephon was tested for unscheduled DNA 
synthesis in the rat hepatocyte system and was found to be negative. 
Based on the data cited above, Aventis contends that the weight of 
evidence indicates that ethephon technical does not pose a risk of 
mutagenicity or genotoxicity.
    3. Reproductive and developmental toxicity. Ethephon has been 
tested for reproductive toxicity in rats and developmental toxicity in 
both rats and rabbits (two studies in each species). The results of 
these studies are summarized below:
    i. In a two generation reproduction study, 28 Sprague-Dawley rats 
per sex per dose were administered 0, 300, 3,000, or 30,000 ppm (0,15, 
150, or 1,500 mg/kg/day of ethephon in the diet. For the offspring, a 
no observed adverse effect level (NOAEL) of 15 mg/kg/day and a lowest 
observed adverse effect level (LOAEL) of 150 mg/kg/day was established 
based on decreased body weight gain in the females at 150 mg/kg/day and 
in both sexes at 1,500 mg/kg/day. No effects were observed on 
fertility, gestation, mating, organ weights, or histopathology in any 
generation.
    ii. In rats, ethephon was administered by gavage at doses of 0, 20, 
600, or 1,800 mg/kg for gestation days 6 through 15.

[[Page 51265]]

 At 1,800 mg/kg/ day, 14 of the 24 treated female rats died. No toxic 
effects were observed at lower doses. The NOAEL for maternal and 
developmental toxicity was 600 mg/kg/day. In a second study, rats were 
dosed by gavage at 0, 125, 250, or 500 mg/kg/day on days 6 through 15 
of gestation. No toxic effects were observed at any dose. The NOAEL for 
maternal and developmental toxicity was 500 mg/kg/day.
    iii. In rabbits, ethephon was administered by gavage at doses of 0, 
50, 100, and 250 mg/kg for gestation days 6 through 19. The number of 
doses with live fetuses were 10, 12, 8, and 5, respectively. 
Resorptions were increased at 100 mg/kg/day and statistically 
significantly increased at 250 mg/kg/day. At 250 mg/kg/day, does were 
depressed, ataxic, showed an increase of clinical observations and 
gross pathology in the gut. The NOAEL for maternal toxicity was 50 mg/
kg/day and the NOAEL for developmental toxicity was 50 mg/kg/day. In a 
second study, rabbits were dosed by gavage at 0, 62.5, 125, or 250 mg/
kg/day on days 6 through 19 of gestation. Maternal morbidity, 
mortality, and clinical signs of toxicity were observed at 250 mg/kg/
day. Fetal toxicity, consisting of decreased number of live fetuses per 
doe, increased early resorptions and post implantation loss was 
observed at 250 mg/kg/day. A NOAEL for maternal and developmental 
toxicity of 125 mg/kg/day was observed.
     Based on the 2-generation reproduction study in rats, ethephon is 
not considered a reproductive toxicant and shows no evidence of 
endocrine effects. The data from the developmental toxicity studies on 
ethephon show no evidence of a potential for developmental effects 
(malformations or variations) at doses that are not maternally toxic. 
The NOAEL for both maternal and developmental toxicity in rats was 500 
mg/kg/day and for rabbits, the NOAEL for both maternal and 
developmental toxicity was 50 mg/kg/day, respectively.
    4. Subchronic toxicity. The subchronic toxicity of ethephon has 
been studied in three human studies and a 21-day dermal study in 
rabbits. These studies are summarized below:
    i. Male and female subjects received ethephon at doses of 0.17 and 
0.33 mg/kg/day for 22 days. The daily doses were divided into 3 gelatin 
capsules. No adverse effects were noted in clinical observations, 
hematology, serum chemistry including red blood cell cholinesterase 
inhibitors (RBC ChE) and urinalysis. There was a significant decrease 
in plasma ChE for both treatment groups, although the effect at 0.17 
mg/kg/day appeared to be very close to the threshold for significance.
    ii. Male and female subjects received ethephon at a dosage of 0.5 
mg/kg/day for 16 days. The daily dose was divided into 3 gelatin 
capsules. No adverse effects were noted in clinical observations, 
hematology, serum chemistry (including RBC ChE) and urinalysis. There 
was a significant decrease in plasma cholinesterase.
    iii. Ethephon was administered to male and female subjects at a 
daily dose of 124 mg/day (1.8 mg/kg/day average for both sexes) divided 
up into 3 gelatin capsules for 28 days. Clinical signs of toxicity were 
observed and included diarrhea, urgency of bowel movements, urinary 
urgency and stomach cramps. No effects were noted with regard to 
hematology, urinalysis or serum chemistry including cholinesterase 
evaluations.
    iv. In a 21-day dermal study, 10 rabbits per sex per group were 
dosed dermally at 0, 25, 75, and 150 mg/kg/day, 5-days per week for 3 
weeks. Skin effects were observed at all doses. Effects ranged from 
erythema and desquamation at the lowest dose to acanthosis and chronic 
inflammation at 150 mg/kg/day. No systemic treatment-related effects 
were observed on body weight, food consumption, organ weight or 
histopathology. The systemic NOAEL was greater than 150 mg/kg/day.
     Based on the results of the three studies in humans, a LOAEL of 
1.8 mg/kg/day was established in the 28-day study. In the 22-day study, 
0.17 mg/kg/day appeared to be very close to the threshold for 
significance. The systemic NOAEL in the 21-day dermal study in rabbits 
was greater than 150 mg/kg/day.
    5. Chronic toxicity. A 2 year chronic toxicity/carcinogenicity 
study in rats, an 18-month mouse carcinogenicity study, a 1-year study 
in dogs, and a 2-year chronic study in dogs were performed on ethephon 
technical. These studies are summarized below:
    i. A combined chronic/carcinogenicity study was performed on 
ethephon in Sprague-Dawley rats. Doses administered in the feed were 0, 
300, 3,000, 10,000, or 30,000 ppm for 95 weeks to the males and 103 
weeks for the females. The doses administered relative to body weight 
were 0, 13, 131, 446, or 1,416 mg/kg/day for males and 0, 16, 161, 543, 
or 1,794 mg/kg/day for females. Plasma and erythrocyte cholinesterase 
was inhibited at all doses (NOAEL <300 ppm). Brain cholinesterase 
inhibition was not observed. A decrease in male body weight was 
observed at 10,000 ppm. At 30,000 ppm a body weight decrease was 
observed in both sexes. Additional effects at 30,000 ppm were 
thyroglossal duct cysts, kidney glomerulo-sclerosis, nephritis, and 
biliary hyperplasia cholangiofibrosis. No carcinogenic effects were 
observed.
    ii. Male and female CD-1 mice were administered ethephon in the 
diet at 0, 100, 1,000, or 10,000 ppm (0, 15.5, 156, or 1,630 mg/kg/day) 
for 78 weeks. An additional dose level of 50,000 ppm was terminated at 
12-weeks because of excessive morbidity and mortality. No evidence of 
treatment related tumors was observed. A NOAEL of 15.5 mg/kg/day was 
determined for plasma cholinesterase inhibition. At 1,630 mg/kg/day 
male body weights were increased and female body weights decreased 
compared to controls.
    iii. Ethephon technical was administered in the feed at 0, 30, 300, 
and 3,000 ppm (0, 0.75, 7.5, or 75 mg/kg/day) to male and female beagle 
dogs for 2 years. Due to toxicity/morbidity, the high dose was reduced 
as follows: 75 mg/kg/day weeks 0-3; 50 mg/kg/day weeks 4-5; 25 mg/kg/
day weeks 6-24; 37.5 mg/kg/day weeks 25-104. Plasma cholinesterase was 
inhibited at all doses (NOAEL< 0.75 mg/kg/day). A NOAEL for erythrocyte 
cholinesterase inhibition of 0.75 mg/kg/day with a LOAEL of 7.5 mg/kg/
day was observed. Histopathology showed smooth muscle atrophy in the 
gut at 7.5 mg/kg/day with a NOAEL of 0.75 mg/kg/day.
    iv. Ethephon was administered in the feed at doses of 0, 100, 300, 
1,000, or 2,000 ppm (0, 2.7, 8.2, 28.5, or 52.1 mg/kg/day) to male and 
female beagle dogs for 52 weeks. A systemic NOAEL of 1,000 ppm (28.5 
mg/kg/day) was observed for decreased spleen weight, body weight, 
hemoglobin and hematocrit in males. The females showed a decreased 
spleen/body weight ratio for the same NOAEL. Cholinesterase inhibition 
was not determined.
     The NOAEL in the chronic rat study was 131 mg/kg/day based on the 
decreased body weight gains in males. The NOAEL in the most recent 1-
year dog study was determined to be 28.5 mg/kg/day based on body 
weight, organ weight effects and hematology effects. Ethephon has been 
tested in both rats and mice for carcinogenic activity. No carcinogenic 
effects were observed.
    6. Animal metabolism. The rat metabolism study consisted of a 
single intravenous dose group at 50 mg/kg, and single and multiple oral 
high dose groups at 50 and 1,000 mg/kg. The oral Cmax (maximum 
concentrations) were reached at 1.3 and 1 hours for the 50 mg/kg dose 
and 1.9 and 2.5 hours for the 1,000 mg/kg dose in males and females, 
respectively. The t1/2 of the

[[Page 51266]]

rapid excretion phase (A-phase) at the 50 mg/kg dose was 7 hours for 
both sexes and 4 and 9 hours at 1,000 mg/kg for the males and females, 
respectively. Oral and intravenous doses were rapidly excreted in the 
urine and accounted for 48 to 71% of the administered radioactivity. 
Approximately 7% was excreted in the feces. Exhaled ethylene was 10-20% 
and CO2 was less than 1% of the administered dose. The highest tissue 
concentrations were found in the blood, bone, liver, kidney, and spleen 
with no significant differences between single and multiple dosing. No 
significant differences were observed in the excretion pattern with 
either sex or multiple dosing.
     In a goat metabolism study, ethephon was incorporated into natural 
products (glutathione conjugates, protein, glycogen, and triglycerides) 
and expired as CO2 and ethylene.
     In a hen metabolism study, ethephon metabolism involved an initial 
removal of chlorine to form 2-hydroxyethanephosphonic acid followed by 
further metabolism which results in the release of ethylene and carbon 
dioxide as well as intermediates which can enter into fundamental 
biochemical pathways leading to the biosynthesis of proteins and 
lipids. Aventis believes that ethephon technical is not metabolized to 
breakdown products that can be reasonably expected to present any 
chronic dietary risk.
    7. Metabolite toxicology. Ethephon degrades to ethylene phosphate 
and chloride. Therefore, no significant toxicity is anticipated from 
these breakdown/metabolites.
    8. Endocrine disruption. EPA is required under the FFDCA, as 
amended by Federal Quality Protection Act (FQPA), to develop a 
screening program to determine certain substances (including all 
pesticide active and other ingredients) ``may have an effect in humans 
that is similar to an effect produced by a naturally occurring 
estrogen, or other such endocrine effects as the Administrator may 
designate.'' Following the recommendations of its Endocrine Disruptor 
Screening and Testing Advisory Committee (EDSTAC), EPA determined that 
there were scientific bases for including, as part of the program, the 
androgen and thyroid hormone systems, in addition to the estrogen 
hormone system. EPA also adopted EDSTAC's recommendation that the 
Program include evaluations of potential effects in wildlife. For 
pesticide chemicals, EPA will use FIFRA and, to the extent that effects 
in wildlife may help determine whether a substance may have an effect 
in humans, FFDCA authority to require the wildlife evaluations. As the 
science develops and resources allow, screening of additional hormone 
systems may be added to the Endocrine Disruptor Screening Program 
(EDSP). When the appropriate screening and/or testing protocols being 
considered under the Agency's EDSP have been developed, ethephon may be 
subjected to additional screening and/or testing to better characterize 
effects related to endocrine disruption.

C. Aggregate Exposure

    1. Dietary exposure--i. Food. Ethephon is registered for use on the 
following food crops: cotton, apple, cherry, tomato, wheat, barley, 
pepper, grape, tobacco, walnut, almond, blackberry, cantaloupe, 
pineapple, sugarcane, and macadamia nuts. In addition, IR-4 has 
conducted work to support new use on coffee. Ethephon has several 
ornamental/non-food applications as well. All residue requirements 
cited in the ethephon RED have been submitted to EPA. As a result of 
this work, increased tolerances have been proposed for cottonseed (6 
ppm, PP 6F4743) and cotton gin byproducts (180 ppm, amendment to PP 
1H5603). As part of the reregistration process, the following 
tolerances will be revoked: cucumber, filbert, lemon, pineapple, 
forage, fodder, pumpkin, tangerine, tangerine hybrids, and sugarcane 
molasses. The tolerances for residues of ethephon in or on food and 
feed commodities are currently based in terms of ethephon per se. An 
enforcement method was submitted to EPA for determination of residues 
of ethephon in/on plant commodities and in milk, ruminant and poultry 
tissues. The ethephon RED lists the number of treated acres by crop for 
all major ethephon uses in the United States.
    ii. Drinking water. Based on the available studies and the use 
pattern, Aventis does not anticipate residues of ethephon in drinking 
water. There is no established Maximum Concentration Level or Health 
Advisory Level for ethephon under the Safe Drinking Water Act.
    2. Non-dietary exposure. The potential for non-occupational 
exposure to the general public is also insignificant since only 
approximately 800 lbs of ethephon technical is sold in the U.S. home 
and garden market annually. The residential lawn or garden uses 
anticipated for these products where the general population may be 
exposed via inhalation or dermal routes are negligible. The home and 
garden formulation that is sold in the United States contains only 3.9% 
ethephon which would further limit exposure.

D. Cumulative Effects

     While ethephon is an inhibitor of ChE of the plasma and RBC, it 
has not demonstrated any ability to inhibit brain ChE in rats, mice, or 
dogs under condition of a chronic dietary dosing regimen. Furthermore, 
unlike classic organophosphate ChE inhibitors, ethephon did not induce 
symptoms of ChE inhibition, such as constriction of the pupils, 
salivation, lacrimation, diarrhea, urination, tremors, and convulsions 
under chronic feeding of doses up to 30,000, 10,000, and 2,000 ppm in 
the rat, mouse, and dog, respectively. In the rat study, the plasma and 
RBC ChE were inhibited approximately 55% and 85%, respectively. In the 
mouse study, both peripheral ChEs were inhibited by approximately 70%. 
Although cholinesterase determinations were not performed in the 1 year 
dog study, in a 2 year dog study, plasma and RBC ChE were inhibited 60% 
and 70%, respectively. Despite these high degrees of inhibition of 
peripheral ChE, no clinical signs or symptoms consistent with ChE 
inhibition occurred in these studies. It is generally only under very 
extreme conditions such as high doses administered via oral gavage or 
under occlusive dermal dressing in rabbits in which signs that are 
consistent with ChE inhibition are observed. These clinical signs 
generally occur at doses that produce acute lethality. However, these 
signs may in fact be unrelated to CNS ChE inhibition and could be a 
non-specific reaction to the acidic and, therefore, highly irritant 
nature of ethephon.
     Ethephon should not be regarded as a classical inhibitor of ChE 
such as the carbamates and organophosphates since it does not produce 
the typical nervous system effects of those compounds. The recently 
updated chronic data base adequately proves that very high dietary 
doses of ethephon do not inhibit brain ChE, that it does not produce 
the classical clinical signs of ChE inhibition, and that it does not 
produce life-shortening effects, despite moderate to severe lifetime 
inhibition of both plasma and RBC ChE. The inhibition of ChE by 
ethephon is only an indicator of exposure and is not a measure of its 
potential for inducing ChE-mediated toxicity. In summary, Aventis 
concludes that consideration of a common mechanism of toxicity is not 
appropriate at this time since there is no significant toxicity 
observed for ethephon. Even at high doses, ethephon does not act as a 
classical inhibitor of cholinesterase.

[[Page 51267]]

 Exposure, even at high doses, does not lead to brain cholinesterase 
inhibition. There is no reliable data to indicate that the effects 
noted would be cumulative with those of organophosphate or carbamate-
type compounds. Therefore, Aventis has considered only the potential 
risks of ethephon in its exposure assessment.

E. Safety Determination

     EPA reference dose (RfD) Peer Review Committee determined that the 
RfD should be based on the 28-day study in humans. Using the LOAEL of 
1.8 mg/kg/day in this study and an uncertainty factor (UF) of 100 to 
account for intraspecies variability and the lack of a NOAEL, an RfD of 
0.018 mg/kg/day was established as the chronic dietary endpoint.
    1. U.S. population. A chronic dietary risk assessment which 
included all proposed changes in ethephon tolerances was conducted on 
ethephon using two approaches: A Tier 1 approach using tolerance-level 
residues for all foods included in the analysis, and Monte Carlo 
simulations using tolerance-level residues for all foods adjusted for 
percent crop treated (PCT) (Tier 3). Using the Tier 1 approach, margin 
of exposure (MOEs) at the percentiles of exposure for the overall U.S. 
population were 25 and 9, respectively. Using Tier 3 procedures in 
which residues were adjusted for the PCT, MOEs were 114 and 42, 
respectively. Acute exposure was also estimated for infants and 
children 1 to 6 years of age. In the Tier 1 analysis, the most highly 
exposed subgroup was infants. For this population, MOEs at the 
95th and 99th percentiles of exposure were 7 and 
4, respectively. Using the Tier 3 method MOEs were 56 and 12, 
respectively. Even under the conservative assumptions presented here, 
the more realistic estimates of dietary exposure (Tier 3 analyses) 
clearly demonstrate adequate MOEs up to the 99th percentile 
of exposure for all population groups analyzed.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of ethephon, the 
available developmental toxicity and reproductive toxicity studies and 
the potential for endocrine modulation by ethephon were considered. 
Developmental toxicity studies in two species indicate that ethephon is 
not a teratogen. The 2 generation reproduction study in rats 
demonstrated that there were no adverse effects on reproductive 
performance, fertility, fecundity, pup survival, or pup development. 
Maternal and developmental NOAELs and LOAELs were comparable, 
indicating no increase in susceptibility of developing organisms. No 
evidence of endocrine effects were noted in any study. It is therefore, 
concluded that ethephon poses no additional risk for infants and 
children and no additional uncertainty factor is warranted. FFDCA 
section 408 provides that an additional safety factor for infants and 
children may be applied in the case of threshold effects. Since, as 
discussed in the previous section, the toxicology studies do not 
indicate that young animals are any more susceptible than adult animals 
and the fact that the proposed RfD calculated from the LOAEL from the 
28-day human study already incorporates an additional uncertainty 
factor, Aventis believes that an adequate margin of safety is, 
therefore, provided by the RfD established by EPA. Additionally, this 
LOAEL is also 8X lower than the next lowest NOAEL (2 generation 
reproduction study, NOAEL=15 mg/kg/day) in the ethephon toxicology data 
base. Ethephon has no endocrine-modulation characteristics as 
demonstrated by the lack of endocrine effects in developmental, 
reproductive, subchronic, and chronic studies.
     An RfD of 0.018 mg/kg/day has been established by EPA based on the 
LOAEL in the 28-day human study. Adequate MOEs exist for all 
populations including infants and children. No additional uncertainty 
factor for infants and children is warranted based on the completeness 
and reliability of the database, the demonstrated lack of increased 
risk to developing organisms, and the lack of endocrine-modulating 
effects.

F. International Tolerances

     The codex maximum residue limits (MRLs) for grape is 10 mg/kg 
verses 2 ppm for U.S. tolerance. The tomato codex MRL is 3 mg/kg verses 
2 ppm for the U.S. tolerance. All other U.S. tolerances are identical 
to corresponding codex MRLs.
[FR Doc. 02-19803 Filed 8-6-02; 8:45 am]
BILLING CODE 6560-50-S