[Federal Register Volume 62, Number 10 (Wednesday, January 15, 1997)]
[Notices]
[Pages 2149-2154]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-983]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-686; FRL-5580-3]
Rhone-Poulenc Ag Company; Pesticide Tolerance Petition Filing
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice of filing.
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SUMMARY: This notice announces the filing of pesticide petitions
proposing to increase and decrease tolerances for ethephon in or on
cottonseed, meat and milk, and proposes establishing new tolerances for
cotton gin trash and poultry. The summary was prepared by the
petitioner, Rhone-Poulenc Ag Company.
DATES: Comments, identified by the docket number [PF-686], must be
received on or before, February 14, 1997.
ADDRESSES: By mail, submit written comments to Public Response and
Program Resources Branch, Field Operations Division (7506C), Office of
Pesticide Programs, Environmental Protection Agency, 401 M St. SW.,
Washington, DC 20460. In person, bring comments to Rm. 1132, CM #2.
1921 Jefferson Davis Highway, Arlington, VA 22202.
Comments and data may also be submitted electronically be sending
electronic mail (e-mail) to: opp-docket@epamail.epa.gov. Electronic
comments must be submitted as an ASCII file avoiding the use of special
characters and any form of encryption. Comments and data will also be
accepted on disks in WordPerfect in 5.1 file format or ASCII file
format. All comments and data in electronic form must be identified by
docket number [PF-686]. Electronic comments on this notice may be filed
online at many Federal Depository Libraries. Additional information on
electronic submissions can be found below this document.
Information submitted as a comments concerning this document may be
claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in
[[Page 2150]]
accordance with procedures set forth in 40 CFR part 2. A copy of the
comment that does not contain CBI must be submitted for inclusion in
the public record. Information not marked confidential may be disclosed
publicly by EPA without prior notice. All written comments will be
available for public inspection in Rm. 1132 at the address given above,
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal
holidays.
FOR FURTHER INFORMATION CONTACT: Philip V. Errico, Acting Product
Manager (PM 22), Rm., 229, CM #2, 1921 Jefferson Davis Highway,
Arlington, VA., 703-305-5540, e-mail: errico.philip@epamail.epa.gov.
SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions (PP)
1H5603 (originally published in the Federal Register of April 3, 1991,
(56 FR 13641)), and 6F4743 from Rhone-Poulenc AG Company, P.O. Box
12014, Research Triangle Park, NC 27709 proposing pursuant to section
408(d) of the Federal Food, Drug and Cosmetic Act, 21 U.S.C. section
346a(d), to amend 40 CFR part 180 by increasing the established
tolerances for residues of the plant growth regulator, ethephon, (2-
chloroethyl phosphonic acid, in or on the raw agricultural commodities
(RACs) cottonseed from 4.0 parts per million (ppm) to 6.0 ppm; meat by-
products (except kidney) of cattle, goats, hogs, horses, and sheep from
0.1 to 0.2 ppm; by decreasing established tolerances for ethephon in or
on RACs milk from 0.1 ppm to 0.01 ppm, fat of cattle, goats, hogs,
horses, and sheep from 0.1 ppm to 0.02 ppm; and by establishing
tolerances for ethephon in or on cotton gin byproducts to 180 ppm;
kidney of cattle, goats, hogs, horses, and sheep at 1.0 ppm; eggs at
0.002 ppm; poultry meat at 0.01 ppm; poultry liver at 0.05 ppm; poultry
fat at 0.02 ppm; and poultry meat byproducts (except liver at 0.01 ppm.
The proposed analytical method is analysis for ethylene release.
Pursuant to the section 408(d)(2)(A)(i) of the FFDCA, as recently
amended by the Food Quality Protection Act, Rhone-Poulenc AG Company
has submitted the following summary of information, data and arguments
in support of their pesticide petition. This summary was prepared by
Rhone-Poulenc AG Company and EPA has not fully evaluated the merits of
the petition. EPA edited the summary to clarify that the conclusions
and arguments were the petitioner's and not necessarily EPA's and to
remove certain extraneous material.
I. Petition Summary
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 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 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 is in review at EPA.
3. Magnitude of residues. Residue studies have been conducted to
support ethephon registrations on: cotton, apples, cherries, tomatoes,
wheat, barley, peppers, grapes, tobacco, walnuts, almonds,
blackberries, cantaloupe, pineapple, sugarcane and macadamia nuts. In
addition, IR-4 is conducting work to support new uses on blueberries,
coffee, cranberries, figs and guavas. All residue data 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 by-products (180 ppm, amendment to PP
1H5603). As part of the reregistration process, the following
tolerances will be revoked: cucumbers, filberts, lemons, pineapple
forage and fodder, pumpkins, tangerines, 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 apples, barley,
cottonseeds, grapes, pineapples, tomatoes, 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,
raisins, 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, horses,
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. Toxicology Profile
1. Acute toxicity--Ethephon technical. A complete battery of acute
toxicity studies for ethephon technical was completed. The acute oral
toxicity study resulted in a LD50 of 1,600 mg/kg for both sexes.
The acute dermal toxicity in rabbits resulted in an LD50 in either
sex of greater than 5000 mg/kg. The acute inhalation study in rats
resulted in a LC50 of 4.52 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.
[[Page 2151]]
Conclusion: Based on the acute toxicity data cited above it is
concluded that ethephon technical does not pose any acute dietary
risks.
2. Genotoxicity--Ethephon technical. 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. The weight of evidence suggests that this
material is non-genotoxic.
Conclusions: Based on the data cited above, 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:
a. 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
NOEL of 15 mg/kg/day and a LOEL 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.
b. In rats, ethephon was administered by gavage at doses of 0, 20,
600, or 1,800 mg/kg for gestation days 6 through 15. At 1,800 mg/kg/
day, 14 of the 24 treated female rats died. No toxic effects were
observed at lower doses. The NOEL 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 NOEL for
maternal and developmental toxicity was 500 mg/kg/day.
c. 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
does 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 NOEL for maternal toxicity was 50 mg/kg/day and the
NOEL 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
NOEL for maternal and developmental toxicity of 125 mg/kg/day was
observed.
Conclusions: Based on the two-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 NOEL for both maternal and developmental toxicity in rats
was 500 mg/kg/day and for rabbits the NOEL 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:
a. 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 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.
b. 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.
c. 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.
d. In a 21-day dermal study, 10 rabbits per sex per group were
dosed dermally at 0, 25, 75, and 150 mg/kg/day, five days per week for
three 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 NOEL was greater than 150 mg/kg/day.
Conclusions: Based on the results of the 3 studies in humans, a
LOEL 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 NOEL in the 21-day dermal study in
rabbits was greater than 150 mg/kg/day.
5. Chronic effects. A 2 year chronic toxicity/oncogenicity study in
rats, an 18 month mouse oncogenicity 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:
a. A combined chronic/oncogenicity 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 (NOEL<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="" and="" nephritis="" and="" biliary="" hyperplasia="" cholangiofibrosis.="" no="" carcinogenic="" effects="" were="" observed.="" b.="" 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="" noel="" 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.="" c.="" 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="" [[page="" 2152]]="" 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=""><0.75 mg/kg/day).="" a="" noel="" for="" erythrocyte="" cholinesterase="" inhibition="" of="" 0.75="" mg/kg/day="" with="" a="" loel="" of="" 7.5="" mg/kg/="" day="" was="" observed.="" histopathology="" showed="" smooth="" muscle="" atrophy="" in="" the="" gut="" at="" 7.5="" mg/kg/day="" with="" a="" noel="" of="" 0.75="" mg/kg/day.="" d.="" 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="" noel="" 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="" noel.="" cholinesterase="" inhibition="" was="" not="" determined.="" conclusions:="" the="" noel="" in="" the="" chronic="" rat="" study="" was="" 131="" mg/kg/day="" based="" on="" the="" decreased="" body="" weight="" gains="" in="" males.="" the="" noel="" in="" the="" most="" recent="" one-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="" oncogenic="" activity.="" no="" oncogenic="" effects="" were="" observed.="" 6.="" animal="" metabolism.="" rat="" metabolism--ethephon="" technical.="" 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="" 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="" accounted="" for="" 48="" to="" 71="" percent="" of="" the="" administered="" radioactivity.="" approximately="" 7="" percent="" was="" excreted="" in="" the="" feces.="" exhaled="" ethylene="" was="" 10-20="" percent="" and="">2 was less than 1 percent 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.
Goat metabolism--Ethephon technical. In a goat metabolism study,
ethephon was incorporated into natural products (glutathione
conjugates, protein, glycogen, and triglycerides) and expired as
CO2 and ethylene.
Hen metabolism--Ethephon technical. 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.
Conclusions: 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. Neurotoxicity. The acute neurotoxicity of ethephon has been
studied. The study is summarized below:
Groups of 12 male and 12 female Sprague Dawley rats were treated
once by gavage with ethephon at dose levels of 0, 500, 1,000, or 2,000
mg/kg in order to assess its potential acute neurotoxicity. The time
for assessing peak behavioral effects was previously determined in
another study to be approximately 6 hours post dosing. At 2,000 mg/kg,
mortality (females only) and transitory effects including pupillary
constriction, increased urination (males only), reduced food
consumption and body weight, decreased body temperature (females only),
and reduced motor activity. Mortality and reduced food consumption was
also observed for the 1,000 mg/kg females, motor activity was decreased
for the 1,000 mg/kg males and constricted pupils were noted for some
animals in all the lower dosage groups. No neuropathological lesions
were seen that were attributed to treatment with ethephon. The nature
of the findings suggests that they were generally isolated
pharmacological effects and not of neurotoxicological significance
given their transitory nature and the lack of treatment related
structural lesions in the nervous system.
Conclusions: The acute neurotoxicity study demonstrated transient
findings that suggested isolated pharmacological effects and no NOEL
was established based on the observation of transient constricts.
Ethephon does not appear to pose any significant acute neurotoxicity.
C. Aggregate Exposure
1. Dietary exposure. a. Food - Ethephon is registered for use on
the following food crops: cotton, apples, cherries, tomatoes, wheat,
barley, peppers, grapes, tobacco, walnuts, almonds, blackberries,
cantaloupe, pineapple, sugarcane and macadamia nuts. In addition, IR-4
is conducting work to support new uses on blueberries, coffee,
cranberries, figs and guavas. 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 by-products (180 ppm, amendment to PP 1H5603). As part of
the reregistration process, the following tolerances will be revoked:
cucumbers, filberts, lemons, pineapple forage and fodder, pumpkins,
tangerines, 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 U.S.
b. Drinking water - Based on the available studies and the use
pattern, Rhone-Poulenc 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. 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 U.S. contains only 3.9 percent 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
[[Page 2153]]
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 percent and 85 percent, respectively. In the mouse
study, both peripheral ChEs were inhibited by approximately 70 percent.
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
percent and 70 percent, 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, Rhone-Poulenc 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.
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, Rhone-Poulenc has considered only the
potential risks of ethephon in its exposure assessment.
E. Safety Determination
The EPA OPP/HED RfD Peer Review Committee determined that the
reference dose (RfD) should be based on the 28-day study in humans.
Using the LOEL 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
NOEL, an RfD of 0.018 mg/kg/day was established as the chronic dietary
endpoint.
1. U.S. population--General. A chronic dietary risk assessment
which included all proposed changes in ethephon tolerances was
conducted on ethephon using two approaches: (1) a Tier 1 approach using
tolerance-level residues for all foods included in the analysis, and
(2) Monte Carlo simulations using tolerance-level residues for all
foods adjusted for percent crop treated (Tier 3). Using the Tier 1
approach, MOEs at the 95th and 99th 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 percent of the crop
treated, 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 NOELs and LOELS 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 LOEL from the 28 day human study
already incorporates an additional uncertainty factor, Rhone-Poulenc
believes that an adequate margin of safety is therefore provided by the
RfD established by EPA. Additionally, this LOEL is also 8X lower than
the next lowest NOEL (2 generation reproduction study, NOEL=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.
Conclusion: A dietary Risk assessment was submitted to EPA in
September, 1996 (MRID #44100203). An RfD of 0.018 mg/kg/day has been
established by EPA based on the LOEL 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 MRL for grapes 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.
II. Administrative Matters
Interested persons are invited to submit comments on the this
notice of filing. Comments must bear a notation indicating the document
control number, [PF-686]. All written comments filed in response to
this petition will be available in the Public Response and Program
Resources Branch, at the address given above from 8:30 a.m. to 4 p.m.,
Monday through Friday, except legal holidays.
A record has been established for this notice under docket number
[PF-686] including comments and data submitted electronically as
described below). A public version of this record, including printed,
paper versions of electronic comments, which does not include any
information claimed as CBI, is available for inspection from 8:30 a.m.
to 4 p.m., Monday through Friday, excluding legal holidays. The public
record is located in Rm. 1132 of the Public Response and Program
resources Branch, Field Operations Division (7506C), Office of
Pesticide Programs, Environmental Protection Agency, Crystal Mall #2,
1921 Jefferson Davis highway, Arlington, VA.
[[Page 2154]]
Electronic comments can be sent directly to EPA at:
opp-docket@epamail.epa.gov
Electronic comments must be submitted as ASCII file avoiding the
use of special characters and any form of encryption.
The official record for this rulemaking, as well as the public
version, as described above will be kept in paper form. Accordingly,
EPA will transfer all comments received electronically into printed,
paper form as they are received and will place the paper copies in the
official rulemaking record which will also include all comments
submitted directly in writing. The official rulemaking record is the
paper record maintained at the address in ``ADDRESSES'' at the
beginning of this document.
List of Subjects
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and
recordkeeping requirements.
Dated: January 7, 1997.
Stephen L. Johnson,
Director, Registration Division, Office of Pesticide Programs.
[FR Doc. 97-983 Filed 1-14-97; 8:45 am]
BILLING CODE 6560-50-F
