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Ethephon (Ethrel, Florel) - Pesticide Tolerance Petition 1/97

CHEMICAL PROFILES/GROWTH REGULATOR/ethephon
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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 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 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
(NOEL<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 CO2 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 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.
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]
[Federal Register: January 17, 1997 (Volume 62, Number 12)] [Notices]
[Page 2641]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]