[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]


-----------------------------------------------------------------------

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.

-----------------------------------------------------------------------

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: <a href="/cdn-cgi/l/email-protection#4f203f3f622b202c242a3b0f2a3f2e222e2623612a3f2e61282039"><span class="__cf_email__" data-cfemail="6e011e1e430a010d050b1a2e0b1e0f030f0702400b1e0f40090118">[email protected]</span></a>. 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: <a href="/cdn-cgi/l/email-protection#8ce9fefee5efe3a2fce4e5e0e5fccce9fcede1ede5e0a2e9fceda2ebe3fa"><span class="__cf_email__" data-cfemail="94f1e6e6fdf7fbbae4fcfdf8fde4d4f1e4f5f9f5fdf8baf1e4f5baf3fbe2">[email protected]</span></a>.

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 LD<INF>50 of 1,600 mg/kg for both sexes. 
The acute dermal toxicity in rabbits resulted in an LD<INF>50 in either 
sex of greater than 5000 mg/kg. The acute inhalation study in rats 
resulted in a LC<INF>50 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 (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 CO<INF>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 
CO<INF>2 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:
    <a href="/cdn-cgi/l/email-protection#5c332c2c7138333f3739281c392c3d313d353072392c3d723b332a"><span class="__cf_email__" data-cfemail="49263939642d262a222c3d092c392824282025672c3928672e263f">[email protected]</span></a>


    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


</pre><script data-cfasync="false" src="/cdn-cgi/scripts/5c5dd728/cloudflare-static/email-decode.min.js"></script></body>
</html>