[Federal Register Volume 63, Number 144 (Tuesday, July 28, 1998)]
[Notices]
[Pages 40273-40279]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-20145]
=======================================================================
-----------------------------------------------------------------------
ENVIRONMENTAL PROTECTION AGENCY
[PF-816; FRL-5799-3]
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: This notice announces the initial filing of pesticide
petitions proposing the establishment of regulations for residues of
certain pesticide chemicals in or on various food commodities.
DATES: Comments, identified by the docket control number PF-816, must
be received on or before August 27, 1998.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Division
(7502C), Office of Pesticides 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.
Comments and data may also be submitted electronically to: opp-
[email protected]. Follow the instructions under ``SUPPLEMENTARY
INFORMATION.'' No confidential business information should be submitted
through e-mail.
Information submitted as a comment 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: The product manager listed in the
table below:
------------------------------------------------------------------------
Office location/
Product Manager telephone number Address
------------------------------------------------------------------------
Bipin Gandhi (PM 21).......... Rm. 707A, CM #2, 703- 1921 Jefferson
308-8380, e- Davis Hwy,
mail:gandhi.bipin@epa Arlington, VA.
mail.epa.gov.
Cynthia Giles-Parker (PM 22).. Rm. 247, CM #2, 703- 1921 Jefferson
305-7740, e- Davis
mail:giles- Hwy.,Arlington,
[email protected] VA.
v.
------------------------------------------------------------------------
SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as
follows proposing the establishment and/or amendment of regulations for
residues of certain pesticide chemicals in or on various food
commodities under section 408 of the Federal Food, Drug, and Comestic
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these petitions
contain data or information regarding the elements set forth in section
408(d)(2); however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data supports granting of
the petition. Additional data may be needed before EPA rules on the
petition.
The official record for this notice of filing, as well as the
public version, has been established for this notice of filing under
docket control number [PF-816] (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 official record is located at the address in
``ADDRESSES'' at the beginning of this document.
Electronic comments can be sent directly to EPA at:
[email protected]
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 5.1 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket number (insert docket number) and appropriate
petition number. Electronic comments on notice may be filed online at
many Federal Depository Libraries.
List of Subjects
Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated:July 9, 1998.
James Jones,
Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Petitioner summaries of the pesticide petitions are printed below
as required by section 408(d)(3) of the FFDCA. The summaries of the
petitions were prepared by the petitioners and
[[Page 40274]]
represent the views of the petitioners. EPA is publishing the petition
summaries verbatim without editing them in any way. The petition
summary announces the availability of a description of the analytical
methods available to EPA for the detection and measurement of the
pesticide chemical residues or an explanation of why no such method is
needed.
1. Fleming Laboratories, Inc.
PP 4G4276
EPA has received a pesticide petition (PP 4G4276) from Fleming
Laboratories, Inc., P.O.Box 34384, Charlotte, NC 28234 proposing
pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act,
21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance
for residues of (4-methylphenyl)arsonic acid in or on the raw
agricultural commodity fresh market grapefruit grown only in Florida at
0.5 parts per million (ppm). EPA has determined that the petition
contains data or information regarding the elements set forth in
section 408(d)(2) of the FFDCA; however, EPA has not fully evaluated
the sufficiency of the submitted data at this time or whether the data
supports granting of the petition. Additional data may be needed before
EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. A plant metabolism study is being conducted at
the proposed use rate of 6.22 lbs active ingredient (6.25 lbs product)
per acre and has revealed approximately 0.46 ppm total radioactive
residue (TRR) in whole fruit, of which 0.13 ppm or 29.2% of the TRR was
parent compound. Four of the 11 metabolites isolated from whole fruit
exceed 10% of the TRR. Metabolite characterization and identification
is still in progress.
2. Analytical method. A High Performance Liquid Chromatography
(HPLC) method is available to verify the certified limits of arsanilic
acid in the end-use product.
Currently there is no validated method for determining any of the
residues of arsanilic acid in/on grapefruit. However, method
development is partially complete for an analytical method to determine
residues of (4-aminophenyl)arsonic acid, per se, the active ingredient
of Pro-Gen(r), in or on whole grapefruit. In principle, a 50 gram
sample of grapefruit is extracted by homogenization with water. The
extract is centrifuged, filtered, concentrated by rotary evaporation,
cleaned up on a florisil column, buffered to pH 4.5, then derivatized
with methyl thioglycolate. The derivative is partitioned into toluene,
which is analyzed by gas chromatography (GC) and an electron capture
detector (ECD). The anticipated Limit of Quantitation (LOQ) is 0.05
ppm. Method development for the metabolite residues will ensue as the
metabolites are identified.
3. Magnitude of residues. Field residue trials are currently in
progress at several sites in Florida. Mature grapefruit samples have
been harvested from trees treated with 6.25 lbs Pro-Gen(r) per acre and
are being stored until residue analytical method development is
complete. However, based on the data from the plant metabolism study,
total residues of arsanilic acid in grapefruit are expected to be less
than 0.5 ppm.
B. Toxicological Profile
1. Acute toxicity. Pro-Gen(r)/arsanilic acid is only moderately
acutely toxic to mammals. The rat acute oral LD50 values
were 1,411 mg/kg for males, 976 (646-2883) mg/kg for females and 1,461
mg/kg for males and females combined. A study with New Zealand white
rabbits established acute dermal LD50 values of 922 mg/kg
for males, 909 (445-1972) mg/kg for females and 921 (577-1402) mg/kg
for males and females combined. Arsanilic acid has caused minimal signs
of toxicity in rats following a 4 hour inhalation exposure to a
measured atmospheric concentration of 5.35 mg/l. The acute inhalation
LC50 is greater than 5.35 mg/l. Arsanilic acid is slightly
irritant to rabbit eyes and is not irritant to rabbit skin.
Arsanilic acid is not considered a skin sensitizer. Arsanilic acid
does not cause sensitization in guinea pigs. Additionally, arsanilic
acid has been manufactured and used since the 1940's as a medicinal
feed additive for poultry and swine with no reported incidents of
hypersensitivity among workers.
2. Genotoxicty. Arsanilic acid is not mutagenic to five strains of
Salmonella typhimurium. In the mouse micronucleus test, arsanilic acid
(99.6% purity) was devoid of micronucleus inducing potential in the
bone marrow of male and female CD-1 mice when tested to maximum
tolerated doses. Arsanilic acid was determined to be weakly mutagenic
in mouse lymphoma L51178Y cells in the presence of S9 mix, when tested
at concentrations extending into the toxic range. However, evidence of
mutagenicity in the absence of S9 mix was inconclusive.
3. Reproductive and developmental toxicity. A review of three
studies detailing the effects of arsanilic acid on reproduction in
swine found no adverse effects on the fertility, fecundity, or health
and survival of swine dams and their offspring at an arsanilic acid
feed concentration of 100 ppm. Furthermore, at the 100 ppm arsanilic
acid feeding level, no gross abnormalities or adverse effects were
found on organ weights or pathology. To the contrary, arsanilic acid in
the diet improved the overall health, improved weight gain, and
increased survival of swine.
No developmental effects were found in rats exposed in utero to
arsanilic acid at levels up to and including that which produced overt
maternal toxicity. Arsanilic acid was administered orally by gavage to
pregnant rats at nominal dose levels of up to 60 mg/kg/day. Reduced
body weight gains early in the treatment period, reduced food
consumption, and the presence clinical signs (60 mg/kg/day group) were
considered evidence of maternal toxicity. No developmental toxicity was
apparent at any dose level. A no observable effect level (NOEL) for
maternal effects (reduced food consumption) was considered to be less
than 6 mg/kg/day (based on a 60.0% of target concentration analysis of
the 10 mg/kg/day formulation used during the first 5 days of dose
administration). The NOEL for maternal clinical signs was 30 mg/kg/day.
The NOEL for developmental toxicity of rats was 60 mg/kg/day.
No developmental effects were noted in rabbits exposed in utero to
arsanilic acid (100%) at levels up to and including that which produced
overt maternal toxicity. Arsanilic acid (Pro-Gen(r)) was administered
orally by gavage to pregnant rabbits at nominal dose levels up to 6 mg/
kg/day. Maternal effects were observed only in the 6 mg/kg/day dosed
dams and were limited to reductions in mean body weight gain and food
consumption. No maternal effects were apparent at dose levels of 1 and
3 mg/kg/day. No developmental toxicity was expressed at any dose level.
The NOEL for maternal effects was 3 mg/kg/day. The NOEL for
developmental toxicity was 6 mg/kg/day.
4. Subchronic toxicity. No mortality occurred during a 91-day
feeding study in which male and female rats were fed nominal
concentrations of up to 750 ppm arsanilic acid in the diet. Some signs
of toxicity (behavior, locomotion and excreta) were observed at feeding
levels of 375 ppm and above. No definite treatment effects were
observed in animals receiving 50 ppm arsanilic acid in the diet. The
NOEL was determined to be 50 ppm (3.77 mg/kg/day for males and 4.76 mg/
kg/day for females).
[[Page 40275]]
No mortality occurred during a 90-day feeding study in which male
and female beagles were fed arsanilic acid at up to 200 ppm in diet. No
ophthalmoscopic abnormalities were observed at any level. Clinical
signs of toxicity were observed in some dogs receiving 200 ppm
arsanilic acid in diet. While there was no observable indication of
toxicity in animals receiving up to 100 ppm arsanilic acid in the diet,
microscopic evaluation of the kidneys revealed dose-related
abnormalities. The NOEL for female beagle dogs was 50 ppm (1.7 mg/kg/
day). The NOEL for male beagle dogs was 25 ppm (0.7 mg/kg/day).
5. Chronic toxicity. Arsanilic acid is not carcinogenic to rats.
Arsanilic acid is approved by the FDA for use as a medicinal feed
supplement for swine and poultry at concentrations up to 0.01% of the
ration and has been extensively used in commercial rations since the
1940's.
Arsanilic acid was fed to rats (two separate studies) at
concentration levels of 100, 500 and 1,000 ppm in the diet for 106 to
116-weeks. In both studies, the presence of arsanilic acid in the diet
was reported to have caused no gross abnormalities or adverse effects
on organ weights, pathology, incidence of tumors or health of rats.
Long term feeding of 0.01% arsanilic acid in pig feed for up to 51
months during a multigeneration study resulted in increased survival
and overall improved health of arsanilic acid-treated pigs.
6. Animal metabolism. Arsanilic acid uniformly labeled with
14C in the benzene ring was used to determine the metabolic
fate of arsanilic acid fed to pigs and chickens. Arsanilic acid was
well absorbed by both species. Urine was the predominant route of
excretion. The bile was a minor (<5% of the dose) route of excretion in
pigs (was not measured in chickens). Arsanilic acid and two other
metabolites, N-acetylarsanilic acid and (4-
acetamidophenyl)dimethylarsine oxide, were identified in the pig urine.
In pigs, somewhere between 17-39% of the urinary 14C
metabolites was excreted as arsanilic acid, 15-29% as N-acetylarsanilic
acid and <5% as (4-acetamidophenyl)dimethylarsine oxide. Only 2-5% of
the radio-labeled arsanilic acid dose remained in the carcass or liver
of pigs while less than 1% remained in the chicken carcasses (liver
included). There was no evidence of any biotransformation of arsanilic
acid in chickens. The study authors also note that the results of this
study corroborate earlier research showing that chickens rapidly
excrete arsanilic acid with no biotransformation.
7. Metabolite toxicology. There is no known information about the
toxicity of any of the currently identified metabolites of arsanilic
acid.
8. Endocrine disruption. Arsanilic acid is not considered to be an
endocrine disruptor. Several studies in which different species were
administered high levels of arsanilic acid have shown no effect on the
time-to-mating or on mating and fertility indices. Radiolabelled
[14C]-arsanilic acid fed to chickens (laying hens) had no
effect on the ability of the hens to produce eggs. Multigeneration
reproduction studies in swine, developmental toxicity studies in rats
and rabbits, chronic studies in rats plus long term medicinal use in
animal husbandry amply demonstrates that arsanilic acid does not affect
the estrous cycle, mating behavior, male or female fertility, or male
or female reproductive tracts.
C. Aggregate Exposure
1. Dietary exposure--Food-- i. From medicinal feed additive use.
Arsanilic acid has been utilized under FDA approval as a medicinal feed
additive in pig, chicken and turkey feeds since the 1940's. However,
the feed additive tolerances established by the FDA are expressed in
terms of total residues of combined arsenic (calculated as As) instead
of as arsanilic acid (21 CFR 558.62 and 556.60). Because arsanilic acid
may be the sole dietary contributor that necessitates the feed additive
tolerances for arsenic, these tolerances can be converted to total
arsanilic acid equivalents by using a conversion factor of 2.9, the
ratio of the molecular weight of arsanilic acid (217.04) to that of its
arsenic content (74.92).
----------------------------------------------------------------------------------------------------------------
Total Residues as
Total Residues as Arsenic (ppm) Arsanilic Acid Commodity
(ppm)
----------------------------------------------------------------------------------------------------------------
0.5...................................................... 1.45 eggs, chicken
0.5...................................................... 1.45 muscle, chicken
2.0...................................................... 5.8 edible by-products, chicken
0.5...................................................... 1.45 eggs, turkey
0.5...................................................... 1.45 muscle, turkey
2.0...................................................... 5.8 edible by-products, turkey
2.0...................................................... 5.8 liver, swine
2.0...................................................... 5,8 kidney, swine
0.5...................................................... 1.45 muscle, swine
0.5...................................................... 1.45 by-products, swine
----------------------------------------------------------------------------------------------------------------
ii. From proposed use on fresh market grapefruit grown only in
Florida. In the amended petition for a Saleable Experimental Use
Permit, the following temporary tolerance is proposed for total
residues of arsanilic acid expressed as arsanilic acid, per se, in or
on fresh market grapefruit.
0.5 ppm in/on grapefruit (whole fruit)
Because the treated fruit are prohibited from being processed under
the amended Experimental Use Permit, no dietary exposure is anticipated
from the processed commodities nor are any temporary tolerances
proposed for the processed commodities, grapefruit juice, dried
grapefruit pulp or grapefruit citrus oil.
iii. From livestock consumption of treated grapefruit and/or
processed products. Under the amended petition for Experimental Use
Permits (EUP), treated fruit may not be fed to livestock. The amended
EUP also restricts livestock grazing or consumption of forage or hay
from Pro-Gen(r) treated orchards. Therefore, no dietary exposure to
arsanilic acid is anticipated from livestock consumption of Pro-Gen(r)
under the auspices of the proposed EUP.
2. Drinking water. No exposure to arsanilic acid is expected from
consumption of drinking water. Arsanilic acid is not proposed for
application to sources of drinking water. Additionally, hydrolysis,
soil metabolism and soil adsorption/desorption studies have shown that
arsanilic acid is stable to environmental degradation and binds tightly
and irreversibly to the organic and mineral fractions of soils. Any
arsanilic acid that
[[Page 40276]]
might be excreted by poultry or swine administered arsanilic acid for
medicinal purposes will be tightly bound to soil if incorporated in to
the soil as a fertilizer. Consequently, potential exposure of surface
and/or ground water to arsanilic acid will be minimized.
3. Non-dietary exposure. There are no known sources of non-dietary
exposure to arsanilic acid, outside of occupational exposure in the
manufacturing and packaging of Pro-Gen(r)/arsanilic acid in its current
usage in animal husbandry, or in its proposed use in Florida fresh
market grapefruit production. There is little concern that children
would be exposed to non-dietary sources of arsanilic acid.
D. Cumulative Effects
For cumulative exposure considerations, Fleming Laboratories
believes it is appropriate to consider only the potential risks of
arsanilic acid noted in the discussion of aggregate exposure (above),
based on the current approaches used by the FDA and EPA for regulating
organic arsenical compounds in animal husbandry and crop production.
Arsanilic acid is an organic arsenical compound. FDA regulations
have established feed additive tolerances, expressed as ppm total
combined arsenic, for the following medicinal organoarsenical
compounds, arsanilic acid, arsanilate sodium, nitarsone, carbarsone,
and roxarsone.
Although FDA has authorized the use of these compounds as medicinal
feed additives, only one of these organoarsenicals may be used at a
time as the sole source of organic arsenic in the feed. Therefore,
there is no exposure from multiple organic arsenicals in animal feeds.
With regards to crop protection, the only known organic arsenicals
registered in the U.S. are the herbicides: cacodylic acid, a cotton
defoliant; and disodium or monosodium methanearsonic acid, contact
herbicides used in cotton and citrus production. With regard to residue
tolerances for these herbicides, residues of cacodylic acid are
regulated discretely for that compound under 40 CFR 180.311. While,
residues of disodium and monosodium methanearsonic acid are regulated
simultaneously as methanearsonic acid under 40 CFR 180.289. Since these
compounds are regulated discretely, it can be assumed that EPA
considers them to have distinct metabolic pathways and modes of action.
Since arsanilic acid has a considerably different chemical
structure (containing a phenyl ring) from these other straight-chained
organic arsenical herbicides, it is reasonable to assume that arsanilic
acid will have a unique mode of action compared to the straight chain
herbicides. The proposed use of arsanilic acid as a plant growth
regulator further illustrates the differences when comparing arsanilic
acid to these herbicides.
Therefore, for cumulative exposure considerations, Fleming
Laboratories believes it is appropriate to consider only the potential
risks of arsanilic acid noted in the discussion of aggregate exposure
(above).
E. Safety Determination
U.S. population. The Acceptable Daily Intake (ADI) is the amount of
pesticide residue that can be ``safely'' ingested by humans and still
be protective of the health of all segments of the population. An ADI
must be established for any pesticide that results in a residue on
crops used for human consumption. The ADI, sometimes referred to as the
Reference Dose (RfD), is a mathematically derived figure based on the
NOEL of a chronic or subchronic toxicity study and safety or
uncertainty factors. Uncertainty factors are used to compensate for
inter- and intra-species differences, type of study, etc. when
extrapolating from toxicity data (animal or human) to human risk
assessments.
For arsanilic acid, the ADI will be based on the results of the dog
subchronic feeding study. The ADI is equal to the NOEL times a safety
or uncertainty factor (UF). It is customary to use a UF of 100 fold
(100x) to account for the species differences from dog to human, as
well as for extrapolating from a subchronic study to chronic exposure
of humans. Assuming that EPA concurs with an uncertainty factor of
100x, the ADI based on the most sensitive NOEL can be calculated as
follows:
NOEL = 25 ppm arsanilic acid in diet of dogs = 0.75 mg/kg/day
Then the ADI or RfD = 0.75 mg/kg/day x (1/100) = 0.0075 mg/kg/day
Based on EPA's total diet survey, sensitive populations, such as
infants, have little or no intake of grapefruit or grapefruit juice.
Therefore the ADI is based on consumption of grapefruit and grapefruit
juice by 70 kg adult humans. Therefore, if the ADI is 0.0075 mg/kg/day,
a 70 kg adult could safely consume 0.525 mg arsanilic acid /day (0.0075
mg/kg/day x 70 kg).
F. Dietary Risk Assessment
The dietary risk assessment evaluates how much of the ADI would be
``used up'' when residue tolerances are proposed for pesticide-bearing
crop or animal commodities that may be consumed by humans. To conduct
the risk assessment for arsanilic acid under the tenets of the proposed
amended Experimental Use Permit for Florida-grown, fresh market fruit
only, one needs to know how much grapefruit would typically be consumed
by humans and the amount of arsanilic acid residues in or on the fruit.
Additionally, human exposure from consumption of swine and poultry
products from medicinally treated animals must be considered.
For estimating grapefruit dietary consumption, EPA's Total Diet
Study, which is used to calculate exposure and dietary risk for
pesticides, reveals that 25-30 year-old men have the highest
consumption of grapefruit compared to all other age and sex groupings.
Consumption rates in this group are listed as 4.3 grams of grapefruit
per day. Consumption of whole grapefruit (4.3 grams/day) contributes to
less than 0.08% of the total diet in this age and sex category.
Dietary exposure from grapefruit consumption will be reduced by the
limited use of Pro-Gen(r) to grapefruit grown in Florida. According to
the Florida Citrus Summary 1993-94, Florida produced 816,800 tons of
grapefruit in 1993-1994, which was 66.10% of the total U.S. production
of grapefruit. This means that grapefruit grown in Florida would
contribute to less than 0.053% (i.e. 0.08% of diet x 66.1% of
grapefruit = 0.053%) of the total diet for the highest consumers of
grapefruit, 25-30 year-old men.
For estimating the dietary consumption of swine and poultry
products, EPA's Total Diet Study reveals that 25-30 year-old men have
the highest consumption of pork (39.5 grams/day) and poultry (chicken
plus turkey; 28.7 grams/day). (Gram servings of pork, chicken and
turkey kidneys and livers were not included). While 60-65 year old men
have the highest consumption of eggs, the 25-30 year-old men have the
second highest consumption rate (31 grams/day). Total consumption of
pork, poultry and eggs accounts for 3.23% of the diet of 25-20 year-old
men. In comparison, the same commodities comprise 3.1% of the diet of 2
year-old children, 2.7 % for females 14-16 years-old, 2.9% for males
14-16 years-old and 2.8% for 25-30 year-old women.
For conducting a dietary risk assessment and to provide
conservative estimates: (1) the total consumption of fruit has been
adjusted up from an estimated 4.3 grams to 5 grams grapefruit consumed
per day (2); total
[[Page 40277]]
residues of arsanilic acid in or on whole fruit are considered to be
0.5 ppm, based on the proposed temporary tolerance for total residues
of Pro-Gen(r) in or on treated grapefruit (3); the total consumption of
pork, poultry and eggs has been adjusted from the estimated 39.5 grams/
day to 40 grams/day; and (4) total FDA allowed residues of arsanilic
acid in pork or poultry products (with the exception of kidneys and
liver) is 1.45 ppm. Since the estimated gram quantities of pork and
poultry organ meats (kidneys and livers) were not provided using the
estimated daily consumption of 2.8 g beef liver provides an extremely
conservative estimate for pork and poultry livers with FDA allowed
arsanilic acid residues of 5.8 ppm.
If it is assumed that all grapefruit in Florida are treated with
Pro-Gen(r), which results in total arsanilic acid residue levels of 0.5
ppm in fruit, and a 70 kg adult consumes 5 grams of grapefruit per day
of which 66.1% is from Florida, then the total dietary intake per day
can be calculated as follows:
5 grams/day grapefruit consumed = 0.005 kg/day grapefruit consumed
0.005 kg/day grapefruit x 0.661 = 0.00331 kg/day Florida fresh
market grapefruit consumed
Total residues of 0.5 ppm arsanilic acid = 0.5 mg total arsanilic
acid residues /kg food
(Amount of Florida fruit consumed) x (residue level) = 0.00331 kg
fruit/day x 0.5 mg total arsanilic acid residues /kg fruit = 0.00166 mg
total arsanilic acid/day in grapefruit
If it is assumed that all swine and poultry received arsanilic
acid-treated, then the total dietary intake per day of arsanilic acid
from pork and poultry products except organ meats, can be calculated as
follows:
40 grams/day pork, poultry and eggs consumed = 0.04 kg/day animal
products consumed
X total residues of 1.45 ppm arsanilic acid = 1.45 mg total
arsanilic acid residues /kg food
(Amount of pork, poultry and eggs consumed) x (residue level) =
0.04 kg/day x 1.45 mg total arsanilic acid residues /kg food = 0.058 mg
total arsanilic acid/day in pork, poultry and eggs.
If it is assumed that all swine and poultry received arsanilic
acid-treated, then the total dietary intake per day of arsanilic acid
from pork and poultry kidneys and liver can be calculated as follows:
2.8 grams/day pork and poultry organs consumed = 0.0028 kg/day
organs consumed
Total residues of 5.8 ppm arsanilic acid = 5.8 mg total arsanilic
acid residues /kg food
(Amount of kidneys and liver consumed) x (residue level) = 0.0028
kg total arsanilic acid /day x 5.8 mg/kg = 0.016 mg total arsanilic
acid/day in pork and poultry kidneys and liver.
Total dietary intake of total arsanilic acid = 0.00166 + 0.058 +
0.016 = 0.07566 mg total arsanilic acid residues per day
This estimate of total dietary intake represents only 14% of the
allowable daily consumption of 0.525 mg arsanilic acid/day for a 70 kg
adult, established by a NOEL of 25 ppm and an ADI of 0.0075 mg/kg/day.
The estimated dietary intake of total arsanilic acid residues from Pro-
Gen(r)-treated fresh market grapefruit is only 0.03% of the ADI of
0.0075 mg/kg/day.
Infants and children. Based on EPA's total diet survey, sensitive
populations, such as infants, have little or no intake of grapefruit or
grapefruit juice. Therefore, the proposed use of Pro-Gen(r) on Florida
grapefruit will pose no additional risk of adverse effects to infants
or children beyond that which already exists from consumption of
poultry and swine products from animals medicinally treated with
arsanilic acid. Even so, it is appropriate to consider the results of
the developmental, reproductive, and chronic studies. The available
data clearly show that there is no increased risk to neonates or young
when arsanilic acid is ingested. Therefore, Fleming Laboratories
concludes that
An additional safety factor for the protection of infants and
children is not needed and
The ADI or RfD of 0.0075 mg/kg/day is appropriate for assessing
arsanilic acid risks to infants and children.
G. International Tolerances
The Applicant is not aware of any international tolerances or Codes
Maximum Residue Limits (MRLs) for arsanilic acid on any crop or
livestock commodities. (Cynthia Giles-Parker)
2. ICI Surfactants
PP 8E4965
EPA has received a pesticide petition (PP 8E4965) from ICI
Surfactants, 3411 Silverside Road, Wilmington, DE, proposing pursuant
to section 408(d) of the Federal Food, Drug, and Cosmetic Act, 21
U.S.C. 346a(d), to amend 40 CFR 180.1001(c) and (e) to establish an
exemption from the requirement of a tolerance for oxirane, methyl-,
polymer with oxirane, mono[2-(2-butoxyethoxy)ethyl]ether (CAS Registry
No. 85637-75-8) when used as an inert ingredient in pesticide
formulations applied to growing crops or to raw agricultural
commodities after harvest or to animals. EPA has determined that the
petition contains data or information regarding the elements set forth
in section 408(d)(2) of the FFDCA; however, EPA has not fully evaluated
the sufficiency of the submitted data at this time or whether the data
supports granting of the petition. Additional data may be needed before
EPA rules on the petition.
A. Residue Chemistry
Magnitude of residues. No residue chemistry data or environmental
fate data are presented in the petition as the Agency does not
generally require some or all of the listed studies to rule on the
exemption from the requirement of a tolerance for an inert ingredient.
B. Toxicological Profile
1. Acute toxicity. ICI believes sufficient information was
submitted in the petition to assess the hazards of oxirane, methyl-
,polymer with oxirane, mono[2-(2-butoxyethoxy)ethyl]ether. No
toxicology data were presented in the petition as the Agency does not
generally require some or all of the listed studies to rule on the
exemption from the requirement of a tolerance for an inert ingredient.
Based on this polymer conforming to the definition of a polymer and
meeting the criteria of a polymer under 40 CFR 723.250 ICI believes
there are no concerns for risks associated with toxicity.
2. Endocrine disruption. ICI has no information to suggest that
oxirane, methyl-, polymer with oxirane, mono[2-(2-
butoxyethoxy)ethyl]ether will have an effect on the immune and
endocrine systems. EPA is not requiring information on the endocrine
effects of this substance at this time; Congress has allowed 3-years
after August 3, 1996, for the Agency to implement a screening program
with respect to endocrine effects.
C. Cumulative Effects
ICI believes sufficient information was submitted in the petition
to assess the hazards of oxirane, methyl-,polymer with oxirane, mono[2-
(2-butoxyethoxy)ethyl]ether. Based on this polymer conforming to the
definition of a polymer and meeting the criteria of a polymer under 40
CFR 723.250 ICI believes there are no concerns for risks associated
with cumulative effects.
D. Safety Determination
1. U.S. population. ICI believes sufficient information was
submitted in
[[Page 40278]]
the petition to assess the hazards of oxirane, methyl-,polymer with
oxirane, mono[2-(2-butoxyethoxy)ethyl]ether. Based on this polymer
conforming to the definition of a polymer and meeting the criteria of a
polymer under 40 CFR 723.250 ICI believes there are no concerns for
risks associated with any potential exposure to adults.
2. Infants and children. ICI believes sufficient information was
submitted in the petition to assess the hazards of oxirane, methyl-
,polymer with oxirane, mono[2-(2-butoxyethoxy)ethyl]ether. Based on
this polymer conforming to the definition of a polymer and meeting the
criteria of a polymer under 40 CFR 723.250 ICI believes there are no
concerns for risks associated with any potential exposure to infants
and children. (Bipin Gandhi)
3. KIM-C1, LLC
PP 7G4906
EPA has received a pesticide petition (PP 7G4906) from KIM-C1, LLC,
6333 East Liberty Avenue, Fresno, CA 93727 proposing pursuant to
section 408(d) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C.
346a(d), to amend 40 CFR part 180 by establishing a tolerance for
residues of N-(2-chloro-4-pyridinyl)-N-phenylurea in or on the raw
agricultural commodities grape, kiwi, almond, apple, blueberries,
cranberries, figs, plums, pears, and olives at 0.01 parts per million
(ppm). EPA has determined that the petition contains data or
information regarding the elements set forth in section 408(d)(2) of
the FFDCA; however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data supports granting of
the petition. Additional data may be needed before EPA rules on the
petition.
A. Residue Chemistry
1. Plant metabolism. The qualitative nature of the residues of CPPU
in almonds, apples, blueberries, cranberries, figs, grapes, kiwis,
olives, pears and plums are adequately understood. Three 14C
radiolabeled plant metabolism studies conducted in apples, grapes and
kiwis shows CPPU leaves the same residue pattern in all three crops,
representing three unrelated botanical species. These studies show that
the residue is in the low parts per billion (ppb) range at harvest and
that the residue is primarily associated with the skin. CPPU does not
translocate any significant distance in the plant, not moving from the
leaves to the fruit nor from the fruit to the leaves. The use level of
10 to 20 grams of CPPU per acre assures that only low residues will
occur. Residue analysis on grapes and kiwis confirm the radiolabel
findings. In grapes and kiwis the residue level was below the level of
quantification (LOQ) in all cases and generally below the level of
validated detection. The LOQ in whole grape was 0.01 ppm; the level of
detection (LOD) was 0.003 ppm. In grape juice, the LOQ was 0.002 ppm
and the LOD was 0.0007 ppm (0.7 ppb). In raisins the LOQ was 0.01 ppm
and the LOD was 0.003 ppm.
2. Analytical method. The analytical method extracted the parent
material and analyzed it using HPLC analysis with UV fluorescence at
wavelength 265 nm.
3. Magnitude of residues. The magnitude of the residues in the
crops are anticipated to be below the level of quantification which,
based on whole fruit, will be 0.01 ppm.
B. Toxicological Profile
1. Acute toxicity. Based on EPA criteria, CPPU would be placed in
EPA toxicity Category III generally, while the dermal irritation
results would be placed in EPA Category IV.
------------------------------------------------------------------------
------------------------------------------------------------------------
Acute Oral 81-1 LD50 4.9 gr/kg
Acute Dermal 81-2 LD50 >2000 mg/kg
Acute Inhalation 81-3 LC50 >3.0 mg/l (the
higest conc achievable)
Eye Irritation 81-4 Mildly irritating; No
corneal or iridial
irritation noted
Dermal Irritation 81-5 Non-irritating
Skin Sensitization 81-6 Non-sensitizing
------------------------------------------------------------------------
2. Genotoxicity. The results from a battery of three genetic
toxicity tests with CPPU show that this compound is not mutagenic or
genotoxic.
Gene mutation - Ames: Slightly Positive
In-vivo structural chromosomal aberration assay: Negative
In-vivo micronucleus aberration assay: Negative
3. Reproductive and developmental toxicity. Results of these
studies indicate that CPPU is not a reproductive toxicant,
developmental toxicant, or a teratogen.
Teratology in rats: NOAEL (maternal) = 100 mg/kg/day; no observed
adverse effect level (NOAEL) (fetal/development) = 200 mg/kg/day
Teratology in rabbits: NOAEL (maternal) = 25 mg/kg/day; NOAEL
(fetal/development) = 100 mg/kg/day
2-Generation reproduction in rats: NOAEL (parental) = 150 ppm;
NOAEL (reproductive) = 2,000 ppm (115 mg/kg/day - males) (205 mg/kg/day
- females).
4. Subchronic toxicity. No treatment-related adverse effects were
noted in subchronic toxicity studies at the highest doses tested.
28 - Day dietary in rats: NOEL 1,000 ppm
13 - Week dietary in rats: NOEL 200 ppm
28 - Day dietary in dogs: NOEL 2,500 ppm
13 - Week Dietary in dogs: NOAEL 500 ppm 13 - Week dietary in mice:
NOAEL 3,500 ppm.
5. Chronic toxicity 1-year chronic toxicity in dogs: not required
for EUP; Test initiated.
18 -month chronic toxicity and carconogeniscity in mice: not
required for EUP will be initiated section 3 reg.
24-month chronic toxicity and carcinogenicity in rats: NOAEL 150
ppm (8 mg/kg/day); NOAEL 7,500 ppm (435 mg/kg/day). #
6. Animal metabolism. Study will be completed prior to section 3
registration requirement. (Not required for an Experiment Use Permit.)
7. Metabolite toxicology. Metabolites occur at levels below 0.1 ppm
and therefore are below levels required to be assayed in animal
testing. The 14C radiolabel plant studies show metabolites
to be glucosides of the parent material.
8. Endocrine disruption. Collective weights and histopathological
findings from the 2-generation rat reproductive study, as well as from
the subchronic
[[Page 40279]]
and chronic toxicity studies in two or more animal species, demonstrate
no apparent effects on the endocrine system. There is no information
available which suggests that CPPU would be associated with endocrine
effects.
C. Aggregate Exposure
1. Dietary exposure--Food. A reference dose (RfD) was calculated
using the most sensitive species data available from the toxicological
testing. This RfD 0.08 mg/kg/day/based on a temporary tolerance of 0.01
ppm, was used to calculate the impact of the estimated residue levels
with results from treatment of the indicated crops. The table below
shows the Theoretical Maximum Residue Concentrations (TMRC) of CPPU on
or in the listed crops requested in this EUP request.
Theoretical Maximum Residue Concentrations for CPPU for the crops
listed in the EUP request.
----------------------------------------------------------------------------------------------------------------
Total Exposure
All-Apples All+Apples -------------------------------------
mg/kg body wt/day Percent of RfD
----------------------------------------------------------------------------------------------------------------
General U.S. Populations, all
seasons............................ 0.000005 0.000011 0.000016 0.02
Non-nursing infants................. 0.000029 0.000064 0.000093 0.12
Children 1 to 6-years of age........ 0.000010 0.000048 0.000058 0.07
Children 7 to 12-years of age....... 0.000005 0.000017 0.000022 0.03
----------------------------------------------------------------------------------------------------------------
The anticipated use rate of 17 grams of CPPU per acre applied once
per year yielding residue levels in the very low ppb range indicates
that less than 1% of the reference dose would be consumed in aggregate
with all of these crops. The crop contributing greatest to the percent
of the reference dose related to the most sensitive of the population
i.e. all nursing infants (less than 1-year old), non-nursing infants
(less than 1-year old), children (1 to 6 years old) would represent 1/
10th of 1% of the reference dose. Making the same risk exposure
calculations, it is shown that no significant impact on reducing the
RfD by using blueberries, cranberries, cranberry juice, grapes-raisins,
pears, pears dried, cherries, cherries dried, cherry juice, plums
(Damsons), plums as prunes (dried), plum/prune juice, figs, kiwifruit,
grapes-wine and sherry, cranberry juice concentrate, pear nectar in
aggregate. Combining the RfD consumption from the large group of crops
with that of the apples would exceed 1% of the reference dose only
slightly if the total acreage of all of these crops were treated. The
intention of this experimental use permit is not to treat all of the
various crops listed; the table below shows the requested acreage of
each crop.
------------------------------------------------------------------------
Acreage % Total
Crop Requested Acreage
------------------------------------------------------------------------
Grape 3,500 0.53
Kiwi 1,000 14.08
Almond 50 0.01
Apple 50 0.14
Blueberries 50
Cranberries 50
Figs 50 0.40
Plums 50 0.03
Pears 50 0.15
Olives 50 0.05
------------------------------------------------------------------------
This program would permit development of requisite data to assure
safe and efficacious use and, yet, not subject any segment of the
public to a health risk.
2. Dietary exposure - drinking water. The very low use rate of CPPU
i.e. 17 grams or less per acre, if used constantly for 20-years, would
apply only 3/4 of a pound of CPPU per acre during that 20-year period.
Computer modeling, using the conservative pesticide root zone model
(PRZM) means of analysis has shown that no CPPU would reach ground
water, even in sandy loam soils. The results of this risk analysis
supported an unambiguous conclusion of ``essentially zero risk to
ground water'' even under reasonable worst case assumptions.
Concentrations are not predicted to exceed 15 to 20 ppb of CPPU in the
soil in the upper soil horizons, even following yearly applications for
as long as 30 years. No secondary exposure is anticipated as a result
of contamination of drinking water.
3. Non-dietary exposure. No non-dietary exposure is expected since
CPPU is not anticipated to be found in the drinking water. It does not
translocate in plants and thus secondary exposure through plants
growing in soil receiving CPPU is not anticipated. The extremely low
application rates will not result in significant buildup in the
environment.
D. Cumulative Effects
There are no cumulative effects expected since CPPU is not taken up
by plants from the soil. It slowly degrades to mineral end points. Its
low use rate is not conducive to buildup in the environment.
E. Safety Determination
1. U.S. population. As pointed out above in dietary exposure-food
the percentage of the reference dose consumed by treating the subject
crops represents only slightly more than 1% of the estimated safe level
for the most sensitive segment of the population, non-nursing infants.
2. Infants and children. No developmental, reproductive or
fetotoxic effects have been associated with CPPU. The calculation of
safety margins with respect to these segments of the population were
taken into consideration in the TMRC estimates with respect to the risk
associated with the percentage of the reference dose being consumed.
F. International Tolerances
There is no Codex maximum residue level established for CPPU.
However, CPPU is registered for use on grapes and other crops in Japan,
Chile, Mexico, and South Africa. (Cynthia Giles-Parker)
[FR Doc. 98-20145 Filed 7-27-98; 8:45 am]
BILLING CODE 6560-50-F