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Notice of Filing of Pesticide Petition
Note: EPA no longer updates this information, but it may be useful as a reference or resource.
[Federal Register: November 26, 1997 (Volume 62, Number 228)]
[Notices]
[Page 63170-63174]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr26no97-98]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-779; FRL-5755-6]
Notice of Filing of Pesticide Petition
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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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-779, must
be received on or before December 26, 1997.
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-
docket@epamail.epa.gov. 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.,
[[Page 63171]]
Monday through Friday, excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: By mail: James Tompkins, Registration
Division (7505C) Office of Pesticide Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. Office location and
telephone number: Rm. 265, CM #2, 1921 Jefferson Davis Highway,
Arlington, VA 22202, (703) 305-7801; e-mail:
tompkins.james@epamail.epa.gov.
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-779] (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:
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. Comment 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 [PF-779] 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: November 4, 1997
James Jones,
Acting 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 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.
Rhone-Poulenc Ag Company
PP 3F4233
EPA has received a pesticide petition (PP 3F4233) from Rhone-
Poulenc Ag Company, 2 Alexander Drive, Research Triangle Park, NC
27709, 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 to extend
the current time-limited tolerances for bromoxynil and its metabolite
DBHA (3,5-dibromo-4-hydroxybenzoic acid) resulting from the application
of octanoic and heptanoic acid esters of bromoxynil to cotton in or on
the raw agricultural commodities undelinted cottonseed at 7 parts per
million (ppm), cotton gin byproducts at 50 ppm, and cotton hulls at 21
ppm for a 1-year period and to increase the current acreage limitation
from 3% to 10% of the U. S. cotton acreage (1,300,000 acres). 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 nature of the bromoxynil residue in
bromoxynil-tolerant cotton is considered to be adequately understood.
The two major components of the terminal residue are parent bromoxynil
and the metabolite 3,5-dibromo-4-hydroxybenzoic acid (DBHA).
2. Analytical method. Adequate analytical methodologies for both
parent bromoxynil and the DBHA are available for enforcement purposes.
The method involves sample reflux in methanolic KOH, partitioning with
ether/hexane and analysis by Gas Chromatography. Limits of quantitation
allow monitoring of residues in cotton commodities at or above
tolerance levels. Multiresidue testing with DBHA has been conducted and
submitted to FDA.
3. Magnitude of residues. Available magnitude of the residue data
from a 60 day phi crop field residue study conducted at a maximum
application rate of 4.5 lb active ingredient/acre indicate that the
currently established time-limited tolerances for bromoxynil and DBHA
will not be exceeded when Buctril 4EC herbicide is used according to
approved label directions.
B. Toxicological Profile
1. Acute toxicity. A complete battery of acute toxicity studies for
bromoxynil (phenol) has been conducted. The acute oral toxicity study
in rats resulted in a LD50 of 81 milligrams/kilogram (mg/kg)
(males) and a LD50 of 93 mg/kg (females). The acute dermal
toxicity study in rabbits resulted in a LD50 of >2,000 mg/kg
for both males and females. The acute inhalation study in rats resulted
in a LC50 of 0.269 milligram/liter (mg/L) for males and
0.150 for females. The primary eye irritation study showed corneal
opacity resolved within 3 days, iritis resolved within 4 days and
conjuctival irritation which persisted for 10 days. There was no
irritation in the primary dermal irritation study and the dermal
sensitization study in guinea pigs was negative.
2. Genotoxicty. Mutagenicity studies conducted include an
unscheduled DNA synthesis study-rat primary hepatocytes (negative); in
vitro transformation assay-mouse cells (negative); sister chromosomal
exchange study-CHO cells (negative); forward mutation study-mouse
lymphoma cells (negative without activation and positive with
activation); DNA repair test-E. Coli (positive); in vitro chromosomal
aberration (negative without activation and positive with activation);
two separate micronucleus assays (both negative); forward mutation-CHO
cells (negative); and Salmonella typhimurium reverse mutation assay
(negative with and without activation). Rhone-Poulenc considers
bromoxynil (phenol) and DBHA to be non-mutagenic.
3. Reproductive and developmental toxicity. A teratology study was
conducted with rats administered (orally) bromoxynil phenol at dose
levels of 0, 4, 12.5, or 40 mg/kg/day. The maternal no-observed-effect
level (NOEL) and lowest-observed-effect level
[[Page 63172]]
(LEL) are 12.5 and 40 mg/kg/day respectively. The developmental NOEL
and LEL are 4.0 and 12.5 mg/kg/day, respectively. Maternal body weights
and food consumption were reduced in the high dose group. Fetal effects
observed were reduced body weight, with associtaed decreases in
ossification. An increase in 14th ribs was observed in the mid and high
dose levels. A teratology study was conducted with rats administered
(orally) bromoxynil phenol at dose levels of 0, 5, 15, or 35 mg/kg/day.
The maternal NOEL and LEL are 5.0 and 15 mg/kg/day, respectively. The
fetotoxicity and developmental NOEL and LEL are less than 5 and 5 mg/
kg/day, respectively. Significant maternal mortality and decreased body
weight gain were associated with the high dose, indicating that the
maximum tolerance dose was exceeded. Decreases in maternal body weight
gain were also observed in the mid and low dose levels. At the mid-dose
level a statistically significant increase in the number of fetuses
with supernumerary ribs, a common fetal variant was observed. A
teratology study was conducted with rats administered (orally)
bromoxynil phenol at dose levels of 0, 1.7, 5, or 15 mg/kg/day. The
maternal NOEL and LEL are 5 and 15 mg/kg/day, respectively. The
developmental NOEL and LEL are 5 and 15 mg/kg/day, respectively. This
study was classified as unacceptable, primarily due to reporting
deficiendies. A teratology study was conducted with rabbits
administered (orally) bromoxynil phenol at dose levels of 0, 15, 30, or
60 mg/kg/day. The maternal NOEL and LEL are 15 and 30 mg/kg/day,
respectively. The developmental NOEL and LEL are less than 15 and 15
mg/kg/day, respectively. Significant body weight gain decrements were
reported at the two highest dose levels along with observed decreases
in food consumption. The severe maternal toxicity among high dose dams
was associated with fetoxicity and teratogenicity. A slight,
nonsignificant increase in supernumerary ribs was reported at the mid
and low dose levels. A teratology study was conducted with mice
administered (orally) bromoxynil phenol at dose levels of 0, 11, 32, or
96 mg/kg/day. Maternal mortality was observed at 32 and 96 mg/kg/day.
Fetal body weight was decreased at the top dose level, associated with
a decrease in caudal vertebral ossification and an increase in
supernumerary ribs. The maternal NOEL and LEL are 11 and 32 mg/kg/day
respectivel. The developmental NOEL and LEL are 32 and 96 mg/kg/day,
respectively.
A reproduction study was conducted with rats administered (orally)
bromoxynil phenol at dose levels of 0. 0.8, 4, or 21 mg/kg/day in the
diet. The systemic adult rat NOEL is 4 mg/kg/day and the LEL is 21 mg/
kg/day. The reproductive NOEL is 21 mg/kg/day, and the LEL is greater
than 21 mg/kg/day. The postnatal developmental NOEL is 4 mg/kg/day, and
the LEL is 21 mg/kg/day. Body weight gain decrements were reported.
However, no adverse effects on fertility, fecundity, reproductive
performance or pre and postnatal development were observed. A
reproduction study was conducted with rats administered (orally)
bromoxynil phenol at dose levels of 0, 1.5, 5, or 15 mg/kg/day in the
diet. The systemic rat NOEL is 1.5 mg/kg/day, and the LEL is is 5 mg/
kg/day. The reproductive NOEL is 15 mg/kg/day, and the LEL is greater
than 15 mg/kg/day. The offspring developmental NOEL is 5 mg/kg/day and
the LEL is 15 mg/kg/day. Body weight gain decrements were reported.
However, no adverse effects on fertility, fecundity, reproductive
performance or pre and postnatal development were observed.
Based on the studies discussed above, it is concluded that
bromoxynil is not teratogenic at doses that are not maternally toxic.
In addition, bromoxynil is not considered a reproductive toxicant and
shows no evidence of endocrine effects.
4. Subchronic toxicity. In a 12-week range-finding study,
bromoxynil (phenol) was administered in the diets of male and female
CD-1 mice at dose levels of 0, 1.3, 3.9, 13, 39, 130, or 390 mg/kg/day.
For male mice, the NOEL is 3.9 mg/kg/day and the LOEL is 13 mg/kg/day
based on increased liver weights and hepatocellular hypertrophy. In
female mice, the NOEL is 13 mg/kg/day and the LOEL is 39 mg/kg/day
based on increased liver weights, hepatocellular hypertrophy,
hepatocellular degeneration, and hepatocellular vacuolization. In a 13-
week subchronic feeding study, bromoxynil (phenol) was administered in
the diet to male and female Sprague-Dawley rats at dose levels of 0,
28, 58, or 168 mg/kg/day. For male rats, the NOEL is 28 mg/kg/day and
the LOEL is 58 mg/kg/day based on decreased body weight gain, increased
ALT and increased alkaline phosphatase. For female rats, no NOEL was
determined in this study and the LOEL is 35 mg/kg/day based on
decreased body weight gain. In a 13-week range-finding study,
bromoxynil (phenol) was administered orally to male and female dogs at
doses of 0, 1, 5, 8, 12, 16, 20, 30, 40, or 50 mg/kg/day. For males, no
NOEL was determined and the LOEL is 1 mg/kg/day based on decreased body
weight gain. For females, the NOEL is 1 mg/kg/day and the the LOEL is 5
mg/kg/day based on decreased body weight gain, panting and liquid
feces. In a 21 day subchronic dermal study, bromoxynil (phenol) was
applied to skin of male and female New Zealand white rabbits at doses
of 0, 30, 300, or 1,000 mg/kg/day for 6 hours/day, 5 days/week.
Treatment produced no observable dermal or systemic toxicity, therefore
the NOEL is 1,000 mg/kg/day.
5. Chronic toxicity. A 1-year oral study was conducted with dogs
administered bromoxynil (phenol) at dose levels of 0, 0.1, 0.3, 1.5,
and 7.5 mg/kg/day in capsules. The NOEL/LEL is 1.5 mg/kg/day for both
females and males based on decreased body weight gain, decreased RBC
count, decreased hemoglobin, decreased PCV, and increased liver
weights. The chronic dog study was determined by Rhone-Poulenc to be
the most appropriate study for setting the Reference Dose (RfD) of
0.015 mg/kg/day (includes a hundredfold safety factor).
A 2-year combined chronic toxicity/carcinogenicity study was
conducted with rats administered (oral) dosages of 0, 60, 190, or 600
ppm (0, 2.6, 8.2, or 28 mg/kg/day in males; 0, 3.3, 11.0, or 41 mg/kg/
day in females) bromoxynil phenol in the diet. In males the no-
observed-effect-level (NOEL) for systemic toxicity is 2.6 mg/kg/day,
and the lowest-effect-level (LEL) is 8.2 mg/kg/day. In females, the
NOEL is 3.3 mg/kg/day, and the LEL is 11.0 mg/kg/day. This study did
not demonstrate any increase in tumor incidences in either male or
female rats.
A 2-year combined feeding/carcinogenicity study was conducted with
rats administered bromoxynil phenol in the diet at dose levels of 0,
10, 30, or 100 ppm (0, 0.5, 1.5, or 5 mg/kg/day). In both males and
females, the NOEL and LOEL for systemic toxicity was 5 mg/kg/day and >5
mg/kg/day, respectively. At the highest dose tested, increased liver
weights were observed at 12 months, but not at 24 months. This study
was considered negative for carcinogenicity. An 18 month
carcinogenicity study was conducted with mice administered bromoxynil
phenol at dose levels of 0, 10, 30, or 100 ppm (0, 1.3, 3.9, or 13 mg/
kg/day) in the diet. For males, dose related increases in hyperplastic
nodules and liver adenomas/carcinomas were observed which were
statistically significant at the 100 ppm. Increased relative liver
weights were also observed. In females,
[[Page 63173]]
increased absolute liver weights and relative liver and kidney weights
were observed. The study was considered negative for carcinogenicity
for females. An 18 month carcinogenicity study was conducted with mice
administered bromoxynil phenol at dose levels of 0, 20, 75, or 300 ppm
(0, 3.1, 12 or 46 mg/kg/day in males and 0, 3.7, 14, or 53 mg/kg/day in
females). Mice given 300 ppm had significantly increased absolute and
relative liver weights. Histopathology of the liver revealed increased
hepatocellular hypertrophy, hepatocellular degeneration, necrosis of
individual hepatocytes, and pigment accumulation in hepatocytes and
Kupffer cells. Male mice had statistically significant increased
numbers of hepatocellular adenomas and carcinomas at 20 ppm, but not 75
ppm. In contrast, no significant increase in tumor incidence was
observed for female mice by pair-wise analysis. The trend test was
significant for adenomas or carcinomas in females, only at p<0.05, not
p<0.01 as would be appropriate for this type of tumor. The trend is due
entirely to the high dose group and therefore is of questionable
validity. It is concluded that bromoxynil is a weak, single sex, single
species, non-metastic, single target organ carcinogen, inducing
hepatocellular tumors in male mice exposed to 300 ppm for 18 months.
These tumors and associated histopathological findings are consistent
with secondary mechanisms such as peroxisome proliferation, a mechanism
known to have marked species differences and questionable relevance for
humans. It is the opinion of Rhone-Poulenc that the data are not
suitable for quantitative risk assessment. A threshold safety factor
approach is more appropriate and is commonly used for single sex,
single species carcinogens such as bromoxynil that are thought to work
through secondary mechanisms. For the purposes of this tolerance
petition, risk assessments have been performed using a low dose linear
extrapolation model (Q1* is 1.03 x 10-1).
6. Animal metabolism. Results of a bromoxynil metabolism study with
the rat (octanoate) demonstrated that 2 mg/kg of radiolabeled
bromoxynil octanoate was rapidly absorbed, hydrolyzed to bromoxynil
phenol, distributed, and excreted in rats following repeated oral
administration. The urine was the major route of excretion,
representing 80.24% of the administered dose in males and 67.91% in
females at 7 days post-dosing. Tissue distribution was similar for both
sexes with the highest radioactivity recovered in the liver and kidney.
Similar results were obtained in a separate rat metabolism study
conducted with bromoxynil heptanoate.
7. Metabolite toxicology. DBHA (3,5-dibromo-4-hydroxybenzoic acid)
is a major plant metabolite of bromoxynil only in bromoxynil-resistant
transgenic cotton. Acute oral toxicity testing with DBHA in rats
resulted in an LD50 of >2,000 mg/kg. Acute dermal toxicity
testing with DBHA in rabbits resulted in an LD50 of >2,000
mg/kg. The primary dermal irritation study with DBHA in rabbits
indicated DBHA to be a slight irritant, and DBHA was not a dermal
sensitizer in Guinea pigs. Mutagenicity studies conducted with DBHA
include a Salmonella typhimurium reverse mutation assay (negative with
and without activation); micronucleus assay (negative); and
TK+/- mouse lymphoma assay (negative with and without
metabolic activation). In subchronic feeding studies in the rat, DBHA
was administered by oral gavage to groups of Sprague-Dawley rats for 28
days at dose levels of 25, 50, 100 and 250 mg/kg/day. No
toxicologically meaningful changes were observed in any of the
parameters measured in this study. The NOEL and LEL for this study were
250 and >250 mg/kg/day, respectively.
C. Aggregate Exposure
1. Dietary (food) exposure. For the purpose of estimating the
potential human dietary exposure resulting from bromoxynil use on
cotton under the existing tolerances, anticipated residues of
bromoxynil and DBHA were used. Anticipated residue values of 1.44 ppm
(cottonseed), 8.74 ppm (cotton gin trash), and 0.43 ppm (cottonseed
meal) were derived by taking the mean residue values from available
crop field trials conducted at the 4.5 lb/A broadcast rate and
adjusting by a factor of 0.333 to extrapolate to the current 1.5 lb/A
application rate. Adjusting these values for % dry matter and the
proposed 10% of crop treated results in anticipated cotton feedstuff
residue values of 0.14 ppm (cottonseed), 0.87 ppm (cotton gin trash),
and 0.043 ppm (cottonseed meal). Based on the use of these exposure
data and a unit risk (Q1* (mg/kg/day)-1, of
bromoxynil of 1.03 x 10-1, the upper-bound human risk
estimate for the general (U.S.) population represented by all sources
of bromoxynil exposure, including use on up to 10% of the U.S. treated
acreage is approximately 2 x 10-6.
2. Drinking water. There is no Maximum Concentration Level or
Health Advisory Level established for bromoxynil under the Safe
Drinking Water Act. Based on field dissipation studies demonstrating a
short half-life of bromoxynil in the environment (average half-life of
3-7 days), bromoxynil residues will degrade in soil before residues can
move downward into ground water. Therefore, no significant potential
exists for bromoxynil residues to be present in drinking water from
ground water. Likewise, contamination of drinking water supplies from
bromoxynil movement through agricultural surface runoff is considered
highly unlikely due to relatively low application rates and rapid
degradation rates in soil. As demonstrated by available monitoring
data, normal dilution and degradation processes will greatly reduce
concentrations in surface water during movement from agricultural
ditches near fields into streams of adequate size for use as drinking
water. It is the conclusion of Rhone-Poulenc that the potential
bromoxynil exposure derived from any use through drinking water is
insignificant and does not significantly increase the aggregate risk
assessment above that estimated to occur through food exposure alone.
3. Non-dietary exposure. The potential for non-occupational
exposure to bromxynil among the general public is insignificant. There
are no residential lawn or garden uses for bromoxynil products where
the general population might be exposed via inhalation or dermal
routes. Turfgrass use is restricted to non-residential areas. Exposure
to bromoxynil following application to non-residential turfgrass is not
likely to be significant in either time or duration. This use will
therefore not significantly add to the aggregate exposure.
D. Cumulative Effects
There are no reliable data suggesting that any toxic effect that
might be caused by bromoxynil would be cumulative with those of any
other compound. Further, bromoxynil does not appear to produce a toxic
metabolite that is produced by other substances. Therefore,
consideration of potential cumulative effects is not appropriate at
this time.
E. Safety Determination
1. U.S. population. Using the present RfD for bromoxynil of 0.015
mg/kg/day, it has been determined that aggregate chronic exposure to
bromoxynil from all uses, including cotton, represents <1% of the RfD
for all population sub-groups. A unit risk, Q1* (mg/kg/
day)-1, of bromoxynil of 1.03 x 10-1 in human
equivalents, has been calculated based on mouse liver tumors. It is the
opinion of Rhone-Poulenc that the bromoxynil data are not suitable for
quantitative risk assessment. A threshold safety factor approach is
more appropriate and is
[[Page 63174]]
commonly used for single sex, single species carcinogens such as
bromoxynil that are thought to work through secondary mechanisms.
Nevertheless, the risk assessments filed with this petition have been
performed using quantitative risk assessment methodology. Accordingly,
the upper-bound risk estimate for the general U.S. population
represented by all sources of bromoxynil exposure, including use of
bromoxynil on up to 10% of the U.S. treated acreage is approximately 2
x 10-6.
2. Infants and children. To estimate acute dietary risk for
systemic effects other than developmental from food sources, an MOE of
270 was calculated using 1-day dietary exposure for infants (the most
highly exposed population group) and a NOEL of 8 mg/kg/day derived from
a 13-week oral toxicity study in dogs. It is concluded that reliable
data support use of the standard hundredfold margin of exposure/safety
factor in assessing the risk to children. The general U.S. population
and all population sub-groups are estimated to be exposed at a level
less than 1 percent of the bromoxynil RfD of 0.015 mg/kg/day. Both
chronic and acute assessments show no appreciable threshold risks to
children and the non-threshold cancer risk is no greater than
negligible. Therefore, there is a reasonable certainty that no harm
will result to infants and children from aggregate exposure to bromoxynil.
Two multi-generation rodent reproduction studies 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 susceptibility
of developing organisms. No evidence of endocrine effects were noted in
any study. It is therefore concluded that bromoxynil poses no
additional risk for infants and children and no additional uncertainty
factor is warranted.
F. International Tolerances
There are no Codex tolerances established for bromoxynil residues,
therefore international compatibility is not considered to be an issue
at this time.
[FR Doc. 97-30812 Filed 11-25-97; 8:45 am]
BILLING CODE 6560-50-F