[Federal Register Volume 60, Number 60 (Wednesday, March 29, 1995)]
[Proposed Rules]
[Pages 16111-16114]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-7714]
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
[PP 3F4233/P609; FRL-4944-7]
RIN 2070-AC18
Bromoxynil; Pesticide Tolerance
Agency: Environmental Protection Agency (EPA).
ACTION: Proposed rule.
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SUMMARY: This document proposes a tolerance for residues of the
herbicide bromoxynil (3,5-dibromo-4-hydroxybenzonitrile), resulting
from the application of its octanoic and heptanoic acid esters. The
proposal would amend the tolerance in or on the raw agricultural
commodity (RAC) cottonseed (transgenic BXN varieties only) at 0.04 part
per million (ppm). Rhone-Poulenc AG Co. submitted petitions requesting
EPA to establish the maximum permissible residue of the herbicide in or
on transgenic cottonseed.
DATES: Written comments, identified by the document control number, [PP
3F4233/P609], must be received on or before April 28, 1995.
ADDRESSES: By mail, submit comments to: Public Docket and Freedom of
Information Section, 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 Hwy., Arlington, VA 22202.
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). Information so marked 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 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: By mail: Robert J. Taylor, Product
Manager (PM) 25, Registration Division (7505C), Environmental
Protection Agency, 401 M. St., SW., Washington, DC 20460. Office
location and telephone number: Rm., 241, CM #2, 1921 Jefferson Davis
Hwy., Arlington, VA 22202, (703)-305-6800; e-mail:
Taylor.Robert@epamail.epa.gov.
SUPPLEMENTARY INFORMATION: EPA issued a notice, published in the
Federal Register of October 21, 1993 (58 FR 54354), announcing that the
Rhone-Poulenc AG Co., P.O. Box 12014, 2 T.W. Alexander Drive, Research
Triangle Park, NC 27709, had submitted a pesticide petition, PP 3F4233,
to EPA proposing to amend 40 CFR 180.324 by establishing a regulation
to permit the residues of the herbicide bromoxynil (3,5-dibromo-4-
hydroxybenzonitrile) resulting from the application of its octanoic and
heptanoic acid esters in or on the raw agricultural commodity (RAC)
transgenic cottonseed at 0.04 ppm. There were no comments or requests
for referral to an advisory committee received in response to the
notice of filing.
The data submitted in the petition and other relevant material have
been evaluated. The toxicology data listed below were considered in
support of this tolerance. Based on bridging studies, the Agency has
determined that bromoxynil octanoate and bromoxynil heptanoate are
toxicologically equivalent. For this reason, studies using the
bromoxynil phenol are accepted in fulfillment of studies required for
bromoxynil octanoate and bromoxynil heptanoate.
Phenol technical-grade bromoxynil
1. Several acute toxicology studies were performed, placing
technical-grade bromoxynil in toxicity Category II.
2. An acute oral toxicity study in rats resulted in LD50 = 81
mg/kg (males) and LD50 = 93 mg/kg (females).
3. A 2-year combined feeding/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 lowest-effect-level (LEL) is 11.0 mg/kg/day. This
study did not demonstrate any increase in tumor incidences in either
male or female rats. This study has not been considered by the RfD
committee. The RfD was set based on the NOEL from the supplementary rat
study (see item #4).
4. 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. This study is considered
supplementary. The RfD is based on this study and an uncertainty factor
of 300 rather than 100 was used since the study is supplementary.
5. A 1-year oral study was conducted with dogs administered
bromoxynil phenol at dose levels of 0, 0.1, 0.3, 1.5, or 7.5 mg/kg/day
in capsules. The NOEL is 0.3 mg/kg/day and the LEL is 1.5 mg/kg/day in
both males and females.
6. 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 13-mg/kg/day dose
level. Increased relative liver weights [[Page 16112]] were also
observed. In females, increased absolute liver weights and relative
liver and kidney weights were observed. The study was considered
negative for carcinogenicity for females.
7. A developmental toxicity study was conducted with rats
administered (orally) bromoxynil phenol at dose levels of 0, 4, 12.5,
or 40 mg/kg/day. The maternal NOEL and LEL are 12.5 mg/kg/day and 40
mg/kg/day, respectively. The developmental NOEL and LEL are 4 mg/kg/day
and 12.5 mg/kg/day, respectively.
8. A developmental toxicity 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 mg/kg/day and 15 mg/kg/
day, respectively. The fetotoxicity and developmental NOEL and LEL are
less than 5 mg/kg/day and 5 mg/kg/day, respectively.
9. A developmental toxicity 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 is 5 mg/kg/day and 15 mg/kg/
day, respectively. The developmental NOEL and LEL are 5 mg/kg/day and
15 mg/kg/day, respectively.
10. A developmental toxicity 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 mg/kg/day and 30 mg/kg/
day, respectively. The developmental NOEL and LEL are less than 15 mg/
kg/day and 15 mg/kg/day, respectively.
11. A developmental toxicity study was conducted with mice
administered (orally) bromoxynil phenol at dose levels of 0, 11, 32, or
96 mg/kg/day. The maternal NOEL and LEL are 11 mg/kg/day and 32 mg/kg/
day, respectively. The developmental NOEL and LEL are 32 mg/kg/day and
96 mg/kg/day, respectively.
12. 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.
13. 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 adult rat NOEL is 1.5 mg/kg/day (tentative),
and the LEL is 5 mg/kg/day (tentative). 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.
14. Mutagenicity data included 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
Ames study Salmonella typhimurium (negative with and without
activation).
Heptanoate technical-grade bromoxynil
1. Several acute toxicology studies were performed, placing
technical-grade bromoxynil in toxicity Category II.
2. An acute oral toxicity study in rats resulted in LD50 = 362
mg/kg (males) and LD50 = 292 mg/kg (females).
3. A general metabolism study was conducted with rats, and the
results were similar when a single low dose (2 mg/kg), a single high
dose (20 mg/kg) or a low dose (2 mg/kg/day) administered for 14
consecutive days were administered. Bromoxynil heptanoate is rapidly
absorbed and widely distributed in most tissues. The highest
concentrations were found in the blood, plasma, liver, kidney, and
thyroid. Higher tissue concentrations were found in females than in
males. Excretion was more rapid in males. Most of the radioactivity was
excreted in the urine, mostly in the form of bromoxynil phenol.
Bromoxynil phenol and bromoxynil heptanoate were present in the feces.
There was no significant retention in tissues after 7 days.
Essentially, bromoxynil heptanoate was metabolized to bromoxynil phenol
via ester hydrolysis.
Octanoate technical-grade bromoxynil
1. Several acute toxicology studies were performed, placing
technical-grade bromoxynil in toxicity Category II.
2. An acute oral toxicity study in rats resulted in LD50 = 400
mg/kg (males) and LD50 = 238 mg/kg (females).
3. A 13-week oral study was conducted with rats administered
bromoxynil octanoate at dose levels of 0, 150, 600, or 1,100 ppm (0,
11, 45, or 91 mg/kg/day in males; 0, 13, 55, or 111 mg/kg/day in
females) in the diet. This is equivalent to 0, 8, 31, or 63 mg/kg/day
in males; 0, 9, 38, or 77 mg/kg/day in females of bromoxynil phenol.
The NOEL and LEL in males are 31 mg/kg/day and 63 mg/kg/day,
respectively. In females, the NOEL and LEL are 9 mg/kg/day and 38 mg/
kg/day, respectively.
4. A developmental toxicity study was conducted with rats
administered (orally) bromoxynil octanoate at dose levels of 0, 2.4,
7.3, or 21.8 mg/kg/day. This is equivalent to 0, 1.7, 5, or 15 mg/kg/
day of bromoxynil phenol. The maternal NOEL and LEL are 5 mg/kg/day and
15 mg/kg/day, respectively. The developmental NOEL and LEL are 5 mg/kg/
day and 15 mg/kg/day, respectively.
5. Mutagenicity data included the following: the Ames study--
Salmonella typhimurium (negative with and without activation);
micronucleus assay (negative); and unscheduled DNA synthesis--rat
primary hepatocytes (negative).
Carcinogenicity Peer Review Committee/SAP
The Scientific Advisory Panel met on June 25, 1992, to review the
scientific issues regarding the Carcinogenicity Peer Review Committee's
classification of bromoxynil as a Group C carcinogen and recommended
that a low- dose extrapolation model, applied to the experimental
animal tumor data, be used for quantification (Q1*) of human risk.
The Panel felt that a Group D classification was more consistent with
the existing data base. The SAP concluded that the available data did
not provide sufficient evidence to classify bromoxynil as Group C and
recommended a Group D classification pending completion of the ongoing
mouse carcinogenicity study. The SAP further recommended that the mouse
study be extended beyond 18 months (e.g., 24 months) if survival was
adequate and that contemporary historical control data be made
available at the time of evaluation.
After the SAP meeting the Carcinogenicity Peer Review Committee met
on July 29, 1992, to further discuss and evaluate the weight-of-the-
evidence on bromoxynil with particular reference to its carcinogenic
potential. The Peer Review Committee (PRC) concluded that the
classification of bromoxynil as a Group C, possible human carcinogen,
should be maintained and recommended that for the purpose of risk
characterization the Reference Dose (RfD) methodology should be used at
this time. The PRC also placed a condition on the decision to defer
utilization of a Q1*. The condition was that additional uses
should not be granted prior to analysis of the new mouse study. The PRC
agreed that the results of the new mouse cancer study were critical to
the ultimate classification and dose-response
[[Page 16113]] assessment. Since the conditional registration involves
a new use, HED has determined that it is prudent to apply the Q1*
to existing data.
Nature of the Residue and Analytical Method
The nature of the residue in transgenic cotton is considered to be
adequately understood. The primary bromoxynil metabolite in transgenic
cotton is 3,5-dibromo-4-hydroxybenzoic acid (DBHA). DBHA is only a
major metabolite in/on bromoxynil treated transgenic cotton. For the
purposes of a time-limited tolerance, only the parent compound will be
regulated as in 40 CFR 180.324. This interim decision is based on the
minimal risk resulting from total residues of the parent and metabolite
in cottonseed contributing only about 1/1000th to the total dietary
exposure from all registered uses of bromoxynil.
Adequate methodology is available for enforcement purposes, based
upon methods for the parent compound. The method is a modified version
of Method I in the Pesticide Analytical Manual (PAM), Vol. II. The
method involves sample reflux in methanolic KOH, partitioning with
ether/hexane, concentration of the organic phase, derivatization with
diazomethane and analysis by GC. The limit of detection (LOD) for this
method is 0.02 ppm.
The nature of the residue in ruminants and poultry is considered to
be adequately understood. Any secondary residues occurring in the fat,
meat, and meat byproducts of cattle, goats, horses, poultry, and sheep
will be covered by existing tolerances.
Risk Assessment
The reference dose (RfD) (acceptable daily intake (ADI)) for
bromoxynil is calculated to be 0.02 mg/kg body weight/day based on a 2-
year rat chronic feeding study with a NOEL of 5.0 mg/kg bwt/day and a
safety factor of 300. The theoretical maximum residue contribution
(TMRC) for published tolerances is 0.450 ug/kg bwt/day or 2.25% of the
RfD for the overall U.S. population. The use on transgenic cotton would
contribute less than 0.0004 ug/kg bwt/day representing approximately 1/
1000 of the total dietary exposure to bromoxynil residue. This analysis
comparing the dietary exposure from bromoxynil to the noncarcinogenic
chronic effects results in a negligible chronic risk.
Although the new mouse study has been received, a full review by
the Agency has not been completed at this time. Therefore, an estimate
of the upper-bound carcinogenic risk has been estimated based on
published tolerances and the previously determined upper bound potency
factor (Q1* = 4.1 X 10-1 (mg/kg/day)-1). The resulting
upper-bound cancer risk was found to be 2 X 10-4. An additional
cancer risk as a result of the use of bromoxynil on transgenic BXN
cotton would be 2 X 10-7, which is incrementally insignificant.
The 10-4 risk includes the assumption that residues were present
in or on every commodity at tolerance level and that one hundred
percent of the acreage for every commodity was treated with bromoxynil.
Thus, this cancer risk should be viewed as an unrealistic ``worst
case'' estimate. The risk resulting from the use of bromoxynil on
transgenic cotton alone will be negligible.
Based on the above information cited, the Agency has determined
that the establishment of the tolerance by amending 40 CFR part 180
will protect the public health. Therefore, the tolerance is established
as set forth below.
The tolerance will expire on April 1, 1997. Based upon the
evaluation of a mouse carcinogenicity study currently under review and
submission of an analytical method, residue data and livestock
metabolism study on the metabolite, the Agency will determine whether
establishing permanent tolerances is appropriate. Residues remaining in
or on the raw agricultural commodity after expiration of this tolerance
will not be considered actionable if the pesticide is legally applied
during the term, and in accordance with the provisions of the
conditional registration.
Any person who has registered or submitted an application for
registration of a pesticide, under the Federal Insecticide, Fungicide,
and Rodenticide Act (FIFRA) as amended, which contains any of the
ingredients listed herein, may request within 30 days after publication
of this document in the Federal Register that this rulemaking proposal
be referred to an Advisory Committee in accordance with section 408(e)
of the Federal Food, Drug, and Cosmetic Act.
Interested persons are invited to submit written comments on the
proposed regulation. Comments must bear a notation indicating the
document control number [PP 8F3671/609]. 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 a.m. to 4
p.m., Monday through Friday, except legal holidays.
The Office of Management and Budget has exempted this regulation
from section 3 of Executive Order 12866.
Pursuant to requirements of the Regulatory Flexibility Act (Pub. L.
96-354, 94 Stat. 1164, 5 U.S.C. 601-612), the Administrator has
determined that regulations establishing new tolerances or raising
tolerance levels or establishing exemptions from tolerance requirements
do not have a significant economic impact on a substantial number of
small entities. A certification statement to this effect was published
in the Federal Register of May 4, 1981 (46 FR 24950).
List of Subjects in 40 CFR Part 180
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and
recordkeeping requirements.
Dated: March 23, 1995.
Daniel M. Barolo,
Director, Office of Pesticide Programs.
Therefore, it is proposed that part 180 be amended as follows:
PART 180--[AMENDED]
1. The authority citation for part 180 continues to read as
follows:
Authority: 21 U.S.C. 346a and 371.
2. In Sec. 180.324, by adding new paragraph (d), to read as
follows:
Sec. 180.324 Bromoxynil; tolerances for residues.
* * * * *
(d) Tolerances are established for residues of the herbicide
bromoxynil (3,5-dibromo-4-hydroxybenzonitrile) resulting from
application of its octanoic and heptanoic acid esters in or on the
following raw agricultural commodity:
[[Page 16114]]
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Commodity Parts per million Expiration date
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Cottonseed (transgenic 0.04.............. April 1, 1997
BXN varieties only).
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[FR Doc. 95-7714 Filed 3-28-95; 8:45 am]
BILLING CODE 6560-50-F
