Document ID: EPA-HQ-OPP-2010-0268-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-06-23T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE

PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: James Tompkins, 703-305-5697

Bayer CropScience LLC

PP# 9F7678

The EPA has received a pesticide petition (9F7678) from Bayer
CropScience LLC, 2 T. W. Alexander Drive, Research Triangle Park, NC
27709 proposing, pursuant to section 408(d) of the Federal Food, Drug,
and Cosmetic Act (FFDCA), 21 U.S.C.346a(d), to amend 40 CFR part 180. by
revising tolerances for residues of the herbicide, bromoxynil including
its metabolites and degradates. Compliance with the tolerance levels
specified is to be determined by measuring residues of bromoxynil
(3,5-dibromo-4-hydroxybenzonitrile) in or on the raw agricultural
commodities [sorghum, grain] at [0.2] parts per million (ppm); [grass,
hay] at [5.0] ppm; and [grass, forage] at [18] 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 residue chemistry database for bromoxynil is
current

and complete and adequate to describe the nature and magnitude of
residues for use in assessing

the human dietary exposure. Residue chemistry data supporting
registration of the end use

product (Huskie Herbicide) are listed in the completed EPA Data Matrix
form accompanying

this petition. HUSKIE is a mixture of pyrasulfotole, bromoxynil, and the
safener mefenpyrdiethyl. A summary of the bromoxynil data follows.

The nature of bromoxynil residues in plants and livestock is adequately
understood. The

residue of concern is bromoxynil (3,5-dibromo-4-hydroxybenzonitrile).

2. Analytical method. Since bromoxynil already has tolerances on

sorghum and grass commodities adequate analytical methods are in place
to support the

desired uses.

3. Magnitude of residues. Twelve field trials were conducted to measure

the magnitude of total bromoxynil residues in/on sorghum forage, grain,
and stover

following two foliar spray applications of HUSKIE herbicide to sorghum.
Residues of

bromoxynil were quantified in the harvested matrices (sorghum grain,
forage and stover)

following the postemergence applications of Huskie Herbicide.

The HAFT bromoxynil residue in sorghum forage harvested at a 0-day PHI
was

25 ppm (maximum residue 27 ppm). The HAFT bromoxynil residue in sorghum
forage

harvested at a target 7-day PHI was 0.58 ppm (maximum residue 0.61 ppm).
The HAFT

bromoxynil residue in sorghum forage harvested at ECH was 0.30 ppm
(maximum

residue 0.31 ppm).

The HAFT bromoxynil residue in sorghum grain was 0.10 ppm (maximum

residue 0.11 ppm). The HAFT bromoxynil residue in sorghum stover was
0.10 ppm

(maximum residue 0.11 ppm). The bromoxynil residue decreased with time
in the

sorghum forage but not in sorghum stover. The decline of bromoxynil
residue with time

in sorghum grain could not be assessed due to residue levels below the
LOQ.

Twelve field trials were conducted to measure the magnitude of
bromoxynil

residues in/on grass forage and hay following two foliar spray
applications of HUSKIE

herbicide to grass. Residues of bromoxynil were quantified in the
harvested matrices

(grass forage and hay) following the postemergence applications of
Huskie Herbicide.

The HAFT bromoxynil residue in grass forage harvested at a 0-day PHI was
37

ppm (maximum residue 38 ppm). The HAFT bromoxynil residue in grass
forage

harvested at a target 7-day PHI was 14 ppm (maximum residue 14 ppm). The
HAFT

bromoxynil residue in grass hay harvested at a target 30-day PHI was 2.1
ppm (maximum

residue 2.3 ppm).

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). Therefore,
bromoxynil (phenol)

and DBHA are 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 (NOAEL) and
lowest-observedadverse-

effect level (LOAEL) are 12.5 and 40 mg/kg/day respectively. The

developmental NOAEL and LOAEL 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 associated 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 NOAEL and LOAEL are 5.0 and 15
mg/kg/day,

respectively. The fetotoxicity and developmental NOAEL and LOAEL 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 NOAEL and LOAEL are 5 and 15
mg/kg/day,

respectively. The developmental NOAEL and LOAEL are 5 and 15 mg/kg/day,

respectively. This study was classified as unacceptable, primarily due
to reporting

deficiencies. 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 NOAEL

and LOAEL are 15 and 30 mg/kg/day, respectively. The developmental NOAEL
and

LOAEL 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 fetotoxicity 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 NOAEL
and LOAEL

are 11 and 32 mg/kg/day respectively. The developmental NOAEL and LOAEL
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 NOAEL is 4 mg/kg/day and the LOAEL is
21 mg/kg/day.

The reproductive NOAEL is 21 mg/kg/day, and the LOAEL is greater than 21

mg/kg/day. The postnatal developmental NOAEL is 4 mg/kg/day, and the
LOAEL 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 NOAEL is 1.5 mg/kg/day, and the LOAEL is 5 mg/kg/day. The
reproductive NOAEL

is 15 mg/kg/day, and the LOAEL is greater than 15 mg/kg/day. The
offspring

developmental NOAEL is 5 mg/kg/day and the LOAEL 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 NOAEL 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 NOAEL 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 NOAEL 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 NOAEL 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 NOAEL

was determined and the LOEL is 1 mg/kg/day based on decreased body
weight gain. For

females, the NOAEL is 1 mg/kg/day and the NOAEL 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 NOAEL
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

NOAEL/LOAEL 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 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 (NOAEL) for systemic toxicity is 2.6
mg/kg/day, and the

lowest-observable-adverse-effect-level (LOAEL) is 8.2 mg/kg/day. In
females, the

NOAEL is 3.3 mg/kg/day, and the LOAEL 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 NOAEL 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, 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.
Therefore, 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 NOAEL
and LOAEL

for this study were 250 and >250 mg/kg/day, respectively.

C. Aggregate Exposure

Assessments were conducted to evaluate potential risks due to chronic
and acute dietary

exposure of the U.S. population and selected population subgroups to
residues of

bromoxynil. These assessments included current and proposed uses of
bromoxynil

including the increased use rates on sorghum and grass grown for seed.

Exponent Inc.'s Dietary Exposure Evaluation Model (DEEM-FCID, Version
2.14),

which is licensed to Bayer, was used to estimate the chronic and acute
dietary exposure.

This software uses the food consumption data from the 1994-1998 USDA
Continuing

Surveys of Food Intake by Individuals (CSFII 1994-1998).

The aRfD for the general U.S. population, including infants and
children, was 0.08

mg/kg/day based on a NOAEL of 8 mg/kg/day and an uncertainty factor of
100. The

aRfD for Females 13-49 was 0.004 mg/kg/day based on a NOAEL of 4
mg/kg/day and an

uncertainty factor of 1000. The cRfD was 0.015 mg/kg/day based on a
NOAEL of 1.5

mg/kg/day and an uncertainty factor of 100. The cancer assessment was
based on a Q*

of 0.103 (mg/kg/day)-1.

i. Dietary (food and water) exposure. For the purpose of estimating the
potential

human dietary exposure resulting from bromoxynil use on sorghum and
grass grown for

seed in addition to all current uses under the existing tolerances,
anticipated residues of

bromoxynil were used for all crops except cotton where anticipated
residues of

bromoxynil and DBHA were used. Based on the use of these exposure data
and the above

reference doses the acute exposure was equivalent to approximately 3.7%
of the acute

reference dose (food and water) for the US Population and 48.6% of the
aPAD for

females 13-49. The chronic cancer risk of bromoxynil, i.e., the
upper-bound human risk

estimate for the general (U.S.) population represented by all sources of
bromoxynil

exposure is approximately 2.8 x 10-6 (food and water). Water exposure is
based on the

USEPA-derived acute EDWC of 12.3 ppb and chronic EDWC of 0.24 ppb.

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 acute reference doses for
bromoxynil (0.08

mg/kg/day for the US Population) and a chronic RfD for bromoxynil of
0.015 mg/kg/day

the total bromoxynil exposure (food and water) was equal to 3.7% of the
acute RfD and

0.2% of the chronic RfD for the US Population. The cancer risk for the
US Population is

2.8 x 10-6. Therefore, the dietary exposure estimates are below EPA's
level of concern

for the overall U.S. population.

2. Females 13-49. Using the acute bromoxynil reference dose for females
13-49

of 0.004 mg/kg/day and a chronic RfD for bromoxynil of 0.015 mg/kg/day
the total

bromoxynil exposure (food and water) was equal to 48.9% of the acute RfD
and 0.1% of

the chronic RfD for Females 13-49. Therefore, the acute and chronic
dietary exposure

estimates are below EPA's level of concern for Females 13-49.

3. Infants and children. To estimate dietary risk for other population
subgroups

(i.e., infants and children) an acute reference dose of 0.08 mg/kg/day
and a chronic

reference dose of 0.015 mg/kg/day were used. 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

NOAELs and LOAELs were comparable indicating no increase susceptibility
of

developing organisms. No evidence of endocrine effects was 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. Dietary assessment based
on the above

acute and chronic reference doses resulted in total exposure (food and
water) equal to

8.6% of the acute RfD (Infants) and 0.6% of the chronic reference dose
(Children 1-2) for

the most exposed population subgroup.

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.