ACIFLUORFEN
August, 1987
DRAFT
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health: when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs.are subject to
change as new information becomes available.
Health Advisories are developed for one-day, ten-day, longer-term
(approximately 7 years, or 10% of an individual's lifetime) and lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
-------
Acifluorfen
II. GENERAL INFORMATION AND PROPERTIES
CAS No. 5094-66-6 (acid)
62476-59-9 (sodium salt)
Structural Formula
August, 198'?
-2-
Sodium 5-(2-chloro-4-(trifluoromethyl)-phenoxy)-2-nitrobenzoate
Synonyms
6 Blazer*; Carbofluorfen; RH-6201; Tackle*; Sodium acifluorfen (Meister,
1983).
Uses
Acifluorfen is used as a selective pre- and post-emergence herbicide to
control weeds and grasses in large-seeded legumes including soybeans
and peanuts (Meister, 1983).
Properties (Windholz et al., 1983; Meister, 1983; CHEMLAB, 1985)
Chemical Formula
Molecular Weight
Physical State (25°C)
Boiling Point
Melting Point
Density
Vapor Pressure (25°C)
Specific Gravity
Water Solubility (25°C)
Log Octanol/Water Partition
Coefficient
Taste Threshold
Odor Threshold
Conversion Factor
C14H7C1F3N05 (acid)
C14H6ClF3NNa05 (sodium salt)
361.66 (acid)
383.65 (sodium salt)
Off-white solid (acid), brown crystalline
powder/white powder (sodium salt)
124-125°C (sodium salt)
151.5-157°C (acid)
>25% (sodium salt) (dimensions not
specified)
-4.85 (acid) (calculated)
Occurrence
0 No information was -found in the available literature on the occurrence
of acifluorfen.
-------
Acifluorfen August, 1987
-3-
Environmental Fate
0 Acifluorfen is stable to hydrolysis; no degradation was observed
in solutions at pH 3, 6 or 9 within a 28-day interval. Varying
temperatures (18 to 40°C) did not alter this stability. The half-life
of the parent compound is 92 hours under continuous exposure to light
approximating natural sunlight. The decarboxy derivative of acifluorfen
was the primary degradate found in solution. It is suspected that a
substantial percentage of the photodegradate parent is lost from
solution (through volatilization or other mechanisms) (Registrant
CBI data).
0 The half-life of acifluorfen in an aerobically incubated soil was
found to be about 170 days; anaerobic degradation was more rapid
(half-life about 1 month). The dominant residue compounds after
6-months aerobic incubation were the parent compound and bound
materials. After 2 months under anaerobic conditions, the acetamide
of amino acifluorfen was the major degradate extracted from soil; the
amino analog itself was also significant, and denitro acifluorfen was
also formed (Registrant CBI data).
0 Acifluorfen applied at 0.75 Ib ai/A to a silt loam in Mississippi
dissipated with a tentative half-life of 59 days. Leaching of the
parent compound below 3 inches in the soil was negl/.gihle during the
179-day study. The dissipation of acifluorfen in two silt loam soils
in Illinois receiving multi-residue treatments was somewhat slower;
half-lives were 101 to 235 days (Registrant CBI data).
0 Acifluorfen applied to soil columns at highly excessive rates indica-
tive of spills (682 Ib ai/A) is very mobile. Acifluorfen leached
from the columns with 10 inches of water accounted for 79 to 93% of
the acifluorfen applied. Aerobic aging of the residues in the column
substantially reduced the mobility and pesticide movement was inversely
proportional to the soil CEC. Results from soil TLC (un-aged residues
only) predict mobility to be intermediate to mobile. Supplementary
data from a batch adsorption study indicate that un-agad acifluorfen
is weakly and reversibly adsorbed (Registrant CBI data).
0 Greenhouse studies have demonstrated that the uptake of acifluorfen
by rotational crops decreases with aging of residues in soil (Registrant
CBI data).
III. PHARMACOKINETICS
Absorption
0 No information was found in the available literature on the absorption
of acifluorfen.
-------
Acifluorfen August, 1987
-4-
Distribution
0 No information was found in the available literature on the distribution
of acifluorfen.
Metabolism
—° No information was found in the available literature on the metabolism
of acifluorfen.
Excretion
0 No information was found in the available literature on the excretion
of acifluorfen.
IV. HEALTH EFFECTS
Humans
Short-term Exposure
0 No information was found in the available literature on the short-term
health effects of acifluorfen in humans.
Long-term Exposure
0 No information was found in the available literature on the long-term
health effects of acifluorfen in humans.
Animals
Short-term Exposure
0 The Whittaker Corporation (no date, a) reported that the oral LDso of
Tackle 2S (a formulation containing 20.2% sodium acifluorfen) in the
rat (strain not specified) was 2,025 mg/kg for males and 1,370 mg/kg
for females.
0 Meister (1983) reported that the acute dermal LD$Q of Blazer* (tech-
nical grade, purity unspecified) in the rabbit is 450 mg/kg. The
acute dermal LDso of Tackle* (purity unspecified) in the rabbit is
2,000 mg/kg.
0 Goldenthal et al. (1978a) presented the results of a two-week range-
finding study in which RH 6201 (a formulation containing 39.4% sodium
acifluorfen) was administered to Charles River CD-1 mice (10/sex/dose)
at dietary concentrations of 0, 625, 1,250, 2,500, 5,000 or 10,000
ppm. Assuming that 1 ppm in the diet of mice is equivalent to 0.15
mg/kg/day (Lehman, 1959), these doses correspond to about 0, 93.8,
187.5, 375.0, 750.0 or 1,500 mg/kg/day. No changes in general behavior
or appearance were reported at any dose level. During the second
week of the study, there was a decrease in body weight and food
-------
Acifluorfen August, 1987
f
-5. r
consumption in animals receiving 10,000 ppm (1,500 mg/kg/day). Gross
pathological findings included pale kidneys, yellowish livers and
reddish foci of hyperemia in the stomachs of several mice at the
5,000- and 10,000-ppm (750 and 1,500 mg/kg/day) dose levels. Absolute
liver weight was increased in all test groups dosed at levels of
2,500 ppm (375 mg/kg/day) or greater. The increases were statistically
significant (p <0.01). A statistically significant (p <0.01) increase
in relative liver weight was reported at all dose levels. Based on
the results of this study, a Lowest-Observed-Adverse-Effect-Level
(LOAEL) of 625 ppm (93.8 mg/kg/day) was identified.
0 Piccirillo and Robbins (1976) administered RH 6201 (a formulation
containing 39.8% sodium acifluorfen) to Wistar rats (5/sex/dose) for
4 weeks at dietary concentrations of 0, 5, 50, 500 or 5,000 ppm
(reported to be equivalent to 0, 0.7, 7.6, 55.4 or 506.4 mg/kg/day
for males and 0, 0.8, 8.3, 60.6 or 528.2 mg/kg/day for females).
Assuming that these dietary levels reflect the concentration of the
test compound and not the active ingredient, corresponding levels
of sodium acifluorfen are 0, 0.3, 3.0, 22.1 and 201.6 mg/kg/day for
males and 0, 0.3, 3.3, 24.0 and 210.2 mg/kg/day for females (Lehman,
1959). Results of the study indicated that body weight was decreased
in males at 22.1 and 201.6 mg/kg/day, and food consumption was decreased
in both males at 201.6 mg/kg/day and females at 210.2 mg/kg/day.
Biochemical analyses revealed that serum glutamic pyruvic transaminase
(SGPT) levels were increased in males at 22.1 and 201.6 mg/kg/day;
in males that received 201.6 mg/kg/day, blood urea nitrogen (BUN)
was increased and glucose levels were decreased. Changes in organ
weights included increased absolute liver and kidney weights in males
at 201.6 mg/kg/day, increased relative liver and kidney weights in
males at 201.6 mg/kg/day and females at 210.2 mg/kg/day and increased
relative liver weight in males only at 22.1 mg/kg/day. Based on the
results of this study, a No-Observed-Adverse-Effect-Level (NOAEL) of
3.0 mg/kg/day was identified.
Dermal/Ocular Effects
0 In a dermal irritation study (Whittaker Corp., no date, b). Tackle 2S
(a formulation containing 20.2% sodium acifluorfen) was applied
occlusively (dose not specified) to the intact and abraded skin of
rabbits. Effects observed included slight erythema, slight edema,
blanching of the skin, and eschar formation. Sign? of dermal
irritation at intact and abraded sites were absent by 8 days post-
application. The test substance was considered to be a moderate
dermal irritant at 72 hours.
0 In a dermal irritation study, Weatherholtz et al. (1979b) applied
RH 6201 (sodium acifluorfen) to the skin of New Zealand White rabbits
(five/sex/dose; ten/sex/control). Three different formulations of
RH 6201 were used in the study and each formulation was tested at
1.0 or 4.0 mL/kg/day. The authors indicated that for all RH 6201
formulations tested, the dose levels correspond to 50 or 200 mg/kg/day
of the active ingredient. The test material was applied once daily
for 5 days, followed by 2 days with no applications, over a 4-week
-------
Acifluorfen August, 198T
-6-
period (total of 20 applications). At both dose levels, two of
the formulations produced slight to well-defined irritation. At
200 mg/kg/day, central nervous system depression and a statistically
significant decrease in body weight gain and food consumption were
noted. The third formulation produced essentially the same effects,
with the addition of "thinness," ataxia, slight tremors and mortality
(2/5 males). Microscopic evaluations revealed chronic dermatitis,
acanthosis and hyperkeratosis at both dose levels for all formulations.
0 Madison et al. (1981) presented the results of the Buhler test for
dermal sensitization in Hartley-derived albino guinea pigs. In this
study, Tackle9 (sodium acifluorfen; purity not specified) was not found
to be a sensitizer when applied topically at a dose of 0.25 mL under
occlusive binding.
0 In an ocular irritation study (Whittaker Corp., no date, c), Tackle 2S
(a formulation containing 20.3% sodium acifluorfen) was instilled
into the eyes of rabbits. Signs of ocular irritation and lesions
included opacities of the cornea, iritis, redness and chemosis of the
conjunctiva and discharges from both washed and unwashed eyes. Four
of six unwashed eyes and one of three washed eyes exhibited blistering
of the conjunctiva. Three of six unwashed and one of three washed
eyes exhibited pannus where corneal opacity had been.
0 In an ocular irritation study (Weatherholtz et al., 1979a), 0.1 mL of
Blazer 2S (purity not specified) was applied to the corneal surface
of the eyes of rhesus monkeys. Corneal opacity and conjunctival
redness, swelling and discharge were observed in both washed and
unwashed eyes. All treated eyes were free of signs of irritation by
1 4 days posttreatment.
Long-term Exposure
0 Harris et al. (1978) administered RH 6201 (a formulation containing
39.4% sodium acifluorfen) in the diet to Sprague-Dawley rats (15/sex/
dose) for 3 months at dose levels of 0, 75, 150 or 300 mg/kg/day.
Assuming that these doses reflect levels of the test compound and not
the active ingredient, corresponding levels of sodium acifluorfen
would be 0, 29.6, 59.1 or 118.2 mg/kg/day. At the highest dose level
(118.2 mg/kg/day), a number of effects were observed in male rats.
These effects included decreased body weight (13%) and decreased food
consumption (8%). Biochemical analyses of blood revealed increased
alkaline phosphatase levels (32%), decreased total protein (8%) and
decreased albumin (14%). No such effects were reported for female
rats. (These biochemical analyses were performed on control and high-
dose animals only.) Increased liver weight and microscopic liver
changes (enlarged hepatocytes) were observed in male rats that received
59.1 or 118.2 mg/kg/day. In terms of the active ingredient, a NOAEL
of 29.6 mg/kg/day was identified.
• Barnett (1982) administered Tackle 2S (a formulation containing
20.4 to 23;6% sodium acifluorfen) to Fischer 344 rats (30/sex/dose)
for 90 days at dietary concentrations of 0, 20, 80, 320, 1,250,
-------
Acifluorfen August, 1987
-7-
2,500 or 5,000 ppm. The author indicated that these dietary levels
correspond to average compound intake levels of 0, 1.5, 6.1, 23.7,
92.5, 191.8 or 401.7 mg/kg/day for males and 0, 1.8, 7.4, 29.7,
116.0, 237.1 or 441.8 mg/kg/day for females. Assuming that these
levels reflect test compound and not active ingredient intake,
corresponding levels of sodium acifluorfen intake are approximately
0, 0.4, 1.4, 5.6, 21.8, 45.3 or 94.8 mg/kg/day for males and 0, 0.4,
1.8, 7.0, 27.4, 56.0 or 104.3 mg/kg/day for females (based on 23.6%
active ingredient in test compound). At 5,000 ppm the following
effects were observed: decreased body weight and food consumption
in both sexes; decreased red blood cell (RBC) count, hemoglobin and
hematocrit in both sexes; increased serum cholesterol and serum calcium,
and decreased serum phosphorous in both sexes; increased alkaline
phosphatase, SGPT and BUN levels in males; elevated urobilinogen in
both sexes; increased liver size and discolored liver and kidneys
in both sexes; and liver cell hypertrophy and increases in mitotic
figures and individual cell deaths in both sexes. At 2,500 ppm the
following effects were observed: decreased body weight in males;
decreased RBC count, hemoglobin and hematocrit in both sexes; increased
BUN levels in males; elevated urobilinogen in both sexes; increased
liver size in both sexes; and liver cell hypertrophy and increases
in mitotic figures and individual cell deaths in both sexes. At
1,250 ppm, the following effects were observed: increased liver
size in males and liver cell hypertrophy in both sexes> The author
identified 320 ppm as the NOAEL in this study. In terms of active
ingredient concentration, this corresponds to a NOAEL of 5.6 mg/kg/day
for males and 7.0 mg/kg/day for females.
Mobil (1981) presented the 6-month interim results of a longer-term
study in which Tackle 2S (a formulation containing approximately 75%
sodium acifluorfen) was administered to beagle dogs (eight/sex/dose)
at dietary concentrations of 0, 20, 320 or 4,500 ppm. These dietary
levels were reported to be equivalent to 0, 0.7, 9.0 or 160 mg/kg/day.
Assuming that these levels reflect test compound and not active
ingredient intake, corresponding levels of sodium acifluorfen intake
are 0, 0.5, 6.8 or 120.0 mg/kg/day (based on 75% active ingredient in
the test compound). Following six months of compound administration,
two animals/sex/dose were sacrificed. The study reported a number of
effects at the highest dose tested. These effects included decreased
body weight and food consumption and increased liver weight in both
sexes. Additionally, RBC count and hemoglobin concentration were
decreased in both sexes. Clinical chemistry analyses revealed
depressed serum cholesterol, increased alkaline phosphatase, and
transient elevation of BUN in both sexes. Males only showed increased
levels of lactic dehydrogenase. No histopathological examinations
were conducted. The NOAEL reported in this study was 320 ppm. In
terms of the active ingredient, this corresponds to a NOAEL of
6.8 mg/kg/day.
Barnett et al. (1982b) administered Tackle 2S (a formulation con-
taining 19.1 to 25.6% sodium acifluorfen) to Fischer 344 rats
(73/sex/dose) for 1 year at dietary levels of 0, 25, 150, 500, 2,500
or 5,000 ppm. Assuming that these dietary levels reflect the
-------
Acifluorfen August, 1987
-8-
concentrations of the test compound and not the active ingredient,
corresponding levels of sodium acifluorfen are 0, 6.4, 38.4,, 128.0,
640.0 or 1,280 ppm (based on 25.6% active ingredient in the test
compound). Assuming that 1 ppm in the diet of rats is equivalent to
0.05 mg/kg/day, these levels correspond approximately to 0, 0.3, 1.9,
6.4, 32.0 or 64.0 mg/kg/day (Lehman, 1959). No excess moribundity or
mortality was associated with the ingestion of the test substance.
At 5,000 ppm, the following effects were observed: decreased mean
body weight in both sexes; increased absolute and relative liver
weight in both sexes; decreased protein production, decreased serum
glucose, decreased triglyceride levels, increased alkaline phosphatase
and creatine phosphokinase levels, and sporadic increases in SCOT and
SGPT in both sexes; a slight increase in the excretion of urobilinogen
in both sexes; and the presence of acidophilic cells that were
considered to be evidence of cytotoxic changes in the livers of both
sexes. At 2,500 ppm, male rats showed increased absolute and relative
liver weights. Based on the information presented in this study, a
NOAEL of 500 ppm was identified for the test compound. In terms of
the active ingredient, this corresponds to a NOAEL of 6.4 mg/kg/day.
Spicer et al. (1983) administered Tackle 2S (a formulation containing
74.5 to 82.8% sodium acifluorfen) to beagle dogs (eight/sex/dose)
for 2 years at dietary concentrations of 0, 20, 300 or 4,500 ppm,
reported to be equivalent to 0, 0.5, 7.3 or >21 mg/kg/day for males
and 0, 0.5, 8.3 or 154 mg/kg/day for females. Assuming that these
dietary levels reflect the concentration of the test compound and not
the active ingredient, corresponding levels of sodium acifluorfen are
0, 0.4, 6.0 or 100.2 mg/kg/day for males and 0, 0.4, 6.9 or 127.5
mg/kg/day for females (based on 82.8% active ingredient in the test
compound). At the highest dose, body weight was decreased (not
statistically significant), and a corresponding (statistically sig-
nificant) decrease in food consumption was also reported. Physical
examination revealed heart anomalies in the high- and mid-dose groups.
At the high dose, irregular heart rhythms and rapid or slow heart
rates were reported in one male and four females. Also at this dose
level, one male was found to have a systolic murmur. At the mid-dose
level, one animal of each sex had an irregular heart rhythm (accompanied
by rapid heart rate in the male). At the highest dose tested, a
number of changes were reported, including a statistically significant
decrease in erythrocyte count, hemoglobin and hematocrit in both
sexes; reductions in albumin and cholesterol; increased absolute ar.-l
relative liver and kidney weights; and histopathological liver changes
including centrilobular hepatocellular fatty vacuolation, bilirubin
pigmentation and minimal foci of alteration. Renal tubules showed
bilirubin pigmentation at all dose levels (most pronounced at the
high dose). The authors concluded that this study showed clear
evidence of target organ toxicity affecting the liver and possibly
the kidney at the highest dose level. The authors identified 300 ppm
(of test compound) as the NOAEL. In terms of the active ingredient,
this corresponds to a NOAEL of 6.0 mg/kg/day.
Goldenthal (1979) administered RH 6201 (a formulation containing 39.4
to 40.5% sodium acifluorfen) to Charles River CD-1 mice (80/sex/dose)
-------
Acifluorfen August, 1987
-9-
for two years in the diet at concentrations that provided dosage
levels of 0, 1.25, 7.5 or 45.0 ppm of the active ingredient. After
16 weeks of administration, the 1.25 ppm dose was increased to 270 ppm.
Assuming that 1 ppm in the diet of mice is equivalent to 0.15 mg/kg/day,
these levels correspond to about 0, 0.19 (increased to 40.5), 1.13 and
6.8 mg/kg/day (Lehman, 1959). Two control groups were used in this
study. One group received acetone in the diet (control 1), and the
other received water in the diet (control 2). At the 40.5 mg/kg/day
dose level, the following effects were observed: slight to marked
elevations in alkaline phosphatase and SGPT levels, in both sexes,
beginning after one year of exposure; increased absolute and relative
liver weight in males; increased absolute liver weight in females;
increased relative kidney weight in males; decreased absolute heart
weight in males; cellular alterations in the livers of males consisting
of focal pigmentation, focal hepatocytic necrosis, focal cellular
alteration, nodular hepatocellular proliferation and hepatocellular
carcinoma (the only statistically significant change was the focal
cellular alteration); and focal pigmentation in the livers of females.
At the 6.8 mg/kg/day dose level, the following effects were observed:
occasional increases in alkaline phosphatase and SGPT levels in both
sexes; decreased absolute heart weight in males; and focal pigmentation
in the livers of females. The author indicated that changes with an
apparent dose-related distribution included focal pigmentation,
hepatocellular vacuolation, focal hepatocytic necrosis and nodular
hepatocellular proliferation. The- incidence of hepatocellular
carcinoma in males of all treatment groups was approximately the same.
A NOAEL of 7.5 ppm (1.13 mg/kg/day) was identified by the author.
Reproductive Effects
0 In a three-generation reproduction study, Goldenthal et al. (1978b)
administered RH 6201 (a formulation containing sodium acifluorfen) in
the diet to Charles River CD rats. During the course of the study,
the test compound was administered at various levels depending on the
age of the animals. The FI generation received dose levels of 2.9,
17.3 or 104 ppm during the first 2 weeks of the study, and 5, 30 and
180 ppm for the remaining weeks of the generation (study weeks 3 to
17) (Time-Weighted Average (TWA) dosage levels 4.8, 28.5 or 171.1 pm).
The ?2 and F$ generations received dosage levels of 180,
10 or 60 ppm during the first and second weeks of the generation;
312, 17.3 or 104 ppm during the third, fourth and fifth weeks of the
generation; and 540, 30 or 180 ppm for the remaining weeks of the
generation (TWA for ?2 generation 486.0, 27.0 or 162.0 ppm; TWA for
F3 generation 483.8, 26.7 or 161.3 ppm). The highest dietary TWA dose
tested in this study was 486 ppm of active ingredient. Assuming that
1 ppm in the diet of rats is equivalent to 0.05 mg/kg/day, this
corresponds to a dose of 24.3 mg/kg/day (Lehman, 1959). No effects
related to compound administration were observed in parents or pups
in terms of general behavior, appearance or survival. Parental and
pup body weights and food consumption were similar to controls.
Fertility, gestation and viability indices were comparable for controls
and treated groups. There were no biologically meaningful teratogenic
effects in the second or third generation, based on mean number of
-------
Acifluorfen August, 1987
-10-
viable fetuses, post-implantation losses, total implantations and
corpora lutea per dam, mean fetal body weight, number of fetal
anomalies and sex-ratio variations. No compound-related gross lesions
were noted in third-generation pups necropsied. Based on the infor-
mation presented, a NOAEL of 486 ppm (24.3 mg/kg/day) was identified.
This NOAEL represents the highest dose tested.
0 In a two-generation reproduction study, Lochry et al. (1986) admini-
stered technical grade Tackle (sodium acifluorfen) of unspecified
purity to rats at levels of 0, 25, 500 and 2,500 ppm. The compound
was administered in the diet ad libitum to groups of 35 rats/sex/dose
beginning at 47 days of age and continuing until sacrifice. In addi-
tion, the compound was also administered to groups of 40 rats/sex/dose
from weaning until sacrifice. Reproductive paramaters, mortality,
body weight and a number of other end points were measured; in addition,
both gross and histopathological examinations were conducted. The
NOAEL for toxicity to both the parents and.offspring was 25 ppm,
based on mortality and kidney lesions at higher doses. Assuming that
1 ppm in the diet of rats is equivalent to 0.05 mg/kg/day, the NOAEL
of 25 ppm in this study corresponds to 1.25 mg/kg/day (Lehman, 1959).
Developmental Effects
0 Lightkep et al. (1980) administered Tackle 2S (a formulation containing
22.4% sodium acifluorfen.) by oral intubation at doses of 0, 3, 12 or
36 mg/kg/day to New Zealand White rabbits (16/dose) on days 6 to 29
of gestation. The authors indicated that the administered doses were
in terms of the active ingredient. At 36 mg/kg/day, there was a
slight (nonsignificant) inhibition of maternal body weight gain and a
marked (significant) inhibition of maternal food consumption. At this
dose level, there was also possible interference with implantation
and a slight decrease in average fetal body weight; neither of these
changes was statistically significant. No gross, soft-tissue or
skeletal malformations were observed in pups, fetuses or late resorp-
tions at any dose level. Based on the information presented in this
study, a NOAEL of 36 mg/kg/day was identified for maternal toxicity,
fetal toxicity and teratogenicity. This NOAEL represents the highest
dose tested.
0 Florek et al. (1981) administered Tackle 2s (a formulation containing
22.4% sodium acifluorfen) by gavnge at doses of 0, 20, 90 or 180
mg/kg/day to Sprague-Dawley rats (25/dose) on days 6 to 19 of gesta-
tion. The authors indicated that the administered doses were in
terms of active ingredient. At 180 mg/kg/day, dams gained signifi-
cantly less weight than controls. At 90 and 180 mg/kg/day, lower
average fetal body weight and significantly delayed ossification of
metacarpals and forepaw and hindpaw phalanges were noted. At 180
ing/kg/day, there was delayed ossification of caudal vertebrae,
sternebrae and metatarsals. Additionally, at the highest dose level
there was a significantly increased incidence of slight dilation of
the lateral ventricle of the brain. The authors stated that the
fetal effects were indicative of delayed fetal development. Based
on the results of this study, a NOAEL of 90 mg/kg/day for maternal
-------
Acifluorfen August, 1987
-11-
toxicity, a NOAEL of 20 mg/kg/day for fetotoxicity and a NOAEL of
180 mg/kg/day (the highest dose tested) for teratogenic effects were
identified.
0 Weatherholtz and Piccirill.o (1979) administered RH 6201 (a formulation
containing 39.8% sodium acifluorfen) by gavage at doses of 0, 20, 60
or 180 mg/kg/day to New Zealand White rabbits on days 7 to 19 of
gestation. Maternal toxicity at 180 mg/kg/day included statistically
significant weight loss and mortality. At 180 mg/kg/day, there was
also evidence of fetal toxicity (mortality). Due to embryotoxicity
and maternal toxicity at 180 mg/kg/day, teratogenic evaluations could
not be performed at this dose level. At lower doses, no teratogenic
effects were observed. Based on the results of this study, NOAELs
of 60 mg/kg/day were identified for teratogenic effects, maternal
toxicity and fetal toxicity.
Mutagenicity
0 Schreiner et al. (1980) tested Tackle 2S (purity unspecified) in an
Ames assay using Salmonella typhimurium strains TA 98, 100, 1535, 1537
and 1538. The test compound was not found to be mutagenic, with or
without metabolic activation, at concentrations up to 1.8 mg/plate.
0 Brusick (1976) tested RH 6201 (purity not specified) in a mutagenicity
assay using Saccharomyces cersvisiae strain D4 and £. typhimurium
strains TA 1535, 1537, 1538, 98 and 100. The compound was not found
to be mutagenic, with or without metabolic activation, at concentrations
up to 500 ug/plate.
0 Putnam et al. (1981) tested Tackle 2S (purity not specified) in a
dominant lethal assay using Sprague-Dawley rats. The compound was
administered by gavage at doses of 0, 80, 360 or 800 mg/kg/day for
5 consecutive days. No detectable mutagenic activity, as defined by
induction of fetal death, was reported.
0 Myhr and McKeon (1981) conducted a primary rat (Fischer 344) hepato-
cyte unscheduled DNA synthesis (UDS) assay using Tackle 2S (purity
not specified). The test compound did not induce a detectable level
of UDS over a concentration range of 0.10 to 25 ug/mL. Treatment of
hepatocytes with 50 ug/mL was almost completely lethal to the cells.
0 Schreiner et al. (1981) tested Tackle 2S (purity not specified) in a
bone marrow metaphase analysis using Sprague-Dawley rats. The animals
were given the test compound by intubation at doses of 0, 0.37, 1.11
or 1.87 g/kg/day for 5 days. The test compound did not significantly
increase clastogenic events in the bone marrow cells.
0 Schreiner et al. (1980) tested Tackle 2S (purity not specified) in
a murine lymphoma assay. The compound was tested without metabolic
activation at 0.11 to 1.7 ug/mL, and with metabolic activation at
0.08 to 0.56 ug/mL. No detectable mutagenic activity was detected
either with or without activation.
-------
Acifluorfen August, 1987
-12-
0 Jagannath (1981) tested Tackle 2S (29.7% purity) in a mitotic recombi-
nation assay using Saccharomyces cerevisiae strain D5. The compound
was tested at 0, 2.5, 5.0 or 7.5 uL/plate without metabolic activation,
and at 7.5, 10.0 and 25.0 uL/plate with metabolic activation. In the
absence of metabolic activation, the compound induced a dose-related
increase in recombination events (significant at 5.0 uL/plate). With
metabolic activation, a dose of 10.0 uL/plate induced an increase in
recombination events. The authors reported that very few survivors
were observed at 25.0 uL/plate.
0 Bowman et al. (1981) tested Tackle 2S (purity not specified) in
mutagenicity assays using Drosophila melanogaster. Assays included
the Biothorax test of Lewis, a dominant lethal assay, an assay for
Y-chromosome loss, and a White Ivory reversion assay. In all cases,
the test compound was tested at concentrations of 15 mg/mL. Results
of these assays were negative for somatic reversions of White Ivory
and the Biothorax test of Lewis and positive for Y-chromosome loss
and dominant lethal mutations.
Carcinogenicity
0 Barnett et al. (1982b) administered Tackle 2S (a formulation
containing 19.1 to 25.6% sodium acifluorfen) to Fischer 344 rats
(73/sex/dose) for one year at dietary levels of 0, 25, 150, 500,
2,500 or 5,000 ppm. Assuming that these dietary levels reflect the
concentrations of the test compound and not the active ingredient,
corresponding levels of sodium acifluorfen are 0, 6.4, 38.4, 128.0,
640.0 or 1,280 ppm (based on 25.6% active ingredient in the test
compound). Assuming that 1 ppm in the diet of rats is equivalent to
0.05 mg/kg/day, these doses correspond to approximately to 0, 0.3,
1.9, 6.4, 32.0 or 64.0 mg/kg/day (Lehman, 1959). Histopathological
examinations revealed no evidence of carcinogenicity at any dose level.
0 Barnett et al. (1982a) administered Tackle* (a formulation containing
24% sodium acifluorfen) to B6C3F^ mice (60/sex/dose) for 18 months at
dietary concentrations of 0, 625, 1,250 or 2,500 ppm. (The high dose
was reported to be the maximum tolerated dose.) The authors reported
that the dietary levels corresponded to average compound intake values
of 0, 118.96, 258.73 or 655.15 mg/kg/day for males, and 0, 142.50,
312.65 or 710.54 mg/kg/day for females. Assuming that these levels
reflect test compound and not active ingredient intake, corresponding
levels of sodium acifluorfen intake are 0, 28.55, 62.10 or 157.24
mg/kg/day for males and 0, 34.20, 75.04 or 170.53 mg/kg/day for
females. An obvious dose-related depression of body weight was
reported for all doses. Beginning in week 52 of the study and
continuing with increasing frequency was the appearance of palpable
abdominal masses. Gross necropsy revealed a dose-related increase in
liver masses in both sexes. Histopathological examinations conducted
at the 52-week interval revealed that the livers -of six animals per
sex of high-dose animals (157.24 mg/kg/day for males; 170.53 mg/kg/day
for females) showed evidence of acidophilic cells. Males receiving
this dose displayed a statistically significant increase in the
frequency of hepatocellular adenomas. After 18 months of treatment,
-------
Acifluorfen August, 1987
-13-
all 40 high-dose males and 27/47 high-dose females sacrificed were
found to have a single benign hepatoma, multiple benign hepatomas or
hepatocellular carcinomas. In the males, the incidence of single
benign hepatoma and hepatocellular carcinomas was statistically
significant. In the females, the incidence of single hepatomas was
statistically significant.
0 Goldenthal (1979) administered RH 6201 (a formulation containing 39.4
to 40.5% sodium acifluorfen) to Charles River CD-1 mice (80/sex/dose)
for two years in the diet at concentrations that provided dose
levels of 0, 1.25, 7.5 or 45.0 ppm of the active ingredient. After
16 weeks of administration, the 1.25 ppm dose was increased to 270 ppm.
Assuming that 1 ppm in the diet of mice is equivalent to 0.15 mg/kg/day,
these doses correspond to approximately 0, 0.19 (increased to 40.5),
1.13 or 6.8 mg/kg/day (Lehman, 1959). Two control groups were used
in this study. One group received acetone in the diet (control 1 )
and the other received water in the diet (control 2). In males
receiving the highest dose there was a nonstatistically significant
increase in the incidence of nodular hepatocellular proliferation and
hepatocellular carcinoma, which indicated to the authors that these
changes were dose-related.
0 Coleman et al. (1978) administered RH 6201 (a formulation containing
39.8% sodium acifluorfen) to Charles River Outbred albino CD COBS
rats (approximately 75/sex/dose) for 2 years at changing dietary
concentrations. Mean sodium acifluorfen intake values over the
course of the study were 0, 1.25, 7.54 and 17.56 mg/kg/day for males
and 0, 1.64, 9.84 and 25.03 mg/kg/day for females.
0 Acifluorfen is structurally similar to nitrofen [2,4-dichloro-1 -(4-
nitrophenoxy) benzene; CAS No. 1836-75-7]. Nitrofen has been shown
to be carcinogenic in Osborne-Mendel rats and B6C3F1 mice (NCI, 1978,
1979; both as cited in HAS, 1985).
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for one-day, ten-day,
longer-term (approximately 7 years) and lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using th« following formula:
where:
HA = (NOAEL or LOAEL) x (BW) = mg/L ( _ uq/L)
(UF) x ( L/day)
NOAEL or LOAEL = No- or Lowest-Observed-Adv.erse-Effeet-Level
in mg/kg bw/day.
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
-------
Acifluorfen August, 1987
-14-
UF = uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
__ L/day = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day). -
One-day Health Advisory
No data were found in the available literature that were suitable for
determination of a One-day HA value for acifluorfen. It is therefore recom-
mended that the Ten-day HA value for a 10-kg child (2 mg/L, calculated below)
be used at this time as a conservative estimate of the One-day HA value.
Ten-day Health Advisory
The study by Florek et al. (1981) has been selected to serve as the
basis for determination of the Ten-day HA for a 10-kg child. In this study,
Tackle 2S (a formulation containing 22.4% sodium acifluorfen) was administered
by gavage at doses of 0, 20, 90 or 180 mg/kg/day to Sprague-Dawley rats
(25/dose) on days 6 to 19 of gestation. The authors indicated that the
administered doses were in tents of active ingredient. At 180 mg/kg/day,
dams reportedly gained significantly less weight than controls. At 90 and
180 mg/kg/day, lower average fetal body weight and significantly^delayed
ossification of metacarpals and forepaw and hindpaw phalanges were noted. At
180 mg/kg/day, there was delayed ossification of caudal vertebrae, sternebrae
and metatarsals. Additionally, at the highest dose level there was a signifi-
cantly increased incidence of slight dilation of the lateral ventricle of the
brain. The authors stated that the fetal effects were indicative of delayed
fetal development. No effects on implantations, litter size, fetal viability,
resorption or fetal sex ratio were reported. Based on the results of this
study, a NOAEL of 20 mg/kg/day for fetotoxicity was identified.
The Ten-day HA for the 10-kg child is calculated as follows:
Ten-day HA = (20 mg/kg/day) (10 kg) = 2 mg/L (2,000 ug/L)
(100) (1 L/day)
where:
20 mg/kg/day = NOAEL, based on absence of fetal toxicity in rats
exposed to aciflucrfen via gavage during days 6 to 19
of gestation.
10 kg = assumed body weight of a child.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
-------
Acifluorfen August, 1987
-15-
Longer-term Health Advisory
The study by Barnett (1982) had been selected to serve as the basis
for determination of the Longer-term HA. In this study, the NOAEL was
5.6 mg/kg/day based on an increase in the size of the liver in male rats.
However, a lower NOAEL, 1.25 mg/kg/day, was recently identified in a two-
generation rat reproduction study by Lochry et al. (1986). Since the NOAEL
in the Lochry et al. (1986) study is numerically identical to the value on
which the Lifetime HA is based and since a two-generation reproduction study
is suitable for calculating a Longer-term HA, it was determined that it is
appropriate to base the Longer-term HA on the Lifetime HA.
The Longer-term HA for a 10-kg child is calculated as follows:
Longer-term HA = (1.25 mg/kg/day) (10 kg) = 0.1 3 mg/L (130 ug/L)
(100) (1 L/day)
where:
1.25 mg/kg/day = NOAEL (see Lifetime Health Advisory below).
10 kg = assumed body weight of a child.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
The Longer-term HA for the 70-kg adult is calculated as follows:
Longer-term HA = 11.25 mg/kg/day) (70 kg) - 0.44 mg/L (440 ug/L)
(100) (2 L/day)
where:
1.25 mg/kg/day = NOAEL (see Lifetime Health Advisory below).
70 kg = assumed body weight of an adult.
100 - uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
2 L/day = assumed daily water consumption of an adult.
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
-------
Acifluorfen August, 1987
-16-
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL {or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
A 2-year Charles River CD-1 mouse dietary study by Goldenthal (1979) was
originally selected to serve as the basis for determination of the Lifetime
HA for acifluorfen. In this study, a NOAEL of 1.13 mg/kg/day was identified.
More recently, however, a two-generation rat reproduction study by Lochry et
al. (1986) was identified that strongly supports the results of the Goldenthal
(1979) study and identifies a NOAEL of 1.25 mg/kg/day.
Using the NOAEL of 1.25 mg/kg/day, the Lifetime HA for acifluorfen is
calculated as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD - <1«2S mg/kg/day) = 0.0125 mg/kg/day
(100)
where:
1.25 mg/kg/day = NOAEL, based on the absence of mortality and kidney
lesions in rats.
100 » uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (0.0125 mg/kg/day) (70 kg) = 0.437 mg/L (437 ug/L)
(2 L/day)
where:
0.0125 mg/kg/day = RfD.
70 kg = assumed body weight of an adult.
2 L/day = assumed daily water consumption of an adult.
-------
Acifluorfen August, 1987
-17-
Step 3: Determination of the Lifetime Health Advisory
Lifetime HA - (0.437 mg/L) (20%) . 0.009 mg/L (9 ug/L)
(10)
where:
0.437 mg/L = DWEL.
20% = assumed relative source contribution from water.
10 = additional uncertainty factor per ODW policy to account
for possible carcinogenicity.
Evaluation of Carcinogenic Potential
0 Four studies that evaluated the carcinogenic potential of sodium
acifluorfen were identified. The results of one of these studies
(Barnett et al., 1982a) indicated that sodium acifluorfen was car-
cinogenic in B6C3F-| mice. The results of the other three studies
(Goldenthal, 1979; Coleman et al., 1978; Barnett et al., 1982b)
provided no evidence of carcinogenicity in two strains of rats and
one strain of mice. However, due to deficiencies in the three negative
studies, the results of these studies are not sufficient to contradict
the results of the positive study. Each of these studies is discussed
briefly below.
- In the positive study (Barnett et al., 1982a), B6C3F-) mice received
sodium acifluorfen in the diet for 18 months. At the end of the
study, the high-dose (157.24 mg/kg/day) male mice displayed a
statistically significant increase in the incidence of single
benign hepatoraas and hepatocellular carcinomas. A statistically
significant increase in the incidence of single hepatomas was
observed in high-dose (170.53 mg/kg/day) females.
- In one of the studies with negative results (Goldenthal, 1979)
Charles River CD-1 mice received sodium acifluorfen in the diet for
two years at doses of 0, 0.19 (increased to 40.5 after 16 weeks),
1.13 or 6.8 mg/kg/day. Although no evidence of carcinogenicity was
observed in this study, the dose levels tested were considerably
lower than the level that produced positive results in the 18-month
mouse feeding study (157.24 mg/kg/day) (Barnett et al., 1982a).
- In the second study with negative results (Coleman et al., 1978),
Charles River outbred albino CD COBS rats received sodium acifluorfen
for two years at dietary levels up to 25.03 mg/kg/day (females) or
17.56 mg/kg/day (males). Although it is difficult to make cross-
species comparisons, these levels are considerably lower than the
level that produced positive results in the 18-month mouse feeding
study (157.24 mg/kg/day) (Barnett et al., 1982a). In addition,
no adverse effects were observed at any dose level used in this
study, indicating that the maximum tolerated dose was not used.
-------
Acifluorfen August, 1987
-18-
- In the third study with negative results (Barnett et al., 1982b),
Fischer 344 rats received sodium acifluorfen for 1 year at dietary
concentrations of 0, 0.3, 1.9, 6.4, 32.0 or 64.0 mg/Jcg/day.
Although the results of this study were negative, a study duration
of 1 year is not sufficient for assessing carcinogenic potential.
0 Acifluorfen is structurally similar to nitrofen [2,4-dichloro-1-(4-
nitrophenoxy) benzene; CAS No. 1836-75-7]. Nitrofen has been shown
to be carcinogenic in Osborne-Mendel rats and B6C3Fj mice [NCI, 1978,
1979; both as cited in NAS (1985)]. Although data on nitrofen cannot
be used to conclude that sodium acifluorfen is carcinogenic, these data
do, to some extent, support the positive results of Barnett et al.
(1982a).
0 The International Agency for Research on Cancer has not evaluated the
carcinogenic potential of acifluorfen.
0 Applying the criteria described in EPA's guidelines for assessment
of carcinogenic risk (U.S. EPA, 1986a), acifluorfen is classified in
Group Cs possible human carcinogen. Category C is for substances
with limited evidence of carcinogenicity in animals in the absence
of human data.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 The U.S. EPA has established residue tolerances for sodium acifluorfen
in or on raw agricultural commodities that range from 0.01 to 0.1 ppm
(CFR, 1985).
0 The EPA RfD Workgroup has concluded that an RfD of 0.013 mg/kg/day
is appropriate for acifluorfen.
VII. ANALYTICAL METHODS
0 Analysis of acifluorfen is by a gas chromatographic (GC) method
applicable to the determination of certain chlorinated acid pesticides
in water samples (U.S. EPA, 1986b). In this method, approximately
1 liter of sample is acidified. The compounds are extracted with
ethyl ether using a separatory f-onnel. The derivatives are hydrolyzed
with potassium hydroxide, and extraneous organic material is removed
by a solvent wash. After acidification, the acids are extracted and
converted to their methyl esters using diazomethane as the derivatizing
agent. Excess reagent is removed, and the esters are determined by
electron capture GC. The method detection limit has not been deter-
mined for this compound, but it is estimated that the detection
limits for analytes included in this method are in the range of 0.5
to 2 ug/L.
-------
Acifluorfen August, 1987?
-19-
VIII. TREATMENT TECHNOLOGIES
0 Reverse osmosis (RO) is a promising treatment method for pesticide-
contaminated water. As a general rule, organic compounds with
molecular weights greater than 100 are candidates-for removal by RO.
Larson et al. (1980) report 99% removal efficiency of chlorinated
pesticides by a thin-film composite polyamide membrane operating at a
maximum pressure of 1,000 psi and at a maximum temperature of 113°F.
More operational data are required, however, to specifically determine
the effectiveness and feasibility of applying RO for the removal of
acifluorfen from water. Also, membrane adsorption must be considered
when evaluating RO performance in the treatment of acifluorfen-
contaminated drinking water supplies.
-------
Aciflilbrfen August, 1987
-20-
IX. REFERENCES
Barnett, J.* 1982. Evaluation of ninety-day subchronic toxicity of Tackle*
in Fischer 344 rats. GSRI Project No. 413-971-40. Rhone-Poulenc
Agrochemie No. 372-80. Unpublished study. MRIO 0122730.
Barnett, J., L. Jenkins and R. Parent.* 1982a. Evaluation of the potential
oncogenic and toxicological effects of long-term dietary administration
of Tackle* to B6C3FI mice. GSRI Project No. 413-984-41. Final Report.
Unpublished Study. MRID 00122732.
Barnett, J., L. Jenkins and R. Parent.* 1982b. Evaluation of the potential
oncogenic and toxicological effects of long-term dietary administration
of Tackle* to Fischer 344 rats: GSRI Project No. 413-985-41. Interim
report. Unpublished study. MRID 00122735.
Bowman, J., C. Mackerer, S. Bowman, D.C. Jessup, R.C. Geil and B.W. Benson.*
1981. Drosophila mutagenicity assays of Mobil Chemical Company compound
MC 10109 (MRI 533). Study No. 009-275-533-9. Unpublished study.
MRID 00122737.
Brusick, D.* 1976. Mutagenicity evaluation of RH-6201. LBI Project No. 2547.
Unpublished study. MRID 00083057.
CFR. 1985. Code of Federal Regulations. July 1, 1985. 40 CFR 180.383.
p. 336.
CHEMLAB. 1985. The Chemical Information System, CIS, Inc. Baltimore, MD.
Coleman, M.E., T.E. Murchison, P.S. Sahota et al.* 1978. Three and twenty-four
month oral safety evaluation study of RH-6201 in rats. DRC 5800. Final
Report. Unpublished study. MRID 00087478.
Florek, M., M. Christian, G. Christian and E.M. Johnson.* 1981. Terato-
genicity study of TACU 06238001 in pregnant rats. Argus Project 113-004.
Unpublished study. MRID 00122743.
Goldenthal, E.I., D.C. Jessup, R.G. Geil and B.W. Benson.* 1978a. Two week
range finding study in mice: 285-016. Unpublished study. MRID 00080568.
Goldenthal, E.I., D.C. Jessup and D. Rodwell.* 1978b. Three generation
rtproduction study in rats: RH-6201, 285-014a. Unpublished study.
MRID 00107486.
Goldenthal, E.I., D.C. Jessup, R.G. Geil and B.W. Benson.* 1979. Lifetime
dietary feeding study in mice: 285-013a. Unpublished study.
MRID 00082897.
Harris, J.C., G. Cruzan and W.R. Brown.* 1978. Three month subchronic rat
study. RH-6201. TRD-76P-30. Unpublished study. MRID 00080569.
Jagannath, D.* 1981. Mutagenicity of 06238001 lot LCM 266830-7 in the mitotic
recombination assay with the yeast strain D5. Genetics Assay No. 5374.
Final Report. Unpublished study. MRID 00122740.
-------
Acifluorfen August, 1987
-21-
Larson, R.E., P.S. Cartwright, P.K. Eriksson and R.J. Petersen. 1982.
Applications of the FT-30 reverse osmosis membrane in metal finishing
operations. Paper presented at Tokohama, Japan.
Lehman, A.J. 1959. Appraisal of the safety of chemicals in foods, drugs and
cosmetics. Association of Food and Drug Officials of the United States.
Lightkep, G., G. Christian et al.* 1980. Teratogenic potential of TACU
06238001 in New Zealand white rabbits (Segment II Evaluation). Argus
Project 113-003. Unpublished study. MRID 00122744.
Lochry, E.A., Hoberman, A.M. and Christian, M.S.* 1986. Two-generation Rat
Reproduction Study, Argus Research Laboratories, Inc. Study No.218-002.
Madison, P., R. Becci and R. Parent.* 1981. Guinea pig sensitization study.
Buhler test for Mobil Corporation. Tackle 2S. FDRL Study No. 6738.
Unpublished study. MRID 00122729.
Meister, R., ed. 1983. Farm chemicals handbook. Willoughby, OH: Meister
Publishing Company.
Mobil Environmental and Health Science Laboratory.* 1981. A study of the oral
toxicity of Tackle 2S in the dog. Mobil Study No. 1091-80. Six-month
status report. Unpublished study. MRID 00122733.
Myhr, B., and M. McKeon.* 1981. Evaluation of 06238001 in the primary rat
hepatocyte unscheduled DNA synthesis assay. MEHSL Study 1022-80. Final
Report. Unpublished study. MRID 00122742.
NAS. 1985. National Academy of Sciences. Drinking Water and Health. Vol. 6.
Chapter 9: Toxicity of Selected Contaminants. Washington, DC. National
Academy Press.
NCI. 1978. National Cancer Institute. Biloassay of nitrofen for possible
carcinogenicity. Technical Report Series No. 26. DHEW Publication No.
(NIH) 78-826. U.S. Department of Health, Education and Welfare.
Washington, DC. 101 pp. Cited in: NAS. 1985. National Academy of
Sciences. Drinking Water and Health. Vol. 6. Chapter 9: Toxicity of
Selected Contaminants. Washington, DC. National Academy Press.
NCI. 1979. National Cancer Institute. Bioassay of nitrofen for possible
carcinogenicity. Technical Report Series No. 184. DHEW Publication No.
(NIH) 79-1740. U.S. Department of Health, Education and Welfare.
Washington, DC. 57 pp. Cited in: NAS. 1985. National Academy of
Sciences. Drinking Water and Health. Vol. 6. Chapter 9: Toxicity of
Selected Contaminants. Washington, DC. National Academy Press.
Piccirillo, V.J., and T.L. Robbins.* 1976. Four week oral range finding
study in rats. RII-6201. Unpublished study. MRID 00071892.
Putnam, D., L. Schechtman and W. Moore.* 1981. Activity of T1689 in the
dominant lethal assay in rodents. MA Project No. T1689.116. Final Report.
Unpublished study. MRID 00122738.
-------
Acifluorfen August, 1987
-22-
Schreiner, C.A., M.A. McKenzie and M.A. Mehlman.* 1980. An Ames Salmonella/
mammalian oicrosome mutagenesis assay for determination of potential
mutagenicity of Tackle 2S MCI0978. Study No. 511-80. Unpublished
study. MRID 00061622.
Schreiner, C., M. Skinner and M. Mehlman.* 1981. Me ta phase analysis of rat
bone marrow cells treated in vivo with Tackle 2S. Study No. 1041-80.
Unpublished study. MRID 00122741.
Spicer, E. , L. Griggs, F. Marroquin, N.D. Jefferson and M. Blair.* 1983. Two
year dietary toxicity study in dogs. (Tackle*) 450-0395. Unpublished
study. MRID 00131162.
U.S. EPA. 1986a. U.S. Environmental Protection Agency. Guidelines for
carcinogenic risk assessment. Fed. Reg. 51 (185) :33992-34003.
September 24.
U.S. EPA. 1986b. U.S. Environmental Protection Agency. U.S. EPA Method #3 -
Determination of Chlorinated Acids in Ground Water by GC/ECD, January
1986 draft. Available from U.S. EPA's Environmental Monitoring and
Support Laboratory. Cincinnati, OH.
Weatherholtz, w., S. Moore and G. Wolfe.* 1979a. Eye irritation study in
monkeys. Blazer 2S. Project No. 417-396. Final Report. Unpublished
study. MRID 00140887.
Weatherholtz, W., K. Peterson, M. Koka and R.W. Kapp.* 1 979b. Four-week
repeated dermal study in rabbits. RH-6201 formulations. Project No.
417-386. Final Report. Unpublished study. MRID 00140889.
Weatherholtz, W., and V. Piccirillo.* 1979. Teratology study in rabbits
(RH-6201 LC). Final Report. Project No. 417-374. Unpublished study.
MRID 00107485.
Whittaker Corporation.* No date, a. Acute oral LDso rats. Study No. 410-0249.
Unpublished study. MRID 00061625.
Whittaker Corporation.* No date, b. Primary dermal irritation — rabbit:
Study No. 410-0286. Unpublished study. MRID 00061629.
Whittaker Corporation.* No date, c. Primary eye irritation — rabbits.
Study No. 410-C252. Unpublished study. MRID 00061628.
Windholz, M., S. Budavari, R.F. Blumetti and E.S. Otterbein, eds. 1983.
The Merck Index, loth ed. Rah way, NJ: Merck and Co., Inc.
Confidential Business Information submitted to the Office of Pesticide
Programs.
------- |