September 1996
HEXAZINONE
Drinking Water Health Advisory
Office of Water ,
O. S. Environmental Protection Agency
The Health Advisory. (HA) Program, sponsored by the Office of Water (OW),
provides information on the health effects, analytical methodology 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 percent of an individual's lifetime),, and
lifetime exposures based on data describing noncarcinogenic endpoints of
. toxicity. For those substances that are known or probable human carcinogens,'
according to the Agency classification scheme (Group A or 8), 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 lifelong
exposure and the consumption of drinking water. The cancer unit risk is
usually derived from the linearized multistage model with 95 percent 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. . •
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II. GENERAL INFORMATION AND PROPERTIES
I
CAS No. 8001-35-2
StructuralFormula
3-Cyclohexyl-6-(dimethylamino)-1 methyl-1,3,5-triazine-2,4{1H,3H)-dione
Svnonvms ' ... .
Velpar; Hexazinone (Budavari et al., 1989; Sine et al., 1989; U.S.
EPA, 1994a) .
Uses
• Broad spectrum, pre- and post-emergence herbicide effective against
woody and herbaceous weeds (Budavari et al., 1989).'
i ,
• Used when plants are actively growing for control of many annual,
biennial and perennial weeds and woody plants on noncropland areas;
gives contact and residual control; rainfall is needed for soil
activation; controls woody plants in reforestation areas; selective
weed control in conifers, sugarcane, pineapple, rubber trees and
alfalfa (Sine et al., 1989).
• Usage areas include plantations of coniferous trees, railroad right-
of-ways,- utilities, pipelines, petroleum tanks, drainage ditches, and
sugar and alfalfa (Kennedy, 1984).
• Neilsen and Lee (1987) estimated that approximately 5,000 kg of.
hexazinone (active ingredient) was used per year for agricultural
purposes (Goodrich et al., 1991).
Properties (Budavari et al., 1989; CHEMLAB, 1985; Kennedy, 1984; Sine et al.,
1989; U.S. EPA, 1982)
Chemical Formula
Molecular Weight
Physical State (25°C)
Boiling Point
Melting Point
Density
Vapor Pressure (25°C)
Specific Gravity (25°C)
Water Solubility (25°C)
Log Octanol/Water
Partition Coefficient
Taste Threshold (Water)
Odor Threshold-(Water)
C12H:,,N,0:
252
White crystalline solid
115 ,to 117°C, or 113.5°C, or 97 to 100.5°C
2 x 10"7 mm Hg (extrapolated from 6.4 x 10"
5 mm Hg at 86°C)
1.25
33,000 mg/L or 29,800 mg/L
-4.40 (calculated)
odorless
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Occurrence
Hexazinone has not been found in any surface water samples (9 sampler
taken at 2 locations) or groundwater samples analyzed (6 samples from
6 locations), STORBT (1988).
Hexazinone has been detected in ground water of five states including
Maine (Yarborough et al., 1995, 1996), North-Carolina, South Carolina
(Vaught, 1995), Colorado (Austin, 1994).. The Maximum concentration
reported in ground water to date is 115 ppb in South Carolina, these
detections resulted from probable nonppint sources; additional
detections in Hawaii resulted from point source mechanisms.
Jennings and Gould (1995, draft) reported extensive use of hexazinone
for blueberry farming in the State of Maine. Low levels of hexazinone
were .detected in ground water near blueberry sites. Water samples . .
from 20 sites had detectable .levels ranging from 0.093 to 5.97 ppb
(/ug/L) for fifteen of these sites, and 5 sites non-detectable levels.
The Maine Cooperative,Extension has been conducting ground water and,
surface water monitoring studies in blueberry-growing areas for the
past several years. All 32 wells in these study areas contained
hexazinone residues sometime during the study period. Concentratios
in ground water from thesewells ranged up to 29.0 ppb In addition,
four ponds and three streams contained.hexazinone residues up to 9.2
ppb (Hess, 1966, yarborough et al., 1995, 1996). According to the
Maine Pesticide Board, another 27 wells .tested positive with
relatively lower concentrations of hexazinone (McLaughlin, 1994a).
In 1992, hexazinone residues were also detected in two wells that
supplied the drinking water of a school in Maine. Concentrations in
these wells ranged from 3 to 10 ppb (McLauglin, 1994b).
Environmental Fate
Hexazinone is generally resistant to hydrolysis and loss by
volatilization, but is subject to both microbial degradation and*
photolysis. Its environmental half-life can vary between 2 weeks and
6'months, but frequently is less than 30 days (Neary et al., 1993).
Hexazinone'did not hydrolyze in water within the pH range of 5.7 to 9
during a period of 8 weeks (Rhodes, 1975a). :
In an aerobic metabolism soil' study, hexazinone was added to .a
Fallsington sandy loam and a Flanagan silt loam at 4 ppm. In these
media, C-Hexazinone and'its residues had a half-life of about 25
weeks. Of the extractablc !'C residues, approximately one-half was
present as parent compound and/or 3-cyclohexyl-l-methyl-6-
methylamino-l,3,5-triazine-2,4-(lH,3H)-dione. Also present were 3-
(4-hydroxycyclohexyl)-6-(dimethylamino)-l-methyl~l-(lH,3H)-
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• A field soil leaching study indicated that ^C-hexazinone residues
were leached into the lower sampling depths with increasing rainfall.
A Keyport silt loam (2.75% organic matter-; pH 6.5) and a Flanagan
silt loam.(4.02% organic matter; pH 5.0) were used. For the Keyport
silt loam, "c residues were found at all depths evaluated one month
after application of hexazinone, including the 8- to 12-inch depth,
when .total rainfall equaled 8.43 inches. For the Flanagan silt loam,
14C residues were found at all depths sampled, including the 12- to
15-inch depth, 1 month after application, when a total of 7.04 inches
of rain had fallen (Rhodes, 1975c).
• A soil thin layer chromatography (TLC) test for Fallsington sandy
loam and Flanagan silt loam gave R, values,for hexazinone of 0.85 and
0.68, respectively. This places hexazinone in Class 4, indicating it
is very mobile in these soils (Rhodes, 1975c).
• In a terrestrial field dissipation study in Delaware using a Keyport
silt loam, hexazinone had a half-life of less than 1 month. In a ,
field study in Illinois (Flanagan silt loam), hexazinone had a half-
life of more than 1 month (62% of the parent, compound remained at
1 month) (Rhodes, 1975b). In a separate study with Keyport silt
loam, some leaching of the parent, compound to a depth of -12 to
18 inches was observed (Holt, 1979).
• Neary et al. (1993) have concluded that most peak pesticide .
(including hexazinone) residue concentrations in groundwater are
associated with storm run-off, principally during the first one to
four storm events after application. However, these peak
concentrations are not always associated with hydrograph peaks, and
may not occur until weeks, months or even a year after application,
and then may persist for only a month or more than a year. Soil
types, water table depth, storm event duration and intensity,
: distance of residues from stream channels, routing and mechanism of
transport were all apparent factors in the appearance and timing of
base flow and run-off concentration peaks.
• Based on the octanol/water coefficient, hexazinone is not expected to
accumulate in fish.
III. PHARMACOKINETICS
Absorption
• Rapisarda (1982)' reported that a dose of 14 mg/kg HC-labeled
hexazinone (>99% pure).was about 80% absorbed in 3 to 6 days (77%
recovery in urine, 20% in feces) when administered by gastric'
intubation to male and female Charles River CD rats with,or without
3 weeks of dietary preconditioning with unlabeled hexazinone.
Similar results were observed in rats dosed with 1000 mg/kg without
preconditioning.
• Rhodes et al. (1978) administered 2,500 ppm (125 mg/kg) hexazinone in
the diet to male rats for"17 days. This was followed by a single
dose of 18.3 mg/300 g (61 mg/kg) MC-labeled hexazinone. The
hexazinone was rapidly absorbed within 72 hours, with 61% detected in
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the urine and 32% in the feces. Trace amounts were found in the
gastrointestinal (GI) tract (0.6%,,tissues not specified) and expired
air (0.08%). > '
Distribution
Orally administered hexazinone has not been demonstrated to
accumulate preferentially in any tissue (Rhodes-et al., 1978; Molt
et al., 1979; Rapisarda, 1982). , , . ,
Studies in rats by Rapisarda (1982) and Rhodes et al. (1978) showed
that only very low levels of "c-hexazinone (about 0.2% .of the
administered dose) were found in any body tissue-3-6 days after the
animals were administered >14 mg/kg hexazinone by gastric intubation
with or without dietary preconditioning. .
In a study with dairy cows by Holt et al. (1979) hexazinone was given
in the diet at 0, 1, 5 or 25 ppm for 30 days. Assuming•that 1 ppm in
the diet of a cow equals 0.015 mg/kg' (Lehman, 1959), these levels
•correspond to 0, 0.015, 0.075 or. 0.37 tng/kg/day. The investigators
reported no detectable residues in milk, fat, liver., kidney or lean
muscle.. • ' .
Metabolism
Major urinary metabolites of hexazinone in rats identified by Rhodes
et al. (1978) were 3-(4-hydroxycyclohexyl)-6-(dimethylamino)l-methyl-
l,3,5-triazine-2,4-(lH,3H)-dione (metabolite A); 3-cyclohexyl-6-
(methylamino)-1-methyl-l,3,5-triazine-2,4-(1H,3H)-dione
(metabolite B); and 3-(4-hydrpxycyclohexyl)-6-(methylamino)-l-methyl-
l,3,5-triazine-2,4~(lH,3H)-dione (metabolite C). The percentages of
.these metabolites detected in the urine'were 46.8, 11.5 and 39.3%,
respectively. The major fecal metabolites detected by Rhodes et al.
(1978) were A (26.3%)^ and C (55.2%). Less than 1% unchanged
hexazinone was detected in the urine or the feces. similar results
were reported by Rapisarda (1982).
. Excretion
Rapisarda (1982) and Rhodes et al. (1978) reported that excretion of
"c-hexazinone and/or its metabolites occurs mostly in the urine (61
to 77%) and in the feces (20 to 32%). .
IV. HEALTH EFFECTS
Humans.
The Pesticide Incident Monitoring System database (U.S. EPA, 1981)
indicated that 3 of 43,729 incident reports involved hexazinone.
Only one report.cited exposure to hexazinone alone, without other.
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compounds involved. A 26-year-old .woman inhaled hexazinone dust
(concentration not specified). Vomiting occurred within 24 hours.
No other effects were reported and no treatment was administered.
The other two reports did not involve human exposure. Three
additional cases of human incidents with haxazinone were reported
since June 1992 to the "Incident Data System" of the Office of
Pesticide Programs: one case involving a number of tree planters not
wearing protective clothing, 30% developed skin-irritation that
desappeared 3-4 days later; and* two other cases involving a backpack
sprayer operator and a utility worker spraying this chemical, both
sustained skin and eye irritation with .rapid* recovery from symptoms.
Animals
Short-term Exposure
• Reported oral LD50 values for technical-grade hexazinone in rats range
from 1,690 to >7,SOO mg/kg (DuPont, 1977a, 1980a; Kennedy, 1984).
• DuPont (1975d) and Kennedy (1984) reported the oral LDs0 value of
technical-grade hexazinone in beagle dogs to be >3,400' mg/kg.
* Reported oral LD"10 values for hexazinone in guinea pigs range from 8OO
to 860 mg/kg (DuPont, 1973a; Kennedy, 1984)\
* Kennedy (1984) studied the response of male rats to repeated oral
doses of hexazinone (89 or 98% active ingredient). Groups of six
rats were intubated with hexazinone, 0 or 300 mg/kg, as a 5%
suspension in corn oil. Animals were dosed 5 days/week for 2 weeks
(10 total doses). Clinical signs and body weights were monitored
daily. At 4 hours to 14 days after exposure to the last dose,
microscopic evaluation of lung, trachea, liver, kidney, heart,
testes, thymus, spleen, thyroid, GI tract, brain and bone marrow was
conducted. No gross or histological changes were noted in animals
exposed to hexazinone.
• In an 8-week range-finding study (Kennedy and Kaplan, 1984), Charles'
River CD-I mice (10/sex/dose) received hexazinone (>98% pure) in the
diet for 8 consecutive weeks at concentrations of 0, 250, 500, 1,250,
2,500 or 10,000 ppm. Assuming 1 ppm in the diet of mice equals
0.15 mg/kg (Lehman, 1959), these dietary concentrations correspond to
doses Of about 0, 37.5, 75.0, 187.5, 375.0 or 1,500 mg/kg/day. No
differences were observed in general behavior and appearance,
mortality, body weights, food-consumption or calculated fbod
efficiency between control and exposed groups. No gross pathologic
lesions were detected at necropsy. • The only dose-related effects
observed were increases in both absolute and relative livei: weights
in mice fed 10,000 ppm. A No-Observed-Adverse-Effect Level (NOAEL) -
of 2,500 ppm (375.0 mg/kg/day) was identified by the authors.
Dermal Ocular Effects
• In an acute dermal toxicity test performed by DuPont (1976a), up to
7,500 mg/kg of-a 24% aqueous solution of hexazinone (reported to be
1,875,mg/kg of active ingredient) was applied occlusively for
24 hours to the shaved backs and trunks of male albino rabbits. Ho
deaths were observed throughout a 14-day observation period. No
other symptoms were reported.
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• DuPont (1973b) reported an acute dermal toxicity test in which 60 mL
of a 24% aqueous solution of hexazinone (reported as 5,278 mg/kg) was
applied occlusively to the shaved trunks' of male albino rabbits for
24 hours. No mortalities were observed through an unspecified•
observation period. One animal exhibited a mild, transient skin
irritation. ' '' <
.
* In a 10-day study conducted by Kennedy -(1984), semiocclusive dermal
application of hexazinone for 6 hours/day for 10 days to male rabbits
at 70 or 680 mg/kg/day resulted in no signs of skin irritation or
toxicity. A trend toward elevated serum alkaline phosphatase (SAP)
and serum alanine aminotransferase (ALT, formerly glutamic pyruvic-
transamiriase or SGPT) activities was observed, but no hepatic damage .
was seen by microscopic evaluation. In a second 10-day study using
35, 150 or 770 mg/kg/day, the highest dose.again resulted in elevated
SAP-and SGPT activities, but they returned to normal after 53 days of
recovery. Histopathological evaluations were not performed in the
second study. /
• DuPont (1977b) applied 6,000 mg/kg hexazinone as a 63% solution
occlusively to the shaved backs and trunks o'f male albino rabbits.
All rabbits showed moderate skin irritation which cleared 7-days
after cessation of treatment. No treatment-related mortalities were
reported after a 14-day observation period. '
• DuPont (1972) reported the results of dermal irritation tests in
which a single dose of 25 or 50% hexazinone.was applied to the
shaved, intact shoulder skin of each of 10 male guinea pigs. To test
for senaitizatiori, four sacral intradermal .injections 'of 0.1 mL of a
15% solution were first given over a 3-week period. After a 2-week
rest period, the guinea pigs were challenged with 25 or 50%
hexazinone applied to the shaved, intact shoulder skin. The test -
material was found to be nonirritating and nonsensitizing at 48 hours
post-application. .
* Using a ,10% solution, DuPont (1976b) repeated the DuPont (1972) study
with guinea pigs and observed no irritation or.sensitization.
* DuPont (1980a) reported that in albino rabbits, a single dose of
hexazinone applied as a 27% (vehicle not specified) solution to one
eye per animal and left unwashed was a severe ocular irritant. When
applied at 27% (vehicle not specified) and washed or at 4% (aqueous
solution) unwashed, mild to moderate corneal cloudiness, iritis
and/or conjunctivitis resulted. By 21 days post-treatment"with the
higher dose, two of the three rabbit eyes had returned to normal; a
small area of mild corneal cloudiness persisted through the 25-day
observation period in one of'the three eyes. Eyes treated with lower
. doses were normal within ,.3 days.
Long-term Exposure
• In a 90-day feeding study, DuPont (1973c) fed beagle dogs ,
(four/sex/dose) hexazinone (97:5% active ingredient) in the diet at
levels of 0, 200, 1,000 or 5,000 ppm. Assuming 1 ppm in the diet of
a dog equals 0.025 mg/kg/day (Lehman, 1959), these levels .correspond
to.about 0, 5, 25 or 125 mg/kg/day. At the highest dose level
tested, decreased food consumption, weight loss, elevated SAP
activity, lowered albumin/globulin ratios and slightly elevated liver
weights were noted. No gross or microscopic lesions were observed at
necropsy. Based on the results of this study, a NOAEL of 1,000 ppm
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(25 mg/kg/day) and a Lowest-Observed-Adverse-Effect Level (LOAEL) of
5,000 ppm (125 mg/kg/day) were identified.
In a 90-day feeding study (DuPont, 1973d), Crl-CD rats (10/eex/dose)
received hexazinone (>98% pure) at dietary .levels of 0, 200, 3,000 or
5,000 ppm. Assuming 1 ppm in the diet of rats equals 0.05 mg/kg/day
(Lehman, 1959), these levels correspond to about 0, 10, SO or
250 mg/kg/day. Hematological and biochemical tests and urinalyses
were conducted on subgroups of animals after 1, 2 or 3 months of
feeding.. Following 94 to 96 days of feeding, the rats were
sacrificed and necropsied. The only statistically significant effect
reported was a decrease in body weight in both males and females
receiving 5,000 ppm. No differences in food consumption were
reported. Results of histopathological examinations from the control
and high-dose groups were unremarkable. The authors identified a
NOAEL of 1,000 ppm (50 mg/kg/day).
Groups of purebred beagle dogs (5/sex/group) were fed ad libitum 0,
200, 1,500 or 6,000 ppm of hexazinone in their diet for 12 months
(DuPont, 199la). Based on monitored food consumption, these doses
corresponded to 0, 5.00, 41.24 and 161.48 mg/kg/day in males,'and 0,
4.97, 37.57 and 166.99 mg/kg/day in females. Increased SAP, aerum
globulin, and hepatocellular vacuolation, as well as decreased serum
albumin were reported for males at the 41.24 mg/kg/day dose.
Increased hepatocellular pigmentation and concentric membranous
bodies, and decreased serum albumin were reported for females at the
41.24 mg/kg/day dose. Also at this dose, one male.appeared
emancieted and one female had pale kidneys. Additional effects were
reported in the high-dose animals, including decreased body weight
and food consumption that was perhaps due, at least in part, to poor
palatability of the diet. The high dose caused also in these animals
moderate macrocytic anemia as evidenced by decreased erythrocyte
counts, hematocrits andfhemoglobins in males, and by increased mean
corpuscular volumes and mean corpuscular.hemoglobins in both sexes.
Clinical chemistry parameters affected at the high dose included
increased blood urea nitrogen (BUN), creatinine (females), serum
alanine aminotransferase, serum aspartate aminotransferase, SAP and
globulin, and decreased glucose, cholesterol, total protein
(females), calcium and inorganic phosphate. The lower cholesterol
and phosphate were considered reflective of poor nutritional status
in some high-dose animals, and the elevated BUN and creatinine of
potential kidney damage. In addition to the histological and
enzymatic indications of liver damage, relative liver weights were
significantly increased at the high dose. No significant effects
were observed at the low dose. The study thus establishes a chronic
oral NOAEL of 200 ppm, or 5.0 mg/kg/day, of hexazinone in the diet.
The LOAEL was determined to be 1,500 ppm, or 41.24 mg/kg/day for
males and 37.57 mg/kg/day for females.
Six-week old CD-I mice (SO/sex/group) were fed ad libitum either 0,
200, 2,500 or 10,000 ppm of hexazinone in the diet for 2 years
(DuPont, 1981).. These doses correspond to approximately 0, 30, 375
or 1,500 mg/kg/day using a conversion of 1 ppm in the diet equal to
0.15 mg/kg/day (Lehman, 1959). No treatment-related changes in
mortality, hematological parameters or gross lesions were reported.
Corneal opacity, sloughing and discoloration of the distal tip of the
tail were .noted as early as the fourth week of the study in some mice
receiving 2,500 or 10,000 ppm. A statistically significant decrease
in body weight was observed in male mice receiving 10,000 ppm and in
female mice-receiving 2,500 or 10,000 ppm. Statistically significant
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Hexazinone'
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September 1996
organ weight changes included increases in the liver at 10,000 ppm *
(males and females) and 2,500 ppm (females), plus several judged by
. the authors not to be treatment-related:, lung increases (absolute and
relative) in males at 200 and 2,500 ppm, kidney decreases in males at
all doses, testicular increases at 2,500 and 10,000 ppm, relative
brain increases in males at 10,000 ppm and females at 2,500 ppm, and
thymus, kidney and heart decreases in females at 10,000 ppm. Liver
hypertrophy, hyperplastic nodules, cellular necrosis and inflammatory
foci were reported in one or both sexes at the mid and/or high doses.
'The identified NOAEL and LOAEL for chronic oral exposure of mice to
hexazinone were 200 ppm (30 mg/kg/day) and 2,500 ppm (375 mg/kg/day),
respectively. . .
• DuPoht (1977c) presented the results of a 2-year feeding study in
which Crl-CD 'rats (36/sex/dose) received hexazinone (94 to 96% pure)
at dietary levels of 0 (two groups), 200, 1,000 or 2,500 ppm
(approximately: 0, 10, 50 or 125 mg/kg/day assuming that 1 ppm in the
,diet of a rat equals 0.05 mg/kg/day) (Lehman, 1959). After ,2 years
of continuous feeding, all rats in all groups .were sacrificed and
examined. Kales fed ,2,500 ppm.and females fed either 1,000 or
2,500 ppm had'significantly lower body weights than controls (p
<0.05). Male rats fed 2,500 ppm had slightly elevated leukocyte
counts with a greater proportion of eosinophils. Hale rats fed
either 1,000 or 2,500 ppm displayed decreased alkaline phosphatase
activity. Statistically significant effects on organ weights
included elevated' relative lung weights in males fed 1,000 ppm; lower
kidney and lower relative liver and heart-weights in males fed
2,500 ppm; increased liver and spleen weights in females fed 200 ppm;
and elevated stomach and relative brain weights in females fed
2,500 ppm. At necropsy,•gross pathologic findings were similar among
all groups. Changes attributed to hexazinone were not apparent in
any of the tissues evaluated microscopically. The authors identified
200 ppm (10 mg/kg/day) as the NOAEL. However, the increased liver
and spleen weights- observed in females would indicate that 200 ppm
might be more appropriately identified as a LOAEL.
Reproductive Effects
• Two rat reproduction studies were performed by DuPont that provided
supplementary or minimum data as judged by EPA (DuPont, 1979c;
Kennedy and Kaplan, 1984). In the first, a one-generation
reproduction study (Kennedy and Kaplan, 1984), Crl-CD rats
(10/sex/dose) received hexazinone (>98% pure) for approximately
90 days at dietary levels of 0, 200, 1,000 or 5,000 ppm. Assuming
that 1 ppm in the diet of rats equals 0.05 mg/kg/day. (Lehman, 1959),
this corresponds to approximately .0, 10, 50 and 250 mg/kg/risy.
Following the 90-day feeding period, six rats/sex/dose were .selected
to serve as the parental generation. The authors concluded that the
rats had normal fertility. The young were delivered in normal
numbers, and survival during the lactation period-was unaffected. In
the 5,000 ppm group, weights of pups at weaning (21 days) were
significantly (p <0.01) lower than controls or other test groups.
The results of this study identify a NOAEL of 1,000 ppm
(50 mg/kg/day) (no decrease in,weanling weight).
• In a seperate, three-generation reproduction study that was part of a
. larger, long-term study, (DuPont; 1979c; Kennedy and Kaplan, 1984),
Crl-CD rats (20/sex/dose) received hexazinone (95.8% pure) at dietary
. levels of 0, 200, 1,000 or 2,500 ppm for 90 days (approximately 0,
10, 50 or 125 mg/kg/day, assuming the above dietary assumptions for a
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rat). Following 90 days of feeding, 20 rats/sex/dose were selected
to serve as the parental (F0) generation. Reproductive.parameters
tested included the number of matings, number of pregnancies and
number of pups per litter. Pups were weighed at weaning, and one
male and female were selected from each litter to nerve s.n parental
rats for the second generation. Similar procedures were used to
produce a third generation; the same reproductive parameters were
evaluated for the second and third generations. . There were no
significant differences between the control and treated groups with
respect to the various calculated indices (fertility, gestation,
viability and lactation), thus identifying a NOAEL of 2,500 ppra
(125 mg/kg/day) for reproductive effects. Body weights at-weaning of
pups in the 2,500 ppm dose group were significantly (p <0.05) lower
than those of controls for the F2 and F3 litters, indicating a NOAEL
of 1,000 ppm (.50 mg/kg/day) and a LOAEL of 2,500 ppm (125 mg/kg/day)
for developmental growth effects. Based upon all effects, the study
supports an overall NOAEL of 1,000 ppm (50 mg/kg/day) and an overall
LOAEL of 2,500 ppm (125 mg/kg/day).
• Groups of Sprague-Dawley rats (30/sex/group) were fed ad"libitum
diets containing O, 200, 2,OOO or 5,OOO ppm of hexazinone during
growth, mating, gestation and lactation in a 2—generation
reproduction study (OuPont, 1991b). pi rats were dosed for 73 days
prior to mating, and Fl rats for 105 days prior their first mating •
for the F2A litters (longer for the F2B litters). Maternal toxicity
effects were noted at the mid- and high doses. Based on reduced body
weights and body-weight gains in Pi and Fl females, the NOAEL and the
LOAEL for systemic effects were determined to be 200 and 2,000 ppm,
respectively (14.3 and 143 mg/kg/day based on body weight and dietary
consumption data for PI females during the premating period;
corresponding.doses for Fl females were somewhat higher). Kale
fertility, female fertility, gestation, viability and lactation
indices were not affected by treatment. Increased absolute (PI) or
relative (Fl) testes weight at 5,000 ppm'was .not deemed
toxicologically significant. The reproductive NOAEL was thus 5,000
ppm or, based upon body weight and dietary consumption data during
the premating periods, 294 mg/kg/day (PI males), 399 mg/kg/day (Fl
• males), 383 mg/kg/day (PI females), or 484 rag/kg/day "(Fl-females).
Decreased Fl, F2A and F2B pup body weights were observed at 2,000 and
5,000 ppm, as was decreased F2B pup survival at 5,000 ppm. Based
upon the decreased pup weights, the developmental NOAEL and LOAEL
were 200 and 2,000 ppm, respectively. Using body weight and dietary
consumption data taken during the premating periods, the
corresponding maternal doses were approximately 14.3 mg/kg/day (PI
females) or 17.7 mg/kg/day (Fl females), and 143 mg/kg/day (PI
females) or 180 mg/kg/day (Fl females). Therefore, this study
supports an overall NOAEL of 200 ppm (14.3 mg/kg/day) and an overall
LOAEL of 2,000 ppm (143 mg/kg/day), and waj judged by EPA to be of
guideline quality.
Developmental Effects
• In a-developmental study in the rat that was conducted by DuPont
.(DuPont, 1974) and later published (Kennedy and Kaplan, 1984),
Charles River Crl-CD rats (25 to 27/dose) received hexazinone (97.5%
pure)- at dietary concentrations of 0, 200, 1,000 or 5,000 ppm
(approximately 0, 10, 50 or 250 mg/kg/day following the previously
stated dietary assumptions for the rat) on days 6 through 15 of
gestation. Rats were observed daily for clinical signs and were
weighed on gestation days 6, 16 and 21. On day 21, all rats were
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Hexazinone
-11-
September 1996
sacrificed and ovaries and uterine horns were weighed arid examined.
The number and location of live fetuses, dead fetuses and resorption
sites were noted and were unaffected by treatment. •Fetuses from the
0 and 5,000 ppm.dose groups were evaluated for developmental' effects
(gross, soft tissue or skeletal abnormalities). Maternal weight gain
during the exposure period was depressed modestly at 1,000 ppm and
substantially at 5,000• ppm. At sacrifice, no adverse effects were
observed for the dams... No malformations or adverse growth effects
'were noted in the fetuses. This study identified a NOAEL of
1,000 ppm (50 mg/kg/day) and a LOAEL of 5,000 ppm (250 mg/kg/day) for
maternal effects based on'substantially depressed maternal weight
gain. A NOAEL of 5,000 ppm (250 mg/kg/day) was established for
. developmental effects in the fetus. ' . ' • . • .
• Mated Sprague-Dawley rats were administered single oral daily doses
of hexazinone by gavage during gestation days 7 through 16 (DuPont,
1987). The following dose levels were tested: 0, 40, 100, '400 and
900 mg/kg/day. Treatment-related effects, observed only in dams from
the 400 mg/kg/day and 900 mg/kg/day groups, included alopecia, and
•stained chin and nose; decreased body weight gain and food
consumption during and after dosing, until the termination of the
study; and increased relative liver weight (liver weight/body weight
ratio). Treatment-related developmental effects, observed only in - _.
the 400 mg/kg/day and 900 mg/kg/day groups, included decreased fetal
body weights;, and increased incidence of fetuses with no kidney
papilla and with unoaai'fied sternebrae. Maternal and developmental
toxic effects observed the 9OO mg/kg/day group were, in most
.instances, statistically significant (p •_' 0.05) when compared with
those observed in the control group.- Maternal and developmental
toxic effects observed in the 400 mg/kg/day group were minimal and,,
only occasionally statistically significant (p i 0.05) when compared
with those noted in the controls. .Based on the above findings,
maternal NOEL and LOEL were 100 mg/kg/day and 400 mg/kg/day,
respectively. The developmental NOEL and LOEL were also
100 mg/kg/day and 400 mg/kg/day, respectively,
• Artificially inseminated New Zealand .white rabbits (17/group) were
exposed to 0; 20, 50 or 125 mg/kg/day hexazinone by gavage for
gestation days 6-19 (DuPont, 1980). Significant changes in maternal'
toxic effects were observed only in the high-dose group and included
increased incidence of depression and discharge from the eyes;
decreased body weight gain;, and increased resorptions. Treatment-
related developmental effects were observed also only in the high-
dose group and included decreased fetal body weight gain and delayed
ossification of extremities. Based on these findings, the NOEL and
LOEL for maternal toxicity were TO mg/kg/day and 125 mg/kg/day,
respectively. The NOEL and LOEL for davelopmental toxi.city were a) BO
50 mg/kg/day and 125 mg/kg/day, respectively. . ,
A ' '
Mutaoenicity ,
• The ability of hexazinone .to induce unscheduled DNA synthesis was
assayed by DuPont (1983) in freshly isolated•hepatocytea from 8-week-
old male Charles River/Sprague-Dawley rats. Hexazinone was tested at
half-log concentrations from 1 x 10~* to 10.0 mM and at 30.0 mM. No
unscheduled DNA synthesis was observed. .,
• DuPont (1982b) conducted an in vitro assay for chromosomal
aberrations in Chinese.hamster ovary cells. Hexazinone was found to
be clastogenic without S-9 -activation at concentrations of 15.85 mM
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Hexazinone
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September 1996
(4.0 mg/mL) or 19.82 mM (5.0 mg/mL); no significant increases in
clastogenic activity were seen at 1.58, 3'.94 and 7.93 mM (0.4, 1.0
and 2.0 mg/mL). With S-9 activation, significant increases in
aberrations were noted only at a concentration of 15.85 mM
(4.0 mg/mL). Concentrations above thsae yielded no analyzable
metaphase cells due to cytotoxicity.
In a study designed to evaluate the clastogenic-potential of
hexazinone in rat bone marrow cells (OuPont, 1982c), Sprague-Dawley
CD rats (12/sex/dose) were given a single dose of 0, 100, 300 or
1,000 mg/kg of hexazinone by gavage (vehicle not reported). No
statistically significant increases.in the frequency of chromosomal
aberrations were observed at any of the dose levels tested. The
authors concluded that, under the conditions of this study,
hexazinone was not clastogenic.
Hexazinone was tested for mutagenicity in Salmonella typhimurium
strains TA1535, TA1537, TA1538, TA98 and TA100 at concentrations up
to 2,OOO ^g/plate. The compound was not found to be mutagenic, with
or without S-9 activation {DuPont, 1977d).
Hexazinone was tested in Chinese hamster ovary (CHO)/hypoxanthine-
guanine-phosphoribosyltransferase assay (HGPRT), both withand without
activation. The compound was not found negative in both tests
(DuPont, 1992). .
CarcJ-nogenieity
* DuPont (1981) fed hexazinone (98% pure) for 2 years to mice
(80/sex/dose) in the diet at 0, 200, 2,500 or 10,000 ppm (0, 30, 375
or 1,500 mg/kg/day, based on Lehman (1959)). A number of liver
changes were observed histologically at the 2,500- and 10,000-ppm
level. These included hypertrophy of the centrilobular parehchymal
cells, increased incidence of hyperplastic liver nodules and liver
cell necrosis. The authors concluded that hexazinone was not
carcinogenic to mice. . . . ,
• No carcinogenic effects were observed in Crl-CD rats (36/sex/dose)
given hexazinone (94 to 96% pure) in the diet at 0, 200, 1,000 or
2,500 ppm (0, 10, 50 or 125 mg/kg/day} for 2 years {DuPont, 1977c? ,
Kennedy and .Kaplan, 1984). The authors concluded that none of the
tumors were attributable to hexazinone.
V.', QUANTIFICATION OF TOXICOLOGICRL EFFECTS
Health Advisories (HAs) are gor.arally tieiarmined loi: one-day, ten-day,
longer-term 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 the following formula:
HA
(NOAEL or LOAEL) x fBW)
(UP) x ( L/day)
mg/L (round
ed to
where:
NOAEL or LOAEL =
No- or Lowest'-Observed-Adverse-Ef feet-Level
mg/kg bw/day.
in
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Hexazinone
-13-
• September 1996
BW =• assumed body-weight 'of a child (10 kg) or an adult
(70'kg).
UF = ,uncertainty factor (10, 100, 1,000 or 10,000), in
accordance with EPA or National Academy of
Sciences/Office of Water (NAS/OW) guidelines.
L/day = assumed daily water consumption o€ a child (1 L/day) or
an adult (2 L/day).
One-day Health Advisory
No suitable information was found in the available literature for >
determining the One-day HA for hexazinpne. The Ten-day HA of 2,000 ^g/L>,
calculated below, is recommended for use as a conservative estimate for a
1-day exposure. • •
Ten-day Health Advisory , ' •
The developmental study in rabbits conducted by DuPont (1980c) has been
selected to serve as the primary basis for the Ten-day HA because it examined,
an exposure of the appropriate duration, and because it established both a
NOAEL and a LOAEL. In this study, artificially inseminated New Zealand white
rabbits (17/group) were exposed to 0, 20, 50 or 125 mg/kg/day hexazinone by
gavage during gestation days 6-19 . Significant changes in maternal toxic
effects were observed only in" the high-dose group and included increased'
incidence of depression and .discharge from the eyes, decreased body weight
gain1, and increased resorptions. Treatment-related developmental effects were
also observed only in the high-dose group, and included decreased fetal body
weight gain and delayed ossification of extremities. Based on these findings/
the NOAEL and LOAEL for both maternal arid developmental toxicity were 50
mg/kg/day and 125 mg/kg/day, respectively. These effect levels are generally
supported by two rat 'teratology 'studies. In rats fed 0, 200, 1,000 or 5,000
ppm of hexazinone (approximately 0, "10, 50 or 250 mg/kg/day) from gestation
days 6 through IS, no significant adverse maternal or fetal effects were
observed, except that, during treatment maternal weight gain was substantially
depressed at 5,000 ppm (Dupont, 1974). This study's NOAEL and LOAEL were thus
1,000 ppm (50 mg/kg/day) and 5,000 ppm;(25Q mg/kg/day),.respectively. The
second -study, in which rats were fed 6, 40, 100, 400 or 900 mg/kg/day of
hexazinone during gestation days 7 through 16, established both maternal and
developmental NOAELs and LOAELs of 100 mg/kg/day.and 400 mg/kg/day,
respectively. , In light of these three studies, the rabbit study (DuPont,
1980c) NOAEL of 50 mg'/kg/day has been selected as the basis of the Ten-day HA.
However, because- rabbit appears tobe more sensisitive than the, rat in these
developmental studies. However, a 90-day dietary exposure study in the dog
suggests that the rat and rabbit may not be the most sensitive test species
for the effects of hexazinone (DuPont, 1973c). Therefore, an extra.
uncertainty factor of three has been incorporated into the derivation of the
Ten-day HA to account for the lack of short-term toxicity data in the dog.
The Ten-day HA for the 10-kg child is calculated as follows:
(50 mQ/ko/davi 110 kg) _ mg/L '
rounded to 2,000 ug/L
fen-day HA =
where:
50 mg/kg/day
.NOAEL, based on absence of maternal systemic'and pup
developmental effects that were observed in rabbits
•after maternal exposure to hexazinone at "higher doses
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Hexazinone
-14-
September 1996
(125 mg/kg/day) via the diet for 10 days {gestation
days 6 through 155 . .
10 kg = assumed weight of child.
• 300 = uncertainty factor; this uncertainty factor was chosen
in accordance with EPA or NAS/OW guidelines in which a
NOAEL from an animal study is employed (a factor of 100
to account for interspecies extrapolation and
variability in human sensitivity, and a factor of 3 to
account for the lack of short-term toxicity data in the
dog, which appears to be the most sensitive test
species for hexazinone). ,
-1 L/dayv = assumed water consumption by a 10-kg child.
Longer-term Health Advisory
The two-generation rat study by DuPont (1991b) has been selected to serve
as the basis for the Longer-term HA because it was well conducted, provides
both a NOAEL and LOAEL, and results in the most conservative (lowest) Longer-
term HA. Groups of Sprague-Dawley rats (30/sex/group) were fed ad libitum
diets containing 0,,200, 2,000 or 5,000 ppm of hexazinone during growth,
mating, gestation and lactation in a 2-generation reproduction study . PI
rats were dosed for "73 days prior to mating, and Fl rats for 105 days prior
their first mating for theiF2A litters (longer for the F2B litters). Maternal
toxicity-effects were noted at the mid and high doses. Based on reduced body
weights and body-weight gains in PI and Fl females, the NOAEL and the LOAEL
for systemic effects were determined to be 200 and 2,000 ppm, respectively
(14.3 and 143 mg/kg/day, based on actual body weight and dietary consumption
data for PI females during the premating period. The respective values
calculated from data for Fl females were 17.7 and 180 mg/kg/day).. Male
fertility, female fertility, gestation, viability and lactation indices were
not affected by treatment. Increased absolute (PI) or relative (Fl) testes
weight at 5,000 ppm was not deemed toxicologically significant. Based upon
decreased pup weights observed at 2,000 and 5,000 ppm, the reproductive NOAEL
and LOAEL'were also determined to be 200 and 2,000 ppm (14.3 and 143
mg/kg/day), respectively. The 90-day feeding study in dogs conducted by
DuPont (1973c) was also strongly considered as a basis for deriving the
Longer-term 'HA. Based on altered food consumption, body weight gain/ -liver
weight, alkaline phosphatase activity and albumin/globulin ratios, this' study
established a NOAEL and LOAEL of 1,000 ppm (25 mg/kg/day) and 5,000 ppm (125
mg/kg/day), respectively. Because the true lowest-effect level cannot be
adequately identified in either study and because 73 to 105+ days more closely
approximates 10 percent of a rat's life than does 90 days for a dog (i.e., in
terms of duration, there was a relatively more appropriate longer-term
exposure for rats than for dogs), the rat reproduction study was selected as
the basis for the 'Longer-term HA determination. The dog study provides good
support for this level:
Longer-term HA
(14.3 mg/kg/day) .(10 kg)
(100) (1 L/day)
1.43
(Rounded to 1, 000 ug/L)
whe re:
14.3 mg/kg/day = NOAEL, based on absence of reduced maternal weight gain
•: and absence of reduced pup weight in rats exposed to
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Hexazinone
-15-
Septeraber 1996
hexazinone via the diet'for 73 to 105+ days prior to
mating and during gestation.'
10 kg = assumed body weight-of child.
100 = uncertainty factor; this uncertainty factor was chosen
in accordance with EPA or NAS/OW guidelines in which a
NOAEL from an animal study is employed.
1 L/day = assumed water consumption by a 10-kg child.
The Longer-term HA for the 70-kg adult is calculated as follows:
Longer-term HA =(14.3 mg/kg/day) (70 kg)
(100) (2 L/day)
where:
= 5.25 mg/L
(Rounded to 5,0,00 ug/LJ
14.3 mg/kg/day
70 kg
100
NOAEL, based on absence of reduced maternal weight -gain
and absence of reduced pup weight in rats exposed to
hexazinone via the diet for 73 to 105+ days prior to
mating and during,gestation.
assumed weight of adult.
i
uncertainty factor, chosen in accordance with EPA or
NAS/OW guidelines for use with a NOAEL from an animal
'study.
2 L/day = assumed water consumption by a 70-kg 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
noncarcinogenic 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
estimate of a daily exposure to the human population that is likely to'be
without 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^1003
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, i'f
data is not available, a value of 20% .is assumed. If the contaminant is
•classified as a known, probable or possible carcinogen,, according to the
Agency's classification scheme of carcinogenic potential (U.S. EPA, 1986),
then caution must be exercised in making a decision on how to deal with
possible lifetime exposure to this substance. For human (A) or probable human
(B) carcinogens,' a Lifetime HA is not recommended. For possible human
carcinogens (,C), an additional 10-fold safety factor is used to-calculate the
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Hexazinone
'-16-
September 1996
Lifetime HA. The-risk manager must balance this assessment of carcinogenic
potential and the quality of the data against the likelihood of occurrence and
significance of health effects related to noncarcinogenic end points of
toxicity. To assist the risk manager in this process, drinking water
concentrations associated with estimated excess lifetime cancer risks over the
range of 1 in 10,000 to 1 in 1,000,000 for the 70-kg adult drinking 2 L of
water/day are provided in the Evaluation of Carcinogenic Potential section.
The one-year dog-feeding study by DuPont (1991a> has been selected to
serve as the basis for the RfD because it was a well conducted study that
established both a NOAEL and a-LOAEL^for relatively less severe effects, and
because the dog may be more sensitive than .rodent species to the toxic effects
of hexazinone. In this study, groups of purebred beagle dogs (5/sex/group) .
were fed ad libitum 0, 200, 1,500 or'6,000 ppm of hexazinone .in their diet for
12 months (DuPont, 1991a). Based on monitored food consumption, these doses
corresponded to 0, 5.00, 41.24 and 161.48 mg/kg/day in males, and 0, 4.9"7,
37.57 and 166.99 mg/kg/day in females. Increased SAP, serum.globulin and
hepatocellular vacuolation, as well as decreased serum albumin were reported
for males at the mid dose. Increased hepatocellular pigmentation and
concentric membranous bodies, and decreased serum albumin were reported for
females at the mid dose. Also at this high dose level, one male appeared
emanciated and one female had ale kidneys. Additional gross, histological,
hematological and enzymatic effects were reported in the. high-dose animals,
while no significant effects were "observed at the low dose. The study thus
establishes a chronic oral NOAEL of 200 ppm, or 5.0 mg/kg/day, of hexazinone
in the diet. The LOAEL was determined to be 1,500 ppm, or 41.24 rag/kg/day, for
males and 37.57 mg/kg/day for females. , '
Step 1: Determination of Reference Dose (RfD)
Based upon the DuPont (1991a) one-year dog-feeding study described above,
and using a 100-fold uncertainty factor to account for intra- and inter-
species variation, an RfD of O.05 mg/kg/day can be established for hexazinone.
RfD* = 5 mg/kg/day
100
0.05 mg/kg/day
*This RfD was peer, reviewed by 'both the Office of Pesticide Programs Peer
Review Committee and the Office of Water Toxicology Review Panel. Further
external peer review of 'the RfD was performed by two external reviewers.
However, due to the 'Agency's revision of the IRIS operational procedures,
the RfD calculated above for this chemical is not on IRIS.
Step 2: Determination of the Drinking Water Equivalent Level (DWEt,)
- (0.05 mg/kg/day) (70 kg) _
- -• <2 L/day) ~ 1'?
(Rounded to 2,000 ug/L)
where: .
0.05 mg/kg/day = RfD ' . -
70 kg * assumed weight of adult.
2 L/day = , assumed water consumption by 70-kg adult.
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Hexaizihone
-17-
September 1996
Step 3: Determination of the Lifetime HA
. Lifetime HA = (1.75 mg/L) (20%) = 0.35 mg/L (rounded to 400 ug/L)
where: - .
• , i
1.75 mg/L = Lifetime HA at 1004 contribution from ingestion of
drinking water.
20% = assumed percentage of daily exposure, contributed by,
ingestion of drinking water.
Evaluation of Carcinogenic Potential
V
• A reassessment of the available carcinogenicity studies in two rodent
"" species, a two-year mouse study by DuPont (1981), and a two-year rat
study by Kennedy and Kaplan (1984), did not provide' evidence that
hexazinone demonstrate either the presence or absence of a
carcinogenic effect. Therefore", applying the criteria described in
EPA's guidelines for assessment of carcinogenic risk (U.S. EPA,
1986), hexazinone may be classified in Group D: not classified.
This category is for agents with inadequate animal evidence of
carcinogenicity." ,
• The -International Agency' for Research on Cancer has not evaluated the
carcinogenic potential of hexazinone. ' • • _ -
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS ' ,
• The tolerances listed in 40 CFR §180.396 for the combined residues of
hexazinone and its metabolites in or on plant and animal commodities .
range from 0.1 to 10 ppm (U.S. EPA, 1994a, 1987).
• Hexazinone meets the triggers for classification as a restricted-use
chemical for .groundwater concerns (U.S. EPA, 1996).'
• Under the Worker Protection Standard (WPS), the interim restricted.
• entry level for all registered uses of hexazinone is currently
24 hours (U.S. EPA, 1994a) . •'
• There are ..no special toxicological concerns that warrant the
establishment of active-ingredient-based personal protective
equipment (PPE) requirements'for hexazinone handlers. The PPE
required for entry when concentrations of the chemical require
restricted entry is: coveralls, chemical-resistant gloves, shoes
plus socks, and protective eyewear (U.S. EPA, 1994a).
VII..ANALYTICAL METHODS '
• Hexazinone. can be analyzed by EPA Method 507..
Determination of'hexazinone using Method 507 — sample'is extracted
with methylene chloride. The methylene chloride extract is dried, and
concentrated during a solvent exchange to methyl tert-butyl ether.
The analytes "in, the extract are separated and identified by a
capillary column gas chromatograph equipped 'with a nitrogen-
-------
Hexazinone September 1996
-18-
phosphorus detector. Confirmation of the compounds may be obtained
using a dissimilar column or by the use of GC-MS (U.S. EPA, 1991).
VIII. TREATMENT TECHNOLOGIES
». A pilot-scale treatability study for the removal of pesticides
including hexazinone was conducted on production wastewaters at
•DuPont in Laporte, Texas. The plant consisted o.f a 100 L aeration
basin, clarifier and sarid filter, and the treatment process included
. > the addition of'powdered activated carbon to the activated sludge.
Operating conditions reported were: hydraulic retention time of 2.1
days, solids retention time of 10 days, and carbon dose of 1,480
mg/L. A 96.2% removal was achieved for hexazinone with an influent
concentration of approximately 658 ^g/L (Meidl and Dietrich, 1989) .
No information was found in the available literature on treatment technologies
used to remove hexazinone from contaminated water.
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Hexazinone
-19-
September 1996
IX. REFERENCES , , .
.• i
Austin Bradford, 1994. Ground Water Monitoring Activities, South Platte River
Alluvial .aquafier, 1992-1993, Report to the Commissioner of Agriculture,
Colorado Department of Agriculture, Colorado department, of Health.
Budavari, S., M.J. O/Neil, A. Smith and P.E. Heckleman, eds. 1989.
.index, eleventh ed. Rahway, NJ: Merck and Co., Inc., p. 742.
The Merck
CHEMLAB. 1985. The- Chemical Information System, CIS, Inc. Baltimore, MD.
DuPont. 1992. E.I. du Pont de Nemours and Company. Mutagenicity Study in
.Chinese Hamster Ovaries (CHO) /Hypoxanthine-Guanine-.Phosphoribosyltransferase
Assay (HGPRT) with and without Acivation. MRID % 00076956.
DuPont. 1991a. E.I. du Pont de Nemours and Company, chronic toxicology
study with hexazinone in dogs. MRID No. 421623-01; HED/OPP Doc. No. 009575. c"
DuPont. 1991b. E.I. du Pont.de Nemours and Company. Reproductive and
fertility effects with IN-A3674-207; multigeneration reproduction study in
rats.. MRID No. ,420665-01; HED/OPP. Doc . No. 009574. Ul
DuPont. 1987. E.I. du Pont de Nemours and Company. Developmental toxicity
'study in the rat. MRID No. 403975-01; 'HED/OPP Doc. No. 007205. "'
DuPont. 1983. E.I. du Poht de Nemours an'd Company. Unscheduled DNA
synthesis/rat hepatocytes in vitro. (INA-3674-112) . ' Haskell Laboratory
report no. 766-82 (study authored by Ford, L. ) MRID 00130708.'"
DuPont. 1982a. E.I. du Pont de Nemours and Company. Metabolism of JIC- -
•labeled hexazinone in the rat (study authored by Rapisarda, C.). Document no.
AMR-79-82. Accession No. 247847.".'
DuPont. 1982b. In vitro assay for chromosome aberrations in Chinese Hamster
Ovary (CHO) cells. Haskell Laboratory report no. 768-82 (study authored by
Vlachos, D., J. Mart'enis and A. HorstJ . MRID 00130709. U)
DuPont. 1982c. E.I. du Pont de Nemours and Company. In vivo bone marrow
cytogenetic assay in rats. . HLA Project rib: ,201-573 . Final report (study
authored by Farrow, M., T. Cartina, M. Zito et al.). MRID 0013155. M.
() This study was submitted to the U.S. EPA Office of,Pesticide Programs and
is subject to Section 10 (Protection of Trade Secrets and Other
Information) of the U.S'. Federal Insecticide, Fungicide and Rodenticide
Act (FIFRA). Section 10 prohibits public disclosure of confidential
business information. , . .
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Hexazinone
-20-
September 1996
DuPont. 1981. E.I. du Pont de Nemours and Company. Two-year feeding study
in mice (study authored by Goldenthal, E.I. and R.R. Trumbull; study published
in 1984 by Kennedy, Jr., G.L and A.M. Kaplan as: Chronic toxicity,
reproductive, x and teratogenic studies of hexazinone. Fund. Appl. Toxicol. -
4:960-971). IRDC No. 125-026. MRIDNo. OO79203, 413593-01, 425093-01;
HED/OPP Doc. No. 001355, 007205, 008659, 008658 .'".
" i 4
DuPont. 1981. E.I. du Pont de Nemours and Company. Two-year feeding study
in mice (study authored by Goldenthal, E.I. and R.R. Trumbull; study published
in 1984 by Kennedy, Jr., G.L and A.M. Kaplan as: Chronic toxicity,
reproductive, and teratogenic studies of hexazinone. Fund. Appl. Toxicol.
4:960-971). IRDC No. 125-026. MRIDNo. OO79203, 413593-01, 425093-01;
HED/OPP Doc. No. 001355, 007205, 008659, 008658. tbl
DuPont. 1980a. E.I. du Pont de Nemours and Company. Eye irritation tests in
rabbits — United Kingdom Procedure. Haskell Laboratory report no. 839-80
(study authored by Dashiell, O.L. and J.E. Henry). MRID 00076958.'"
DuPont. 1980b. E.I. du Ront de Nemours and Company. Oral LD5(1 test in
rats — EPA proposed guidelines. Haskell Laboratory report no. 943-80 (study
authored by Dashiell, O.L. and L. Hinckle) . MRID 00062980. ul
DuPont. 1980c. E.I. du Pont de Nemours- and Company. Developmental toxicity
study in the rabbit (study published in 1984 by Kennedy, Jr., G.L and A.M.
Kaplan as: Chronic toxicity, reproductive, and teratogenic studies of
.hexazinone. Fund. Appl. Toxicol. 4:960-971). MRIDNo. 0.0028863; HED/OPP
Doc. No. 00230, 007205. , ' -
DuPont. 1979a. E.I. du Pont de Nemours and Company. Residues resulting from
application of DPX-3674 to soil (study authored by Holt, R.F.). Wilmington,
DE: E.I. du Pont de Nemours and "Company, Inc. •
/'
DuPont. 197 9b. E.I. du Pont de Nemours and Company. Hexazinone livestock
feeding studies; milk and meat (study authored by Holt, R.F.. , F.J. Baude and
D.W. Moore. MRID 00028657.""
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reproduction study in the rat. Haskell Laboratory Report No. 35377 (study
published in 1984 by" Kennedy, Jr., G.L and A.M. Kaplan as: chronic toxicity,
reproductive, and teratogenic studies of hexazinone. Fund. Appl. Toxicol.
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weed killer in the rat (study authored by Rhodes, R., R.A. Jewel.! and H.
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00028864. ul * . .
DuPont. 1977a. E.I. du Pont de Nemours and Company. Oral LD5() test.
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' 0011477. Ul
MRID
{) This study was submitted to the U.S. EPA Office of Pesticide Programs and
• . La subject to Section 10 (Protection of Trade Secrets and Other
information) of the U.-S. Federal Insecticide, Fungicide and Rodenticide
Act (FIFRA). Section 10 prohibits public disclosure of confidential
- business information. . • • .
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Hexazihone
-21-
September 1996
DuPont. 1977b. E.I. du Pont de Nemours and Company. Acute skin absorption
test on rabbits LD5|j. Haskell Laboratory report.no. 841-77 (study authored by
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in rats with hexazinone: Haskell -Laboratory Report No: 353-77 (study authored
by Kaplan, A.M., C.V. Frazier, L.L. Adams, et al.; study published in 1984 by
Kennedy, Jr., G.L and A.M. Kaplan as: Chronic toxicity/ reproductive, and
teratogenic studies of hexazinone. Fund. Appl. Toxicol. 4:960-971). MRID No.
00078045, 00108686-38; HED/OPP DOC. No. 002331, 007205."'.
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Gene mutation assay in
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00063971. U)
i
DuPont. 1976b. E.I. du Pont de Nemours and Company. Primary skin irritation
and sensitization tests on guinea pigs. Haskell Laboratory Report no. 434-76
(study authored by Goodman, N). MRID 00104433.'" " ' ,
\ . ^
DuPont.- 1975a. E.I. du Pont de Nemours and Company. 'Studies with'"Velpar"-
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Company, Inc. -••"•'•
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(a) 'This study was submitted to the USEPA Office of Pesticide Programs and.is
is subject to Sen 10 (Protection of Trade Secrets and Other Information) of
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10 prohibits public disclosure of confidential business information.
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Hexazinone
-22-
September 1996
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DuPont. 1973b. E.I. du Pont de Nemours and Company. Skin-absorption
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i
DuPont. 1973c. E..I. du Pont de Nemours and Company. Three month feeding
study in dogs with sym-triazine-2,4{1H,3H)dione, 3-cyclohexyl-l-methyl(-6-
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September 1996
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