820K88145
August, 1987
HEXAZINONE
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, Logif 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 thar another.
Btcause each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
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Hexazinone August, 1987
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II. GENERAL INFORMATION AND PROPERTIES
CAS No.: 51235-04-2
Structural Formula:
a
• V
.A
CH,
3-Cyclohexyl-6-(dimethylamino)-1 methyl-1,3,5-triazine-2, 4( 1H, 3H)-dione;
Synonyms
0 Velpar; Hexazinone.
Use
0 Contact and residual herbicide (Meister, 1983).
0 Usage areas include plantations of coniferous trees, railroad right-
of-ways, utilities, pipelines, petroleum tanks, drainage ditches, and
sugar and alfalfa (Kennedy, 1984).
Properties (Kennedy, 1984; CHEMLAB, 1985)
Chemical Formula C11H20°2N3
Molecular Weight 226 (calculated)
Physical State (25°C) White crystalline solid
Boiling Point —
Melting Point 115-117°C
Density
Vapor Pressure (86°C) 6.4 x 10~5 mm Hg
Specific Gravity
Water Solubility (25°C) 33,000 mg/L
Log Octanol/Water Partition -4.40 (calculated)
Coefficient
Taste Threshold
Odor Threshold odorless
Conversion Factor
Occurrence
0 Hexazinone has been found in none of the surface water samples
or ground water samples analyzed from 13 samples taken at 6
locations (STORET, 1987).
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Hexazinone August, 1987
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Environmental Fate
0 Hexazinone did not hydrolyze in water within the pH range of 5.7 to 9
during a period of 8 weeks (Rhodes, 1975a).
0 In a soil aerobic metabolism study, hexazinone was added to a Fallsington
sandy loam and a Flanagan silt loam at 4 ppm. I4c-Hexazinone residues
had a half-life of about 25 weeks. Of the extractable 14c residues,
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)-dione
and the triazine trione (Rhodes, 1975b).
0 A soil column leaching study used 14c-hexazinone, half of which was
aged for 30 days and applied to Flanagan silt loam and Fallsington
sandy loam. Leaching with a total of 20 inches of water showed that
unaged hexazinone leached in the soils; however, leaching rates were
slower for the aged samples, indicating that the degradation products
may have less potential for contaminating ground water (Rhodes, 1975b).
0 A field soil leaching study indicated that l^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, ^4C residues were found at all depths measured, including
the 8- to 12-inch depth, when total rainfall equaled 8.43 inches,
1 month after application of hexazinone. 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).
0 A soil TLC test for Fallsington sandy loam and Flanagan silt loam
gave Rf 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).
0 In a terrestrial field dissipation study using a Keyport silt loam
in Delaware, 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). Tn 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).
III. PHARMACOKINETICS
Absorption
0 Rapisarda (1982) reported that a dose of 14 mg/kg 14c-labeled
hexazinone (>99% pure) was about 80% absorbed in 3 to 6 days
(77% recovery in urine, 20% in feces) when administered by gastric
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Hexazinone November 11, 1986
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intubation to male and female Charles River CD rats with or without
3 weeks of dietary preconditioning with unlabeled hexazinone.
0 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) 14c-labeled hexazinone. The hexazinone
was rapidly absorbed within 72 hours, with 61% detected in the urine
and 32% in the feces. Trace amounts were found in the gastro-
intestinal (GI) tract (0.6%, tissues not specified) and expired air
(0.08%).
Distribution
8 Orally administered hexazinone has not been demonstrated to accumulate
preferentially in any tissue (Rhodes et al., 1978; Holt et al., 1979;
Rapisarda, 1982).
0 Studies in rats by Rapisarda (1982) and Rhodes et al. (1978) showed
that no detectable levels of 1^C-hexazinone were found in any body
tissues when the animals were administered >14 mg/kg hexazinone by
gastric intubation with or without dietary preconditioning.
0 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 mg/kg/day. The investigators
reported no detectable residues in milk, fat, liver, kidney or lean
muscle.
Metabolism
0 Major urinary metabolites of hexazinone in rats identified by Rhodes
et al. (1978) were 3-(4-hydrocyclohexyl)-6-(dimethylamino)1-methyl-
1,3,5-triazine-2,4-(lH,3H)-dione (metabolite A); 3-cyclohexyl-6-
(methylamino)-1-methyl-1,3,5-triazine-2,4-(1H, 3H)-dione (metabolite B);
and 3-(4-hydrocyclohexyl)-6-(methylamino)-!-methyl-1,3,5-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
14c-hexazinone and/or its metabolites occurs mostly in the urine
(61 to 77%) and in the feces (20 to 32%).
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Hexazinone August, 1987
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IV. HEALTH EFFECTS
Humans
The Pesticide Incident Monitoring System data base (U.S. EPA, 1981)
indicated that 3 of 43,729 incident reports involved hexazinone.
Only one report cited exposure to hexazinone alone, without other
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.
Animals
Short-term Exposure
0 Reported oral LD^g values for technical-grade hexazinone in rats range
from 1,690 to >7,500 mg/kg (Matarese, 1977; Dashiell and Hinckle,
1980; Kennedy, 1984).
0 Henry (1975) and Kennedy (1984) reported the oral LD50 value of
technical-grade hexazinone in beagle dogs to be >3,400 mg/kg.
0 Reported oral LD5Q values for hexazinone in guinea pigs range from
800 to 860 mg/k9 (Dale, 1973; Kennedy, 1984).
0 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, 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 either
active ingredient percentage of hexazinone.
0 In an 8-week range-finding study (Kennedy and Kaplan, 1984), Charles
River CD-1 mice (10/sex/ddse) 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 food 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 liver 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.
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Hexazinone August, 1987
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Dermal/Ocular Effects
0 In an acute dermal toxicity test performed by MeAlack (1976), 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. No
deaths were observed throughout a 14-day observation period.
0 Morrow (1973) 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.
0 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 glutamic pyruvic-transaminase (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.
0 Edwards (1977) applied 6,000 mg/kg hexazinone as a 63% solution occlu-
sively to the shaved backs and trunks of male albino rabbits. No
treatment-related mortalities were reported after a 14-day observation
period.
0 Morrow (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 sensitization,
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.
0 Using a 10% solution, Goodman (1976) repeated the Morrow study with
guinea pigs and observed no irritation or sensitization.
0 Dashiell and Henry (1980) reported that in albino rabbits, a single
dose of hexazinone applied as 27% (vehicle not specified) solution to
one eye per animal and 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 35-day
observation period in one of the three eyes. Eyes treated with lower
doses were normal within 3 days.
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Hexazinone August, 1987
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Long-term Exposure
0 In a 90-day feeding study, Sherman et al. (1973) 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 alkaline phosphatase
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
(25 mg/kg/day) and a Lowest-Observed-Adverse-Effect-Level (LOAEL) of
5,000 ppm (125 mg/kg/day) were identified.
0 In a 90-day feeding study (Kennedy and Kaplan, 1984), Crl-CD rats
(16/sex/dose) received hexazinone (>98% pure) at dietary levels of
0, 200, 1,000 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, 50 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).
0 In a 1-year feeding study (Kaplan et al., 1975) weanling Charles River
CD rats (36/sex/dose) received hexazinone (94 to 96% pure) at dietary
levels of 0, 200, 1,000 or 2,500 ppm (which, according to the authors,
corresponds to 0, 11, 60 or 160 mg/kg/day for males and 0, 14, 74 or
191 mg/kg/day for females). Results of this study indicated a decrease
in weight gain by both sexes at 2,500 ppm and by females at 1,000 ppm.
The authors indicated that various unspecified clinical, hematological
and biochemical parameters revealed no evidence of adverse effects.
No significant gross or histopathological changes attributable to
hexazinone were noted. From the information presented in the study,
a NOAEL of 200 ppm (11 mg/kg/day for males and 14 mg/kg/day for
females) can be identified.
0 In a 2-year study, Goldenthal and Trumball (1981) fed hexazinone
(95 to 98% pure) to Charles River CD-1 mice (80/sex/dose) at dietary
levels of 0, 200, 2,500 or 10,000 ppm. Assuming that 1 ppm in the
diet of a mouse equals 0.15 mg/kg/day (Lehman, 1959), these levels
correspond to 0, 30, 375 or 1,500 mg/kg/day. Corneal opacity sloughing
and discoloration of the distal tip of the tail were noted as early
as the fourth week of the study in 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 increases in liver weight were
noted in male mice receiving 10,000 ppm; male and female mice in the
10,000-ppm dose group also displayed statistically significant increases
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Hexazinone August, 1987
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in relative liver weight. Sporadic occurrence of statistically
significant changes in hematological effects were considered by
the authors to be unrelated to hexazinone treatment. Histologically,
a number of liver changes were observed among mice fed 2,500 or
10,000 ppm. The most characteristic finding was hypertrophy of
centrilobular parenchymal cells. Other histological changes included
an increased incidence of hyperplastic liver nodules and an increased
incidence and severity of liver cell necrosis. Mice fed 200 ppm
showed no compound-related histopathological changes. A NOAEL of
200 ppm (30 mg/kg/day) was identified by the authors.
0 Kennedy and Kaplan (1984) 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. Males fed 2,500 ppm and females fed either 1,000 or 2,500
ppm had significantly lower body weights than controls (p 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/day.
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).
0 In a three-generation reproduction study (DuPont, 1979), Crl-CD rats
(36/sex/dose) received hexazinone (98% pure) at dietary levels of 0,
200, 1,000 or 2,500 ppm for 90 days (approximately 0, 10, 50 or 125
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Hexazinone August, 1987
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"ig/kg/day, assuming the above assumptions for a rat). Following
90 days of feeding, 20 rats/sex/dose were selected to serve as the
parental (Fg) 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 serve as parental rats for the second
generation. Similar procedures were used to produce a third generation;
the same reproductive parameters were collected for the second and
third generations. The authors stated that there were no significant
differences between the control and treated groups with respect to
the various calculated indices (fertility, gestation, viability and
lactation). However, 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. The results of this study identify a
NOAEL of 1,000 ppm (50 mg/kg/day).
Developmental Effects
8 Kennedy and Kaplan (1984) presented the results of a study in which
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 (approxi-
mately 0, 10, 50 or 250 mg/kg/day following the previously stated
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 sacrificed and ovaries
and uterine horns were weighed and examined. The number and location
of live fetuses, dead fetuses and resorption sites were noted.
Fetuses from the 0 and 5,000 ppm dose groups were evaluated for
developmental effects (gross, soft tissue or skeletal abnormalities).
At sacrifice, no adverse effects were observed for the dams. No
malformations were noted in the fetuses. However, pup weights in the
high-dose group were significantly lower than in the controls. This
study identified a NOAEL of 1,000 ppm (50 mg/kg/day).
0 Kennedy and Kaplan (1984) presented the results of a study in which
New Zealand white rabbits (17/dose) received hexazinone suspended in
a 0.5% aqueous methyl cellulose vehicle by oral intubation on days 6
through 19 of gestation at levels of 0, 20, 50 or 125 mg/kg/day.
Rabbits were observed daily and body weights were recorded throughout
gestation. On day 29 of gestation, all rabbits were sacrificed, uteri
were excised and weighed, and the number of live, dead and resorbed
fetuses was recorded. Each fetus was examined externally and internally
for gross, soft tissue and skeletal abnormalities. No clinical signs
of maternal or fetal toxicity were observed. Pregnancy rates among
all groups compared favorably. The numbers of corpora lutea and
implantations per group were not significantly different. Resorptions
and fetal viability, weight and length were also similar among all
groups. Based on the information presented in this study, a minimum
NOAEL of 125 mg/kg/day for maternal toxicity, fetal toxicity, and
teratogenicity can be identified.
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Hexazinone August, 1987
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Mutagenicity
0 The ability of hexazinone to induce unscheduled DNA synthesis was
assayed by Ford (1983) in freshly isolated hepatocytes from the livers
of 8-week-old male Charles River/Sprague-Dawley rats. Hexazinone
was tested at half-log concentrations from 1 x 10~5 to 10.0 mM and at
30.0 mM. No unscheduled DNA synthesis was observed.
0 Valachos et al. (1982) 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
(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 aber-
rations were noted only at a concentration of 15.85 mM (4.0 mg/mL).
0 In a study designed to evaluate the clastogenic potential of hexazinone
in rat bone marrow cells (Farrow et al., 1982), Sprague-Dawley CD rats
(12/sex/dose) were given a single dose of 0, 100, 300 or 1,000 mg/kg
of the 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.
0 Hexazinone was tested for mutagenicity in Salmonella typhimurium
strains TA1535, TA1537, TA1538, TA98 and TA10O at concentrations up
to 7,000 ug/plate. The compound was not found to be mutagenic, with
or without S-9 activation (DuPont, 1979).
Carcinogenicity
0 Goldenthal and Trumball (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 lag/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
parenchymal cells, increased incidence of hyperplastic liver nodules
and liver cell necrosis. The authors concluded that hexazinone was
not carcinogenic to mice.
0 No carcinogenic effects were observed in C.:1-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 (Kennedy and
Kaplan, 1984). The authors concluded that none of the tumors were
attributable to hexazinone.
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 the following formula:
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Hexazinone August, 1987
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HA = (NOAEL or LOAEL) X (BW) , /L ( u /L)
(UF) x ( L/day)
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day.
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
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 information was found in the available literature that was suitable
for determination of the One-day HA for hexazinone. It is, therefore,
recommended that the Longer-term HA value of 2.5 mg/L (2,500 ug/L, calculated
below) for a 10-kg child be used at this time as a conservative estimate of
the One-day HA value.
Ten-day Health Advisory
The study reported by Kennedy and Kaplan (1984) in which pregnant rabbits
(17/dose) received hexazinone by oral intubation at levels of 0, 20, 50 or
125 mg/kg/day on days 6 through 19 of gestation was considered to serve as
the basis for deriving the Ten-day HA for a 10-kg child. Since no signs of
maternal or fetal toxicity were observed in this study, a NOAEL of 125 mg/kg/day
(the highest dose tested) was identified. The NOAEL from this study is
greater than that identified in a 90-day rat feeding study (50 mg/kg; Kennedy
and Kaplan, 1984). The LOAEL from the one-generation rat reproduction study
was 250 mg/kg based on decreased weanling weight. Effects at doses between
50 and 250 mg/kg have not been reported for the rat. However, in a 90-day
dog study, a LOAEL of 125 mg/kg was identified (Sherman et al., 1973).
Therefore, the rabbit study was hot selected to derive a Ten-day value.
It is, therefore, recommended that the Longer-term HA value of 2.5 mg/L
(2,500 ug/L) for the 10-kg child be used at this time as a conservative
estimate of the Ten-day HA value.
Longer-term Health Advisory
The 90-day feeding study in dogs (Sherman et al., 1973) has been selected
to serve as the basis for determination of the Longer-term HA for hexazinone.
In this study, dogs received hexazinone in the diet at levels of 0, 200,
1,000 or 5,000 ppm (0, 5, 25, or 125 mg/kg/day) for 90 days. Decreased food
consumption and body weight gain, elevated alkaline phosphatase activity,
lowered albumin/globulin ratios and elevated liver weights were observed at
the highest dose. A NOAEL of 1,000 ppm (25 mg/kg/day) and a LOAEL of 5,000 ppm
(125 mg/kg/day) were identified. This NOAEL is generally supported by a 90-day
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Hexazinone August, 1987
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rat feeding study that reported a NOAEL of 50 mg/kg/day (Kennedy and Kaplan,
1984). Effects in dogs exposed to hexazinone at 50 mg/kg/day have not been
reported.
Using a NOAEL of 25 mg/kg/day, the Longer-term HA for a 10-kg child
is calculated as follows:
Longer-term HA = (25 mg/kg/day) (10 kg) = 2.5 mg/L (2,500 ug/L)
(100) (1 L/day)
where:
25 mg/kg/day = NOAEL, based on absence of hepatic effects or weight loss
in dogs exposed to hexazinone via the diet for 90 days.
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 a 70-kg adult is calculated as follows:
Longer-term HA = (25 mg/kg/day) (70 kg) , 8<75 /L (8,75o Ug/L)
(100) (2 L/day)
where:
25 mg/kg/day = NOAEL, based on absence of hepatic effects or weight
loss in dogs exposed to hexazinone via the diet for
90 days.
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
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
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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. Itie 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 rat feeding/oncogenicity study (Kennedy and Kaplan, 1984) was
selected as the basis for determination of the Lifetime HA for hexazinone.
Crl-CD rats (36/sex/dose) received 0, 200, 1,000, or 2,500 ppm hexazinone (0,
10, 50, or 125 mg/kg/day) for 2 years. Body weight gain in males and females
in the 2,500-ppm group, and females in the 1,000-ppm group, was significantly
lower than that in controls. No clinical, hematological or urinary evidence
of toxicity was reported. Based on decreased body weight gain, a NOAEL of
200 ppm (10 mg/kg/day) and LOAEL of 1,000 ppm (50 mg/kg/day) were identified.
Using a NOAEL of 10 mg/kg/day, the Lifetime HA is calculated as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD = (10 mg/kg/day) = 0.03 mg/kg/day
(100) (3)
where:
10 mg/kg/day = NOAEL, based on absence of body weight effects in rats
exposed to hexazinone via the diet for 2 years.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
3 = modifying factor; to account for data gaps (chronic
dog-feeding study) in the total data base for hexazinone.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (0.03 mg/kg/day) (70 kg) . 1<05 mg/day (1,050 ug/L)
(2 L/day)
where:
0.03 mg/kg/day = RfD.
70 kg = assumed body weight of an adult.
2 L/day = assumed daily water consumption of an adult.
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Hexazinone August, 1987
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Step 3: Determination of Lifetime Health Advisory
Lifetime HA = (1.05 mg/L) (20%) = 0.21 mg/L (210 ug/L)
where:
1.05 mg/L = DWEL.
20% = assumed relative source contribution from water.
Evaluation of Carcinogenic Potential
0 No evidence of carcinogenicity in rats or mice has been observed.
0 The International Agency for Research on Cancer has not evaluated
the carcinogenic potential of hexazinone.
0 The criteria described in EPA's guidelines for assessment of car-
cinogenic risk (U.S. EPA, 1986), place hexazinone in Group D: not
classified. This category is for substances with inadequate animal
evidence of carcinogenicity.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 Residue tolerances range from 0.5 to 5.0 ppm for the combined residues
of hexazinone and its metabolites in or on the raw agricultural
commodities pineapple, pineapple fodder and forage (U.S. EPA, 1985a).
VII. ANALYTICAL METHODS
0 Analysis of hexazinone is by a gas chromatographic method applicable
to the determination of certain organonitrogen pesticides in water
samples (U.S. EPA, 1985b). This method requires a solvent extraction
of approximately 1 liter of sample with methylene chloride using a
separatory funnel. The methylene chloride extract is dried and
exchanged to acetone during concentration to a volume of 10 mL or
less. The compounds in the extract are separated by gas chromatography,
and measurement is made with a thermionic bead detector. The method
detection limit for hexazinone is 0.72 ug/L.
VIII. TREATMENT TECHNOLOGIES
0 No information was found in the available literature on treatment
technologies used to remove hexazinone from contaminated water.
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August, 1987
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