August, 1987
820K88104 FIR APT
CYANAZINE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program,- sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for one-day, ten-day, longer-term
(approximately 7 years, or 10% of an individual's lifetime) and lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
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II. GENERAL INFORMATION AND PROPERTIES
CAS No. 21725-46-2
Structural Formula
HC = kJ
w—PI
N-C(CH,)2
N
H
-[ [4-Chloro-6-(ethylamino)-1 , 3, 5-triazin-2-yl]amino]-2-methylpropanenitrile
Synonyms
e Cyanazine (common name), Bladex, Fortrol, Payze, SD1518, VL19804,
DW3418 and WL19805 (Meister, 1983).
Uses
0 Cyanazine is used as a pre- and postemergence herbicide for the
control of annual grasses and broad leaf weeds (U.S. EPA, 1984a).
Properties (U.S. EPA, 1984a; Meister, 1983; CHEMLAB, 1985)
Chemical Formula CgH
Molecular Weight 240.7
Physical State ( °C) White crystalline solid
Boiling Point
Melting Point 167.5 to 169°C
Density 0.35 (fluffed) to 0.45 (packed) g/cc
Vapor Pressure (20°C) 1.6 x 10-9 to 7.5 x 10-9 mm Hg
Water Solubility (259C) 171 mg/L
Log Octanol/Water Partition 2.24
Coefficient
Taste Threshold
Odor Threshold
Conversion Factor
Occurrence
A range of 0.0 to 900 ug/L of cyanazine in water from the analyses of
1,790 samples of water and whole water (water plus sediment) has been
reported using the U.S. EPA STORET (1987) data base. A total of
seven sediment-only samples were analyzed and found to have a range
of 0.008 to 0.10 mg/kg cyanazine.
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0 Cyanazine was identified in drinking water in New Orleans, Louisiana,
in concentrations ranging from 0.01 to 0.35 ug/L.
0 Cyanazine was monitored in a newly-built reservoir on the Des Moines
River in Iowa during September 1977 through November 1978. Agri-
cultural runoff (from corn and soybeans) was a major source of
pollution in the river: levels of 71 to 457 ng/L were detected
during the active months of May through August; levels of 2 to 151
ng/L wre detected during September through December; and zero levels
were found from January through April (U.S. EPA, 1984a; NAS, 1977).
0 Cyanazine has been found in surface water in Ohio river basins
(Datta, 1984).
0 Cyanazine has also been found in ground water in Iowa and Pennsylvania;
typical positives found were 0.1 to 1.0 ppb (Cohen et al. , 1986).
0 Cyanazine has been found in 4,312 of 4,285 surface water samples
analyzed and in 21 of 1,564 ground water samples (STORET, 1987).
Samples were collected at 337 surface water locations and 1,066 ground
water locations, and cyanazine was found in 11 states. The 85th
percentile of all non-zero samples was 4.11 ug/L in surface water and
.20 ug/L in ground water sources. The maximum concentration found in
surface water was 900 ug/L and in ground water it was 3,500 ug/L.
Environmental Fate
0 14c-Cyanazine, at 5 to 10 ppm, degraded with a half-life of 2 to
4 weeks in an air-dried sandy clay loam soil, 7 to 10 weeks in a
sandy loam soil, 10 to 14 weeks in a clay soil, and 9 weeks in a
fresh sandy clay soil incubated in the dark at 22°C and field capacity
(Osgerby et al., 1968). Three degradation products, the amide and
two acids, were identified in all four soils; a fourth degradate,
the amine, was found only in the air-dried sandy clay loam soil.
0 Freundlich K values were 0.72 for a sandy loan soil (2.0% organic
matter), 2.0 for a sandy clay soil (5.4% organic matter), 1.25 for
a sandy clay loam soil (6.8% organic matter) and 6.8 for a clay soil
(16% organic matter) treated with unaged l^C-cyanazine (Osgerby
et al., 1968). No linear correlation was found between organic
matter content and adsorption.
0 14c-Cyanazine readily moved through columns of sandy clay loam (52%
of applied compound) and loamy sand (18% of applied) soil leached with
78 cm of water over a 13-day period; unaged 14c-cyanazine was inter-
mediately mobile on sandy clay loam and of low mobility on loamy sand
soil thin-layer chromatography (TLC) plates (Rf 0.36 and 0.20,
respectively) (McMinn and Standen, 1981). Aerobically and anaerobically
aged 14c-cyanazine residues, primarily the amide degradate (SD 20258),
were intermediately mobile to mobile on sandy clay loam soil TLC plates.
0 Aged 1^C-cyanazine residues readily leached through columns containing
sand (47.8% of applied), loamy sand (69.7% of applied) and sandy
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Cyanazine August, 1987
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loam (26'.9% of applied) soils eluted with 20 cm of water (Eadsforth,
1984). The amide degradation product (SD 20258) was predominant in
the leachate from the sandy soil (45% of radioactivity in leachate);
the acid degradate (SD 20196) was predominant in leachate from the
loamy sand (84%) and sandy loam (47%) soils. Unaltered cyanazine
and SD 31222 were also identified in leachate from all three soils
(<6% of recovered).
III. PHARMACOKINETICS
Absorption
0 Studies by Shell Chemical Company (Shell Chemical Company, 1969) and
Hutson et al. (1970) indicated that cyanazine is rapidly absorbed
from the gastrointestinal tract when administered orally at low
dosage levels to three different animal species: rat, dog and cow.
Measurements of urinary, fecal and biliary excretion indicated that
80 to 88% of 2,4,6-14C-labeled cyanazine was eliminated within 4 days
from the rat and dog, and within 21 days from the cow. The initial
dosages were 1 to 4 mg/kg for the rat, 0.8 mg/animal for the dog and
5 ppm in the total ration of the cow. The dosages were administered
by gavage in the rat studies and in gelatin capsules in the dog study.
Distribution
0 In rats treated with a single oral dose of 4 mg/kg cyanazine,
samples of the carcass, skin and gut reflected 2.02, 0.62 and 2.73%
residual radioactivity, respectively, 4 days after exposure (Shell,
1969).
0 In cows, samples of brain, liver, kidney, muscle and fat reflected
concentrations of 0.55, 0.27, 0.24, 0.14 to 0.06 and less than 0.06
ppm cyanazine, respectively, after 21 days of continuous exposure
to feed that contained 5 ppm cyanazine; however, when a lower dosage
(0.2 ppm) was used in the feed, the detectable residues in each of
these tissues were less than 0.05 ppm (Shell, 1969).
Metabolism
0 Based on the analyses of metabolites in urine, the major metabolic
pathways of cyanazine in the rat and cow involved: (1) conversion of
the cyano group to an amide to form 2-chloro-4-ethylamino-6-(1-amido-
1-methylethyla:nino)-s-thiazine; (2) N-deethylation to form 2-chloro-4-
amino-6-(1-cyano1-methyl-ethylamino)-s-triazine; (3) conversion of the
cyano group of deethylate cyanazine to form the amide of deethylated
cyanazine, 2-chloro-4-amino-6( 1-amino-1-methylethylamino)-s-triazine;
(4) dechlorination via glutathione, partial hydrolysis of glutathione
conjugate and N-acetylation to form mercapturic acid, N-acetyl-S-
[4-amino-6-(1-cyano-1-methylethylamino) L-cysteine; and (5)
dechlorination via hydrolysis (occurs only in the cow) to form
2-hydroxy-4-ethylamino-6-( 1 -carboxy-1-methylethylamino)-s-triazine
and 2-hydroxy-4-amino-6-( 1,carboxy-1-methylamino)-s-triazine,
•respectively (Shell, 1969).
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Studies by Shell Chemical Company (1969) and Hutson et al. (1970)
with ring-labeled and side-chain-labeled cyanazine (cyano-14c,
isopropyl-14c and ethylamino-1 4C) indicated that only the ethylamino-1
side chain underwent extensive degradation, since 47% of the initial
radioactivity was detected in the exhaled carbon dioxide. Thus,
N-deethylation was found to be a major route of degradation of
cyanazine.
Crayford and Hutson (1972) identified 5 metabolites in urine, an
additional 2 (total 7) in feces and 4 metabolites in bile.
Crayford et al. (1970) studied the metabolism of two major plant
metabolites, DW4385 and DW4394, in rats. These two compounds were
identified in the rat metabolism studies by Crayford and Hutson (1972)
as 2-hydroxy-4-ethylamino-6-(1-carboxy-1-methylamino)-s-triazine)
(DW4385) and as 2-hydroxy-4-amino-6-(1-carboxy-1 -methylethylamino)-
s-triazine) (DW4394). Approximately 91% of compound DW4385 and 84%
of compound DW4394 were recovered unchanged from urine and feces.
Excretion
Orally administered low doses of cyanazine were rapidly excreted
in the urine and feces of rats and dogs (Shell, 1969; Hutson et al.,
1970; Crayford and Hutson, 1972). See discussion of these studies
in the above sections.
In rats treated with 1 to 4 mg/kg cyanazine by gavage, a total of
88% of cyanazine was eliminated in 4 days. Elimination via urine was
almost equal to elimination via feces; about 5.37% of the administered
cyanazine remained in the body; and approximately 21% of the 1 mg/kg
dose appeared in the bile within the first 20 hours (Shell, 1969).
Hutson et al. (1970) reported that 33% of an oral dose of cyanazine
was excreted in the urine of rats within 24 hours.
A study in rats with 14c-labeled 4-ethyl-amino cyanazine indicated
that 47% of the radioactivity was eliminated in carbon dioxide
(Shell Chemical Company, 1969).
In dogs administered 0.8 mg of cyanazine in gelatin capsules, 51.67
and 36.29% of the dose were eliminated in the urine and feces,
respectively, over a 4-day period (Shell Chemical Company, 1969).
In cows exposed to treated feed (5 ppm cyanazine) for 21 consecutive
days, the amount of daily excretion of radioactivity in urine and
feces was constant throughout the study period. The total cyanazine
equivalents in urine and feces were 53.7 and 26.8% of the dose,
respectively. The concentration in milk was reported as 0.022 ppm
(Shell Chemical Company, 1969).
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IV. HEALTH EFFECTS
Humans
No information was found in the available literature on the health
effects of cyanazine in humans.
Animals
Short-term Exposure
0 The acute oral LD50 in rats ranged from 149 to 369 mg/kg (SRI, 1967b;
NIOSH, 1977; Young and Adamik, 1979b; Meister, 1983). In these
studies, the percentage of active ingredient (a.i.) in the tested
product(s) was not clearly identified. However, studies by Walker
et al. (1974) with technical cyanazine (97% a.i.) in three different
animal species reflected LD5QS of 182, 380 and 141 mg/kg for the rat,
mouse and rabbit, respectively.
0 The acute dermal LD50 in rabbits treated with technical cyanazine
(purity unspecified) was >2,000 mg/kg (SRI, 1967a; Young and Adamik,
1979c); in rats, the LD50 was >1,200 mg/kg (97% a.i.) (Walker et al.,
1974).
0 The acute inhalation LCso for cyanazine dust (% a.i. not specified)
in rats was >2.28 mg/L/hr (Bishop, 1976) (toxicity category III).
0 In a study by Walker et al. (1968), groups of 10 female CFE rats,
5 months old, were treated by gavage with single oral doses of 1,
5 or 25 mg/kg of a wettable powder formulation (75% a.i.); the control
group received water. No diuretic effects were produced in the rats
receiving the formulation; however, serum protein and potassium
concentrations increased at the high dose, and serum osmolality
increased at 5 mg/kg, the Lowest-Observed-Adverse-Effect-Level (LOAEL).
The No-Observed-Adverse-Effect-Level (NOAEL) in this study appeared
to be 1 mg/kg; however, this study did not provide enough information
to determine the presence or absence of more significant effects at
this dosage level.
0 A 4-week oral toxicity study by Walker et al. (1968) was performed
using groups of 10 male and 10 female CFE rats, 5 weeks of age,
receiving diets containing 1, 10 or 100 ppm cyanazine (75% or 97% a.i.)
for 4 weeks; These doses are equivalent to 0.05, 0.5 or 5 mg/kg/day
(Lehman, 1959). A control group of 20 animals/sex was used. After
4 weeks, urine samples were collected for 16 hours (overnight), and
blood samples were used to determine the kidney function. Reductions
in body weight and food intake were noted at the high-dose level.
Osmolal clearance decreased in males, and this change was associated
with a decrease in free water clearance -in both the low- and mid-dose
groups. In females, decreased urine and increased serum osmolality
were observed in the mid-dose group, and both creatinine clearance
and urine potassium concentrations increased in the low-dose group.
The LOAEL in this study appeared to be 0.05 mg/kg/day (lowest dose
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Cyanazine August, 1987
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tested) based on kidney function tests, although additional
information was not available to determine if any other significant
adverse effects were noted at this level.
Dermal/Ocular Effects
0 Cyanazine caused mild eye irritation (100 mg) and slight skin irrita-
tion (2,000 mg) in rabbits. A skin sensitization test in guinea pigs
was negative (Walker et al., 1974; Young and Adamik, 1979d).
Long-term Exposure
0 In a 13-week oral study in dogs (Walker and Stevenson, 1968a, 1974),
groups of 5- to 7-month old beagle dogs, four animals/sex/treatment
group, were given daily doses of 1.5, 5 or 15 mg/kg/day cyanazine
in gelatin capsules. A control group of five animals/sex was given
empty capsules. The test material caused emesis within the first
hour of dosing in all of the high-dose males. Reduced body weight
gain was also noted in the high-dose group during the second half of
the study period as well as increased kidney and liver weights in the
females of this group. Thus, the LOAEL was 15 mg/kg/day and the
NOAEL was 5 mg/kg/day.
0 In a 13-week mouse feeding study (Fish et al., 1979), groups of 12
animals/sex/dose were fed diets containing 10, 50, 500, 1,000 or
1,500 ppm, equivalent to 1.5, 7.5, 75, 150 or 225 mg/kg/day (Lehman,
1959). The control group consisted of 24 animals/sex. Body weight
gain reduction was observed in both sexes at 75 mg/kg/day and above.
Statistically significant increases in liver weights were observed in
both sexes at 75 mg/kg/day and above. Thus, the LOAEL was 75 mg/kg/day
and the NOAEL was 7.5 mg/kg/day.
0 An initial 13-week rat feeding study by Walker and Stevenson (1968a)
was performed using 0.1, 1.0 or 100 ppm (equivalent to 0.005, 0.05
or 0.5 mg/kg/day; Lehman, 1959) of technical cyanazine (purity not
specified: 97% or 75% a.i. WP) in feed. Each dosage group had 20
animals/sex; the control group had 40 animals/sex. Body weight gain
decreased in all dosage groups in males and in the high-dose female
group. A NOAEL was not reflected in this study for males, although
it appeared to be 0.05 mg/kg/day for females.
0 Walker and Stevenson (1968b) repeated the above study in rats at dose
levels of 1.5, 3, 6, 12, 25, 50 or 100 ppm; these levels are equivalent
to 0.075, 0.15, 0.30, 1.25, 2.5 or 5 mg/kg/day (Lehman, 1959). Similar
effects were noted; however, a NOAEL of 25 ppm (1.25 mg/kg/day) was
identified.
0 In a 2-year study in dogs (Walker et al., 1970a), groups of 4- to
6-month-old beagle dogs were treated with technical cyanazine (97%
a.i., in gelatin capsules) at dose levels of 0.625, 1.25 or 5 mg/kg/
day. Each group consisted of four animals/sex. The control group
consisted of six animals/sex and received empty gelatin capsules.
Frequent emesis within 1 hour of dosing was observed throughout the
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study period in the high-dose group; this effect was associated with
reduction of growth rate and serum protein. The NOAEL appeared to be
1.25 mg/kg/day; however, this NOAEL should be considered with reser-
vations because the study did not provide adequate explanation relative
to missing histological data on one of four female dogs in the 1.25-
mg/kg/day dosage group. In addition, the reported data were limited
to a summary report.
0 In a 2-year study in mice (Shell, 1981), cyanazine technical (purity
not specified) was given in feed to CD mice at 10, 25, 50, 250 or
1,000 ppm, equivalent to 1.5, 3.75, 7.5, 37.5 or 150 mg/kg/day (Lehman,
1959); 50 animals/sex were used in the treatment groups, and 100
animals/sex were used as controls. Toxic effects reported at the two
high-dose levels, 37.5 and 150 mg/kg/day, included poor appearance
and skin sores, increased mortality in the female animals in both
groups, increased relative brain weight in both sexes, increased
relative liver weight in the two female groups, and decreased absolute
and differential leukocyte values in both sexes. Anemia was noted at
150 mg/kg/day in the females, as well as increased blood protein and
increased relative kidney weight. Cyanazine did not demonstrate an
oncogenic potential in this study. The NOAEL for systemic toxicity
in mice appeared to be 50 ppm (7.5 mg/kg/day).
0 Two chronic feeding studies in rats were available for review. In
one study (Walker et al., 1970b; also cited in Walker et al., 1974),
groups of 24 CFE rats/sex/dose received diets containing 6, 12, 25
or 50 ppm, equivalent to 0.3, 0.6, 1.25 or 2.5 mg/kg/day (Lehman,
1959) cyanazine (97% a.i.); 45 rats/sex were used as controls. The
authors indicated that no effects due to cyanazine were noted in this
study, although reduction in growth rate was noted in both sexes at
2.5 mg/kg/day and in females at 1,25 mg/kg/day. A review of this
study (U.S. EPA, 1984b) indicated that cyanazine appeared to be
tumorigenic in both male and female rats based on the increased
incidences of thyroid tumors in all treatment groups as compared to
the study's control group; increased incidences of adrenal tumors
also were noted in all male treatment groups. However, this study
was considered unacceptable because of several deficiencies: a
limited number of tissues per animal were examined microscopically;
the tumor incidences were calculated based on the number of animals
tested rather than on the number of specific tissues histologically
examined; gross examination and histologic findings for nonneoplastic
lesions were not adequately reported; and only limited hematology,
clinical blood chemistry and urinalyses data were presented.
0 Simpson and Dix (1973) repeated the above 2-year study using 1, 3 or
25 ppm, equivalent to 0.05, 0.15 or 1.25 mg/kg/day (Lehman, 1959);
however, convulsions were noted in the rats 3 months after the study
initiation and throughout the remainder of the study period.
Approximately 42% of the animals were affected, and the incidence was
not considered to be dose-related. The incidence of animals with
convulsions was similar in both the control and high-dose male groups
(21/48 and 11/24, respectively).
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Reproductive Effects
0 A three-generation reproduction study in Long-Evans rats (Eisenglord
et al., 1969) using technical cyanazine (unknown percentage a.i.) at
dietary levels of 3, 9, 27 or 81 ppm (0.15, 0.45, 1.35 or 4.05 mg/kg/day)
did not reflect a significant effect on reproduction parameters. The
NOAEL in this study appeared to be 1.35 mg/kg/day; the LOAEL was
4.05 mg/kg/day (highest dose tested) based on findings related to
reduced body weight gain in parental animals, and increased relative
brain weight and decreased relative kidney weight in F3J-, female
weanlings.
Developmental Effects
0 Cyanazine appeared to cause teratogenic effects and developmental
toxicity in two animal species, the rabbit and the rat (Bui, 1985b).
0 In the rabbit study (Shell Toxicology Laboratory, 1982), 7- to 11-
month-old New Zealand White rabbits were orally dosed with cyanazine
(98% a.i.) in gelatin capsules at levels of 0, 1, 2 or 4 mg/kg/day on
gestation days 6 through 18 (22 dams/dose/group). At 2 and 4 mg/kg/day,
maternal toxic effects included anorexia, weight loss, death and
abortion. Alterations in skeletal ossification sites, decreased
litter size, and increased postimplantation loss were observed at
2 and 4 mg/kg/day. Malformations were also noted at 4 mg/kg/day as
demonstrated by anophthalmia/microphthalmia, dilated brain ventricles,
domed cranium and thoracoschisis; however, these responses were
observed at levels in excess of maternal toxicity. The maternal and
developmental toxicity NOAELs were 1 mg/kg/day.
0 In a rat study by Lu et al. (1981, 1982), 122-day-old Fischer 344
rats (30 dams/group) were administered cyanazine (97% a.i.) by gavage
at dose levels of 0, 1.0, 2.5, 10.0 or 25.0 mg/kg/day on gestation
days 6 through 15; the dosages were suspended in a 0.2% Methocal
emulsion as vehicle. Maternal body weight reductions during dosing
were noted at the 10- and 25-mg/kg/day levels. Diaphragmatic hernia.
associated with liver microphthalmia was observed at the 25 mg/kg/day
dose level. A teratogenic NOAEL could not be determined from this
study.
0 The above study was repeated in the same strain of rats, Fischer 344,
by Lochry et al. (1985) in order to further examine the malformations
reported in the study by Lu et al. (1981). In this study, the dams
(70/dosage group) were 86 days old. Cyanazine (98% a.i.) was admini-
stered by gavage in an aqueous suspension of 0.25% (w/v) methyl
cellulose at dose levels of 0, 5, 25 or 75 mg/kg/day on days 6 through
15 of gestation. One-half of the dams in each group were selected
for Cesarean delivery on day 20 of gestation. The remaining half of
the dams in each group were allowed to deliver, and both they and
their pups were observed for 21 days before sacrifice. Maternal body
weight reductions during dosing were noted in all dosage groups and
appeared to be partly associated with lower food intake during the
dosing period. Alteration in skeletal ossification sites were also
observed in the fetuses at all dose levels. Teratogenic effects were
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demonstrated at 25 and 75 mg/kg/day as anophthalmia/microphthalmia,
dilated brain ventricles and cleft palate in the fetuses, and abnor-
malities of the diaphragm (associated with liver protrusion) in pups
sacrificed at time of weaning. The maternal and developmental toxicity
NOAELs were lower than 5 mg/kg/day (lowest dose tested), and the
teratogenic NOAEL was 5 mg/kg/day (Bui, 1985a).
0 An additional study in Sprague-Dawley rats (Shell Development Company,
1983) did not reflect any maternal or developmental toxicity at the
highest dose tested, 30 mg/kg/day.
Mutagenicity
8 The mutagenic potential of cyanazine has not been investigated
adequately, and only limited information was available for evaluation.
0 A study by Dean et al. (1975) using technical cyanazine (80% a.i.)
in mice of both sexes did not reflect any increase in chromosomal
aberrations in the bone marrow cells. The animals were examined at
8- and 24-hour intervals after oral dosing with 50 or 100 mg/kg
cyanazine. However, the sensitivity of this test was potentially
compromised because the positive control data did not reflect a
significant number of aberrations: the percent of cells showing
chromatid gaps in the positive control (cyclophosphamide) was not
statistically significant at the p <0.05 level (U.S. EPA, 1985b).
0 Dean et al. (1974) used technical cyanazine (purity not specified)
to induce dominant lethal effects in male CF1 mice. The test
was negative at the dose levels tested (80, 160 and 320 mg/kg).
However, this study appeared to be invalid because there was no
positive control for comparison of data, and a range-finding test was
not performed to select the appropriate dosages used in this study
(U.S. EPA, 1984b).
0 Cyanazine is a member of the triazine family of herbicides. It is known
that the triazines follow similar metabolic pathways (i.e., N-dealkyla-
tion, S-dealkylation or 0-dealkylation and conjugation with glutathion)
that result in common or closely related metabolites. Waters, et al.
(1980) noted that a triazine herbicide (atrazine) gave a positive
mutagenic response in the Drosophila sex-linked recessive lethal test
(DRL), although this chemical gave a negative response in an in vitro
test battery with microorganisms. Hence, the potential for cyanazine
to give a positive response in a similar test exists (U.S. EPA, 1984b).
Carcinogenicity
0 Cyanazine was not determined to have a carcinogenic potential in a
2-year mouse study (Shell, 1981).
0 Cyanazine was not oncogenic in 2-year rat studies by Walker et al.
(1970b) or by Simpson and Dix (1973); however, these studies were
deficient (see description of these studies under the section entitled
Long-term Exposure) and are considered to be inadequate by design to
determine the oncogenic potential of cyanazine.
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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:
HA = (NOAEL or LOAEL) X (BW) = mg/L ( ug/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 for determination
of the One-day HA for cyanazine. It is, therefore, recommended that the
Ten-day HA value for a 10-kg child, calculated below as 0.10 mg/L (100 ug/L),
be used at this time as a conservative estimate of the One-day HA value.
Ten-day Health Advisory
The teratology study in rabbits by Shell Toxicology Laboaratory (1982) has
been selected as the basis for determination for the Ten-day HA for cyanazine
because it provides a short-term NOAEL (1 mg/kg/day for 13 days) for both
maternal and fetal toxicity. This study also reflects the lowest NOAEL when
compared with the teratology studies in rats described earlier, two in
Fischer 344 rats (Lu et al., 1981; Lochry et al., 1985) and one in Sprague-
Dawley rats (Shell Development Company, 1983).
Using a NOAEL of 1 mg/kg/day, the Ten-day HA for a 10 kg child is
calculated as follows:
Ten-day HA = (1 mg/kg/day) (10 kg) = 0.10 mg/L (100 ug/L)
(100) (1 L/day)
where:
1 mg/kg/day = NOAEL based on maternal and fetal effects in rabbits
exposed to technical cyanazine orally for 13 days.
10 kg = assumed body weight of a child.
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Cyanazine August, 1987
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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 by a child.
Longer-term Health Advisory
No information was suitable for the determination of the Longer-term
HA for cyanazine. It is, therefore, recommended that the adjusted Drinking
Water Equivalent Level (DWEL) of 0.013 mg/L (13 ug/L) be used for a 10-kg
child as a conservative estimate for the Longer-term HA value and the DWEL
of 0.046 mg/L (46 ug/L), calculated below, be used for 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 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
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
Four chronic studies were available for evaluation: (1) a 2-year
oncogenic study in mice (Shell, 1981) with a potential NOAEL of 50 ppm
(approximately 7.5 mg/kg/day when using a conversion factor for food consumption
of 15% of the body weight); (2) a 2-year feeding study in dogs (Walker et al.,
1970a) with a NOAEL of 1.25 mg/kg/day; (3) a 2-year feeding/oncogenic study
in rats (Walker et al., 1970b, also cited in Walker et al., 1974) with a
NOAEL of 12 ppm (approximately 0.6 mg/kg/day when using a conversion factor
for food consumption of 5% of the body weight); however, this study was
considered unacceptable (U.S. EPA, 1984b) due to several deficiencies in the
study report (see Longer-term Exposure); and (4) a second 2-year feeding
study in rats (Simpson and Dix, 1973), which was also considered inadequate
because the control group reflected an effect, i.e., convulsions, that was
suggestive of cross-dosing.
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Cyanazine August, 1987
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The NOAEL in the mouse study (7.5 mg/kg/day) can be considered for this
calculation; however, this NOAEL is higher than the NOAEL in the Walker et al.
(1970a) dog study (1.25 mg/kg/day) or in the Walker et al. (1970b) rat study
(0.6 mg/kg/day). Since this rat study is considered unacceptable and since
the second rat study (Simpson and Dix, 1973) appeared to be flawed by the
invalidity of the control group, it is concluded that the 2-year dog study
(Walker et al., 1970a) will be used for the Lifetime HA.
The NOAEL of 1.25 mg/kg/day is used; however, because the data in this
study were of marginal acceptability, an uncertainty factor of 1,000 fold
will be applied to the HA calculations. This study NOAEL is also similar
to the NOAEL reflected in the suchronic study in rats by Walker and Stevenson
(1968b); thus the RfD value calculated below can be equally based on either
one of these studies (or both) using the same uncertainty factor.
Using a NOAEL of 1.25 mg/kg/day, the Lifetime HA is calculated as
follows:
Step 1: Determination of the Reference Dose (RfD)
RfD = (1.25 mg/kg/day) = Q.0013 mg/kg/day
(1,000)
where:
1.25 mg/kg/day = NOAEL based on absence of toxicity in both the
2-year dog study and the 13-week rat study.
1,000 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study
of less-than-lifetime duration (as in the 13-week
rat study) or for a study with limited acceptability
(as in the 2-year dog study).
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (0.0013 mg/kg/day) (70 kg) = Q.0455 mg/L (46 ug/L)
(2 L/day)
where:
0.0013 mg/kg/day = RfD.
70 kg = assumed body weight of an adult.
2 L/day = assumed daily water consumption by an adult.
Step 3: Determination of the Lifetime Health Advisory
Lifetime HA = (0.046 mg/L) (20%) = 0.009 mg/L (9 ug/L)
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Cyanazine August, 1987
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where:
0.046 mg/L = DWEL.
20% = assumed relative source contribution from water.
Evaluation of Carcinogenic Potential
0 Available toxicity data indicate that cyanazine was not carcinogenic
in mice (Shell, 1981) or rats (Walker et al., 1970b, 1974; Simpson
and Dix, 1973); however, in the rat, some increases were noted in the
incidences of both thyroid tumors (male and female rats) and adrenal
tumors (male rats); however, these increases were not statistically
significant.
0 Cyanazine is a chloro-s-triazine derivative that has a chemical
structure analagous to atrazine, propazine and simazine, the first
two of which were found to significantly (p <0.05) increase the
incidence of mammary tumors in rats. A new oncogenic study in rats
using simazine is not yet completed. Based on structure-activity
relationship, cyanazine may reflect a similar patteinof toxicity in
the rat. A new 2-year oncogenic study is required from the manufacturer
of this chemical to fill this data gap in the toxicity profile of
this chemical.
0 Applying the criteria described in EPA's guidelines for assessment of
carcinogenic risk (U.S. EPA, 1986), cyanazine may be classified in
Group D: not classified. This category is used for substances with
inadequate animal evidence of carcinogenicity.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 U.S. EPA Office of Pesticide Programs (OPP) has established residue
tolerances for cyanazine ranging from 0.05 to 0.10 ppm in or on raw
agricultural commodities (U.S. EPA, 1985a) based on a Provisional ADI
(PADI) of 0.0013 mg/kg/day.
VII. ANALYTICAL METHODS
0 Analysis of cyanazine is by a high-performance liquid chromatographic
(HPLC) method applicable to the determination of cyanazine in water
samples (U.S. EPA, 1985b). In this method, 1 L of sample is solvent
extracted with methylene chloride using a separatory funnel. The
methylene chloride extract is dried and exchanged to methanol during
concentration to a volume of 10 mL or less. Separation and measure-
ment of cyanazine is by HPLC with an ultraviolet (UV) detector. The
estimated method detection limit for cyanazine is 6 ug/L.
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Cyanazine August, 1987
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VIII. TREATMENT TECHNOLOGIES
0 Available data indicate that granular-activated carbon (GAC) adsorption
will remove cyanazine from water.
0 Whittaker (1980) experimentally determined adsorption isotherms for
cyanazine on GAC.
0 GAC adsorption appears to be an effective method of cyanazine removal
from water. However, selection of individual or combinations of
technologies to attempt cyanazine removal from water must be based
on a case-by-case technical evaluation, and an assessment of the
economics involved.
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Cyanazine August, 1987
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•Confidential Business Information submitted to the w^fice of Pesticide
Programs
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