August, 1987
         820K88104          FIR APT


                                  Health Advisory
                              Office of Drinking Water
                        U.S.  Environmental Protection Agency

         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

         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.

    Cyanazine                                                      August,  1987



    CAS No.  21725-46-2
    Structural Formula
                                         HC = kJ



     -[ [4-Chloro-6-(ethylamino)-1 , 3, 5-triazin-2-yl]amino]-2-methylpropanenitrile
         e  Cyanazine  (common  name),  Bladex,  Fortrol,  Payze,  SD1518,  VL19804,
            DW3418  and WL19805 (Meister,  1983).
         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
            Taste Threshold
            Odor Threshold
            Conversion Factor
            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.

Cyanazine                                                     August, 1987

     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

     Cyanazine                                                     August, 1987

             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).


          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.


          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,

          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).


          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).

Cyanazine                                                     August, 1987

        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

        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.
        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).

    Cyanazine                                                      August,  1987


            No  information  was  found  in  the  available  literature  on  the health
            effects  of  cyanazine  in humans.
       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.,

         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

Cyanazine                                                     August, 1987

        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

     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

Cyanazine                                                     August, 1987
        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).

Cyanazine                                                     August,  1987


   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

   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

     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

Cyanazine                                                     August, 1987

        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.


     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).


     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.

   Cyanazine                                                     August, 1987



        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)


           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)
           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.

Cyanazine                                                     August,  1987

                      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.

Cyanazine                                                     August, 1987

     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

Step 1:  Determination of the Reference Dose (RfD)

                  RfD =  (1.25 mg/kg/day) = Q.0013 mg/kg/day


        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)


         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)

     Cyanazine                                                     August, 1987



             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

          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.


          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.


          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.

      Cyanazine                                                     August, 1987



           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.

   Cyanazine                                                     August, 1987



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Cyanazine                                                     August, 1987

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Cyanazine                                                     August, 1987

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Cyanazine                                                     August, 1987

                                     -19-                             '
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Cyanazine                                                   August, 1987

                                     -20-                   .           «
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