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    CYROMAZINE

    EXPLANATION

    First draft prepared by Mrs E. Arnold,
    Health and Welfare Canada, Ottawa, Canada

         Cyromazine is an insecticide that interferes with the first
    dipteran larval moult and to a certain extent with metamorphosis. It
    was reviewed for the first time at the present meeting.

    EVALUATION FOR ACCEPTABLE INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution and excretion

    Oral exposure

    Rats

         A single dose of 0.5 mg/kg bw of 14C-cyromazine (uniformly
    triazine ring labelled) was given orally to two male and one female
    Charles River white rats (not further identified).  By 72 hours after
    dosing, 95% of the administered dose had been excreted in urine,
    essentially all within the first 24 hours.  

         About 3% was excreted in faeces, again predominantly in the first
    24 hours. Negligible amounts were excreted as volatiles or CO2 in
    another two males and one female given the same dose.  Tissue residues
    were below the level of detection except in liver; however, liver
    levels were too low to permit accurate quantitation (about 0.007 ppm)
    (Simoneaux and Cassidy, 1978).

    Chickens

          Two chickens (strain not indicated) were given daily oral doses
    of 14C-cyromazine (uniformly triazine ring labelled) of 0.75
    mg/hen/day by capsule for seven days.  By 24 hours after the last dose
    99.1% of the administered radioactivity had been recovered in the
    excreta with essentially none in volatiles and CO2.  Both egg whites
    and egg yolks contained about 0.12-0.15 ppm consistently. Tissue
    levels were: byproducts (i.e. head and feet) 0.047 ppm test material
    equivalents; reproductive tract 0.047 ppm; liver 0.032 ppm; all other
    tissues 0.008-0.019 ppm (Simoneaux and Cassidy, 1979).

    Sheep

         One sheep (strain not given) was given a daily dose of
    14C-cyromazine (uniformly triazine ring labelled) of 0.15 mg/kg bw/day
    by capsule for nine days.  By 24 hours after the last dose about 90%
    of the administered dose had been recovered in urine.  A further 3.7%
    was recovered in faeces. Only a trace was detected in CO2.  Blood
    levels appeared to plateau at about 0.1% of the administered dose
    after five days.  Tissue levels were: 0.174 ppm in liver, 0.164 ppm in
    the GI tract, 0.048 ppm in kidney, 0.012-0.013 ppm in muscle, brain
    and heart, and at or below the level of detection in fat (Simoneaux
    and Cassidy, 1981).

    Goats

         One lactating goat/dose level was given a daily oral dose of
    14C-cyromazine (uniformly triazine ring labelled) of 5 or 50
    mg/goat/day by capsule for ten consecutive days.  By 24 hours after
    the last dose 90.4% of the low dose and 82.1% of the high dose had
    been recovered in urine.  Faecal excretion accounted for 7.5% of the
    low dose and 5.7% of the high dose.  There was some evidence of
    plateauing of urinary and faecal excretion after 5 days.  Blood levels
    changed little on days 2-10 and were in the range of 0.05-0.09% of the
    dose at both dose levels.  Tissue levels were 0.01 ppm or less in the
    low dose goat and 0.14 ppm or less in the high dose goat except in
    liver (0.79 and 1.522 ppm, respectively), kidney (0.04 and 0.437 ppm)
    and GI tract (contents) (1.27 and 1.11% of the administered dose). 
    Daily milk levels accounted for about 0.3% of the administered dose
    (Simoneaux and Marco, 1984).

    Monkeys

         A single dose of 0.05 or 0.5 mg/kg bw of 14C-cyromazine
    (uniformly triazine ring labelled) was given by capsule to groups of
    two male and two female monkeys (Macaca fasicicula).  Twenty four
    hours after dosing 62.9-96.1% of the low dose and 47-82.2% of the high
    dose had been recovered in urine.  Only a small additional amount was
    excreted in urine in the period 24-96 hours after dosing.  Excretion
    in faeces accounted for 1.14-1.31% of the low dose and 1.42-1.92% of
    the high dose most of which was recovered in the first 24 hours after
    dosing (Staley, 1986).

         Because of the low total recovery of radioactivity in the above
    study, a second study was undertaken using one male and one female of
    the same strain of monkey and at the same dose levels given by
    capsule.  Greater recovery of radioactivity was not achieved.  At the
    high dose the results were similar to those in the above study.  Most
    of the recovered radioactivity was in urine excreted during the first
    24 hours after dosing with only a small amount in faeces again mainly
    in the first 24 hours.  About 14% of the administered dose was
    excreted in faeces mainly in the first 48 hours after dosing (Staley
    and Simoneaux, 1986).

    Dermal Exposure

         In a preliminary study two male Harlan Sprague-Dawley albino rats
    were exposed to 14C-cyromazine (uniformly triazine ring labelled) at
    1.0 mg/rat applied dermally to a shaved area on the upper back.  After
    eight hours exposure 5.8-7.5% of the applied material had been
    absorbed (recovered in urine, carcass, faeces and blood, listed in
    order of decreasing amounts).  About 16-22% of the applied dose was
    detected in skin which had been washed to remove the test material. 
    About 60% of the administered dose was recovered in skin and cage

    washes.  Essentially no radioactivity was detected in volatiles. 
    Blood levels were at or below the level of detection (Murphy and
    Simoneaux, 1985).

         In the main part of this study, groups of three male Harlan
    Sprague-Dawley albino rats/dose/time period were exposed to
    14C-cyromazine (uniformly triazine ring labelled) at 0.1,1.0 or 100
    mg/rat applied to a shaved area on the upper back.  The rats were
    sacrificed 1, 2, 4 and 10 hours after treatment.  The percent of the
    total dose applied which was absorbed was 4.5-11.0% at the low dose,
    3.5-11.4% at the mid dose and 2.2-7.1% at the high dose with the
    amount absorbed increasing with duration of exposure at all dose
    levels.  The amount of material bound in the skin also increased with
    time.  As in the preliminary study the highest recovery of absorbed
    material was in the urine, followed by the carcass.  Faecal and blood
    levels were very low (Murphy and Simoneaux, 1985).

         In a second dermal study, groups of male Harlan Sprague-Dawley
    albino rats were exposed to  14C-cyromazine (uniformly triazine ring
    labelled) at dose levels of 0.1, 1.0 or 10.0 mg/rat applied to shaved
    areas on the upper back.  The treated area was enclosed and covered by
    a nonocclusive bandage.  The hind legs of the rats were shackled to
    prevent scratching of the treated area.  Groups of four rats/dose were
    sacrificed 2, 4, 10 and 24 hours after treatment.  Additionally, two
    groups of four rats/dose had the bandages removed and the treated area
    washed 10 or 24 hours after treatment and then were returned to
    metabolism cages for a 48 hour period prior to sacrifice.  In all
    groups, 62-86% of the applied dose was recovered in skin and cage
    washings and bandages, thus was not absorbed. The amount bound in skin
    tended to increase with duration of exposure but was reduced during a
    post-exposure period.  The amount absorbed (recovered in urine,
    carcass, faeces and blood) appeared to be higher in the rats which
    were maintained for 48 hours post-treatment.  These data suggest that
    the material apparently bound in the skin was absorbed into the body
    (Murphy et al., 1987).

    Biotransformation

    Rats

         Urine from a female rat given a single oral dose of
    14C-cyromazine (uniformly triazine ring labelled) of 0.5 mg/kg bw was
    analyzed using TLC and a cation exchange column chromatography system. 
    With both systems the majority of the urinary radioactivity was
    determined to be in the form of unchanged parent compound.  Unchanged
    parent compound in urine accounted for about 80% of the administered
    dose.  Three metabolites were detected with each system and were
    presumed to be the same compounds.  These metabolites accounted for
    2.2-3.2%, 3.0-5.5%, and 4.6-5.3% of the administered dose,
    respectively, but no identification was made. Faecal material from a

    male rat given the same dose as the above female was found to contain
    little unchanged parent compound: <0.1% of the administered dose. 
    The same three metabolites as observed in urine were found and
    represented 0.1, 0.1 and 4.1% of the administered dose, respectively
    (Simoneaux and Cassidy, 1978).

         One male and one female albino Sprague-Dawley rats were given
    diet containing 3000 ppm of 14C-cyromazine for 10 days.  In the male
    the liver was found to contain 31.3 ppm cyromazine and 0.96 ppm
    melamine and the kidney 62.4 ppm cyromazine and 1.3 ppm melamine. In
    the female liver residues were 13.2 ppm and 0.51 ppm and kidney
    residues 22.2 and 0.68 ppm of cyromazine and melamine, respectively. 
    This study indicated that there was some conversion of cyromazine to
    melamine in vivo (Smith et al., 1983).

    Chickens

         Two chickens were each given one capsule containing 0.75 mg of
    14C-cyromazine (uniformly triazine ring labelled) daily for seven
    days.  The chickens were sacrificed 24 hours after the last dose. 
    Parent compound accounted for about 75-78% of the radioactivity
    recovered in excreta, 58% in egg white and 70 % in egg yolk.  Other
    metabolites in excreta were not resolved.  In egg white and egg yolk
    the major other peak accounted for 24.5% and 6.7% of the extractable
    radioactivity, respectively.  This metabolite was identified as
    melamine.  Minor peaks were present, accounting for 26% and 23.9% of
    the radioactivity in whites and yolks, respectively, but none of the
    metabolites was identified (Simoneaux and Cassidy, 1979).

         Groups of two chickens were given diets containing 14C-cyromazine
    (uniformly triazine ring labelled) at levels of 7.7, 32.9 or 84.3 ppm
    daily for 7 days.  All chickens were killed 24 hours after the last
    dose.  Egg fractions and livers from the high and low dose groups were
    analyzed.  At the low dose cyromazine accounted for 18.4%, 69.3% and
    61.7% of the extractable radioactivity in egg white, egg yolk and
    liver, respectively, while melamine accounted for 38.3%, 1.0% and
    7.0%, respectively.  At the high dose the extractable radioactivity
    was 79.5%, 86.3% and 84.2% cyromazine and 3.8%, 2.0% and 5.6% melamine
    in egg whites, egg yolks and liver, respectively. Another metabolite
    designated "Metabolite A" was detected in egg white and accounted for
    19.9% of the extractable radioactivity at the low dose and <1.0% at
    the high dose.  This metabolite was probably ammeline formed by
    deamination of one of the amino groups of melamine (Simoneaux, 1981).

         Groups of 30 hens were given diet containing 0 and 5 ppm
    cyromazine (as 0.3% Larvadex Premix) for 56 days.  The control group
    received an equivalent amount of rice hulls in the diet. Following the
    treatment period surviving birds in both groups were maintained on the
    control diet for a 14 day depletion period.  Three hens/group were
    sacrificed on dose days 14, 28, 42 and 56 and on depletion days 1, 3,

    7 and 14. Melamine was not detected in any of the tissue (breast,
    thigh, liver, fat and skin) or egg samples.  Maximum cyromazine
    residues in eggs and tissues were reached in 3 and 14 days,
    respectively, with no further increase with continued dosing. 
    Residues were no longer detectable in eggs and tissues 2 and 1 day
    after removal of cyromazine from the diet (Boone and Cheung, 1985). 

    Goats

         One lactating goat/dose level was given 14C-cyromazine (uniformly
    triazine ring labelled) at nominal levels of 5 or 50 mg/goat/day for
    10 consecutive days by capsule.  The goats were sacrificed 24 hours
    after the last dose.  Unchanged cyromazine accounted for 43.7, 35.9,
    0.2 and 32.5% of the extractable radioactivity in urine, faeces, liver
    and milk, respectively, at the low dose and 78.8, 58.7, 1.9 and 41.0%
    at the high dose, respectively.  Melamine levels in urine, faeces,
    liver and milk were 11.9, 14.3, 1.7 and 9.2% at the low dose and 7.8,
    10.4, 5.6 and 4.5% at the high dose, respectively.  An unidentified
    metabolite designated "zone 4" accounted for 44.4, 17.4, 92.7 and 1.0%
    of the extractable radioactivity at the low dose and 13.4, 1.8, 71.7
    and 0.2% at the high dose in urine, faeces, liver and milk,
    respectively (Simoneaux and Marco, 1984).

    Sheep

         One sheep was given a daily dose of 14C-cyromazine of 0.15 mg/kg
    bw/day for nine days by capsule and then sacrificed 24 hours after the
    last dose.  Analysis by ion exchange column chromatography indicated
    that parent compound accounted for 84% of the radioactivity in urine,
    44% in faeces and 11.6% in liver.  In all of these extracts four
    metabolites were detected, accounting for: 0.1-6.8% of recovered
    radioactivity in urine (metabolite b highest, metabolite d lowest);
    0.3-6.4% in faeces (metabolite c highest, metabolite d lowest); and in
    liver 1.3-2.9% as metabolites a, b and c but 43.0% as metabolite d. 
    Metabolite d cochromatographed with melamine.  The other three
    metabolites were not identified but one was expected to be the
    hydroxy-CGA-72662 compound (Simoneaux and Cassidy, 1981).

    Monkeys

         Urine from male and female monkeys (Macaca fasicicula) given
    single oral doses of 14C-cyromazine (uniformly triazine ring labelled)
    of 0.05 or 0.5 mg/kg bw by capsule was found to have the majority of
    the radioactivity present in the form of unchanged parent compound. 
    Regardless of dose 93.6-96.1% of the urinary radioactivity was present
    as unchanged cyromazine.  Additionally, 2.9-6.4% of the radioactivity
    as identified as melamine (Staley, 1986).

         In a second study with the same strain of monkey given the same
    dose levels, urine collected during the first 24 hours after dosing

    had 95-100% of the recovered radioactivity in the form of unchanged
    cyromazine.  In one male dosed at 0.05 mg/kg bw, no melamine was
    detected in the urine.  In one female at 0.05 mg/kg bw and one monkey
    of each sex given 0.5 mg/kg bw 3.0-3.9% of the urinary radioactivity
    was in the form of melamine (Staley and Simoneaux, 1986).

    Toxicological studies

    Acute toxicity

         The acute toxicity of cyromazine to rats, mice and rabbits is
    given in Table 1. 

    Table 1.  Results of acute toxicity assays with cyromazine.

                                                                       

    Species    Sex      Route          LD50      Reference
                                                                       

    Mouse      M, F     oral           2029      Bathe and Sachsse, 1978a

    Rat        M        oral           4050      Sabol, 1987
               F        oral           3530      ibid
               M, F     oral           3920      ibid
               M, F     oral           3387      Bathe and Sachsse, 1978b

    Rabbit     M, F     oral           1467      Ullmann and Sachsse, 1978

    Rat        M, F     dermal         >1370     Bathe and Sachsse, 1978c

    Rat        M, F     inhalation     >2.7      Ulrich and Blair, 1979
                                                                       

    Short-term studies

    Oral studies

    Rats

         Groups of 20 weanling Charles River CD rats/sex/dose were given
    diet containing 0, 30, 300, 1000 or 3000 ppm cyromazine (96.3% pure)
    for 90 days.  Additionally groups of 5 rats/sex/dose were given diet
    containing 0 or 3000 ppm cyromazine for 90 days followed by control
    diet for a 4 week recovery period.  No treatment-related changes were
    noted in behavior, appearance, haematological parameters, clinical
    biochemistry or urinalysis. Mean body weight was about 5-10% lower
    than controls in the 3000 ppm group and up to 4% lower in the 1000 ppm
    group.  In the recovery period males approached control weights but
    the female weights were 5-6% lower than the controls.  Food

    consumption expressed as g/kg bw/day was reduced in both sexes at 3000
    ppm during the first week of treatment.  Absolute liver weights were
    lower than controls in the 1000 and 3000 ppm groups in both sexes.
    Liver/body weight ratios were lower than controls at 300 ppm and above
    in males and at 30 or 1000 ppm in females.  Liver/brain weight ratios
    were lower than controls at 1000 and 3000 ppm in males and 30, 300 and
    1000 ppm in females.  The significance of these observations is not
    clear.  No treatment-related pathology was observed.  Since there were
    no pathological lesions to explain the liver weight effects the NOAEL
    in this study was considered to be 300 ppm (equal to 23.5-26.9 mg/kg
    bw/day) (Goldenthal and Hughes, 1979).

    Dogs

         Groups of 4 beagle (Ridglan) dogs/sex/dose were given diet
    containing cyromazine (96.3%) at 0, 30, 300, 1000 or 3000 ppm for 90
    days.  An additional 2 dogs/sex/dose were given the 0 and 3000 ppm
    diets for 90 days followed by control diet for a 4 week recovery
    period.  Slightly relaxed nictating membranes were observed quite
    frequently in dogs at all levels of treatment. Slightly dry nose was
    seen in dogs at 1000 and 3000 ppm.  Body weight gain during the
    treatment period was slightly reduced in males at 3000 ppm and females
    at 1000 ppm or more.  Some recovery of body weight was noted in the
    recovery period, particularly in males.  Food consumption was lower in
    both sexes given 3000 ppm than in the controls during treatment and
    higher during the recovery phase.  RBC count, haemoglobin and
    haematocrit were lower than controls in the males given 3000 ppm. 
    Haemoglobin was still depressed at the end of the recovery period.  No
    treatment- related effects were noted in clinical biochemistry
    parameters, urinalyses or ophthalmoscopy.  Absolute and relative liver
    weights in 3000 ppm males were higher than controls.  In females
    relative liver weight was slightly but not statistically significantly
    higher than controls.  No treatment-related pathology was observed in
    any of the groups.  The NOAEL in this study was 300 ppm (equal to
    11.4-12.0 mg/kg bw/day) since the incidence of relaxed nictating
    membranes was apparently not dose-related and not clearly
    treatment-related (Jessup and Hughes, 1979).

         Groups of 6 young adult purebred beagle (Hazleton) dogs/sex were
    given diet containing 0, 30, 300 or 3000 ppm of cyromazine (96.3%
    pure) for 26 weeks.  An additional 2 dogs/sex/group were given 0 or
    3000 ppm for 26 weeks and then control diet for a 4 week recovery
    period.  There were no clearly treatment-related changes in behavior
    or appearance.  Body weight gains were lower in females at 30 and 300
    ppm and both sexes at 3000 ppm.  At 30 ppm body weight in females was
    3.9% lower than controls.  Some recovery of body weight was noted in
    the recovery period.  Food consumption was generally similar in all
    groups although occasionally lower than controls in males at 3000 ppm. 
    Haematocrit, haemoglobin and RBC count were lower than controls in
    both sexes at 3000 ppm.  The differences were generally statistically

    significant in males and occasionally in females.  Serum cholesterol
    levels were reduced at 3000 ppm especially in males, rising after
    cessation of treatment in the recovery animals.  SGOT was elevated in
    males at 3000 ppm throughout the treatment period, returning to
    control level in the recovery period.  Serum glucose was slightly
    increased in both sexes at 3000 ppm but the differences were
    statistically significant only occasionally.  There were no
    treatment-related effects on urinalysis or ophthalmoscopy.  In the
    3000 ppm dogs organ weights tended to be higher than controls but this
    was attributed to the reduced body weights.  No treatment-related
    pathology was observed.  The body weight changes in females at 30 and
    300 ppm were small and no other changes were noted in these groups.
    Effects at 3000 ppm were more prominent in males than in females.  It,
    therefore, seems justified to consider 300 ppm (equal to 8.86-9.29
    mg/kg bw/day) as an NOAEL for this study (Burdock et al,1980).

    Inhalation study

    Rats

         Groups of 5 Tif:RAIf(SPF) albino rats (hybrids of
    RII/1xRII/2)/sex were exposed to measured cyromazine aerosol
    concentrations of 0, 57, 206 or 706 mg/m3 4 hours/day, 7 days/week
    for 4 weeks.  Satellite groups of 5 rats/sex/dose were exposed to 0 or
    706 mg/m3 and then allowed a 3 week recovery period.  Median
    aerodynamic diameter of the particles was 1.6-6.0 m with 52-57% of
    the particles <3 m.  In all treated groups, piloerection, dyspnoea
    and hunched position were observed in all animals with severity
    increasing with dose.  Reduced spontaneous activity was seen in the
    two higher dose groups.  In the recovery period activity returned to
    normal and dyspnoea decreased but piloerection remained moderate. All
    of the treated males had lower body weight gains than controls during
    the treatment period but the differences were not dose-related. 
    Females had no body weight effects during treatment. Both sexes gained
    more weight than controls in the recovery period.  Food consumption
    followed the same pattern as body weight.  The high exposure males had
    slightly higher RBC count, haemoglobin and haematocrit than controls
    at the end of the treatment period which was not apparent after 2
    weeks recovery.  There were no treatment-related effects on clinical
    biochemistry parameters.  In the mid and high exposure females
    absolute liver weight, liver/body weight ratio and liver/brain weight
    ratio were higher than controls.  In males, absolute pituitary weight
    and pituitary/brain weight ratio were lower than controls.  At the end
    of the treatment period all the females in the mid and high exposure
    groups had cytoplasmic vacuolation of liver hepatocytes which was not
    seen in control or low exposure rats.  However, after the recovery
    phase 5/5 controls and 4/5 high exposure animals showed this change. 
    An NOAEL was not demonstrated in this study since clinical signs of
    toxicity were apparent at all exposure levels (Hartmann et al.,
    1988).

    Long term/carcinogenicity studies

    Mice

         Groups of 68 Charles River CD-1 mice/sex/dose were given diet
    containing 0, 50, 1000 or 3000 ppm cyromazine (95.3-95.5% pure).  Of
    these animals 8 mice/sex/dose  were sacrificed after 12 months on test
    and survivors to 24 months were all sacrificed.  Homogeneity analyses
    at the beginning of the study indicated a problem in obtaining uniform
    dispersion of the test material in the diet especially at the low dose
    level (50 ppm).  The method of preparation was changed and better
    homogeneity was achieved for the remainder of the study.  For the
    entire study weekly analyses indicated levels of 58-162% of nominal at
    the low dose and 77-133% at the other two levels; mean concentrations
    were 97-102% of nominal at all three dose levels.  There were no
    treatment-related clinical signs of toxicity.  Mortality to 93 weeks
    did not indicate a treatment-related effect.  Survival at 104 weeks
    was slightly lower in mid and high dose males and low and high dose
    females.  However, the mid dose females showed higher survival than
    the controls suggesting that the differences observed were incidental. 
    Body weights of mid and high dose males were consistently about 5% and
    7-9% lower than controls.  Differences in low dose males and all
    groups of females were not consistent.  Although food consumption in
    all treated groups was slightly lower than in controls there was no
    dose-relationship to the differences.  There were no treatment-related
    effects on haematological parameters examined for 8 mice/sex/dose at
    either 12 or 24 months.  There were no treatment-related changes in
    weights of liver, kidney, heart, testes or brain.  A slight increase
    in the liver/body weight ratio in high dose males was related to the
    reduced body weight in these animals.

         A slight increase in hepatocellular neoplasms (adenomas and
    carcinomas) was noted in treated males but, since there was no
    dose-relationship, no increase in nonneoplastic proliferative lesions
    and no similar effect in females, it was not considered to be
    treatment-related.  There was a small increase in malignant lymphomas
    (lymphocytic and histiocytic) in treated males that did increase with
    dose.  However, the incidence in the high dose group was only slightly
    higher than in historical controls for the two types combined.  There
    was no similar trend in females.  In high dose females the incidence
    of mammary gland adenocarcinomas was higher than in controls or the
    mid and low dose groups: 16% at 3000 ppm cf 4% in controls, 8.3% at 50
    ppm and 5.7% at 1000 ppm.  Historical control data indicated an
    expected range of 0-5%. The lack of a dose-response relationship
    suggests that these observations were not treatment-related.  The
    NOAEL in this study was 50 ppm (equal to 6.5 mg/kg bw/day) based on
    the body weight effects in the male (Blair and Hardisty, 1982a).

    Rats

         Groups of 60 Charles River Sprague-Dawley CD rats/sex/dose level
    were given diets containing 0, 30, 300 or 3000 ppm of cyromazine
    (95.3-95.5% pure) for 104 weeks.  Additionally, groups of 10 rats/sex
    were given diets containing 0 or 3000 ppm of cyromazine for 52 weeks;
    5/sex/group were sacrificed at 52 weeks and 5/sex/group were given a
    4 week recovery period prior to sacrifice.  Diets were prepared
    weekly.  During the study the method of preparation was altered to
    improve the homogeneity of the diet particularly at the lowest dose
    level.  Overall mean concentrations were 96-101% of the nominal
    concentrations.  There were no treatment-related effects on general
    clinical condition or on survival.  At termination of the study
    survival was 60-67% in males and 53-70% in females (lowest in
    controls).  Body weights were reduced in the high dose males and
    females; weights were 11-13% lower than controls by Week 4 and about
    30% lower by Week 79.  Body weight was also reduced in the mid dose
    females during much of the study (Weeks 12-79); the reduction in
    weight was about 10% by Week 49 and remained in that range.  During
    the recovery period in rats treated at 3000 ppm for 52 weeks females
    showed essentially complete recovery of body weight while males showed
    some recovery but at the end of the four week period still had about
    20% lower weights than the controls.  Food intakes expressed as
    g/rat/day were reduced in the high dose males and females but were
    similar to the controls in the other two dose groups.  Food intakes
    expressed as g/kg bw/day were higher than controls in the high dose
    males and females.  Efficiency of food utilization was not
    consistently affected during the first 25 weeks of the study.  There
    were no treatment-related effects on any of the haematology or
    clinical biochemistry parameters examined.  There was a tendency for
    urine volumes to be greater in the high dose males and females but
    unusually large volumes were seen only in occasional animals.  The
    observation was not consistent throughout the study and specific
    gravity showed no consistent changes.  Organ weight differences were
    restricted to the high dose group and appeared to be related to the
    body weight effects at this dose level rather than indicating a direct
    effect on the organs.

         There was a slight increase in the incidence of bronchiectasis in
    the high dose males and females; however, the incidence was considered
    to be within the observed range in aging rats and not, therefore,
    indicative of a treatment-related effect.  Renal pelvic epithelial
    hyperplasia was observed at a higher incidence in high dose females
    than in other groups.  The incidence at other dose levels was not
    dose-related and the incidence of chronic nephropathy was lower in the
    high dose group than in other groups. Since pelvic hyperplasia is
    generally observed as part of the complex of changes comprising
    chronic nephropathy the observed incidence probably relates to
    variability in degree of change as a result of aging and was not
    treatment-related.  There was a slightly higher incidence of

    interstitial cell tumours in high dose males (6/57 compared to 1/60 in
    controls) and mammary gland adenocarcinomas in high dose females (9/59
    compared to 3/53 in controls).  Both of these incidences are within
    the historical control range for the laboratory performing the in-life
    portion. The NOAEL in this study was 30 ppm (equal to 1.8 mg/kg
    bw/day) based on the body weight changes noted in females (Blair and
    Hardisty, 1982b).

    Reproduction study

         Groups of 15 male and 30 female weanling Sprague-Dawley COBS CD
    (Charles River) rats were given diets containing 0, 30, 1000 or 4000,
    then 3000 ppm of cyromazine (95.3% pure). The high dose was reduced
    from 4000 ppm to 3000 ppm at 4 weeks because of toxicity. The F0
    animals were fed their respective diets for 100 days prior to mating. 

         Weekly diet analyses showed considerable variability in achieved
    concentration, particularly in the 30 ppm diet.  Mean concentrations
    over the duration of the study, however, were close to the target
    concentrations.  There were no treatment-related changes in the
    general condition of the animals during the study. Bodyweights were
    lower than controls in male and female F0 and F1 rats given 1000 ppm
    or 3000 ppm; the differences were statistically significant except in
    the F1 males given 1000 ppm.  Food consumption on a g/rat/day basis
    was reduced in both sexes of both generations given 1000 ppm or 3000
    ppm.  There was no treatment-related effect on pregnancy in females. 
    In the F0 generation 6/15 males at 3000 ppm failed to sire a litter
    compared to 2/15 males in each of the other groups suggesting an
    effect on male fertility.  However, this effect was not observed in
    the F1 males.  There was no effect on duration of gestation.  Mean
    litter size was slightly reduced in the 3000 ppm group in the F1
    generation.  In both generations there was an increase in perinatal
    mortality at 3000 ppm (dead at birth or dying by Day 4).  In both
    generations pup weights in the 3000 ppm group were lower than controls
    at birth and throughout the lactation period.  In the 1000 ppm group
    only the F1 male pups at 21 days of age were statistically
    significantly lighter than the controls.  There were no
    treatment-related effects noted on pup behavior or appearance. Organ
    weight differences appeared to be attributable to the body weight
    changes observed and were not indicative of toxic effects per se. 
    No treatment-related gross or histopathology was noted in any tissue
    in either adults or pups.  The NOAEL in this study was 30 ppm (equal
    to 2.0 mg/kg bw/day) based on body weight effects in adult animals
    (Blair et al., 1981b).

    Special studies on genotoxicity

         Cyromazine was negative in 10 of 11 genotoxicity studies.  In the
    inconclusive study, a mammalian spot test in mice, interpretation of
    the results was confounded by reduced reproductive performance of the

    high dose group resulting in a much smaller number of observations. 
    Survival of offspring to 12 days of age was reduced at the top two
    dose levels, the levels which gave equivocally positive results.  This
    study cannot be considered to be conclusive (Table 2).

    Special studies on embryo/fetoxicity

    Rats

         Groups of 25 mated Charles River COBS CD female rats were given
    daily oral (gavage) doses of cyromazine (96.3% pure, suspended in 0.1%
    aqueous carboxymethylcellulose) at 0, 100, 300 and 600 mg/kg bw/day in
    a volume of 10 mg/kg bw/day on Days 6 through 19 of gestation.  The
    day evidence of mating was observed was designated Day 0 of gestation.

         A red nasal discharge was observed in all rats given 300 or 600
    mg/kg bw/day approximately 1 1/2 hours after dosing on one occasion
    during the first part of the dosing period. At 600 mg/kg bw/day this
    was accompanied by increased activity.  A clear oral discharge and
    inactivity were observed in all animals at 600 mg/kg bw/day on several
    days in the middle of the dosing period about 1-4 hours after dosing
    and in 11 of these rats at subsequent dosing.  An oral discharge was
    observed in five rats at 300 mg/kg bw/day prior to dosing on several
    days at the end of the dosing period and in two rats at 100 mg/kg
    bw/day on two occasions.  There were no deaths during the study.  Dams
    given 300 and 600 mg/kg bw/day lost weight during the first three days
    of dosing and had reduced weight gains for the entire dosing period
    compared to the controls.  There were no effects on the number of dams
    with litters, the numbers of viable fetuses/litter or the number of
    resorptions/litter.  No dead fetuses were observed in any group. Mean
    body weight of fetuses from dams dosed at 600 mg/kg bw/day were
    statistically significantly lower than that of controls.  At 300 mg/kg
    bw/day fetal body weight was slightly lower than controls but was not
    statistically significant.  Sex ratio was similar in all groups. 
    There was no evidence of a treatment-related teratogenic effect in the
    fetuses.  The incidence of unossified sternebrae was increased
    significantly at 600 mg/kg bw/day and slightly at 100 and 300 mg/kg
    bw/day.  A NOAEL was not clearly demonstrated in this study but
    effects at 100 mg/kg bw/day were very slight (Rodwell et al., 1979).

    Rabbits

         Groups of 16 virgin female Dutch Belted rabbits were artificially
    inseminated with sperm from one of six males of the same strain and
    then given an injection with chorionic gonadotropin to induce
    ovulation.  The day of insemination was considered to be Day 0 of
    gestation.  Each female was given daily oral (gavage) doses of
    cyromazine (96.3% pure suspended in 1% aqueous carboxymethylcellulose)
    at 0, 25, 50 or 75 mg/kg bw/day on Days 6 through 27 of gestation in
    a volume of 1 mg/kg bw/day.


        Table 2.  Results of mutagenicity assays on cyromazine
                                                                                                                          

    Test system              Test organism                 Concentration*      Results        Reference

                                                                                                                          

    Ames test                Salmonella typhimurium        20-5000 g/0.1 ml   negative       Deparade and Arni, 1988
                             TA98, TA100,
                             TA1535, and
                             TA1537

    Chromosome assay         Human Lymphocytes             0-1000 g/ml        negative       Strasser and Arni, 1985

    DNA repair assay         Rat hepatocytes               0.0001-1 mg/ml      negative       Tong, 1982

    DNA repair assay         Mouse Hepatocytes             0.0005-1 mg/ml      negative       Tong, 1983

    Dominant lethal test     Mouse                         0, 226, 678         negative       Hool and Muller, 1981
                                                           mg/kg bw

    Mammalian                Mouse                         0-600 mg/kg bw      inconclusive   Strasser and Arni, 1986

    Micronucleus test        Mouse                         0, 360, 1080        negative       Strasser et al., 1987
      (bone marrow)                                        mg/kg bw

    Mouse lymphoma assay     Mouse L5178Y TK +/-           0-500 g/ml         negative       Beilstein and Muller, 1985

    Nucleus anomaly test     Hamster                       0-8000 mg/kg bw     negative       Hool, et al., 1980

    Point mutation test      V79 Chinese hamster           0-4000 g/ml        negative       Dollenmeier and Muller, 1986
                             cells

    Yeast assay              Saccharomyces cerevisiae D7   375-3000 g/ml      negative       Hool and Arni, 1984
                                                                                                                          

    * Purity range 96.2 - 98.9%
    

         There were 0, 1, 2 and 4 deaths at 0, 25, 50 and 75 mg/kg bw/day,
    respectively.  Two of these females (one each at 25 and 75 mg/kg
    bw/day) died of heart failure.  Another 75 mg/kg bw/day animal died
    with pneumonia-pleuritis.  Cause of death of the remaining animals was
    not established.  No treatment-related changes in appearance or
    behavior of the animals was noted.  Two of the animals that died
    aborted prior to death: one each at 50 and 75 mg/kg bw/day.  Three
    other females aborted: one at 50 mg/kg bw/day and two at 75 mg/kg
    bw/day.  All three treated groups had a mean body weight loss over the
    treatment period.  Pregnancy rates were low in all groups apparently
    partially due to technical error but were slightly lower in all
    treated groups than in the controls.  Pre-implantation loss was higher
    in all treated groups than in the controls but a dose-relationship was
    not apparent.  Post-implantation loss was similar in controls and the
    two lower dose groups but was slightly higher in the high dose group
    (2.4 cf 0.6 in controls). Post-implantation loss in the 75 mg/kg
    bw/day group was nearly equally attributable to early and late
    resorptions while early resorptions accounted for nearly all the
    post-implantation loss in the other groups.  The mean number of viable
    fetuses/dam was reduced in the 75 mg/kg bw/day group.  Fetal weights
    did not appear to be affected but there were fewer male fetuses in the
    litters of dams given 75 mg/kg bw/day.  Only three fetuses had
    malformations: one fetus at 25 mg/kg bw/day had fused sternebrae and
    two fetuses (from one litter) at 75 mg/kg bw/day showed fetal
    anasarca.  The incidence of fetal variations was not treatment-related
    (Blair et al., 1981a).

         The above study was repeated in the same strain of rabbit using
    dose levels of 0, 10, 30 and 60 mg/kg bw/day.  In this study there
    were two deaths, both at 60 mg/kg bw/day, with severe lung congestion
    and edema.  A reduction in faecal excretion which was dose-related in
    duration was reported in the treated groups.  Two dams each at both 30
    and 60 mg/kg bw/day aborted.  In this study weight loss during
    treatment was noted only at 60 mg/kg bw/day. Weight gain was lower
    than in controls in the other two groups but the difference at 10
    mg/kg bw/day was small and not considered to be biologically
    significant.  Pregnancy rates in this study were in the expected range
    in all groups.  No treatment-related effect was observed on numbers of
    implantations/dam or numbers of viable fetuses/dam.  Post-implantation
    loss was slightly higher in the 60 mg/kg bw/day group than in the
    controls (1.1 cf 0.6 in controls). In this study no malformations were
    observed in control fetuses but there were a few in each of the
    treated groups.  Fetal anasarca was seen in one fetus at 30 mg/kg
    bw/day.  Fused sternebrae were observed in 1, 1 and 3 fetuses at 10,
    30 and 60 mg/kg bw/day, respectively; the fetus at 30 mg/kg bw/day was
    the same one that showed anasarca. Hydrocephalus was observed in two
    fetuses: one each at 10 and 60 mg/kg bw/day; the latter also had skull
    anomalies (nasals, premaxillae and jugals malformed and small
    bilaterally). Two fetuses from the same litter at 60 mg/kg bw/day had
    abdominal closure defects (omphalocele).  The total numbers of

    malformed fetuses were 5, 6 and 7 from 5, 4 and 4 litters at 10, 30
    and 60 mg/kg bw/day, respectively.  All treated groups had increased
    incidences of 27 presacral vertebrae and a 13th full rib but there was
    no dose-relationship to this observation.  No treatment-related gross
    pathology was observed in the dams (Blair et al., 1981a).

         A second study conducted in the same strain of rabbit and at the
    same laboratory could not be evaluated due to an infection of the dams
    (Schardein, et al., 1985).

         In a study in New Zealand White (BUK(CRL)NZW fBR), Charles River
    derived, closed colony, outbred, SPF rabbits, groups of 18 sexually
    mature virgin females were artificially inseminated with sperm from
    one of four males of the same strain and source. Immediately after
    insemination the females were injected with chorionic gonadotropin to
    ensure ovulation.  On gestation days 7 through 19 the groups were
    given daily oral (gavage) doses of cyromazine (95.2% pure, suspended
    in 0.5% aqueous carboxymethylcellulose) at 0, 5, 10, 30 or 60 mg/kg
    bw/day.  An additional group was untreated as an environmental
    control.

         One female died or was sacrificed in each of the 0, 30 and 60
    mg/kg bw/day groups.  Two treated animals reportedly died from
    intubation errors.  No treatment-related changes in appearance or
    behavior were noted.  Four females aborted: 1, 1 and 2 at
    0(untreated), 30 and 60 mg/kg bw/day.  During the early part of the
    treatment period the 60 mg/kg bw/day group lost weight and the 30
    mg/kg bw/day group gained less weight than the other groups. 
    Following treatment the 60 mg/kg bw/day group showed increased weight
    gain but failed to completely recover to control weight.  In this
    group food consumption was reduced during treatment and increased
    following treatment compared to controls.  The number of females
    pregnant was similar in all groups except the 10 mg/kg bw/day group in
    which 11/18 (61.1%) were not pregnant.  This was considered to be a
    random occurrence.  The numbers of early resorptions/dam were somewhat
    higher than controls at 30 and 60 mg/kg bw/day as was the number of
    late resorptions at 60 mg/kg bw/day but the numbers of live
    fetuses/dam was similar in all groups.  Mean fetal weight was not
    affected by treatment.  There were statistically significant
    differences in sex ratio at 5, 10 and 30 mg/kg bw/day but not at 60
    mg/kg bw/day.  No dose-relationship was observed and the differences
    were considered to be incidental.  Malformations were observed in
    7(6), 2(2), 4(3), 3(2), 10(6) and 15(6) fetuses (litters) at 0
    (vehicle control), 0 (untreated control), 5, 10, 30 and 60 mg/kg
    bw/day, respectively.  At 60 mg/kg bw/day 4 fetuses from one litter
    had open eyelids and 3 fetuses from another litter had short tails.
    These malformations were not seen in any other group but since all
    affected fetuses in each case were from a single litter it is doubtful
    the observations were treatment-related.  A number of unusual
    malformations were observed in one or more groups.  Cyclopia with

    multiple head anomalies was seen in 2 fetuses: one each at 10 and 30
    mg/kg bw/day.  One fetus at 60 mg/kg bw/day had externally apparent
    skull anomalies with cleft palate.  All three of these fetuses were
    sired by the same male.  Hydrocephalus was observed in 1(1), 2(2) and
    2(2) fetuses (litters) at 10, 30 and 60 mg/kg bw/day.  Spina bifida
    was observed in one fetus at 60 mg/kg bw/day, diaphragmatic hernia in
    1(1) and 3(2) fetuses (litters) at 10 and 30 mg/kg bw/day and
    umbilical hernia in one fetus at each 30 and 60 mg/kg bw/day.  Some
    fetuses in each group had vertebral anomalies and/or rib anomalies but
    the numbers of litters involved did not suggest a treatment-related
    effect.  The incidence of accessory skull bones and rudimentary 13th
    ribs was increased in the 60 mg/kg bw/day group (Nemec and Rodwell,
    1985).  

         A study was conducted in order to determine the possible genetic
    origin of the observed malformations.  Three groups of females were
    utilized.  Two of the groups of 56 females were inseminated with sperm
    from the male which sired the two cyclopic fetuses; one group was sham
    gavaged, the other untreated.  The third group of 59 females was
    inseminated with sperm from two alternate males.  No cyclopic fetuses
    were observed in these groups; however, various head anomalies were
    observed including cleft palate, acrania and anophthalmia. 
    Hydrocephalus, spina bifida, diaphragmatic hernia, gastroschisis,
    short tail and vertebral anomalies with or without rib anomalies were
    observed in some fetuses in one or more of these control groups.  Some
    additional malformations were also seen: conjoined twins,
    carpal/tarsal flexure and bradydactyly.  These results indicate that
    the malformations observed in the treated groups of the cyromazine
    study (Nemec and Rodwell, 1985) are consistent with those seen in this
    colony of rabbits (BUK:(CRL)NZWfBR).  In these control groups the
    highest incidence of hydrocephalus was 1.1% of the fetuses (Nemec and
    Rodwell, 1986a).

         Another teratology study was carried out in New Zealand White,
    Hra;(NZW)SPF (Hazleton-Dutchland), rabbits.  Groups of 74 sexually
    mature virgin females were artificially inseminated with semen from
    seven bucks of the same strain and source.  Immediately after
    insemination the females were injected with chorionic gonadotropin to
    induce ovulation.  The day of insemination was designated Day 0 of
    gestation.  On gestation days 7 through 19 the females were given
    daily oral (gavage) doses of cyromazine (95.2% pure, suspended in 0.5%
    aqueous carboxymethylcellulose) at 0, 5, 10 or 30 mg/kg bw/day in a
    volume of 1 ml/kg bw.

         There were 4, 3, 3 and 1 deaths and 4, 5, 2 and 5 abortions at 0,
    5, 10 and 30 mg/kg bw/day, respectively.  The incidences of decreased
    defecation and urination was highest at 30 mg/kg bw/day and somewhat
    higher than controls at 10 mg/kg bw/day.  The group given 30 mg/kg
    bw/day lost weight during treatment and had a higher weight gain
    following treatment than controls.  The other groups were similar to

    controls.  Food consumption was reduced in the 30 mg/kg bw/day group
    during treatment and increased following treatment.  There were
    similar numbers of females pregnant in all groups.  For the teratology
    phase of the study a minimum of 25 females with viable fetuses were
    examined from each group.  There was no apparent treatment-related
    effect on numbers of dead fetuses or early or late resorptions but the
    numbers of viable fetuses and total implantations was slightly lower
    in the 30 mg/kg bw/day group than in the other groups.  The difference
    was not statistically significant and was probably not biologically
    significant.  Fetal body weights and sex ratios were similar in all
    groups.  There were a total of 8(7), 11(8), 12(8) and 6(5) fetuses
    (litters) at 0, 5, 10 and 30 mg/kg bw/day which had malformations. 
    Soft tissue malformations were observed only in the treated groups but
    were not dose-related.  The only soft tissue anomaly seen in more than
    one fetus was diaphragmatic hernia which was seen in 1(1), 3(2) and
    1(1) fetuses (litters) at 5, 10 and 30 mg/kg bw/day, respectively. 
    External malformations seen only in treated groups included
    omphalocele (1 at 5 mg/kg bw/day), umbilical hernia (1 at 5 mg/kg
    bw/day), gastroschisis(1 at 30 mg/kg bw/day), spina bifida (1 at 30
    mg/kg bw/day), microphthalmia(1 at 5 mg/kg bw/day), macroglossia (1 at
    10 mg/kg bw/day) and agnathia (1 at 10 mg/kg bw/day).  Skeletal
    malformations and visceral and skeletal variations were similar in all
    groups.

         The females not sacrificed for the teratology portion of the
    study were allowed to deliver their litters and rear their offspring
    to weaning.  Mean gestation length was 31.7, 31.8, 32.3 and 32.4 days
    at 0, 5, 10 and 30 mg/kg bw/day, respectively.  No treatment-related
    effects were noted in the number of dams with live litters, the number
    of kits/litter, the total number of dead kits/group, kit survival to
    day 4, the number of dams which failed to raise their litter to
    weaning, sex ratio of kits or body weights of kits.  Following culling
    day 4 there was a slightly higher number of kit deaths in the 30 mg/kg
    bw/day group during days 4-28 (37 cf 12 in controls).  Among the kits
    culled at day 4 only one (at 5 mg/kg bw/day) had a cataract; no other
    malformations were observed.  Among kits examined at weaning one
    control kit had carpal flexure and one kit at each of 5 and 30 mg/kg
    bw/day had a cataract; no other malformations were reported.  Among
    the kits that died during days 0-4, 1, 0, 0 and 4(2) fetuses (litters)
    had malformations.  The control had omphalocele.  One kit at 30 mg/kg
    bw/day had cyclopia, omphalocele and cleft palate.  Other
    malformations in this group were tarsal flexure, absent kidney and
    ureter (each in one kit) and hydrocephalus (in 2 kits).  No
    malformations were observed in kits dying at days 4-28.  No
    treatment-related gross pathology was observed in dams at any dose
    level. The NOAEL in this study was considered to be 5 mg/kg bw/day
    (Nemec and Rodwell, 1986b).

    Special studies on irritation and sensitization

    Guinea pigs

         A series of 10 sensitizing injections of cyromazine was given to
    10 male and 10 female Pirbright white guinea pigs every other day
    intracutaneously in the back.  Fourteen days later a challenge
    injection was given in the flank.  Following the third and fourth
    sensitizing injections each of the cyromazine-treated animals showed
    some reaction.  After the challenge injection only two of the animals
    showed any reaction and in both cases the reaction was less than that
    following the sensitizing injection.  None of the animals was scored
    as positive.  There was no evidence of skin sensitizing (contact
    allergic) potential of cyromazine in guinea pig (Ullman and Sachsse,
    1978c).

    Rabbits

         Following treatment of the left eyes of 3 male and 3 female
    Himalayan rabbits with 0.1g cyromazine, the eyes of the females were
    flushed about 30 seconds after treatment.  No irritation was observed
    in cornea, iris or conjunctiva in any rabbit with or without rinsing
    after treatment (Ullman and Sachsse, 1978a).

         In Himalayan rabbits treated dermally with technical cyromazine
    very slight to well-defined erythema and very slight to moderate
    oedema was observed on scarified skin and no reaction to very slight
    erythema and oedema on intact skin at 24 hours after treatment.  By 72
    hours after the start of treatment (48 hours after removal of
    dressings) no reactions were observed on either intact or scarified
    skin.  The mean score was 1.1 of a possible 8. The test material
    caused mild irritation to rabbits (Ullman and Sachsse, 1978b).

    Observations in humans

         No information available.

    Oncogenicity studies of melamine, a metabolite

         Several toxicological studies of melamine have been conducted in
    rats and mice by the U.S. National Toxicology Program (NTP/NIH, 1983).

    COMMENTS

         Cyromazine administered orally to rats, monkeys, sheep or goats
    was rapidly absorbed and excreted, predominantly in urine.  Absorption
    and excretion were also rapid in the hen.  Tissue levels were highest
    in the livers of rats, sheep and goats.  Other tissue levels were low. 
    Cyromazine was excreted in small amounts in goat milk and in eggs.

         The majority of the material excreted in the urine of rats,
    monkeys, sheep and goats and in the excreta of hens was unchanged
    cyromazine.  Melamine was determined to be the major metabolite of
    cyromazine in all these species.  Other metabolites were not
    identified. 

         WHO has classified cyromazine as slightly hazardous on the basis
    of its acute toxicity and has concluded that it is "unlikely to
    present acute hazard in normal use" (WHO, 1990).

         In short-term rat and dog studies and in long-term studies in
    mice and rats, the most consistent effect was a reduction in body
    weight gain at high dose levels during the treatment period.  The
    effect appeared to the largely reversible upon cessation of treatment. 
    Red blood cell counts and haemoglobin levels were reduced in male dogs
    at 3000 ppm.  There was a slight increase in the number of females
    with mammary gland adenocarcinomas in the high dose group (3000 ppm)
    in both mice and rats.  However, in rats the incidences at other dose
    levels did not suggest a dose-response relationship and in the mouse
    the incidence was within the historical control range.  Therefore,
    this effect was not considered to be treatment-related.  No other
    tumour incidence appeared to be affected by treatment.

         There were ten negative genotoxicity studies and one inconclusive
    study (mouse spot test).

         In a multigeneration study in rats, cyromazine did not affect
    fertility, but at maternally toxic doses there was increased perinatal
    pup mortality and reduced pup weight.  Studies in rats did not
    demonstrate a teratogenic effect.  Data from several rabbit
    teratogenicity studies showed inconsistent results but no dose-related
    effects.  The Meeting felt that there was no evidence of
    teratogenicity in rabbits.

         The Meeting was aware of toxicological data on melamine, notably
    the National Toxicology Program (USA) carcinogenesis bioassays on mice
    and rats.  The observation of bladder tumours in the rats in one of
    these studies was related to the formation of bladder stones when the
    rats were given high doses of melamine.  Since this is an indirect
    mechanism of carcinogenesis limited to this species, concern was
    alleviated with respect to melamine residues in food.

         The ADI was estimated utilizing a hundred-fold safety factor and
    the NOAELs in the rat long-term (1.8 mg/kg bw/day) and reproduction (2
    mg/kg bw/day) studies.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Mouse:    50 ppm in the diet, equal to 6.5 mg/kg bw/day
         Rat:      30 ppm in the diet, equal to 1.8 mg/kg bw/day
         Rabbit:   5 mg/kg bw/day
         Dog:      300 ppm in the diet, equal to 9.1 mg/kg bw/day

    Estimate of acceptable daily intake for humans

         0-0.02 mg/kg bw

    Studies which will provide information valuable in the
    continued evaluation of the compound

         -    Observations in humans
         -    Identification of unknown metabolites

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    technical CGA 72662. Unpublished report, project no. Siss 6446 from
    CIBA-GEIGY Ltd., Basle, Switzerland.

    Bathe, R. and Sachsse, K., (1978b). Acute oral LD50 in the rat of
    technical CGA 72662. Unpublished report, project no. Siss 6446 from
    CIBA-GEIGY Ltd., Basle, Switzerland.

    Bathe, R. and Sachsse, K., (1978c). Acute dermal LD50 in the rat of
    technical CGA 72662. Unpublished report, project Siss 6446 from
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    Beilstein, P. and Muller, D., (1985). L5178Y/TK+/- Mouse Lymphoma
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    Blair, M., McMeekin, S.O. and Schardein, J.L., (1981a). CGA-72662
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    Dollenmeier, P. and Muller, D., (1986). V79 Chinese hamster point
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    Goldenthal, E.L. and Hughes, R., (1979). 90 day subacute toxicity
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    Hartmann, H.R., Schneider, M., Gretener, P., Froehlich, E.,
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    Switzerland.

    Hool, G. and Arni, P., (1984). Saccharomyces cerevisiae
    D7/mammalian-microsome mutagenicity test in vitro (Test for mutagenic
    properties in yeast cells) - CGA 72662 techn. Unpublished report,
    project no. 831167 from CIBA-GEIGY Ltd., Basle, Switzerland.

    Hool, G., Langauer, M. and Muller, D., (1980). Nucleus anomaly test in
    somatic interphase nuclei - CGA 72662 - Chinese hamster (Test for
    mutagenic effects on bone marrow cells). Unpublished report, project
    no. 791347 from CIBA-GEIGY Ltd., Basle, Switzerland.

    Hool, G. and Muller, D., (1981). Dominant lethal study - CGA 72662
    -mouse (Test for cytotoxic or mutagenic effects on male germinal
    cells). Unpublished report,project no. 790033 from CIBA-GEIGY Ltd.,
    Basle, Switzerland.

    Jessup, D.C. and Hughes, R., (1979). 90 day subacute oral toxicity
    study with CGA-72662 in purebred beagle dogs. Unpublished report no.
    382-048 from International Research and Development Corporation,
    Mattawan, MI., USA. Submitted to WHO by CIBA-GEIGY Ltd., Basle,
    Switzerland.

    Murphy, T.G. and Simoneaux, B., (1985). Percutaneous absorption of
    cyromazine in rats. Unpublished report no. ABR-85035 from CIBA-GEIGY
    Corporation, Greensboro, NC, USA. Submitted to WHO by CIBA-GEIGY Ltd.,
    Basle, Switzerland.

    Murphy, T.G., Brown, K. and Doornheim,D., (1987). Dermal absorption of
    cyromazine in rats. Unpublished report no. ABR-86069 from CIBA-GEIGY
    Corporation, Greensboro, NC, USA. Submitted to WHO by CIBA-GEIGY Ltd.,
    Basle, Switzerland.

    Nemec, M.D. and Rodwell, D.E., (1985). A teratology study (segment II)
    in albino rabbits with cyromazine technical - final report.
    Unpublished report, project no. WIL-82001 from WIL Research
    Laboratories Inc., Ashland, OH, USA. Submitted to WHO by CIBA-GEIGY
    Ltd., Basle, Switzerland.

    Nemec, M.D. and Rodwell, D.E., (1986a). A study of the incidence of
    foetal malformations in the control population of BUK:(CRL) NZWfBR
    rabbits. Unpublished report, project no. WIL-82005 from WIL Research
    Laboratories Inc., Ashland, OH, USA. Submitted to WHO by CIBA-GEIGY
    Ltd., Basle, Switzerland.

    Nemec, M.D. and Rodwell, D.E., (1986b). A teratology and postnatal
    study in albino rabbits with cyromazine technical - final report.
    Unpublished report, project no. WIL-82008 from WIL Research
    Laboratories Inc., Ashland, OH, USA. Submitted to WHO by CIBA-GEIGY
    Ltd., Basle, Switzerland.

    NTP/NIH, 1983. Carcinogenesis bioassay of melamine in F344/N rats and
    B6C3F1 mice (feed study). US NIH Publication No. 83-2501, March,
    (1983).

    Rodwell, D.E., Tasher, E.J. and Jessup, D.C., (1979). CGA-72662
    technical - teratology study in rats. Unpublished report, study no.
    382-070 from International Research and Development Corporation,
    Mattawan, MI, USA. Submitted to WHO by CIBA-GEIGY Ltd., Basle,
    Switzerland.

    Sabol,R.J., (1987). Acute oral toxicity study in rats - EPA guidelines
    no. 81-1. Unpublished report, project no. 5020-87 from Stillmeadow
    Inc., Houston, TX., USA.  Submitted to WHO by CIBA-GEIGY Ltd., Basle,
    Switzerland.

    Schardein, J.L., Aldridge, D. and Blair, M., (1985). Cyromazine -
    teratology study in rabbits. Unpublished report, study no. 382-104
    from International Research and Development Corporation, Mattawan, MI,
    USA. Submitted to WHO by CIBA-GEIGY Ltd., Basle, Switzerland.

    Simoneaux, B., (1981). Identification of a major metabolite of
    14C-CGA-72662 in chickens. Unpublished report no. ABR-81035 from
    CIBA-GEIGY Corporation, Greensboro, NC, USA. Submitted to WHO by
    CIBA-GEIGY Ltd., Basle, Switzerland.

    Simoneaux, B. and Cassidy, J.E., (1978). Metabolism and balance study
    of 14C-CGA 72662 in the rat. Unpublished report no. ABR-78072 from
    CIBA-GEIGY Corporation, Greensboro, NC, USA. Submitted to WHO by
    CIBA-GEIGY Ltd., Basle, Switzerland.

    Simoneaux, B. and Cassidy, J.E., (1979). Metabolism and balance study
    of 14C-CGA-72662 in a chicken. Unpublished report no. ABR-79043 from
    CIBA-GEIGY Corporation, Greensboro, NC, USA. Submitted to WHO by
    CIBA-GEIGY Ltd., Basle, Switzerland.

    Simoneaux, B. and Cassidy, J.E., (1981). Metabolism and balance study
    of 14C-CGA-72662 in a mature sheep. Unpublished report no. ABR-80055
    from CIBA-GEIGY Corporation, Greensboro, NC, USA. Submitted by
    CIBA-GEIGY Ltd., Basle, Switzerland.

    Simoneaux, B. and Marco, G., (1984). Balance and metabolism of
    14C-cyromazine in lactating goats.  Unpublished report no. ABR-84067
    from CIBA-GEIGY Corporation, Greensboro, NC, USA. Submitted to WHO by
    CIBA-GEIGY Ltd., Basle, Switzerland.

    Smith, J., Boone, T. and Harper, J., (1983). Residues in rat tissues
    resulting from the feeding of cyromazine. Unpublished report no.
    ABR-83088 from CIBA-GEIGY Corporation, Greensboro, NC, USA. Submitted
    to WHO by CIBA-GEIGY Ltd., Basle, Switzerland.

    Staley, J.A., (1986). Distribution and characterization of
    14C-labelled cyromazine in monkeys. Unpublished report no. ABR-85100
    from CIBA-GEIGY Corporation, Greensboro, NC, USA. Submitted to WHO by
    CIBA-GEIGY Ltd., Basle, Switzerland.

    Staley, J.A. and Simoneaux, B., (1986). Distribution and
    characterization of 14C-labelled cyromazine in monkeys. Unpublished
    report no. ABR-86008 from CIBA-GEIGY Corporation, Greensboro, NC, USA.
    Submitted to WHO by CIBA-GEIGY Ltd., Basle, Switzerland.

    Strasser, F. and Arni, P., (1985). Chromosome studies on human
    Lymphocytes in vitro with CGA 72662 techn. Unpublished report, project
    no. 850013 from CIBA-GEIGY Ltd., Basle, Switzerland.

    Strasser, F. and Arni, P., (1986). Mammalian spot test, mouse, 8 weeks
    - CGA 72662 techn. Unpublished report, project no. 850616 from
    CIBA-GEIGY Ltd., Basle, Switzerland.

    Strasser, F., Langauer, M. and Arni, P., (1987). Micronucleus test
    (mouse) - CGA 72662 tech. Unpublished report, project no. 861345 from
    CIBA-GEIGY Ltd., Basle, Switzerland.

    Tong, C., (1982). The hepatocyte primary culture/DNA repair assay on
    compound CGA-72662 using rat hepatocytes in culture. Unpublished
    report, project no. 042782 from Naylor Dana Institute for Disease
    Prevention, American Health Foundation, Valhalla, N.Y. Submitted to
    WHO by CIBA-GEIGY Ltd., Basle, Switzerland.

    Tong, C., (1983). The hepatocyte primary culture/DNA repair assay on
    compound CGA-72662 using mouse hepatocytes in culture. Unpublished
    report, project no. 050382 from Naylor Dana Institute for Disease
    Prevention, American Health Foundation, Valhalla, N.Y.. Submitted to
    WHO by CIBA-GEIGY Ltd.,Basle, Switzerland.

    Ullmann, L. and Sachsse, K., (1978a). Eye irritation in the rabbit of
    technical CGA 72662. Unpublished report, project no. 6446 from
    CIBA-GEIGY Ltd., Basle, Switzerland

    Ullmann, L. and Sachsse, K., (1978b). Skin irritation in the rabbit
    after single application of technical CGA 72662. Unpublished report,
    project no. 6446 from CIBA-GEIGY Ltd., Basle, Switzerland.

    Ullmann, L. and Sachsse, K., (1978c). Skin sensitizing (contact
    allergenic) effect in guinea pigs of technical CGA 72662. Unpublished
    report, project no. 6446 from CIBA-GEIGY Ltd., Basle, Switzerland.

    Ullmann, L. and Sachsse, K., (1978d). Acute oral LD50 in the rabbit
    of technical CGA 72662. Unpublished report, project no. Siss 6446 from
    CIBA-GEIGY Ltd., Basle, Switzerland.

    Ulrich, C.E. and Blair, M., (1979). Acute inhalation study on
    CGA-72662 tech. Unpublished report no. 382-075 from International
    Research and Development Corporation, Mattawan, MI., USA. Submitted to
    WHO by CIBA-GEIGY Ltd., Basle, Switzerland.

    WHO (1990).  The WHO recommended classification of pesticides by
    hazard and guidelines to classification 1990-1991 (WHO/PCS/90.1). 
    Available from the International Programme on Chemical Safety, World
    Health Organization, Geneva, Switzerland.


    See Also:
       Toxicological Abbreviations