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    XYLAZINE

    First draft prepared by
    Dr Pamela L. Chamberlain
    Center for Veterinary Medicine
    Food and Drug Administration,
    Rockville, Maryland, USA

    1.   Explanation

    2.   Biological data
         2.1   Biochemical aspects
               2.1.1   Pharmacodynamics
               2.1.2   Absorption, distribution and excretion
               2.1.3   Biotransformation
         2.2   Toxicological studies
               2.2.1   Acute toxicity studies of xylazine and 2,6-xylidine
               2.2.2   Short-term toxicity studies
               2.2.3   Long-term toxicity/carcinogenicity studies
               2.2.4   Special studies on teratogenicity
               2.2.5   Special studies on genotoxicity
               2.2.6   Special studies on methaemoglobin and haemoglobin
                       adduct formation with 2,6-xylidine
         2.3   Observations in humans

    3.   Comments

    4.   Evaluation

    5.   Acknowledgements

    6.   References

    1.  EXPLANATION

         Xylazine is a clonidine analogue that acts on presynaptic and
    postsynaptic receptors of the central and peripheral nervous systems.
    It is an alpha2-adrenergic agonist used in animals, including
    cattle, horses, dogs, cats and deer, for its tranquillizing, muscle
    relaxant and analgesic effects, but it has numerous other
    pharmacological effects. It inhibits the effects of postganglionic
    cholinergic nerve stimulation.

         Xylazine is administered by the intramuscular, intravenous or
    subcutaneous (in cats) routes, often in combination with other
    anaesthetic agents, e.g., barbiturates, chloral hydrate, halothane and
    ketamine.

         Xylazine had not been previously evaluated by the Committee. The
    molecular structure of xylazine is shown below.

    CHEMICAL STRUCTURE 3

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

    2.1.1  Pharmacodynamics

         With respect to xylazine's sedative effect, there are marked
    species differences in the dose rates required to achieve this state.
    Table 1 illustrates dosages required for various animal species
    (Gross & Tranquilli, 1989).

    Table 1.  Dosage of xylazine in various animal species
                                                                        

                          Xylazine (mg/kg bw)
                                                                        

    Species               Intravenous         Intramuscular
                                                                        

    Horses                0.5 to 1.1          1 to 2
    Cattle                0.03 to 0.11        0.1 to 0.21
    Sheep                 0.05 to 0.11        0.1 to 0.31
    Goats                 0.01 to 0.51        0.05 to 0.51
    Swine                                     2 to 3
    Dogs                  0.5 to 1            1 to 2
    Cats                  0.5 to 1            1 to 2
    Birds                                     5 to 10
                                                                        

    1    Lower end of dose range should be used if sedation without
         recumbency is desired (Gross & Tranquilli, 1989).

         Mydriasis is a feature of xylazine-induced sedation in the cat.
    The mechanism has been determined as central inhibition of
    parasympathetic tone in the iris due to xylazine's activation of
    post-synaptic alpha-2 receptors (Hsu  et al., 1981).

         Thermoregulatory control is impaired in cats administered
    xylazine. They become more susceptible to hyper- and hypothermia both
    during and after recovery from the sedative effects of the drug. Foals
    have demonstrated a hypothermic response to xylazine. Thermoregulatory
    effects in cattle have been variable (Ponder & Clark, 1980;
    Booth, 1988; Robertson  et al., 1990).

         Cardiovascular effects of xylazine include decreased heart rate
    and variable effects on blood pressure. Xylazine-induced arrhythmia is
    common in the horse due to sinoatrial and atrioventricular blocks.
    Arrhythmias have also been recorded in dogs, but could not be induced

    in sheep. The induction of cardiovascular effects may be influenced by
    route of administration, e.g., xylazine administered epidurally to
    horses produced no cardiovascular changes, whereas cattle injected by
    this route experienced decreases in heart rate and arterial blood
    pressure (Sagner  et al., 1969; Holmes & Clark, 1977; Freire
     et al., 1981; Hsu  et al., 1981; Wasak, 1983; Singh  et al., 1983;
    Leblanc & Eberhart, 1990; Skarda  et al., 1990).

         The effects of xylazine on respiration, acid-base balance and
    blood gas values vary according to species and anaesthetic
    combination. In cattle, xylazine causes a slowing of the respiratory
    rate. This is accompanied by an increase in pH and metabolic acidosis.
    Respiratory rate is also slowed in dogs administered xylazine, but
    arterial pH, pO2 or pCO2 are not significantly affected. The
    literature contains conflicting reports on the effect of xylazine on
    the respiratory rate of horses. Tachypnoea is characteristic of the
    ovine response to xylazine. Hypoxaemia induced by xylazine in sheep
    can be life-threatening (DeMoor & Desmet, 1971; Klide  et al., 1975;
    Holmes & Clark, 1977; Hsu  et al., 1989; Carter  et al., 1990;
    Wagner  et al., 1991).

         Hyperglycaemia is induced by xylazine in adults of all target
    species. Increased blood glucose concentrations are accompanied by a
    decrease in insulin levels. In adult horses, hyperglycaemia is
    accompanied by increased urine volume without glycosuria. Xylazine
    administered to neonatal foals did not result in hyperglycaemia. The
    hyperglycaemic effect of xylazine is thought to be due to its direct
    effect on alpha-2-adrenoceptors of pancreatic islet beta cells
    resulting in an inhibition of insulin release (Symonds, 1976; Feldberg
    & Symonds, 1980; Hsu & Hummel, 1981; Thurmon  et al., 1982, 1984;
    Benson  et al., 1984).

         Serum chemistry and cerebral spinal fluid alterations were
    observed in adult female goats administered intramuscularly with
    0.2 mg xylazine/kg bw. Significant elevations of urea nitrogen, total
    protein and total cholesterol were found in serum. Glucose and urea
    nitrogen levels were significantly increased (P<0.01) and chloride
    levels were significantly decreased (P<0.05) in the cerebral spinal
    fluid (Amer & Misk, 1980).

         Erythrocyte counts, haematocrit values and haemoglobin
    concentrations in cattle and dogs have shown significant but
    reversible decreases following xylazine administration
    (Eichner  et al., 1979; Wasak, 1983).

         Gastrointestinal effects in ruminants include decreased gut
    motility, prolongation of gastrointestinal transit time and inhibition
    of reticulorumen contractions. Xylazine causes decreased muscle tone
    of the colon and rectum which facilitates rectal examination. Xylazine
    inhibition of rumen contractions can lead to tympany, which is a

    potential cause of death in xylazine-sedated ruminants. Ruminants are
    fasted prior to sedation and maintained in sternal recumbency during
    sedation to reduce the risk of xylazine-induced tureen tympany.
    Because xylazine also impairs deglutition, the head and neck of
    xylazine-sedated ruminants are lowered to avoid aspiration of saliva
    or ruminal fluid. Tolazoline (an alpha-2-adrenergic antagonist) has
    shown effectiveness in reversing recumbency, gastric paresis and loss
    of voluntary lingual control caused by xylazine in cattle
    (Swift, 1977; Bolte & Stupariu, 1978; Ruckebusch & Toutain, 1984).

         Gastrointestinal effects in dogs and cats include decreased
    transit time and vomiting. The mechanism for induction of vomiting is
    thought to involve the effect of xylazine on alpha-2-adrenoceptors in
    the area postrema (the chemoreceptor trigger zone for vomiting) in the
    medulla oblongata (Cullen & Jones, 1977; Colby  et al., 1981; Hsu &
    McNeel, 1983; Hikasa  et al., 1987, 1989).

    2.1.2  Absorption, distribution and excretion

    2.1.2.1  Rats

         Male Sprague-Dawley rats (170 g bw) were administered xylazine at
    dosages of 0.02 to 10 mg/kg bw (i.v.) or 0.02 to 100 mg/kg bw (oral).
    The drug was labelled with both 35S and 14C on the thiazine ring.
    Following oral administration, absorption was > 95% with a half-life
    of approximately 5 minutes. After i.v. administration, the drug was
    distributed within a few minutes to almost all organs but primarily to
    the kidneys and central nervous system. Relatively high activity
    concentrations occurred in the pancreas, thyroid glands, liver and
    cranial glands (e.g., extraorbital, sublingual). Several hours
    following i.v. administration of 2 mg/kg bw, only small concentrations
    (< 0.3 g/g tissue) were present in the musculature. Following oral
    or i.v. administration, approximately 70% of the administered dose was
    eliminated in urine and 30% in faeces. Renal elimination following
    oral or i.v. administration was associated with a half-life of 2 to 3
    hours. High oral doses (100 mg/kg bw) were associated with a delay in
    renal elimination. Faecal elimination was comparable to biliary
    elimination after oral or i.v. administration. Enterohepatic
    circulation did not occur to a notable extent (Duhm  et al., 1968,
    1969).

    2.1.2.2  Cattle

         Three male calves (200-250 kg) and one dairy cow (450 kg) were
    injected intramuscularly with a 0.33 mg/kg dose of 14C-xylazine
    labelled in the thiazine ring. Radioactivity in blood plasma reached
    its peak in the first 1.5 hours after injection. Total excretion of
    radioactivity in urine and faeces was 68, 86, 83 and 100% at 10, 24,
    48 and 72 hours, respectively (Murphy & Jacobs, 1975).

         In another study, five 2-month old calves and four lactating cows
    were administered a single intramuscular dose (0.3 or 0.6 mg/kg bw) of
    xylazine hydrochloride. Maximum concentrations of xylazine were
    achieved in blood 20 minutes after dosing. These were 0.04 mg/litre
    for the 0.3 mg/kg bw dose and 0.06 mg/litre for the 0.6 mg/kg bw dose.
    No xylazine was found in blood 8 hours after administration
    (Takase  et al., 1976).

         Three lactating cows were administered an i.m. dose of 0.2 mg
    xylazine/kg bw and two others were administered an i.m. dose of 0.4 mg
    xylazine/kg bw. Milk was analysed for the presence of xylazine at 5
    and 21 hours following administration. No xylazine was found at either
    time point for either dose. The limit of detection was 0.06 mg/litre
    (Ptter & Sagner, 1973).

         Urinary excretion of xylazine was studied in three cows. Two were
    administered an i.m. dose of 0.2 mg xylazine/kg bw and one was
    administered an i.m. dose of 0.5 mg xylazine/kg bw. Less than 1% of
    the dose was excreted unchanged in the urine. Unchanged xylazine was
    no longer detectable 6 hours following administration. Metabolites
    were no longer detected in urine 10 hours after administration. The
    limit of detection for unchanged xylazine was 1-5 g/litre (Ptter &
    Sagner, 1973).

    2.1.2.3  Comparative pharmacokinetics in dogs, sheep, cattle and
             horses

         The comparative pharmacokinetics of xylazine in dogs, sheep,
    cattle and horses are summarized in Table 2.

         Pharmacokinetic parameters do not vary greatly between species
    following intravenous administration. The rapid elimination of
    xylazine is attributed to extensive metabolism, and not to rapid renal
    excretion of unchanged xylazine. Significant amounts of parent
    xylazine were not found in the urine of sheep collected at 10-minute
    intervals after dosing. The pharmacokinetics of xylazine were
    unmodified when it was administered to rabbits with occluded renal
    arteries. The lack of correlation between pharmacokinetic parameters
    and clinical effects of xylazine in cattle suggests that clinical
    effects in cattle are due to a rapidly produced long-acting
    metabolite(s) and not due to an increased sensitivity to xylazine
    (Garcia-Villar  et al., 1981).

        Table 2.  Single-dose pharmacokinetics of xylazine in domestic species (Garcia-Villar et al., 1981)
                                                                                                             

                       Species          Dog             Sheep           Cattle          Horse
        Body weight range (kg)          14-24           42-65           240-440         415-550
         Dose rate (mg/kg bw)1          1.4             1.0             0.2             0.6
                        Number          4               6               4               4
                                                                                                             

    Intravenous2
    Distribution half-life (min)        2.57            1.89            1.21            5.97
    Volume of distribution (l/kg)       2.52            2.74            1.94            2.46
    Elimination half-life (min)         30.13           23.11           36.48           49.51
    Body clearance (ml/min/kg)          81              83              42              21

    Intramuscular2
    Absorption half-life (min)          3.44            5.45            ND              2.72
    Elimination half-life (min)         34.65           22.36           ND              57.7
    Cmax (mg/ml)                        0.43            0.13            ND              0.17
    Tmax (min)                          12.7            14.68           ND              12.92
    Bioavailability:
      mean (%)                          73.9            40.8            ND              44.6
      standard deviation (%)            17.89           23.81                           4.16
      range (%)                         52-90           17-73                           40-48
                                                                                                             

    1    Dosage expressed as xylazine-base
    2    Blood sampling times after injection: 1, 2, 4, 8, 16, 30 and 120 minutes.
    ND = Not determined (assay was not sensitive enough to determine xylazine plasma
         concentrations lower than 0.01 mg/litre)
    
    2.1.3  Biotransformation

    2.1.3.1  Rats

         Studies were conducted with urine and bile of rats administered
    2 mg xylazine (35S or 14C)/kg bw intravenously. Approximately 20
    metabolites were detected and quantified as xylazine equivalents.
    Approximately 8% of the dose was eliminated as unchanged compound in
    the urine 24 hours after dosing. The major metabolite comprised 35% of
    the administered dose. Final products of metabolism were inorganic
    sulfate and carbon dioxide (Duhm  et al., 1968).

         Specific metabolites of xylazine were identified following
    incubation of xylazine with rat liver microsomes. Those metabolites
    were 2-(4'-hydroxy-2',6'-dimethylphenylamino)-5,6-dihydro-4H-1,3-
    thiazine, 2-(3'-hydroxy-2',6'-dimethylphenylamino)-5,6-dihydro-4H-
    1,3-thiazine,  N-(2,6-dimethylphenyl)thiourea and 2-(2',6'-
    dimethylphenylamino)-4-oxo-5,6-dihydro-1,3-thiazine.  N-(2,6-dime-
    thylphenyl)thiourea was the major metabolite produced  in vitro.
    Figure 1 shows the proposed metabolic pathways of xylazine based on
    these findings (Mutlib  et al., 1992).

    2.1.3.2  Horses

         One mare was administered a 1 g dose of xylazine (route not
    stated) and urine was collected over 24 hours. Metabolites were
    recovered from horse urine only after the urine was hydrolysed with
    beta-glucuronidase. The major urinary metabolites detected were the
    same as those produced by incubating xylazine with rat liver
    microsomes, described in section 2.1.3.1 (Mutlib  et al., 1992).

    2.1.3.3  Cattle

         Urine from three cows administered an i.m. dose of 0.2 mg
    xylazine/kg bw (two cows) or 0.5 mg xylazine/kg bw (one cow) was
    examined for metabolites. One urinary metabolite, identified as
    2,6-xylidine1, was found in both free and conjugated forms. The
    authors concluded that xylazine was essentially eliminated in cattle
    by rapid biotransformation. Breakdown of the thiazine ring, resulting
    in formation of 2,6-xylidine, was proposed as the primary
    biotransformation pathway (Patter & Sagner, 1973).

              

    1    2,6-xylidine is also known as 1-amino-2,6-dimethylbenzene and as
         2,6-dimethylaniline

    CHEMICAL STRUCTURE 4

    2.2  Toxicological studies

         Because 2,6-xylidine is also a chemical intermediate used in
    dyes, a component of tobacco smoke and a degradation product of
    aniline-based pesticides, its toxicology has been studied extensively.
    Toxicological studies conducted with this compound were also reviewed
    and will be presented in addition to the review and results of
    toxicological studies of xylazine.

    2.2.1  Acute toxicity studies of xylazine and 2,6-xylidine

         The acute systemic toxicity of xylazine has been investigated in
    both laboratory and domestic species. It is generally recognized that
    ruminants are much more sensitive than most other species to the
    pharmacological and toxicological effects of xylazine.

         Results of LD50 studies of xylazine and 2,6-xylidine are
    summarized in Table 3.

    2.2.1.1  Acute toxicity of xylazine in dogs

         Adult dogs (four males, four females) and cats (two males, four
    females) were administered a single i.m. or i.v. dose of 22 mg
    xylazine/kg bw (10 times the recommended therapeutic dose). One cat
    out of three receiving the i.v. dose died, and two dogs out of four
    receiving the i.m. dose died. All others recovered from convulsions,
    unconsciousness and respiratory depression with no apparent
    after-effects. The authors concluded that xylazine was slightly toxic
    in this study (Crawford  et al., 1970a).

        Table 3.  Results of acute toxicity studies on xylazine and 2,6-xylidine
                                                                                                             

    Species          Sex1                   Route         LD50              Reference
                                                          (mg/kg bw)
                                                                                                             

    Xylazine
    Rat              NA                     p.o.          130               Sagner, 1967
    Cat              male & female2         s.c.          100-110           Bauman & Nelson, 1969
    Dog              male & female3         i.m           47                Nelson et al., 1968b
    Dog              4 male & 3 female      i.v           20-25             Nelson et al., 1968b
    Horses           NA4                    i.m.          60-705            Nelson et al., 1968a
                                            i.v.          15-285

    2,6-Xylidine
    Mouse            male                   p.o.          710               Vernot et al., 1977
    Rat                                     p.o.          2042              Lindstrom et al., 1969
                     male                   p.o.          840               Jacobson, 1972
                     male                   p.o.          630               Short et al., 1983
                     male                   p.o.          1230              Vernot et al., 1977
                     female                 p.o.          1160 & 1270       US National Toxicology
                                                                            Program, 1990
                     male                   p.o.          620-1250 &
                                                          1310
                                                                                                             

    1    NA = Information not available
    2    Number per sex not stated; 10 animals were used
    3    Number per sex not stated; 17 animals were used
    4    Sex of test animals was not stated; 5 animals were used
    5    Minimum lethal dose
    
    2.2.1.2  Acute toxicity of xylazine in horses

         Adult horses were administered 11 mg xylazine/kg bw, i.v. (three
    mares, one gelding) or 22 mg xylazine/kg bw, i.m. (two mares, two
    geldings). One mare died following i.v. administration. All other test
    animals recovered from treatment-related effects 24 hours following
    i.v. administration and 48 hours following i.m. administration. The
    authors concluded that the i.v. dose was slightly toxic and that the
    i.m. dose produced no apparent toxicity in this study (Crawford
     et al., 1970b).

    2.2.2  Short-term toxicity studies

    2.2.2.1  Xylazine

    a) Rats

         Xylazine was administered in the diet to Wistar rats (10/sex/
    group) for 32 weeks. Dosages administered were 0, 50, 100, 250
    or 500 mg/kg diet (equal to 0, 3, 6, 21 or 41 mg/kg bw per day for
    males and 0, 4, 8, 19 or 45 mg/kg bw per day for females).
    Haematology, urinalysis and gross and histopathological evaluations
    were performed.

         Decreases in body weight observed in females in the two
    highest-dose groups (statistically significant (p<0.02) at 500 mg/kg
    diet) were considered by the author to be treatment-related.
    Microscopic examination of livers, lungs and kidneys revealed that
    animals in all groups were diseased but no treatment-related pathology
    was identified. Based on the dose-related decrease in weight gain
    observed in females at 250 and 500 mg/kg diet, the NOEL in this study
    was 100 mg/kg diet, equal to 6 mg/kg bw per day. The author regarded
    the dose of 250 mg/kg diet as the non-toxic application rate. The
    reliability of any NOEL derived from this study should be considered
    questionable, owing to the presence of infection in all groups
    (Tettenborn & Hobik, 1968a; Trossmann & Hobik, 1970).

    b) Dogs

         Dogs of undetermined breed or source were given xylazine orally
    in gelatin capsules for 14-16 weeks at dose levels of 25, 50 or
    100 mg/kg bw per day, 5 days/week. The low-dose group consisted of one
    male and one female, the mid-dose group of two males and the high-dose
    group of two males and two females. Haematology, clinical chemistry,
    blood coagulation, urinalysis and postmortem gross and microscopic
    evaluations were performed.

         During week 8 of the test, one animal in the high-dose group died
    and was replaced with a new animal. Postmortem gross findings in this
    animal included diffuse reddening of the stomach and intestinal mucous
    membrane.

         Histopathological findings in livers (fatty degeneration and
    necrosis) and kidneys (tubular epithelial necrosis and fat
    accumulation) of the high-dose group were considered treatment-
    related. Fatty deposits were noted in the liver and kidneys of the
    low-dose female. These findings were attributed to parturition, which
    occurred 3 weeks before the animal was killed. The author concluded
    that the NOEL for this study was 50 mg/kg bw per day. The reliability
    of any NOEL derived from this study should be considered questionable
    due to the lack of a control group and small numbers of animals in
    each test group (Tettenborn & Hobik, 1968b).

         Beagle dogs (two/sex/group) were administered xylazine orally by
    dietary admixture for 13 weeks. Dosages administered were 0, 10, 30 or
    100 mg/kg diet (equal to 0, 0.3, 0.9 or 3 mg/kg bw per day). At the
    beginning of the test the animals were approximately 8.5 months old
    and weighed 7-10 kg. Parameters evaluated included general appearance,
    ophthalmology, electrocardiography, haematology, clinical chemistry,
    urinalyses and gross and microscopic pathology.

         No treatment-related adverse effects were observed in any of the
    parameters evaluated. The NOEL for this study was 3 mg/kg bw per day
    (Tettenborn, 1969; Mawdesley-Thomas, 1970).

    2.2.2.2  2,6-Xylidine

    a) Rats

         Three groups (nine or ten/group) of male Fischer-344 rats were
    given oral (gavage) doses of 160 mg 2,6-xylidine/kg bw per day for 5,
    10 or 20 days. The dosage administered was 25% of the estimated LD50
    determined by the investigator. A significant increase in splenic
    haemosiderosis (indicative of erythrocyte damage) after 20 days was
    noted as a treatment-related effect in this study. Splenic congestion
    and evidence for increased erythropoiesis were minimal
    (Short  et al., 1983).

         Three groups of Sprague-Dawley rats (five/sex/group for controls,
    low and mid dose; four/sex/group for high dose) were administered
    0, 20, 100 or 500-700 mg 2,6-xylidine/kg bw per day by gavage for 4
    weeks. Treatment-related effects included decreased weight gain,
    decreased haemoglobin levels and hepatomegaly. In this study, the rat
    appeared to be about 10 times less susceptible to hepatotoxicity of
    2,6-xylidine than the dog (see section 2.2.2.2b) (Magnusson  et al.,
    1971; IARC, 1993).

         Two groups of 8-week-old Sprague-Dawley rats (5/sex/group) were
    orally administered (gastric intubation) a dose of 0 or 400 mg
    2,6-xylidine per kg bw per day for 1 week immediately followed by a
    daily dose of 0 or 500 mg/kg bw for 3 weeks. Decreased body weight
    gain and hepatomegaly (most pronounced in centrilobular regions) were
    noted as treatment-related effects. Electron microscopy of liver
    tissue showed proliferation of hepatic smooth endoplasmic reticulum,
    which was deemed responsible for the observed hepatomegaly in treated
    rats. An increase in microsomal glucuronyltransferase was observed in
    males while aniline hydroxylase levels were increased in females.
    Decreases in liver glycogen and glucose-6-phosphatase activity were
    also observed in the centrilobular regions of treated animals
    (Magnusson  et al., 1979).

         Male Osborne-Mendel rats were administered up to 10 000 mg
    2,6-xylidine per kg in the diet for 3-6 months. Treatment-related
    effects included 25% weight reduction, anaemia, hepatomegaly with no
    associated microscopic changes, splenic congestion and renal toxicity
    (Lindstrom  et al., 1963).

         Groups of F-344/N rats (five/sex/group) were administered doses
    of 0, 80, 160, 310, 620 or 1250 mg/kg bw of 2,6-xylidine in corn oil
    by gavage 5 days/week for 2 weeks. Parameters evaluated included
    clinical observations, body weight, urinalysis, haematology, blood pH
    and carbon dioxide determinations, and gross postmortem findings.

         Treatment-related deaths occurred at and above 620 mg/kg bw. All
    animals in the highest dose group died before the end of the study. A
    decrease of more than 10% in body weight was observed in males at and
    above 310 mg/kg bw and in females at and above 160 mg/kg bw.
    Generalized leukocytosis and an increase in the number of nucleated
    red blood cells were observed in male rats administered 310 or
    620 mg/kg bw. Slight anisocytosis, poikilocytosis and polychromasia of
    the red blood cells occurred more frequently in dosed animals than in
    vehicle control animals. Moderate poikilocytosis occurred at 310 mg/kg
    bw and moderate polychromasia at 310 and 620 mg/kg bw. Slightly
    macrocytic erythrocytes were observed at the two highest doses. Slight
    anisocytosis, poikilocytosis and polychromasia were observed in female
    rats at 310 and 620 mg/kg bw. The NOEL for this study was 80 mg/kg bw
    per day (US National Toxicology Program, 1990).

         Groups of F-344/N rats (10/sex/group) were given doses of 0, 20,
    40, 80, 160 or 310 mg/kg bw of 2,6-xylidine in corn oil by gavage, 5
    days/week for 13 weeks. Parameters evaluated included clinical
    observations, haematology, urinalysis, serum chemistry and enzyme
    analyses, gross and histopathological postmortem examinations.

         A decrease in body weight gain of more than 10% occurred in males
    and females in the highest dose group and in females at 40 and
    160 mg/kg bw per day. In the highest dose group, relative liver
    weights were significantly (P=0.003) increased for males and females.
    Relative liver weight was also increased for males in the 160 mg/kg bw
    group. The liver weight to brain weight and kidney weight to brain
    weight ratios were significantly increased in females at 310 mg/kg bw
    per day.

         Treatment-related effects on haematology included significantly
    decreased total leukocyte counts in males at doses of 40 mg/kg bw or
    more. These were accompanied by decreases in the percentage of
    lymphocytes and increases in the percentage of segmented neutrophils
    at doses of 80 mg/kg bw or more. In males, haemoglobin levels were
    significantly decreased at 160 and 310 mg/kg bw and erythrocyte and
    haematocrit levels were decreased at 310 mg/kg bw. The NOEL for this
    study was 20 mg/kg bw per day (US National Toxicology Program, 1990).

    b) Dogs

         Four groups of beagle dogs (one/sex/group) were given an oral
    (gelatin capsule) dose of 0, 2, 10 or 50 mg 2,6-xylidine/kg bw per day
    for 4 weeks. Treatment-related effects included vomiting (mid- and
    high-dose groups), poor condition and decreased body weights
    (high-dose group), hyperbilirubinaemia (mid- and high-dose groups),
    hypoproteinaemia (mid-and high-dose groups) and fatty degenerative
    changes in the liver that increased in severity with increasing dose
    (Magnusson  et al., 1971; IARC, 1993).

    2.2.3  Long-term toxicity/carcinogenicity studies

    2.2.3.1  Xylazine

         No carcinogenicity studies have been performed with xylazine

    2.2.3.2  2,6-Xylidine

         Four groups of Charles River CRL:COBS CD (SD) BR rats
    (56/sex/group) were fed diets containing 2,6-xylidine (99.06% pure) at
    concentrations of 0, 300, 1000 or 3000 mg/kg diet (equivalent to
    0, 15, 50 or 150 mg/kg bw per day) for 102 weeks. The animals assigned
    to this study were F1a, generation weanlings from a multigeneration
    study in which animals were fed diets containing 0, 300, 1000 or
    3000 mg/kg 2,6-xylidine beginning at 5 weeks of age. Parameters
    evaluated in the carcinogenicity study included clinical observations,
    haematology, blood urea nitrogen, glucose, SGOT, alkaline phosphatase
    and gross and microscopic postmortem examinations.

         Treatment-related clinical effects included a decrease in mean
    body weight gain in high-dose males and females (>10%). Mortality was
    significantly (P < 0.001) increased (relative to controls) in males
    in the high-dose group. Mortality was also increased for mid-dose
    males. Survival at 105 weeks was 43/56, 40/56, 33/56 and 14/56 for
    males in the control, low-, mid- and high-dose groups, respectively.
    For females, survival was 33/56, 25/56, 32/56 and 24/56 for the
    controls, low-, mid- and high-dose groups, respectively.

         Microscopically, a significant increase in carcinoma of the nasal
    cavity was observed in high-dose males (26/56; P < 0.001, life table
    test). For females, the incidence of carcinomas of the nasal cavity
    were 0/56, 0/56, 1/56 and 24/56 in the low-, mid- and high-dose
    groups, respectively (P<0.001, life table test). Two adenocarcinomas
    were diagnosed in high-dose males. The incidence of papillary adenomas
    in males was 0/56 in controls, 0/56 in low-dose, 2/56 in mid-dose and
    10/56 in high-dose rats (P=0.001, incidental tumour test). For
    females, nasal adenomas occurred in 0/56 in controls, 0/56 in low-
    dose, 1/56 in mid-dose and 6/56 in high-dose rats (P=0.02, incidental
    tumour test). Several unusual neoplasms of the nasal cavity were also
    considered to be related to treatment. These included one undifferen-
    tiated sarcoma identified in one high-dose female, rhabdomyosarcomas
    which occurred in two high-dose male and two high-dose females and
    malignant mixed tumours having features associated with both adenocar-
    cinoma and rhabdomyosarcoma were observed in one high-dose male and
    one high-dose female rat. Non-neoplastic nasal cavity lesions included
    acute inflammation (rhinitis), epithelial hyperplasia and squamous
    metaplasia. These occurred at increased incidence (relative to
    controls) in high-dose male and female rats. The incidence of
    subcutaneous fibromas and fibrosarcomas combined in males was 0/56,
    2/56, 2/56 and 5/56 for the control, low-, mid- and high-dose groups,
    respectively (P=0.001, life table test; P<0.001 life table trend
    test). For females, the incidence of these tumours combined was 1/56,
    2/56, 2/56 and 6/56 for controls, low-, mid- and high-dose groups,
    respectively ((P=0.01, life table trend test). Neoplastic nodules occurred
    in livers of female rats with a significant positive trend. The
    incidence was 0/56, 1/56, 2/56 and 4/55 for the controls, low-, mid-,
    and high-dose groups, respectively (P=0.03, incidental test; P=0.012,
    incidental trend test).

         Treatment-related effects on haematology included decreases in
    erythrocyte counts and haemoglobin levels at 18 months in the
    high-dose males. Decreases in these parameters were also observed in
    the mid- and high-dose females at 12 months. The author remarked that
    these changes were not severe enough to be considered indicative of
    anaemia.

         The author concluded that under the conditions of this study,
    2,6-xylidine was dearly carcinogenic for male and female Charles River
    CD rats. This was based on the observed significant increases in the
    incidence of adenomas and carcinomas of the nasal cavity. Additionally
    the author stated that the increased incidence of subcutaneous
    fibromas and fibrosarcomas in male and female rats and increased
    incidence of neoplastic nodules of the liver in female rats could have
    been treatment-related (US National Toxicology Program, 1990).

         The International Agency for Research on Cancer (IARC) has
    evaluated the carcinogenic risk of 2,6-xylidine to humans. The Working
    Group concluded that there was inadequate evidence in humans but
    sufficient evidence in experimental animals for the carcinogenicity of
    2,6-xylidine. The IARC classified 2,6-xylidine as Group 2B (possibly
    carcinogenic to humans) (IARC, 1993).

    2.2.4  Special studies on teratogenicity

         Xylazine was administered by gavage to groups of pregnant rats
    (22 animals/group) on gestation days 6 to 15, then killed on day 20
    for examination of uterine contents. Dosages administered were 0, 1, 4
    or 16 mg/kg bw per day. The study was conducted in accordance with the
    principles of Good Laboratory Practice Standards and Guidelines of the
    OECD, United Kingdom, FDA and Japan.

         Treatment-related maternal effects included partial closing of
    the eyelids, underactivity, ataxia, flat posture and slightly reduced
    body weight gain in the high-dose group only. Fetal effects included a
    decrease in mean fetal weight in the high-dose group only. A
    teratogenic potential of xylazine was not evident at levels up to and
    including 16 mg/kg bw per day. The NOEL in this study was 4 mg/kg bw
    per day (Reynolds, 1994).

    2.2.5  Special studies on genotoxicity

         The results of genotoxicity studies with xylazine and
    2,6-xylidine are summarized in Table 4.

         The results of bacterial mutagenicity testing of xylazine were
    considered to be negative by the author. Reviewing the data, the
    Committee concluded that a more than two-fold reproducible increase in
    revertant colonies in tester strains TA1535 and TA1538 represents weak
    mutagenic activity, even in the absence of a clear dose-response.

    2.2.6  Special studies on methaemoglobin and haemoglobin adduct
           formation with 2,6-xylidine

    2.2.6.1  Cats and dogs

         Cats and dogs (numbers not specified) were administered an i.v.
    dose of 30 mg 2,6-xylidine/kg bw or an oral dose of 164 mg N-acetyl
    2,6-xylidine/kg bw. 2,6-Xylidine induced a 10% methaemoglobinaemia in
    cats, and N-acetyl 2,6-xylidine induced a 5% methaemoglobinaemia in
    cats. Haemoglobin was unaffected in dogs in this study (McLean
     et al., 1967).

         Five adult cats (>24 months old) were administered an i.v. dose
    of 30 mg 2,6-xylidine/kg bw. Blood samples were drawn at 1, 2, 3, 4
    and 5 hours after dosing and analysed for methaemoglobin formation.
    The mean methaemoglobin concentration determined from these sampling
    intervals was 7% (range = 4.8% to 8.7%). Prior to treatment the mean
    methaemoglobin concentration of the 152 cats used in this study was
    approximately 1% (Mclean  et al., 1969).

    2.2.6.2  Humans

         2,6-Xylidine-haemoglobin adduct levels have been found to be
    elevated in human patients receiving lidocaine treatment for local
    anaesthesia (1 mg/kg bw) or cardiac arrhythmias (up to 50 mg/kg bw,
    i.v.). 2,6-Xylidine-haemoglobin adducts are also found in humans with
    no known exposure to lidocaine. This is attributed to the 120-day
    lifespan of the erythrocyte and chronic exposure to environmental or
    iatrogenic sources of aromatic amines, e.g., cigarette smoke. The
    levels of 2,6-xylidine-haemoglobin adducts found correspond to at an
    estimated daily exposure (from iatrogenic and environmental sources)
    of 23 g (IARC, 1993; Bryant  et al., 1994).

         Methaemoglobinaemia induced by i.v. administration of lidocaine
    was studied in 40 human cardiac patients. Treatment consisted of a
    1 mg/kg bw i.v. bolus followed 15 minutes later with a 0.5 mg/kg bw
    i.v. bolus. Patients were maintained between and after bolus doses
    with an infusion rate of 1-4 mg lidocaine/min. Blood samples were
    drawn before treatment and 1 and 6 hours after treatment. Although the
    investigators found methaemoglobin levels in these patients to be
    significantly elevated, the increase was not large enough to be of
    clinical concern. The highest methaemoglobin level attained was 1.2%.
    The author did not address the possible role of the 2,6-xylidine
    metabolite in the observed increases in methaemoglobin levels in
    treated patients (Weiss  et al., 1987).

        Table 4.  Genotoxicity assays with xylazine and 2,6-xylidine
                                                                                                             

    Test system        Test object             Concentration         Results           Reference
                                                                                                             

    Xylazine
     In vitro
    Reverse            S. typhimurium
    mutation1          TA1535,                 0.4-12 mg/plate       Weak positive     Herbold, 1984
                                                                     (-S9)
                       TA1538                  0.4-12 mg/plate       Weak positive     Herbold, 1984
                                                                     (-S9)
                       TA100,                  0.4-12 mg/plate       Negative          Herbold, 1984
                       TA98,                   0.4-12 mg/plate       Negative          Herbold, 1984
                       TA1537                  0.4-12 mg/plate       Negative          Herbold, 1984

    Mammalian          V79/HGPRT               62-1250 g/ml         Negative          Brendler-
      cell forward                             (-S9)                                   Schwaab,
      mutation1                                2-40 g/ml (+S9)                        1994

     In vivo
      Cytogenetic      Mouse bone              50 mg/kg bw,          Negative          Herbold, 1995
      assay            marrow                  i.p.2
                                                                                                             

    Table 4.  Genotoxicity assays with xylazine and 2,6-xylidine (cont'd).
                                                                                                             

    Test system        Test object             Concentration         Results           Reference
                                                                                                             

    2,6-Xylidine
     In vitro
    Reverse            S. typhimurium
    mutation1          TA1535                  100-9900              Negative          US National
                                               g/plate                                Toxicology
                                                                                       Program, 1990
                                               3 mol/plate          Negative          Florin et al.,
                                                                                       19804
                                               0.1-10 mg/plate       Negative          Zeiger et al., 1988

                       TA100                   100-9900              Negative          US National
                                               g/plate                                Toxicology
                                                                                       Program, 1990
                                               360 g/plate          Negative          Florin el al.,
                                                                                       19804
                                               0.1-10 mg/plate       Neg (-S9),        Zeiger et al.,
                                                                     Pos (+S9)         19883
                                               480-4000              Negative          Kugler-
                                               g/plate                                Steigmeier
                                                                                       et al., 1989
                                                                                                             

    Table 4.  Genotoxicity assays with xylazine and 2,6-xylidine (cont'd).
                                                                                                             

    Test system        Test object             Concentration         Results           Reference
                                                                                                             

                       TA1537                  100-9900              Negative          US National
                                               g/plate                                Toxicology
                                                                                       Program, 1990
                                               360 g/plate          Negative          Florin et al.,
                                                                                       19804
                                               0.1-10 mg/plate       Negative          Zeiger et al.,
                                                                                       1988

                       TA98                    100-9900              Negative          US National
                                               g/plate                                Toxicology
                                                                                       Program, 1990
                                               360 g/plate          Negative          Florin et al.,
                                                                                       19804
                                               0.1 - 10 mg/plate     Negative          Zeiger et al.,
                                                                                       1988

    Gene               Mouse lymphoma          Not given             Positive          Rudd et al.,
    mutation1          L5178Y cells,                                                   19837
                       tk locus

    Sister             Chinese                 30-1500 g/ml         Positive          Galloway et al.,
      chromatid        hamster                                                         1987
      exchange1        ovary cells
                                                                                                             

    Table 4.  Genotoxicity assays with xylazine and 2,6-xylidine (cont'd).
                                                                                                             

    Test system        Test object             Concentration         Results           Reference
                                                                                                             

     In vivo
    Cytogenetic        ICR mouse               350 mg/kg bw,         Inconclusive6     Parton et al.,
    assay              bone marrow             p.o.                                    1988
                                               375 mg/kg bw,         Inconclusive6     Parton et al.,
                                               p.o.                                    1990

    In vivo-           Rat primary             40-850 mg/kg          Negative          Mirsails et al.,
    in vitro DNA       hepatocytes             bw, p.o.                                1989
    repair assay

    Covalent           Rats                    87.2 Ci              Positive          Short et al., 1989
    DNA                                        14C-labelled
    binding                                    2,6-xylidine/rat,
                                               i.p5
                                                                                                             

    1    Both with and without rat liver S9 fraction
    2    Cyclophosphamide positive control
    3    Weakly positive in two of three laboratories, negative in the third
    4    Spot tests only
    5    Pretreatment with unlabelled 262.5 mg/kg bw 2,6-xylidine daily for 9 days
    6    Results suggest test article may not have reached target tissue (bone marrow)
    7    Reference was an abstract and doses were not stated in that reference
    
    2.3  Observations in humans

         A 34-year-old man self-injected 10 ml of a 100 mg/ml solution of
    xylazine intramuscularly. The estimated dose was 15 mg/kg bw. The
    individual was discovered (30 minutes after retiring for bed) in a
    deeply comatose, apnoeic and areflexic state. An empty Rompun
    (xylazine) bottle (known to have contained 10 cc earlier) lay by his
    side. He was immediately admitted to the hospital. Upon admission his
    pupils were of moderate size and responded slowly to light. Other
    findings included a blood pressure of 120/70 mmHg and heart rate of
    60 bpm with stable sinus rhythm. Lactate dehydrogenase (LDH) activity
    was elevated, with the LDH-1 isoenzyme predominating. Creatine
    phosphokinase (CPK) activity was also elevated, particularly in the
    CPK-3 and CPK-2 isoenzymes. These enzyme changes persisted for 5 to 7
    days. Plasma glucose level was also elevated. Two days following
    hospital admission sinus tachycardia developed, interspersed with runs
    of multifocal premature ventricular contractions which were controlled
    with lidocaine infusion. Blood pressure remained approximately 120/80
    for the duration of hospitalization. Coma and respiratory depression
    lasted 60 hours. The patient was discharged from the hospital 17 days
    after admission.

         The author noted that the patient might have died if he had not
    been found shortly after the injection was administered, owing to the
    marked respiratory depression that occurred. Hypotension, which has
    been reported as an effect of xylazine in humans, did not occur in
    this case. According to the author, the enzyme activity increases
    indicated that myocardial muscle damage had occurred and an intrinsic
    cardiotoxic effect of xylazine was suspected. Finally, in this case
    the greatest threat to life was the CNS-depressant effect of xylazine
    (Carruthers  et al., 1979).

         A 20-year-old woman ingested 400 mg of xylazine. Approximately 2
    hours later she became drowsy, incontinent (urine), difficult to
    arouse and occasionally unresponsive to verbal commands. She was
    admitted to the hospital approximately 3 hours after the ingestion. In
    a similar way to the case of human poisoning described by Carruthers
    et al. (1979), she experienced a relatively low initial cardiac rate,
    which later gradually increased, significant central nervous system
    and respiratory depression, transient hyperglycaemia and ventricular
    arrhythmias. However there was no evidence of myocardial damage. A
    sample of this patient's urine was analysed using a gas chromatograph-
    mass spectrometer computer system. Xylazine was found largely unchanged
    in the urine as shown by a lack of any structurally related compounds
    in the basic urine extract. No xylazine was found in a blood sample
    taken at the time of admission. The author concluded that plasma
    levels were below the limit of detection of the method (100 ng/ml).
    The patient was discharged ambulatory and without apparent adverse
    effects two days following admission to the hospital (Gallanosa
     et al., 1981).

         A 36-year-old man died following ingestion of alcohol and
    clorazepate combined with an injection of approximately 40 ml of
    xylazine (100 mg/ml). Xylazine was found in the decedent's blood,
    brain, kidney, liver, lung, fat and urine at concentrations of 0.2,
    0.4, 0.6, 0.9, 1.1, 0.05 and 7 ppm, respectively (Poklis  et al.,
    1985).

         A 29-year-old woman self-injected 40 mg of xylazine
    intramuscularly. The estimated dose was 0.73 mg/kg bw. Clinical
    findings included disorientation, miosis, hypotension and bradycardia,
    but no cardiac arrhythmias were noted. The abnormalities resolved
    spontaneously (Spoerke  et al., 1986).

         A 37-year-old woman self-injected 24 ml (2400 mg) xylazine
    intramuscularly. The estimated dose was 22 mg/kg bw. Twenty minutes
    after the injection her blood pressure was 166/130 mmHg, heart rate
    was 76 bpm and respirations 18 per minute. The serum glucose level was
    175 mg/dl. Blood pressure later decreased to 130/90 mmHg and she
    became apnoeic. No cardiac arrhythmias were observed during her 3 days
    of hospitalization. Hypotension and bradycardia occurred two days
    after the injection. The patient survived (Spoerke  et al., 1986).

         A 29-year-old woman self-injected an unknown amount of xylazine
    intravenously. She became apnoeic and had an initial blood pressure of
    130/90 mmHg with a pulse of 60 bpm. Serum glucose levels did not
    exceed 90 mg/dl. Twenty-four hours after the injection the patient
    experienced hypotension and bradycardia. Spontaneous respiration
    resumed 18 hours after hospital admission. The patient recovered fully
    (Spoerke  et al., 1986).

         A 19-year-old man accidentally injected himself subcutaneously
    with 2 ml (100 mg/ml) of xylazine. The dose administered was 3 mg/kg
    bw. Thirty minutes later he became difficult to rouse and was
    hospitalized. Clinical findings included miosis, hyporeflexia,
    hypotension, bradycardia, respiratory and central nervous system
    depression and hyperglycaemia. He was treated with intravenous fluids
    and assisted ventilation. Eight hours after hospitalization the
    patient was alert and responsive. Twenty-four hours later he was
    released (Samanta  et al., 1990).

         A 39-year-old woman was admitted to the hospital with symptoms of
    tiredness, faintness and blurred vision. Clinical findings included
    sinus bradycardia with a blood pressure of 130/90. Xylazine was found
    in the urine and serum at concentrations of 1674 g/litre and
    30 g/litre, respectively (Lewis  et al., 1983).

    3.  COMMENTS

         The Committee considered toxicological data on xylazine,
    including the results of acute and short-term toxicity studies as well
    as studies on pharmacodynamics, pharmacokinetics, reproductive and
    developmental toxicity, genotoxicity and effects in humans. In
    addition, toxicological studies on 2,6-xylidine, a metabolite of
    xylazine, were reviewed; these included studies on acute and
    short-term toxicity, carcinogenicity and genotoxicity.

         Numerous pharmacological side-effects of xylazine have been
    observed in treated animals, including mydriasis, impairment of
    thermo-regulatory control, various effects on the cardiovascular
    system, acid-base balance and respiration, hyperglycaemia, and
    haematological and gastrointestinal effects. Cattle and sheep are
    approximately 10 times more sensitive to xylazine than horses, dogs
    and cats.

         Rats were administered radiolabelled xylazine intravenously at
    doses of 0.02 to 10 mg/kg bw or orally at doses of 0.02 to
    100 mg/kg bw. More than 95% of the oral dose was absorbed, with a
    half-life of approximately 5 minutes. Following oral or intravenous
    administration, approximately 70% of the administered dose was
    eliminated in urine and 30% in faeces. Renal excretion following oral
    or intravenous administration was associated with a half-life of 2 to
    3 hours. Enterohepatic circulation did not occur to a notable extent.
    In cattle administered an intramuscular dose of 0.2 or 0.5 mg
    xylazine/kg bw, less than 1% of the dose was excreted unchanged in the
    urine, and the parent compound was detected in the urine up to 6 hours
    following administration. Metabolites of xylazine were detected in
    urine from these cattle up to 10 hours following administration.

         Pharmacokinetic parameters following intravenous administration
    showed minor variations between species. Xylazine disappeared rapidly
    from plasma following intravenous administration, with an elimination
    half-life of approximately 40 minutes in cattle and approximately 20
    minutes in sheep. Xylazine could not be detected in the plasma of
    cattle following intramuscular administration of a single therapeutic
    dose.

         In rats administered an intravenous dose of 2 mg/kg bw radio-
    labelled xylazine, approximately 20 metabolites were quantified as
    xylazine equivalents in urine and bile. The major metabolite comprised
    35% of the administered dose. Approximately 8% of the dose was
    eliminated as unchanged xylazine 24 hours after dosing. In an
     in vitro study, 4 metabolites were identified when xylazine was
    incubated with rat liver microsomes. The same metabolites were

    identified in the urine of horses treated with xylazine. The major
    metabolite in both cases was identified as  N-(2,6-dimethylphenyl)
    thiourea. In cattle administered an intramuscular dose of 0.2 mg
    xylazine/kg bw (two cows) or 0.5 mg xylazine/kg bw (one cow),
    2,6-xylidine was identified as a metabolite excreted in urine in both
    conjugated and unconjugated forms.

         The acute oral toxicities of xylazine and 2,6-xylidine were
    tested in mice and rats. Xylazine was determined to be moderately
    toxic (LD50 = 121-240 mg/kg bw) and 2,6-xylidine to be slightly
    toxic (LD50 = 600-1000 mg/kg bw).

         Three studies on the short-term toxicity of xylazine were
    reviewed. A 32-week dietary study in rats and a 16-week oral
    (capsules) study in dogs were considered inadequate for the
    determination of the toxicity of xylazine owing to the use of
    insufficient numbers, poor quality animals and inadequate study
    design. The third was a 13-week oral study in beagle dogs fed
    diets containing 0, 10, 30 or 100 mg/kg xylazine in the feed (equal
    to 0.3, 0.9 or 3 mg/kg bw per day). No treatment-related effects
    were observed in any of the treated groups.

         In a two-week oral (gavage) toxicity study in rats with
    2,6-xylidine, rats were dosed with 80, 160, 310, 620 or 1250 mg
    2,6-xylidine/kg bw per day, 5 days per week. Treatment-related effects
    included increased mortality (all animals in the high-dose group
    died), decreased body weight (males at 310 mg/kg bw per day and above
    and females at 160 mg/kg bw per day and above) and various effects on
    haematological parameters as indicated by leukocytosis and changes in
    red blood cell parameters indicative of increased erythropoiesis
    (males and females at 310 mg/kg bw per day and above). The NOEL in
    this study was 80 mg/kg bw per day.

         In a 13-week oral (gavage) toxicity study in rats with
    2,6-xylidine, rats were dosed with 20, 40, 80, 160 or 310 mg
    2,6-xylidine/kg bw per day, 5 days per week for 13 weeks. Treatment-
    related effects included decreased body weight gain (males at 310
    mg/kg bw per day and females at 40 mg/kg bw per day and above),
    increased absolute and relative liver weights (females at 160 mg/kg bw
    per day and above; males at 310 mg/kg bw per day), leukopenia (males
    at 40 mg/kg bw per day and above), haemoglobinaemia (males at
    160 mg/kg bw per day and above) and anaemia (males at 310 mg/kg bw per
    day). The NOEL was 20 mg/kg bw per day.

         In a carcinogenicity study, male and female rats were fed diets
    containing 2,6-xylidine at concentrations of 300, 1000 or 3000 mg/kg
    food (equivalent to 15, 50 or 150 mg/kg bw per day). Significant
    increases in the incidences of papillomas and carcinomas of the nasal
    cavity were observed in high-dose males and females. There was a
    significant dose-related increase in the incidence of adenomas in the

    nasal cavity in both males and females. In addition, unusual rhabdo-
    myosarcomas and malignant mixed tumours of the nasal cavity were
    observed in the high-dose males and females. There was a dose-related
    significant increase in the incidence of subcutaneous fibromas and
    fibrosarcomas in both treated males and females. In females,
    neoplastic nodules occurred in livers with a significant positive
    trend and the increase was significant in the high-dose group by the
    incidental tumour test. The Committee concluded that 2,6-xylidine was
    carcinogenic in this study.

         The International Agency for Research on Cancer has evaluated the
    carcinogenic risk of 2,6-xylidine and has classified it as Group 2B
    (possibly carcinogenic to humans).

         In a teratogenicity study, xylazine was administered to pregnant
    rats at doses of 1, 4 or 16 mg xylazine/kg bw per day on gestation
    days 6 to 15. Treatment-related maternal effects included partial
    closing of the eyelids, hypoactivity, ataxia, flat posture and
    slightly reduced body weight gain in the high-dose group only. A
    decrease in mean fetal weight was seen in the high-dose group. No
    teratogenic effects were noted in this study. The NOEL for maternal
    and fetal effects was 4 mg/kg bw per day.

         Xylazine has been tested in reverse mutation assays in
    Salmonella, a forward mutation assay in cultured mammalian cells and
    in an in vivo cytogenetic assay. In  Salmonella, weak positive
    results were obtained. Negative results were observed in a forward
    mutation assay on cultured mammalian cells and in a mouse bone marrow
    micronucleus test. The Committee concluded that xylazine is weakly
    mutagenic.

         2,6-Xylidine was tested in a series of  in vitro and  in vivo
    genotoxic assays. It was weakly positive for reverse mutation in
    Salmonella. In mammalian cells, it induced forward mutation and was
    positive in a sister chromatid exchange test. Inconclusive results
    were obtained in a mouse bone marrow micronucleus test because there
    was no assurance that the bone marrow had been adequately exposed.
    2,6-Xylidine was found to be inactive in an  in vivo-in vitro rat
    hepatocyte unscheduled DNA synthesis assay. Covalent binding of the
    compound to DNA was observed in rats. The Committee concluded that
    2,6-xylidine is genotoxic.

         The potential for 2,6-xylidine to induce methaemoglobinaemia was
    reviewed by the Committee. Single doses of 30 mg 2,6-xylidine/kg bw
    intravenously or 164 mg/kg bw  N-acetyl-2,6-xylidine orally have
    been shown to induce methaemoglobinaemia in cats but not in dogs.
    2,6-Xylidine has also been shown to be a product of lidocaine
    metabolism in humans. Methaemoglobin and 2,6-xylidine-haemoglobin
    adduct levels have been shown to increase in human cardiac patients
    receiving lidocaine treatment.

         Effects of xylazine on humans poisoned following accidental or
    intentional self-injection (0.7-15 mg/kg bw) or ingestion (7 mg/kg bw)
    included symptoms of central nervous system depression, respiratory
    depression, hypo- and hypertension, bradycardia, tachycardia,
    ventricular arrhythmias, and transient hyperglycaemia.

    4.  EVALUATION

         The Committee was unable to establish an ADI for xylazine because
    it concluded that the 2,6-xylidine metabolite was genotoxic and
    carcinogenic. Annex 4 lists the information that would be required for
    further review.

    5.  ACKNOWLEDGMENTS

         The preparer of the first draft would like to recognize the
    following individuals for their assistance and contributions to the
    preparation of the first draft:

    Ms. Deborah Brooks, information specialist, Center for Veterinary
        Medicine

    Dr. Steve Brynes, residue chemist, Center for Veterinary Medicine

    Dr. Jennifer Burris, veterinary pathologist, Center for Veterinary
        Medicine

    Dr. Robert Condon, biostatistician, Center for Veterinary Medicine

    Dr. Haydee Fernandez, toxicologist, Center for Veterinary Medicine

    Dr. Devaraya Jagannath, genetic toxicologist, Center for Veterinary
        Medicine

    Dr. Alan Pinter, toxicologist, National Institute of Public Health,
        Budapest, Hungary

    Dr. Leonard Schechtman, genetic toxicologist, Center for Veterinary
        Medicine

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    Bauman, E. K. & Nelson, D.L. (1969). Toxicity of BAY Va 1470 to cats.
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    Benson, G.J., Thurmon, J.C., Neff-Davis, C.A., Corbin, J.E.,
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    Booth, N.H. (1988). Nonnarcotic analgesics. In: Booth N.H.&
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    See Also:
       Toxicological Abbreviations
       XYLAZINE (JECFA Evaluation)