IPCS INCHEM Home

    SPECTINOMYCIN

    First draft prepared by
    Dr K. Woodward
    Veterinary Medicines Directorate
    Ministry of Agriculture, Fisheries and Food
    Addlestone, Surrey, United Kingdom


    1.  EXPLANATION

          Spectinomycin is an aminocyclitol antibiotic produced by
     Streptomyces spectabilis. It is used in human medicine for the
    treatment of uncomplicated gonorrhoea. In veterinary medicine
    spectinomycin is used therapeutically for bacterial respiratory and
    enteric infections. Spectinomycin is administered singly or in
    combination with other antibiotics to cattle, pigs and poultry by
    injectable solutions and orally as aqueous solutions or in feed.
    Spectinomycin has not been reviewed previously by the Committee.
    The structure of spectinomycin is shown in Figure 1.

    FIGURE 1


    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

    2.1.1  Absorption, distribution and excretion

    2.1.1.1  Rats

          When spectinomycin hydrochloride labelled with tritium in the
    4-position of the pyran ring was given to groups of 4
    Sprague-Dawley rats (2 males, 2 females) by oral intubation at a
    dose of 5 mg/kg bw/day for 2, 4, or 5 days, 60-80% of the
    administered dose was recovered in the faeces, with only 2-3% in
    the urine. Most of the radioactivity found in the animals was
    detected in liver, kidney and muscle, but it was found to be
    present as tritiated water. In faeces, only 1% of the radioactivity
    was tritiated water, but 1-43% of radioactivity in urine was
    recovered as tritiated water. This exploratory study demonstrated
    that the label was not stable (Hamlow & Jaglan, 1988).

          A group of 4 Sprague-Dawley rats (2 males, 2 females) was
    given 3 oral doses of 5 mg/kg bw/day spectinomycin labelled with
    tritium at the 6'-methyl of the pyran ring. Absorption appeared to
    be poor, with around 10-84% of the administered dose being found in
    faeces and 4-7% in urine. Low levels of radioactivity were detected
    in kidney, liver, muscle, and fat (Jaglan  et al., 1991a). 

          As part of the study that was summarized in the previous
    paragraph, 5 groups of Sprague-Dawley rats (1 male, 1 female per
    group) were given i.m. injections of 5 mg/kg bw/day radiolabelled
    spectinomycin for 1-5 days. The majority of the dose was excreted
    in the urine (54-73%), with the remainder (1-24%) in the faeces
    (Jaglan  et al., 1991a).

          A group of 4 Sprague-Dawley rats was given approximately 5
    mg/kg bw/day spectinomycin sulfate as the 3H-6-methyl derivative,
    orally or i.m. for 3 days. After oral administration, the majority
    of the dose (10-84%) was recovered in faeces, with approximately 5%
    in urine. After i.m. administration, approximately 66% of the dose
    was recovered from urine, with 10-21% in faeces. Very low levels
    were found in tissues (Roof & Jaglan, 1993).

    2.1.1.2  Dogs

          Spectinomycin hydrochloride was administered orally (single
    dose) by gavage to 3 dogs at 100 and 500 mg/kg bw. Antimicrobial
    activity was assayed in serum over the following 24 hours using
     Rhodopseudomonas sphaeroides. Mean peak serum concentrations of

    22 g/ml and 80 g/ml with 100 and 500 mg/kg bw doses,
    respectively, were noted approximately 4 hours after
    administration. The plasma half-life after the 100 mg/kg bw dose
    was approximately 3 hours (Stern  et al., 1984a).

          A group of 3 dogs were given single i.m. injections (40 mg/kg
    bw) of 6'-n-propylspectinomycin, a drug closely related
    structurally to spectinomycin. The drug was rapidly absorbed with
    a mean peak serum concentration of 136 g/ml 15 minutes after
    injection and a plasma half-life of approximately 0.7 hours (Stern
     et al., 1984b).

    2.1.1.3  Sheep

          A single dose (2 mg/kg bw/day) of spectinomycin hydrochloride
    was administered i.v. or i.m. to groups of 3 Awassi ewes. The drug
    was assayed in milk and serum using  Escherichia coli.
    Antimicrobial activity in serum and milk declined rapidly after
    i.v. administration and was undetectable after 6 hours. The
    elimination half-life was approximately 1 hour. After i.m.
    administration, the elimination half-life was around 3 hours, and
    serum levels were undetectable after 8 hours (Ziv & Sulman, 1973).

    2.1.1.4  Pigs

          A pig (mixed breed) was given a single oral dose of
    3H-6-methyl spectinomycin (44 mg/kg bw), and then maintained in
    a metabolism cage for 24 hours. Most of the dose (79%) was
    recovered from the gastrointestinal tract, with approximately 3% in
    the urine. Less than 1.5% of these recoveries were tritiated water.
    Only low levels of radioactivity, equivalent to 0.2% of the dose or
    less, were detected in other tissues, but around 3% of the dose was
    found in muscle. However, 30-100% of tissue radioactivity was
    tritiated water (Jaglan  et al., 1991b; Roof & Jaglan, 1993).

          When pigs consumed feed containing lincomycin/spectinomycin
    (44 ppm of each, equivalent to 1.6 mg/kg bw/day) or spectinomycin
    alone (1.6 mg/kg bw/day) for 8 days, lincomycin concentrations
    averaged around 40 ng/ml 3 and 6 hours after cessation of
    treatment, with none detectable at 12 hours, whereas spectinomycin
    was not detected in pigs given either lincomycin and spectinomycin
    together or spectinomycin alone (limit of detection of 100 ng
    spectinomycin/ml) (Hovius  et al., 1989).

          When pigs were given single i.v. injections of 20 or 40 mg/kg
    bw, or single i.m. injections of 40 mg/kg bw spectinomycin, the
    majority of the dose was excreted in urine in 12 hours. Similarly,
    when pigs were given single i.v. injections of 40 mg/kg bw

    spectinomycin, the majority of the dose was excreted in the urine
    in 12-15 hours. In these studies around 70-80% of the dose was
    recovered in the urine samples and total recovery was over 90%
    (Seymour, 1964, 1965).

          Rapid declines in plasma spectinomycin concentrations to below
    the limit of detection (within 14 hours) occurred in pigs given
    single i.m. injections of the drug (Barbiers  et al., 1968).

    2.1.1.5  Cattle

          A group of 4 Friesan dairy cows was given single i.v. or i.m.
    injections of 20 mg/kg bw spectinomycin and antimicrobial activity
    was assayed in milk and serum. Activity declined rapidly after i.v.
    administration and was undetectable after 6 hours. The elimination
    half-life was approximately 1 hour. After i.m. administration, the
    elimination half-life was 3 hours and serum levels were
    undetectable after 8 hours (Ziv & Sulman, 1973).

          In a preliminary study where cattle (2) were given single i.m.
    injections of 0.15 mg/kg bw 3H-6-methyl spectinomycin, most of
    the administered dose (55%) was found in urine before one animal
    was killed after 24 hours. From 2 to 5% of the radioactivity in
    urine and faeces was tritiated water. Only low levels (less than 1%
    of the dose) were found in liver, lung, kidney and muscle. The
    other animal was killed 72 hours after administration and most of
    the radioactivity was found in the urine (45%) and faeces (38%)
    during the first 24 hours after injection. Again, very low levels
    were found in liver, lung, kidney, and muscle (Roof & Jaglan,
    1993).

          In a further study, cattle (2, 150 kg) were given single i.m.
    injections of 0.15 mg/kg bw 3H-6-methyl spectinomycin sulfate. One
    animal was killed 24 hours after dosing and the other at 72 hours.
    The majority of the dose was detected in the first 24 hours in
    urine (56%) and faeces (20%) in the animal killed at 24 hours.
    Similar values were found for the animal killed at 72 hours (47%
    and 43% in the first 24 hours in urine and faeces, respectively).
    Approximately 3-4% of the radioactivity in these urine and faecal
    samples was tritiated water. Very low levels of radioactivity (less
    than 1%) were found in liver, lung, kidney, and muscle (Roof  et
     al., 1993).

          A group of 6 Friesan calves was given single i.v. injections
    of 20 mg/kg bw spectinomycin and a group of 12 Friesan calves was
    given the same dose as single i.m. injections. After i.v.
    injection, blood levels rose rapidly and declined rapidly; the
    plasma elimination half-life was of the order of 1-2.5 hours.
    Following i.m. injection, the blood levels also rose rapidly
    (tmax = 0.1-0.8 hours). The plasma elimination half-life was of
    the order of 1-2 hours (Bligny, 1988).

          A group of 3 steers was treated daily for 4 consecutive days
    with 20 mg/kg bw/day spectinomycin i.m.; a fourth animal served as
    a control (animals were Angus/Hereford cross, Hereford or
    Limousin). The animals were slaughtered 6 hours or 3 or 7 days
    after the final dose.  The majority of the dose was excreted in the
    urine within 24 hours; 78% of the dose had been collected by 7
    days. At the 6-hour slaughter time, liver, kidney, muscle, and fat
    had the highest levels of drug (around 1-1.5% of the administered
    dose); at day 3 levels in these tissues had declined significantly
    (0.3-0.6% of the dose). A further decline had occurred by day 7
    (0.1-0.3% of the dose) (Wilkes, 1990).

    2.1.1.6  Humans

          In humans, absorption after oral administration of
    spectinomycin is poor, but it is rapidly absorbed after i.m.
    injection. Peak serum concentrations occur approximately 1 hour
    after injection of 2 g spectinomycin (approximately 30 mg/kg bw)
    and 2 hours after injection of 4 g spectinomycin (approximately 60
    mg/kg bw). The mean plasma elimination half-life was approximately
    2 hours. In humans, the volume of distribution was 10-13 kg and
    there was no significant binding to plasma. Around 75% of the i.m.
    dose was excreted in the urine. Patients with renal impairment
    excreted the drug more slowly than otherwise normal subjects; the
    half-life ranged from 4.7 to 29 hours after a 2 g (approximately 30
    mg/kg bw) i.v. dose. Spectinomycin penetrated genital tract tissues
    but it did not appear to reach cerebrospinal fluid (Delgado  et
     al., 1980; Elder  et al., 1976; Ksiezyk & Danek, 1973; Kusumi
     et al., 1981; Wagner  et al., 1967; Holloway, 1982).

    2.1.2  Biotransformation

    2.1.2.1  Animals

          No information available.

    2.1.2.2  Humans

          Spectinomycin appears not to be metabolized; 70-100% of the
    administered dose (route not specified but probably i.m.) was
    excreted unchanged in urine within 48 hours (Dollery, 1991).

    2.1.3  Effects on enzymes and other biochemicals parameters

          No information available.

    2.2  Toxicological studies

    2.2.1  Acute toxicity studies

          The results of acute toxicity studies with spectinomycin are
    shown in Table 1.

          Spectinomycin sulfate and hydrochloride salts were of low
    toxicity in the mouse and rat with i.p. LD50 values often in
    excess of 3000 mg/kg bw. The substance was of low oral toxicity in
    the rat. Where death did occur, it was preceded by depression and
    mild convulsions.

          Spectinomycin sulfate was of low toxicity to newborn rats when
    given; the LD50 value was in excess of 5000 mg/kg bw although
    2/10 animals given this dose died (Gray & Purmalis, 1961a). No
    toxic effects were seen in dogs given 200 - 270 mg/kg bw rally
    (Gray & Purmalis, 1962a,b). Low acute toxicity has also been
    observed in poultry given spectinomycin orally, either alone or in
    combination with lincomycin (Glenn  et al., 1969a-c; Glenn  et
     al., 1970b).

    2.2.2  Short-term toxicity studies

    2.2.2.1  Rats

          Groups of 10 male and 10 female rats were given oral doses of
    0, 200, 500, 1000, 2000, or 3000 mg/kg bw/day spectinomycin in
    water by gavage for 28 days. There were no effects on body weights,
    behaviour, food consumption or mortality during the study and, at
    necropsy, there were no drug-related gross or histopathological
    findings. Organ weights and clinical chemistry parameters were
    unaffected by drug administration (Wedig, 1990).

          A 1:1 solution of spectinomycin and lincomycin in aqueous
    methylcellulose was given by oral intubation to groups of 20
    TUC-SPD rats (10 male, 10 female) at doses of 0, 100, 300, or 1000
    mg/kg bw/day for 90 days. Food consumption and body-weight gain
    were similar in treated and control groups and the only observation
    made was that faeces from treated groups appeared darker than those
    from controls. Haematological parameters were similar in treated
    and untreated animals.

          Changes were seen in clinical chemistry parameters, notably
    elevations in serum glucose, uric acid and protein. However, there
    was no clear dose-response. Moreover, glucose levels in control
    animals were slightly higher than in historical controls. Changes
    occurred in serum aspartate aminotransferase levels, but these
    could not be related to administration of the drugs and occurred

        Table 1.  Acute toxicity of spectinomycin
                                                                                   

    Species    Sex        Route     LD50          References
                                    (mg/kg bw)
                                                                                   

    Mouse      -          oral      > 20 000      Hwang  et al., 1961

    Mouse      F          oral      10 000        Hwang  et al., 1961

    Mouse      -          ip        > 3800        Raab, 1975

    Mouse      -          ip*       3577          Highstrete, 1964

    Mouse      -          ip*       3867          Jones, 1959

    Mouse      -          ip        5724          Gray & Weaver, 1966a

    Mouse      -          ip        4472          Gray & Weaver, 1967a

    Mouse      -          ip        4472          Gray & Weaver, 1967b

    Mouse      -          iv        1022          Highstrete, 1964

    Mouse      -          iv        > 2000        Anonymous, 1992

    Mouse      F          iv        2500          Hwang  et al., 1961

    Mouse      M          iv        2850          Hwang  et al., 1961

    Rat        -          oral*     > 5000        Jones, 1959

    Rat        -          sc*       > 5000        Gray & Purmalis, 1961b

    Rat        -          ip        > 5000        Gray & Weaver, 1966b

    Rabbit     -          ic**      5             Hwang  et al., 1961

    Cat        -          iv        400           Hwang  et al., 1961

    Dog        -          oral      1000          Hwang  et al., 1961

    Dog        -          iv        800           Hwang  et al., 1961

    Monkey     -          oral      > 500         Hwang  et al., 1961
                                                                                   
    *   Sulfate; others are hydrochloride salt.
    **  Intracisternal in anaesthetized rabbits.
    
    only in males given 1000 mg/kg bw/day and in females given 300
    mg/kg bw/day spectinomycin. LDH was decreased at 300 mg/kg bw/day
    but not at 1000 mg/kg bw/day in males. Histopathological
    examination revealed no compound-related lesions. The NOEL in this
    study was 100 mg/kg bw/day spectinomycin: lincomycin, equivalent to
    50 mg/kg bw/day spectinomycin (Glenn & Burr, 1970a).

          Groups of 10 (5 male, 5 female) Sprague-Dawley rats were given
    daily s.c. injections of spectinomycin (salt not specified) in
    isotonic saline at 0, 30, 100, or 300 mg/kg bw/day, for 28 days. No
    clinical signs were observed although males in the highest dose
    group gained less weight than controls. There were no
    haematological effects and organ weights were comparable to
    controls. Slight inflammatory reactions were seen at the injection
    sites. The NOEL in this study was 100 mg/kg bw/day based on the
    body-weight reductions in males (Gray  et al., 1960a).

          Spectinomycin was given s.c. to groups of 10 male and 10
    female TUC rats at doses of 0, 300, or 1000 mg/kg bw/day for 3
    months. The major change noted in this study was a lowering of
    haemoglobin in males (19%) and females (24%) given the highest
    dose, with lower packed cell volumes in both sexes. There were no
    gross or histopathological findings that could be related to drug
    administration. The NOEL was 300 mg/kg bw/day (Ray & Ceru, 1969a).

    2.2.2.2  Dogs

          Two male dogs (unspecified breed) were given single oral doses
    of 50 mg/kg/bw/day spectomycin for 5 weeks, followed by 500 mg/kg
    bw/day for a further 4 weeks. No signs of toxicity occurred and
    there were no gross or microscopic abnormalities seen at necrosy
    (Hwang  et al., 1961).

          In a one-week oral range-finding study groups of 2 male and 2
    female beagle dogs were given 0, 1000, or 3000 mg/kg bw/day
    spectinomycin in gelatine capsules. No signs of toxicity were seen
    during the study except for a dose-related increase in the
    incidences of emesis and soft stools. At necropsy, the large
    intestines of all spectinomycin-treated dogs contained a
    green-yellow material. Dogs given the lowest dose had minimal
    chronic colitis while those given the highest dose had minimal
    catarrhal enteritis in the ileum with slight colitis in the colon
    (Krohmer, 1990a).

          Based on the results of the range-finding study summarized in
    the previous paragraph, groups of 4 male and 4 female beagle dogs
    were given daily oral doses of 0, 100, 250, 500, 750, or 1000 mg/kg
    bw spectinomycin in gelatine capsules for 28 days. The only effect

    seen during the study was an increase in soft faeces at the highest
    dose. There were no effects on clinical biochemistry parameters
    and, at necropsy, there were no gross or microscopic abnormalities.
    The NOEL in this study was 750 mg/kg bw/day (Krohmer, 1990b).

          A 1:1 mixture of spectinomycin and lincomycin as a powder in
    gelatine capsules was administered to groups of 4 male and 4 female
    beagle dogs at doses of 0, 100, 300, or 1000 mg/kg bw/day for 90
    days. Intermittent diarrhoea occurred at 1000 mg/kg bw/day while
    soft faeces were the only clinical signs seen. All other
    observations, including food consumption, body weights, gross
    pathology, histopathology, urinalysis and clinical chemistries were
    comparable with control values. The NOEL was 100 mg/kg bw/day,
    equivalent to 50 mg/kg bw/day spectinomycin (Glenn & Burr, 1970b).

          Pairs of 2 beagle dogs were given spectinomycin hydrochloride
    i.v. in aqueous solution for 5 or 8 days at doses of 30, 100, or
    300 mg/kg bw/day, in half doses administered twice daily. No
    adverse effects were noted on body weight, clinical chemistry,
    haematology or urinalyses, but no controls were used in this study
    therefore no firm conclusions could be drawn (Gray & Purmalis,
    1960, 1966).

          Three groups of beagle dogs (2 male, 2 female) were treated
    with 0, 300, or 1000 mg/kg bw/day spectinomycin hydrochloride by
    infusion at 4 ml/minute into the cephalic or saphenous veins, 6
    days per week, for one month. Vomiting, salivation and thirst were
    observed in the high-dose animals but not in controls or low-dose
    dogs. This was thought to be due to the volume of infusate and its
    hypertonic nature. No drug-related effects were observed in this
    study (Sawa & Frielink, 1969).

          Spectinomycin hydrochloride injected i.m. at doses of 3.2
    g/day for 4 days or 6.4 g/day for 3 days had no effect on beagle
    dogs, except for a slight inflammatory reaction at the injection
    site (Gray & Weaver, 1966c).

          Four groups of 6 beagle dogs (3 animals of each sex) were
    given daily i.m. injections of 0, 50, 100 or 150 mg/kg bw/day for
    14 days. Signs of transient pain at the injection site were noted
    2-8 hours after administration, and inflammation occurred at the
    injection site in the 100 and 150 mg/kg bw/day groups. Clinical
    biochemistry, urinalyses and haematology parameters remained normal
    while organ weights were comparable with controls (Gray & Purmalis,
    1961a).

          Similar findings were made in a study where dogs, presumably
    beagles although this was not specified, were given daily i.m.
    injections of 0, 300, or 800 mg/kg bw/day spectinomycin for 3
    months. Blood biochemistry parameters were normal throughout the
    study and the only clinical signs were limping and local
    irritation, possibly due to the large volumes injected. No gross or
    histopathological changes at necropsy were observed (Ray & Ceru,
    1969b).

    2.2.2.3  Pigs

          Groups of 8 neonatal pigs (breed unspecified) were given daily
    oral doses of 0, 8, 25, or 50 mg/kg bw spectinomycin for 9 days.
    There was no evidence of toxicity and leucocyte counts and
    haemoglobin determinations at 8, 11, 15, and 29 days after
    treatment were normal (Welter & Johnson, 1963).

          A group of 12 pigs was fed a diet containing 20 g/ton of 1:1
    lincomycin/spectinomycin for 28-50 days. No information was
    provided on dietary intake, nor on age of the pigs, and so it was
    not possible to estimate intake. Two pigs were given control diets
    only. No adverse effects other than soft faeces were noted, and
    there were no gross or histopathological findings (Glenn & Burr,
    1970c).

          In a similar study, 11 pigs were fed diets containing 1:1
    lincomycin/spectinomycin 1000 g/ton for 35 (6 pigs) or 85 (5 pigs)
    days. Two further groups of pigs were fed the control diet only.
    Soft faeces were noted in treated animals. There were no adverse
    effects on behaviour, haematology, clinical chemistry, organ
    weights, or gross pathology, and there were no histopathological
    findings (Glenn  et al., 1970a).

          No adverse effects were noted when pigs were fed diets
    containing 0, 40, or 400 g/ton 1:1 lincomycin/spectinomycin for 56
    days (Glen  et al., 1976).

          In a further experiment, groups of 6-9 neonatal pigs were
    given daily i.m. injections of 0, 5, 15, or 30 mg/kg bw
    spectinomycin for 9 days. There were no signs of toxicity in
    treated pigs, which showed better rates of weight gain than
    untreated controls. There were no gross or microscopic
    abnormalities seen at necropsy (Welter & Woods, 1963).

    2.2.3  Long-term toxicity/carcinogenicity studies

          The only available study was a 2-year oral toxicity study in
    the rat (Abbott Laboratories, 1970). However, this study was
    conducted by Industrial Bio-Test Laboratories, a testing
    laboratory, which around the time the study was conducted, was
    involved with the production of a number of toxicology studies that
    have been found to be invalid. The manufacturer was unable to
    obtain the individual animal data or slides from this study and
    hence was unable to validate it (Maxey, 1990). Hence, the study
    cannot be used to assess the carcinogenicity or long-term toxicity
    of spectinomycin.

    2.2.4  Reproduction studies

    2.2.4.1  Rats

          Groups of 10 male and 20 female Sprague-Dawley rats were
    treated with 100 or 300 mg/kg bw/day spectinomycin hydrochloride,
    s.c. from 40 days of age through breeding for males and 14 days
    before breeding through gestation and lactation for females. A
    group of 10 untreated males and 10 untreated females served as
    controls. No treatment-related effects were seen on reproductive
    performance in either sex. Litters from treated females were
    slightly larger than controls, and pup weights were higher (Graham
     et al., 1969).

          In a 3-generation study, spectinomycin was given orally to
    groups of 10 male and 20 female Sprague-Dawley rats at doses of 0,
    100, 200, or 400 mg/kg bw/day by incorporation into the diet. The
    parental animals of all generations were fed the diets for 10
    weeks. The parents of the first two generations were then subjected
    to two subsequent matings, and the parents of the third generation
    to three subsequent matings. Body weight, food consumption,
    parental survival, pregnancy rates, numbers of implantations,
    offspring survival, sex ratios, necropsy, and histopathological
    findings were all evaluated as part of the study.

          Survival rates, body-weight gain, and food consumption were
    comparable to controls in all generations. Reproductive performance
    was unaffected by treatment at 100 and 200 mg/kg bw/day, but at the
    high dose the pregnancy rate was significantly reduced. The sex
    ratio of live pups at birth was also reduced (0.4-0.5) in the
    second and third generations at the high dose when compared with
    controls (1.0).

          There were no abnormalities on gross necropsy of litters in
    the F1, F2, or F3 generations, but histopathological
    examination revealed hepatocellular swelling and clumped basophilic
    material in the cytoplasm of hepatocytes in some of the F1b
    animals. The NOEL in this study was 100 mg/kg bw/day based upon
    altered hepatic histology. No drug-related histopathological
    alterations were observed in any of the F3b pups at 400 mg/kg
    bw/day (Reno  et al., 1976).

    2.2.4.2  Pigs

          Pairs of sows (numbers unspecified) were fed diets containing
    0 or 100 g/ton spectinomycin equivalent to 4 mg/kg bw/day, for 2
    weeks before breeding until 2 weeks after breeding, and for one
    week before farrowing until the piglets were weaned when 2 weeks
    old. The experiment was carried out for 4 farrowings. Conception
    rates, average number of piglets per litter, and average number of
    live piglets per litter were slightly higher in treated animals,
    while the number of deaths at birth per litter was slightly lower.
    Similarly, the average number of surviving piglets at weaning were
    higher in treated pigs. No adverse effects were noted (Boston,
    1966).

    2.2.5  Special studies on embryotoxicity/teratogenicity

    2.2.5.1  Mice

          Spectinomycin dihydrochloride in 0.9% benzyl alcohol was
    administered i.p. to groups of 20 or 21 pregnant SCL-ICR mice on
    days 7-12 of gestation at 0, 400, or 1600 mg/kg bw/day. No
    treatment-related effects were observed in dams with respect to
    body weights, implants per litter, fetal mortality, sex ratio,
    average body weights of pups at term, external or visceral
    abnormalities, or skeletal development (Inoue, 1974a).

          Pregnant ICR mice were given spectinomycin i.p at 0, 400, or
    1600 mg/kg bw/day from days 7 to 12 of gestation. On day 21 of
    gestation the animals were killed and the uterine contents
    examined. There were no effects on body weights in the dams and no
    increases in fetal mortality occurred. The sex ratios in treated
    and untreated mice were similar. The number of external and
    internal abnormalities was similar in fetuses from treated and
    untreated mice (Katsuya  et al., 1974).

    2.2.5.2  Rats

          Spectinomycin dihydrochloride in 0.25% methylcellulose was
    administered by gastric intubation at doses of 0, 100, or 300 mg/kg
    bw/day to groups of 10 pregnant TUC/SPD rats from days 6-15 of
    gestation. No major effects were noted in dams in this study and
    the incidence of visceral or skeletal anomalies in fetuses was
    unremarkable (Carlson  et al., 1969a).

          Groups of 6 pregnant Sprague-Dawley rats were given 0, 100,
    300, 1000, or 3000 mg/kg bw/day spectinomycin in water by gavage on
    days 6 to 15 of gestation. Animals were killed on day 20 of
    gestation and the uterine contents examined. Maternal body weights
    were normal during the study. There were no adverse effects on
    litter sizes, the numbers of corpora lutea, live fetuses,
    resorptions, dead fetuses, or non-implantations. There were no
    increases in the incidences of skeletal or visceral abnormalities
    attributable to spectinomycin (Krohmer, 1990c).

          Spectinomycin dihydrochloride in 0.9% benzyl alcohol was
    administered i.p. to groups of 16-18 JCL-SD rats on days 9-14 of
    gestation at doses of 0, 400, or 1600 mg/kg bw/day. There were no
    treatment-related effects on body weights of dams, average numbers
    of implants per litter, fetal mortality, sex ratio, average body
    weight of live pups at term, or on external or internal anomalies.
    The average incidence of ossified coccygeal vertebra centrum was
    significantly reduced in pups from dams given 400 mg/kg bw/day
    spectinomycin, but this was not seen in the high-dose group.
    Postnatal development of pups was normal (Inoue, 1974b).

          Groups of 10 pregnant TUC/SPD rats were given daily s.c.
    injections of 0, 100, or 300 mg/kg bw spectinomycin in 0.9% benzyl
    alcohol. There was no evidence of teratogenicity in this study, but
    one litter in the 300 mg/kg bw/day group was undersized and two
    pups in this litter had no centres of ossification in the hind and
    forepaws, no supraoccipital bones and no pubic bones. The NOEL in
    this study was 100 mg/kg bw/day (Bollert & Highstrete, 1969).

          In a similar study, groups of 20 pregnant SPF CD rats were
    given daily s.c. injections of 0, 150, or 300 mg/kg bw
    spectinomycin or 0.9% saline on days 6-15 of gestation. There were
    no effects on the dams nor on litter parameters or embryonic or
    fetal development (Feenstra, 1973a).

          Spectinomycin dihydrochloride was administered as single s.c.
    injections at doses of 0, 300, 900, or 2500 mg/kg bw to groups of
    5 pregnant SPF Sprague Dawley rats on one of the days 6-15 of
    gestation. No treatment-related effects were seen in dams, the
    numbers of resorption sites, litter size, or pup weights. There
    were no effects on the incidences of skeletal or visceral anomalies
    (Bollert  et al., 1971).

    2.2.5.3  Rabbits

          In a preliminary study, groups of 6 New Zealand white rabbits
    were given 400 or 600 mg/kg bw/day spectinomycin for 6 days by s.c.
    injection. High toxicity occurred in both groups with anorexia,
    weight loss and one death in the high-dose group, probably due to
    the effects of the drug on the gastrointestinal flora following
    biliary excretion (Feenstra 1973b).

          Groups of 13 pregnant New Zealand white rabbits were given
    daily s.c. doses of 0, 150, or 300 mg/kg bw spectinomycin or 0.9%
    saline on days 8-18 of gestation. Pregnancy rates and
    pre-implantation losses were similar to controls. Litter sizes and
    weights were reduced in both treated groups but embryonic and fetal
    development were unaffected. The effects seen were most probably
    due to the effects of spectinomycin on the maternal
    gastrointestinal tract (Feenstra, 1973b).

          Aqueous spectinomycin dihydrochloride was administered by i.m.
    injection at doses of 0, 100, or 300 mg/kg bw/day on days 6-18 of
    gestation to groups of 17-18 inseminated Dutch belt rabbits. Only
    12/17 controls, 8/18 low dose, and 7/18 high-dose rabbits were
    pregnant. Maternal body weights were reduced in a dose-dependent
    manner in treated animals. One low-dose dam and 2 high-dose dams
    died, but the cause of death was unclear.

          Several animals were recorded as being pregnant, but no pups
    (dead or alive) and no resorption sites were recorded. Dorsiflexion
    of the digits of the foot was noted in 3/9 pups from 2 litters in
    the high dose group; the significance of this was unclear. No other
    compound-related effects, including visceral or skeletal anomalies,
    were reported. The NOEL in this study was probably 100 mg/kg bw/day
    but the study was inadequate because of the low number of pregnant
    animals and poor reporting (Carlson  et al., 1969b).

          To investigate the teratogenic potential of spectinomycin
    further, a second study was undertaken. Groups of 20 inseminated
    Dutch belt rabbits were given daily i.m. injections of 0 or 100
    mg/kg bw spectinomycin dihydrochloride on days 6-18 of gestation.
    There were no effects on treated dams, nor on pregnancy rates, pups
    per litter, average pup weight, resorption sites, or total implants
    per dam. Several anomalies (e.g., absence of left kidney and
    ureter, exencephaly, submandibular edema, rib defects, and
    incomplete skull ossification) were noted but they were considered
    by the authors to be spontaneous or were present at a similar rate
    in controls. However, no data were provided for the incidence of
    abnormalities in historical controls in this strain of rabbit, and
    no data were provided on clinical observations, maternal body

    weights or food intake. Therefore, even though the apparent NOEL
    was 100 mg/kg bw/day it was not possible to draw any conclusions on
    the teratogenicity of spectinomycin in the rabbit from this study
    (Bollert  et al., 1970).

    2.2.5.4  Pigs

          Groups of 8 domestic white pregnant sows were treated daily
    with spectinomycin in 0.9% aqueous benzyl alcohol by i.m. injection
    at doses of 0, 75, or 150 mg/kg bw/day on days 12 to 42 of
    gestation. Animals were slaughtered on day 100 of pregnancy. One
    low-dose and 2 high-dose animals had localized reactions at the
    injection sites and all groups experienced a transient reduction in
    mean body-weight for the first 7 days of the study. The effect was
    slightly more marked in treated pigs. During the second week group
    mean body weights recovered to initial values in all groups. There
    were no effects on pregnancy rates, litter parameters, or embryonic
    and fetal development (Feenstra, 1974).

    2.2.6  Special studies on genotoxicity

          The results of genotoxicity studies with spectinomycin are
    shown in Table 2. Spectinomycin gave negative results in several
     in vitro and  in vivo studies covering a range of endpoints.

    2.2.7  Special studies on irritation

          I.M. injections of spectinomycin in benzyl alcohol and
    carboxymethyl cellulose in the rabbit have been shown to result in
    moderate local irritant effects characterized by haemorrhage and
    necrosis at the injection site (Gray 1966; Gray  et al., 1960b;
    Johnston & Schwikert, 1961a,b; Weaver & Gray, 1975). Spectinomycin
    hydrochloride produced only mild conjunctivitis when applied
    directly to the rabbit eye without a vehicle (Coombs & Leong,
    1982a) and was not irritating when applied to intact and abraded
    rabbit skin using an occlusive dressing for 24 hours or for 5
    consecutive days (Coombs & Leong, 1982b).

    2.2.8  Special studies on ototoxicity

          Spectinomycin was administered i.m. to groups of 3 cats at
    doses of 0, 30, 60, or 120 mg/kg bw/day for 75-90 days.
    Twice-weekly investigations of cochlear function revealed no
    abnormalities and there was no evidence of diminished eighth nerve
    function (Gray  et al., 1960c,d).

    2.2.9  Special studies on microbiological effects

          One article cites MIC values for a range of bacterial species,
    most of which were said to be of animal origin. These are shown in
    Table 3.

        Table 2.  Results of genotoxicity assays on spectinomycin
                                                                                      

    Test system      Test object        Concentration        Results   Reference
                                                                                      

    Ames test1        S.typhimurium     250-2000 g/plate    Negative  Mazurek &
                     TA98, 100, 1535,                                  Swenson, 1981
                     1537, 1538

    Ames test1        S.typhimurium     250-2000             Negative  Mayo & Aaron,
                     TA97a, 98, 100,    g/plate                       1990
                     102, 1535

    Ames test1        S.typhimurium     100-5000 g/plate    Negative  Lawlor, 1991
                     TA98, 100, 1535,
                     1537, 1538

    Forward1         Chinese hamster    100-1000 g/ml       Negative  Bichet, 1990
    mutation assay   V-79 fibrolasts
                     (HPRT assay)

    Forward1         Mouse lymphoma     0.5-5.0 mg/ml        Negative  Cifone, 1991
    mutation assay   (L5178Y TK +/-)

    Unscheduled      Rat lymphocytes    100-3000 g/ml       Negative  McKeon, 1991
    DNA synthesis

     In vitro        Chinese hamster    1270-5060 g/ml      Negative  Murli, 1991
    cytogenetics     ovary cells

     In vitro  1     Human              9.8-5000 g/ml       Negative  Brooker  et al.,
    cytogenetics     lymphocytes                                       1990

     In vitro  1     Chinese hamster    40-5000 g/ml        Negative  Aaron, 1991a
    cytogenetics

    Unscheduled      Rat hepatocytes    10-3000 g/ml        Negative  Harbach &
    DNA synthesis                                                      Filipunas, 1990

    Micronucleus     CD-1 mouse bone    0, 625, 1250,        Negative  Aaron, 1991b
    test             marrow             2500 mg/kg bw

    Micronucleus     Sprague-Dawley     0, 750, 1500,        Negative  Trzos  et al.,
    test             rat bone marrow    3000 mg/kg bw                  1981
                                                                                      

    1    With and without metabolic activation.

    Table 3.  Minimum inhibitory concentrations of spectinomycin
         (Burrows, 1980)

              Organism                                     MIC (g/ml)

               Staphylococcus aureus                              50
               Streptococcus pyrogenes                           100
               Corynebacterium pyogenes                          100
               Escherichia coli                                   20
               Klebsiella and Enterobacter                        25
               Proteus spp.                                       25+
               Salmonella typhimurium                             30
               Pasteurella multicoda and                          25
                 P. haemolytica
               Pseudomonas aeruginosa                            200+
               Actinobacillus equuli                              15
               Brucella canis                                      0.5
               Bordetella bronchisepticus                        100
               Bacteroides melaninogenicus                        60
               Bact. nodosus                                      60
               Clostridium perfringens                           100+
               Mycoplasma hyosynoviae                              3
               M. bovigenitalium                                   5
    

          In another study, the MIC values for a range of human
    isolates were determined for several antibiotics, including
    spectinomycin. These results are shown in Table 4.

          Full details of the origins of the isolates for incubation
    conditions, media, etc., were provided in the paper by Zurenko  et
     al., 1988. However, neither of the two papers summarized in
    Tables 3 and 4 cover all the species usually considered most
    relevant and representative of human gut flora. In particular,
    there is a need for data on the effects of spectinomycin on Gram
    positive strict anaerobes such as  Bifidobacterium spp.,
     Eubacterium spp., and  Peptostreptococcus spp. Information on
    another Gram positive facultative anaerobe such as  Lactobacillus
    spp., would be useful. However, there was sufficient information on
    Gram negative strict anaerobes (e.g., bacteroides) and Gram
    negative facultative anaerobes (e.g.,  E. coli and  Proteus
    spp.). From the information available, the lowest relevant MIC50
    was 16 g/ml in  E. coli.

        Table 4.    MIC values for spectinomycin against a range of human
                      isolates (Zurenko  et al., 1988).
                                                                                   

                  Organism1                  Range               MIC(g/ml)2
                                                                50%        90%
                                                                                   

     Staphylococcus aureus (23)               64->256           64         >256

     Staphylococcus epidermidis (12)          32-64             64         64

     Streptococcus faecalis (10)              64                64         64

     Streptococcus pneumoniae (13)            16-32             16         32

     Streptococcus spp. (10)                  16-32             16         16

     Acinetobacter spp. (10)                  16->512           32         256

     Citrobacter diversus (10)                16->512           16         16

     Citrobacter freundii (10)                16->512           32         >512

     Enterobacter spp. (20)                   16-512            16         16

    * Escherichia coli (11)                   16->512           16         >512

    Haemophilus influenza:                                                
    (-lactamase negative) (10)               8-32              16         16
    (-lactamase positive) (10)               8-32              8          16

     Klebsiella pneumoniae (10)               16-512            16         32

     Morganella morgani (9)                   16->512           32         -

    * Proteus mirabilis (10)                  16-512            32         256

    * Proteus rettgari (10)                   16->512           64         >512

    * Proteus vulgaris (10)                   16-512            32         256

     Providencia stuartii (10)                512->1024         >1024      >1024

     Pseudomonas aeruginosa (11)              8-1024            128        >1024

     Pseudomonas spp. (9)                     8->1024           128        -

     Salmonella spp. (10)                     32-128            64         64
                                                                                   

    Table 4. (cont'd) MIC values for spectinomycin against a range of human
                      isolates (Zurenko  et al., 1988).
                                                                                   

                  Organism1                  Range               MIC(g/ml)2
                                                                50%        90%
                                                                                   

     Serratia marcescens (10)                 32-128            32         128

     Shigella spp. (10)                       64->512           64         64

    * Bacterioides fragilis (11)              16-128            128        128

    * Bacterioides spp. (8)                   8>-128            32         -
                                                                                   

    1      Numbers in parentheses are numbers of isolates.
    2      MICs for 50% and 90% of isolates tested.
    
          In a study specifically designed to determine the effects of
    spectinomycin on the human gut flora, bacterial strains were
    obtained from the faeces of healthy human volunteers at Toulouse
    hospital, France. The following bacteria were isolated:
     Escherichia coli, Bifidobacterium spp. and  Bacteroides
     fragilis. MIC values were determined using serial dilutions of
    spectinomycin and an 18-hour incubation period.

          The following concentrations were without effect:

                E. coli                    - 4 g/ml
                Bifidobacterium            - 32 g/ml
                Bacteroides fragilis       - 16 g/ml

          The MIC50 for  E. coli was determined to be 7 g/ml, while
    the MIC90 was 19 g/ml. The MICs for the other two bacteria were
    in excess of 32 g/ml (Richez, 1992).

          Several studies have investigated the antibacterial effects of
    spectinomycin and have reported MIC values. One such study examined
    the activity of the drug against a number of anaerobes in different
    agar media. The following ranges of MIC values were obtained:

                Bacteroides fragilis             - 25-138 g/ml
                B. melanogenicus                 - 8-13 g/ml
                Clostridium perfringens 64       ->128 g/ml
                C. ramosum                       - 16-64 g/ml

          All the bacteria were human clinical isolates (Rosenblatt &
    Gerdts, 1977).

          In a study of bacteriological susceptibility to spectinomycin,
    MICs were in the range of 8-38 g/ml with  Bacteroides fragilis
    (Phillips & Warren, 1975).

           In vitro studies of spectinomycin against a range of
    bacteria in different media produced a range of MIC values (Mason
     et al. ; date unspecified):

                Staphyloccoccus aureus           - 16.5-83 g/ml
                Diplococcus pneumoniae           - 4.1-21 g/ml
                Streptococcus faecalis           - 6-165 g/ml
                Clostridium perfringens          - 66-165 g/ml
                Proteus vulgaris                 - 8.3-83 g/ml
                Salmonella spp.                  - 4.1-83 g/ml
                Shigella dysentariae             - 8.3-83 g/ml
                S. flexneri                      - 8.3-41 g/ml
                Klebsiella pneumoniae            - 4.1-21 g/ml

          In a study to investigate the  in vitro activity of
    spectinomycin against a number of aerobic and anerobic organisms,
    MIC50 and MIC90 values were determined. The results are shown
    below (Montiel  et al., 1990):

                    Organism              MIC50     MIC90
                                          g/ml     g/ml

                Bacteroides fragilis      320       >320
                B. distasonis             320       >320
                B. vulgatus               160       >320
                B. melaninogenicus        80        >320
                Peptococcus spp.          80        >320
                Peptostreptococcus spp.   80        >320
                Clostridium perfringens   320       >320
                Clostridium spp.          160       160
                Fusobacterium spp.        160       320

          A study was specifically designed to examine the effects on
    anerobic organisms commonly found in the human gut. MIC values
    against  Bifidobacterium and  Eubacterium strains were
    determined. The MICs against Eubacterium ranged from 4-256 g/ml
    and for  Bifidobacterium from 2-64 g/ml. Within experiments
    several strains showed 2- to 8-fold increases in MIC values when
    the inoculum densities were higher, but these were within the
    variations expected (Thurn  et al., 1993).

          An extensive  in vitro study investigated the effects of
    spectinomycin on representative organisms of the human gut flora.
    These included several species of  Bifidobacterium, Eubacterium,
     Bacteroides, Peptococcus,  and  Fusobacterium. The effects of
    pH, inoculum density and serial passage were also investigated.

    Many had MIC50 values of greater than 50 g/ml but  Bifidobacteria 
    were more sensitive with MIC values in the range 2-32 g/ml. The 
    modal MIC for  Bifidobacteria was 16 g/ml with an inoculum density 
    of 106 and 8 g/ml with an inoculum density of 104 (Kotarski, 1993).

    2.3  Observations in humans

          Urticaria, dizziness, nausea, chills and fever have been
    reported after single doses of spectinomycin in clinical trials.
    Anaphylactic reactions have been rarely reported (Dollery, 1991;
    Reynolds, 1993).

          Spectinomycin produced no signs of ototoxicity in 15 healthy
    male volunteers given 8 g/day (130 mg/kg bw/day) i.m. for 21 days
    as evidenced by tests of cochlear and vestibular function. The only
    untoward effect noted was pain at the injection site (Novak  et
     al., 1974).

    3.  COMMENTS

          A range of studies on spectinomycin was submitted for
    assessment including data on pharmacokinetics and metabolism, as
    well as information from acute, short-term, reproductive,
    developmental and genotoxicity studies.

          Toxicokinetic studies suggested poor absorption after oral
    dosing in rats, dogs, pigs and cattle, with most of the orally
    administered dose found in the faeces. Absorption was also poor in
    humans following oral administration. There were no data available
    on biotransformation in animals, but limited information in humans
    suggested that the drug is not extensively metabolized.

          Single oral doses of spectinomycin were of low toxicity to
    mice and rats (LD50 = 3000 - 20 000 mg/kg bw) although the drug
    appeared to be more toxic to dogs (LD50 = 1000 mg/kg bw) and
    monkeys (LD50 = 500 mg/kg bw).

          No major toxicological effects were noted following repeated
    oral or parenteral administration to rats or dogs. The most common
    findings were changes in the consistency of the faeces in treated
    animals, and the NOELs for these findings varied from 50 to 750 mg/
    kg bw/day.

          Adequate carcinogenicity studies were not available. However,
    both  in vitro and  in vivo genotoxicity studies covering a
    variety of end-points were negative and spectinomycin does not
    share structural similarities with known carcinogens. Therefore,
    the Committee was of the opinion that the drug did not present a
    carcinogenic risk and carcinogenicity studies were not deemed
    necessary.

          A multi-generation reproduction study in rats in which
    spectinomycin was administered orally showed no adverse effects on
    reproductive parameters up to the highest dose tested, 400 mg/kg
    bw/day. Hepatocellular swelling and clumped basophilic material in
    the cytoplasm of hepatocytes were noted. This occurred only in some
    animals of the F1b generation. The NOEL was 100 mg/kg bw/day.

          Developmental toxicity was examined in mice, rats and rabbits.
    Spectinomycin was not teratogenic in rats after oral doses of up to
    3000 mg/kg bw/day. There was no evidence of teratogenic effects
    after i.p. or s.c. administration in this species. It was not
    teratogenic in mice after i.p. doses of up to 1600 mg/kg bw/day.
    The study in rabbits revealed no teratogenic effects after s.c. or
    i.m. doses of up to 300 mg/kg bw/day.

          There was no evidence of ototoxicity in cats after i.m. doses
    of up to 120 mg/kg bw/day for periods of 75 to 90 days, nor in
    humans (males) after an i.m. dose of 130 mg/kg bw/day for 21 days.
    The Committee concluded that there were no major toxicological
    effects associated with spectinomycin in humans or animals.

          The potential for adverse effects on the human GI tract flora
    was considered.  In vitro MIC data covering a wide range of animal
    and human pathogens and commensals was submitted for assessment.

          The Committee examined MIC data for a number of bacterial
    species representative of the anaerobic microbial flora in the
    human gastrointestinal tract including  Bacteroides,
     Peptostreptococcus, Fusobacterium, Eubacterium and  Clostridium
    spp. Many had MIC50 values greater than 50 g/ml.
     Bifidobacterium spp. were more sensitive, with MIC values for
    spectinomycin in the range of 2-32 g/ml. The modal MIC for
     Bifidobacterium spp.was 16 g/ml with an inoculum density of
    106 cells and 8 g/ml with an inoculum density of 104 cells.
    The Committee used the value of 16g/ml in its calculations.

          In calculating the ADI, the formula developed at the
    thirty-eighth meeting of the Committee (Annex 1, reference 97) was
    used:

                           Concentration without
                           effect on human gut x Daily faecal bolus (g)
    Upper limit of         flora (g/ml)
    temporary ADI    =     ____________________________________________
    (g per kg of          Fraction of 
    body weight            oral dose x Safety factor x Weight of human (60
    kg)                    bioavailable

                     =     16  x  150
                           __________
                           1 x 1 x 60

                     =     40 g/kg bw

    1.    The Committee concluded that sufficient experimental data had
          been provided and that no specific factors to account for the
          range of MICs to cover sensitive bacteria, the anaerobic
          environment, bacterial density, or pH were required to adjust
          the modal MIC of 16 to a "microbiological no effect level".

    2.    The Committee noted that absorption of spectinomycin from the
          gastrointestinal tract was poor. It therefore adopted a
          conservative factor which assumed 100% availability of
          ingested spectinomycin to organisms in the gastrointestinal
          tract.

    3.    A substantial amount of MIC data covering a variety of
          organisms were available. In addition, recently published data
          suggested that variability among populations was low. A safety
          factor of 1 was therefore adopted by the Committee.

    4.  EVALUATION

          Taking into account all of these factors, an ADI of 0-40 g/kg
    bw was established. In view of the extensive range of organisms
    examined, and as data were provided on the effects of pH, inoculum
    density and resistance to spectinomycin, and taking into account
    the discussions on the microbiological safety of residues held
    during the meeting (Annex 1, reference 110), the Committee
    considered that in this instance, a full ADI was appropriate.

    5.  REFERENCES

    AARON, C.S. (1991a). Evaluation of U-18409E in the  in vitro
    chromosome aberration assay using Chinese Hamster Ovary (CHO)
    cells. Unpublished report 7228-91-007. Submitted to WHO by Upjohn
    Company, Kalamazoo, MI, USA.

    AARON, C.S. (1991b). Evaluation of U-18409E in the micronucleus
    test in polychromatic erythrocytes of the bone marrow of CD-1 mice.
    Unpublished report 7228-91-010. Submitted to WHO by Upjohn Company,
    Kalamazoo, MI, USA.

    ABBOTT LABORATORIES (1970). 24-Month oral toxicity study of Abbott
    25683 (Spectinomycin) in swine and albino rats. Unpublished report.
    Submitted to WHO by Upjohn Company, Kalamazoo, MI, USA.

    ANONYMOUS (1992). Registry of Toxic Effects of Chemical Substances.
    On-line interrogation.

    BARBIERS, A.R., CHAPMAN, D.D., PETZFOLD, E.N., SMITH, L.J. &
    VANGORDER, T.J. (1968). Residues of spectinomycin in swine
    following treatment via i.m. injection. Unpublished report No.
    723-9760-17. Submitted to WHO by Upjohn Company, Kalamazoo, MI,
    USA.

    BICHET, N. (1990). Spectinomycin.  In vitro gene mutation assay at
    the locus HPRT in Chinese hamster V-79 fibroblasts. Unpublished
    report RA 860900625/ALI. Submitted to WHO by Sanofi Sant Nutrition
    Animale, Libourne, France.

    BLIGNY, S. (1988). Spectam Injectable. Pharmacokinetic study on
    calves. Unpublished report PK 5488/E-00, 9 May 1988. Submitted to
    WHO by Sanofi Sant Nutrition Animale, Libourne, France.

    BOLLERT, J.A. & HIGHSTRETE, J.D. (1969). U-18, 409AE; Teratology
    study in the rat. Unpublished report No. 5401/69/7263/029.
    Submitted to WHO by Upjohn Company, Kalamazoo, MI, USA.

    BOLLERT, J.A., HALL, T., HIGHSTRETE, J. & ANDERSON, S. (1970).
    U-18, 409AE; Teratology study in the rabbit. Unpublished report No.
    5401/70/7263/010. Submitted to WHO by Upjohn Company, Kalamazoo,
    MI, USA.

    BOLLERT J.A., HIGHSTRETE, J.D. & PURMALIS, B.P. (1971). U-18,409AE;
    (Trobicin); Teratology study in the rat-single dose administration.
    Unpublished report No. 5401/71/7263/017. Submitted to WHO by Upjohn
    Company, Kalamazoo, MI, USA.

    BOSTON, W.D. (1966). Effect of spectinomycin on reproduction in
    swine. Unpublished report No. 395G-104-020-90. Submitted to WHO by
    Sanofi Sant Nutrition Animale, Libourne, France.

    BROOKER, P.C, AKHURST, L.C. & KING, J.D. (1990). Unpublished report
    by Huntingdon Research Centre, UK, CLN 51/906/89, 18 July 1990.
    Submitted to WHO by Sanofi Sant Nutrition Animale, Libourne,
    France.

    BURROWS, G.E. (1980). Pharmacotherapeutics of macrolides,
    lincomycins and spectinomycin.  J. Amer. Vet. Assoc., 176:
    1072-1077.

    CARLSON, R.G., GOODENOUGH, L.N., HALL, T.L. & HIGHSTRETE, J.D.
    (1969a). U-18,409AE; teratology study in the rat. Unpublished
    report No. 5401/68/7263/007. Submitted to WHO by Upjohn Company,
    Kalamazoo, MI, USA.

    CARLSON R.G., HALL, T.L., HIGHSTRETE, J.D. & BOLLERT, J.A. (1969b).
    U-18, 409AE; Teratology study in the rabbit (Final Report).
    Unpublished report No. 5401/69/7263/007. Submitted to WHO by Upjohn
    Company, Kalamazoo, MI, USA.

    CIFONE, M.A. (1991). Mutagenicity test on spectinomycin
    dihydrochloride pentahydrate in the L5178Y TK+/- mouse lymphoma
    forward mutation assay. Unpublished report by Hazleton, USA,
    12582-0-421, 3 May 1991. Submitted to WHO by Sanofi Sant Nutrition
    Animale, Libourne, France.

    COOMBS, J.K. & LEONG, B.K.J (1982a). Preliminary eye irritation
    study on spectinomycin hydrochloride.5H20 in albino rabbits.
    Unpublished report 7263/82/7263.041. Submitted to WHO by Upjohn
    Company, Kalamazoo, MI, USA.

    COOMBS, J.K. & LEONG, B.K.J. (1982b). Preliminary dermal irritation
    study on spectinomycin hydrochloride.5H20 in albino rabbits.
    Unpublished report 7263/82/7263/040. Submitted to WHO by Upjohn
    Company, Kalamazoo, MI, USA.

    DELGADO, D.G., BRAN, C.J. & AVENT, C.K. (1980). Penetration of
    spectinomycin into cerebrospinal fluid during experimental
    meningitis.  Antimicrob. Agents Chemother., 17: 286-287.

    DOLLERY, C. (1991). Spectinomycin. In: Therapeutic Drugs,
    Churchill-Livingstone, London, Volume 2, S78-S80.

    ELDER, M.G., BYWATER, M.J. & REEVES, D.S. (1976). Pelvic tissue and
    serum concentrations of various antibiotics given as pre-operative
    medication.  Brit. J. Obstet. Gynaecol., 84: 887-893.

    FEENSTRA, E.S. (1973a). Trobicin; effect on pregnancy of the rat.
    Unpublished report No. 7263/73/7263/006. Submitted to WHO by Upjohn
    Company, Kalamazoo, MI, USA.

    FEENSTRA, E.S. (1973b). Trobicin; effect on pregnancy of the New
    Zealand white rabbit. Unpublished report No. 7263/73/7263/001.
    Submitted to WHO by Upjohn Company, Kalamazoo, MI, USA.

    FEENSTRA, E.S. (1974). U-18409AE; Effect of Trobicin on pregnancy
    of the pig. Unpublished report No.0013/74/7263/001. Submitted to
    WHO by Upjohn Company, Kalamazoo, MI, USA.

    GLENN, M.W., BURR, W.M., WILLIAMS, T. & NOWAKOWSKI, D. (1969a).
    Acute oral LD50 of lincomycin-spectinomycin soluble powder in
    laying hens. Unpublished report No. 723-9610-3. Submitted to WHO by
    Upjohn Company, Kalamazoo, MI, USA.


    GLENN, M.W., BURR, W.M., WILLIAMS, T. & NOWAKOWSKI, D. (1969b).
    Acute oral LD50 of lincomycin-spectinomycin soluble powder in
    one-day old chickens. Unpublished report No. 723-9610-4. Submitted
    to WHO by Upjohn Company, Kalamazoo, MI, USA.

    GLENN, M.W., BURR, W.M. & WILLIAMS, T. (1969c).
    Lincomycin-spectinomycin (1:2). Subacute oral toxicity in broiler
    chickens. Unpublished report No. 723-9610-MWG-69-9. Submitted to
    WHO by Upjohn Company, Kalamazoo, MI, USA.

    GLENN, M.W. & BURR, W.M. (1970a). Lincomycin/spectinomycin (1:1).
    90-day oral toxicity study in the rat. Unpublished report No.
    518-9610-MWG-70-2. Submitted to Veterinary Medicines Directorate,
    UK, by Upjohn Company, Kalamazoo, MI, USA, and cited with
    permission.

    GLENN, M.W. & BURR, W.M. (1970b). Lincomycin/spectinomycin (1:1).
    90-day oral toxicity study in the dog. Unpublished report No.
    518-9610-MWG-70-1. Submitted to Veterinary Medicines Directorate,
    UK, by Upjohn Company, Kalamazoo, MI, USA, and cited with
    permission.

    GLENN, M.W. & BURR, W.M. (1970c). Lincomycin/spectinomycin (1:1).
    Toxicity in growing pigs fed at the rate of 1000 gms/ton of ration.
    Gross and histopathology. Unpublished report No.518-9610-MWG-70-4.
    Submitted to WHO by Upjohn Company, Kalamazoo, MI, USA.

    GLENN, M.W., BURR, W.M. & EVAN, R. (1970a).
    Lincomycin-spectinomycin. (1:1) subacute toxicity study in feeder
    pigs fed at the rate of 1000 gms per ton of ration. Unpublished
    report No. 518-9610-MWG-70-5. Submitted to WHO by Upjohn Company,
    Kalamazoo, MI, USA.

    GLENN, M.W., BURR, W.M. & WILLIAMS, T. (1970b). Lincospectin 128
    soluble powder, acute oral LD50 in the ten-day old chicks.
    Unpublished report No.723a- 9610-MWG-70-10. Submitted to WHO by
    Upjohn Company, Kalamazoo, MI, USA.

    GLENN, M.W., EVANS, R. & NIELSEN, R.W. (1976). Lincospectin
    (Eluate) - 20 Premix, 56 day oral tolerance study in weanling pigs.
    Unpublished study No. 520X-9610-MWG-75-5. Submitted to WHO by
    Upjohn Company, Kalamazoo, MI, USA.

    GRAHAM W.R., GOODENOUGH, L.N., BAXTER, G. & BOLLERT, J. (1969).
    U-18, 409AE; one generation rat reproduction study. Unpublished
    study No. 5401/69/7263/016. Submitted to WHO by Upjohn Company,
    Kalamazoo, MI, USA.

    GRAY, J.E. (1966). Spectinomycin hydrochloride U-18,409AE.
    Intramuscular irritation in rabbits. Unpublished report. Submitted
    to WHO by Upjohn Company, Kalamazoo, MI, USA.

    GRAY, J.E. & PURMALIS, A. (1960). Intravenous tolerance study in
    the dog; terminal blood level assay-muscular pain evaluation in the
    dog. Unpublished report. Submitted to WHO by Upjohn Company,
    Kalamazoo, MI, USA.

    GRAY, J.E. & PURMALIS, A. (1961a). Subacute (two weeks)
    intramuscular toxicity in the dog. Unpublished report. Submitted to
    WHO by Upjohn Company, Kalamazoo, MI, USA.

    GRAY, J.E. & PURMALIS, A. (1961b). Subcutaneous LD50
    determinations in new-born rats; parallel study with
    chloramphenicol. Effect on reproduction - placental and milk
    transfer. Unpublished report. Submitted to WHO by Upjohn Company,
    Kalamazoo, MI, USA.

    GRAY, J.E. & PURMALIS, A. (1962a). Oral absorption in the dog.
    Blood assay. Unpublished report. Submitted to WHO by Upjohn
    Company, Kalamazoo, MI, USA.

    GRAY, J.E. & PURMALIS, A. (1962b). Oral absorption in the dog.
    Blood assay appended. Unpublished report. Submitted to WHO by
    Upjohn Company, Kalamazoo, MI, USA.

    GRAY, P.E. & PURMALIS, A. (1966). Intravenous tolerance study in
    the dog. Unpublished report. Submitted to WHO by Upjohn Company,
    Kalamazoo, MI, USA.

    GRAY, J.E. & WEAVER, R.N. (1966a). Spectinomycin hydrochloride.
    Acute toxicity. Unpublished report. Submitted to WHO by Upjohn
    Company, Kalamazoo, MI, USA.

    GRAY, J.E. & WEAVER, R.N. (1966b). Spectinomycin hydrochloride.
    Acute toxicity. Unpublished report. Submitted to WHO by Upjohn
    Company, Kalamazoo, MI, USA.

    GRAY, J.E. & WEAVER, R.N. (1966c). Multiple dose intramuscular
    tolerance in the dog. Unpublished report. Submitted to WHO by
    Upjohn Company, Kalamazoo, MI, USA.

    GRAY, J.E. & WEAVER, R.N. (1967a). U-18409A; Spectinomycin
    hydrochloride. Acute toxicity in the mouse. Unpublished report
    No.11,501-1/67/7330/008. Submitted to WHO by Upjohn Company,
    Kalamazoo, MI, USA.

    GRAY, J.E. & WEAVER, R.N. (1967b). U-18409A + U-5015; spectinomycin
    hydrochloride (U-18,409AE) and atabrine (U-4015). Acute toxicity in
    the mouse. Unpublished report No.11, 501-1/67/7330/009. Submitted
    to WHO by Upjohn Company, Kalamazoo, MI, USA.

    GRAY, P.E., PURMALIS, A. & HIGHSTRETE, J. (1960a). Subcutaneous
    subacute toxicity in the rat. Unpublished report submitted to WHO
    by Upjohn Company, Kalamazoo, MI, USA.

    GRAY, P.E., PURMALIS, A. & HIGHSTRETE, J. (1960b). Intramuscular
    irritation in rabbits. Unpublished report. Submitted to WHO by
    Upjohn Company, Kalamazoo, MI, USA.

    GRAY, P.E., PURMALIS, A. & HIGHSTRETE, J. (1960c). Ototoxicity in
    the cat (75-day report); blood level assay. Unpublished report.
    Submitted to WHO by Upjohn Company, Kalamazoo, MI, USA.

    GRAY, P.E., PURMALIS, A. & HIGHSTRETE, J. (1960d). Ototoxicity in
    the cat (90-day report); blood level assay. Unpublished report.
    Submitted to WHO by Upjohn Company Kalamazoo, MI, USA.

    HAMLOW, P.J. & JAGLAN, P.S. (1988). Metabolic stability of
    4'-tritium labelled spectinomycin in rats. Unpublished report No.
    803-9760-88-002. Submitted to WHO by Upjohn Company, Kalamazoo, MI,
    USA.

    HARBACH, P.R. & FILIPUNAS, A.L. (1990). Evaluation of U-18409E in
    the  in vitro unscheduled DNA synthesis (UDS) assay in rat primary
    hepatocytes. Unpublished report No. 7228/90/094. Submitted to WHO
    by Upjohn Company, Kalamazoo, MI, USA.

    HIGHSTRETE, J.D. (1964). Spectinomycin sulfate. Acute toxicity.
    Unpublished report; 16 October 1964. Submitted to WHO by Upjohn
    Company, Kalamazoo, MI, USA.

    HOLLOWAY, W.J. (1982). Spectinomycin.  Med. Clin. North Amer.,
    66: 169-172.

    HOVIUS M.Ph.J., HAAGSMA, N., PIJPERS, A., MIGNOT, A. & VERHEIJDEN,
    J.H.M. (1989). Plasma concentration of lincomycin and spectinomycin
    in healthy pigs after oral treatment with Linco-Spectin Premix and
    spectinomycin - Preliminary study I. Unpublished study No.
    803-9760-88-001. Submitted to WHO by Upjohn Company, Kalamazoo, MI,
    USA.

    HWANG, K., COEN, L., JOHNSON, H.E., HUNTER, W.W. & CUGIER, P.
    (1961). M-141, a new antibiotic. III. Pharmacology.  Antimicrob.
     Agents Chemother., 507-515.

    INOUE, S. (1974a). Effects of Trobicin (spectinomycin
    dihydrochloride pentahydrate) administered to pregnant mice on
    their fetuses and newborns. Unpublished report. Submitted to WHO by
    Upjohn Company, Kalamazoo, MI, USA.

    INOUE, S. (1974b). Effects of Trobicin (spectinomycin
    dihydrochloride pentahydrate) administered to pregnant rats on
    their fetuses and newborns. Unpublished report. Submittted to WHO
    by Upjohn Company, Kalamazoo, MI, USA.

    JAGLAN, P.S., ROOF, R.D. & ARNOLD, T.S. (1991a). Disposition of
    3H- spectinomycin (6'-methyl) in rats from oral and intramuscular
    treatments. Unpublished report No. 803-7926-91-001. Submitted to
    WHO by Upjohn Company, Kalamazoo, MI, USA.

    JAGLAN, P.S., ROOF, R.D., ARNOLD, T.S., COX, T.D. & FLOOK, T.F.
    (1991b). Disposition and metabolism of 3H-spectomycin in pigs from
    an oral and intra-muscular dose. A pilot study. Unpublished report
    No. 803-7926-91-003. Submitted to WHO by Upjohn Company, Kalamazoo,
    MI, USA.

    JOHNSTON, R.L. & SCHWIKERT, R.S. (1961a). Intramuscular irritation
    in rabbits. Unpublished report. Submitted to WHO by Upjohn Company,
    Kalamazoo, MI, USA.

    JOHNSTON, R.L. & SCHWIKERT, R.S. (1961b). Intramuscular irritation
    in rabbits. Unpublished report. Submitted to WHO by Upjohn Company,
    Kalamazoo, MI, USA.

    JONES, P.M. (1959). Antibiotic 153a or actinospectin. Acute
    toxicity. Unpublished report. Submitted to WHO by Upjohn Company,
    Kalamazoo, MI, USA.

    KATSUYA, T., SAITOZ, C. & HIRANO, K. (1974) Effects of Trobicine
    (spectinomycin dihydrochloride pentahydrate) on mouse fetuses and
    newborn mice.  Kiso to Rinsho, 8: 3008-3017.

    KOTARSKI, S. (1993) Evaluation of spectinomycin exposure to
    bacteria found in the gastrointestinal tract. Unpublished report.
    Submitted to WHO by Upjohn Company, Kalamazoo, MI, USA.

    KROHMER, R.W. (1990a). One week rangefinding oral toxicity study of
    spectinomycin in dogs. Unpublished report # 395E-503-020-89.
    Submitted to WHO by Sanofi Sant Nutrition Animale, Libourne,
    France.

    KROHMER, R.W. (1990b). 28-day oral toxicity evaluation of
    spectinomycin in dogs. Unpublished report # 395D-502-020-89.
    Submitted to WHO by Sanofi Sant Nutrition Animale, Libourne,
    France.

    KROHMER, R.W. (1990c). Teratology rangefinding evaluation of
    spectinomycin in rats. Unpublished report # 395G-104-020-90.
    Submitted to WHO by Sanofi Sant Nutrition Animale, Libourne,
    France.

    KSIEZYK, M. & DANEK, A. (1973). Studies on absorption and
    elimination of drugs. V. Fitting of a double experimental curve to
    the observed concentration after a single IV injection.  Int. J.
     Clin. Pharmacol. Therap. Toxicol., 8: 222-227.

    KUSUMI, R., METZLER, C. & FASS, R. (1981). Pharmacokinetics of
    spectinomycin in volunteers with renal insufficiency.  Chemotherapy,
    27: 95-98. 

    LAWLOR, T.E. (1991) Mutagenicity test on spectinomycin
    dihydrochloride pentahydrate in the  salmonella /mammalian
    microsome reverse mutation assay (Ames Test) with a confirmatory
    assay. Unpublished report by Hazleton, USA, 1582-0-401R. Submitted
    to WHO by Sanofi Sant Nutrition Animale, Libourne, France.

    MASON, D.J., SKOLSKI, W.T. & CLAPP, H.W. (date unspecified).  In
     vitro studies of actinospectin. Submitted to WHO by Upjohn
    Company, Kalamazoo, MI, USA.

    MAXEY, B.W. (1990) Spectinomycin lifetime study by Abbott.
    Unpublished report. Submitted to WHO by Upjohn Company, Kalamazoo,
    MI, USA.

    MAYO, J.K. & AARON, C.S. (1990). Evaluation of U-18,409E in the
     Salmonella/microsome test (Ames Assay). Unpublished report
    7228/90/095. Submitted to WHO by Upjohn Company, Kalamazoo, MI,
    USA.

    MAZUREK, J.H. & SWENSON, D.H. (1981). Evaluation of U-18, 409 AE in
    the  Salmonella/microsome (Ames Assay). Unpublished report No.
    0013/81/7263/003. Submitted to WHO by Upjohn Company, Kalamazoo,
    MI, USA.

    McKEON, M.E. (1991) Genotoxicity test on spectinomycin
    dihydrochloride penta-hydrate in the assay for unscheduled DNA
    synthesis in rat liver primary cell cultures with a confirmatory
    trial. Unpublished report by Hazleton, USA, 12582-0-447R. Submitted
    to WHO by Sanofi Sant Nutrition Animale, Libourne, France.

    MONTIEL, F., KALTWASSER, G. & LAM, M. (1990). Evaluation of U-63,
    366 F trospectomycin sulfate for  in vitro activity against
    anaerobes. Unpublished report No. 9171/90/007. Submitted to WHO by
    Upjohn Company, Kalamazoo, MI, USA.

    MURLI, H. (1991). Mutagenicity test on spectinomycin
    dihydrochloride pentahydrate measuring chromosomal aberrations in
    Chinese hamster ovary (CHO) cells. Unpublished report by Hazleton,
    USA, 12582-0-437. Submitted to WHO by Sanofi Sant Nutrition
    Animale, Libourne, France.

    NOVAK, E., GRAY, J.E. & PFEIFER, R.T. (1974). Animal and human
    tolerance of high-dose intramuscular therapy with spectinomycin.
     J. Infect. Dis., 130: 50-55.

    PHILLIPS, I. & WARREN, C. (1975). Susceptibility of  Bacteroides
     fragilis to spectinomycin.  J. Antimicrob. Chemother., 1:
    91-95.

    RAAB, W. (1975). Spectinomycin. Indikationen und unerwunschte
    wirkungen.  Schweitz Med. Wschr., 105: 1116-1123.

    RAY, J.A. & CERU, J.G. (1969a). U-18, 409AE (Trobicin); a 3-month
    subcutaneous toxicology study in rats (dose levels 0, 300 and 1000
    mg/kg/day). Unpublished Report No.5401/69/7263/015. Submitted to
    WHO by Upjohn Company, Kalamazoo, MI, USA.

    RAY, J.A. & CERU, J.G. (1969b). U-18, 409AE (Trobicin); a 3 month
    intramuscular toxicology study in dogs. Unpublished report No.
    5401/69/7263/018. Submitted to WHO by Upjohn Company, Kalamazoo,
    MI, USA.

    RENO, F.E. (1976). A three-generation reproduction study in rats.
    Final Report. Unpublished report No. A-25683. Submitted to WHO by
    Upjohn Company, Kalamazoo, MI, USA.

    REYNOLDS, J.E.F. (Ed). (1993). Martindale. The Extra Pharmacopoeia.
    30th Ed., The Pharmaceutical Press, London, 202.

    RICHEZ, P. (1992). Antibacterial activity of spectinomycin against
    human gut flora. Unpublished report No SF006. Submitted to WHO by
    Sanofi Sant Nutrition Animale, Libourne, France. 

    ROOF, R.D. & JAGLAN, P.S. (1993). Amounts of tritiated water found
    in pigs and rats from oral and intramuscular treatment and bovine
    from intramuscular treatment with 3H-spectinomycin. Unpublished
    report. Submitted to WHO by Upjohn Company, Kalamazoo, MI, USA.

    ROOF, R.D., ARNOLD, T.S., COX, T.D., FLOOK, T.F., JANOSE, R.L. &
    JAGLAN, P.S. (1993). Disposition of 3H-spectinomycin in bovine
    from a single intramuscular dose. A pilot study. Unpublished report
    No. 803-7826-93-001. Submitted to WHO by Upjohn Company, Kalamazoo,
    MI, USA.

    ROSENBLATT, J.E. & GERDTS, A.M. (1977). Activity of spectinomycin
    against anaerobes.  Antimicrob. Agents Chemother., 12: 37-39.

    SAWA, T.R. & FRIELINK, R.D. (1969). U-18,409AE; one-month
    intravenous toxicity study in dogs. Unpublished study No.
    5401/69/7263/017. Submitted to WHO by Upjohn Company, Kalamazoo,
    MI, USA.

    SEYMOUR, E.W. (1964). Summary M-141 in swine urine S-R-F-6402.
    Unpublished report. Submitted to WHO by Sanofi Sant Nutrition
    Animale, Libourne, France.

    SEYMOUR, E.W. (1965a). Summary M-141 in swine urine S-RF-6501.
    Unpublished report. Submitted to WHO by Sanofi Sant Nutrition
    Animale, Libourne, France.

    STERN, K.T., STAPERT, D. & FORD, C.W. (1984a). Dog blood levels of
    spectinomycin following oral administration. Unpublished report
    7254/84/045. Submitted to WHO by Upjohn Company, Kalamazoo, MI,
    USA.

    STERN, K.T., FORD, C.W. & CAPUTO, J. (1984b). Dog blood levels of
    U-18,409AE (spectinomycin) and U-63,366F (6'-n-propylspectinomycin
    sulfate) following intramuscular administration. Unpublished report
    7254/84/015. Submitted to WHO by Upjohn Company, Kalamazoo, MI,
    USA.

    THURN, K.K., GREENING, R.C., WARGOLET, D.A., BAKER, K.D. &
    KOTARSKI, S.F. (1993). Minimum inhibitory concentrations of
    spectinomycin against anaerobes commonly found in the human
    intestine. Unpublished report No. 823-7928-93-001. Submitted to WHO
    by Upjohn Company, Kalamazoo, MI, USA.

    TRZOS, R.J., JOHNSON, M.A. & SWENSON, D.H. (1981). The micronucleus
    test with Trobicin (U-18, 409AE). Unpublished report
    No.0013/81/7263/005. Submitted to WHO by Upjohn Company, Kalamazoo,
    MI, USA.

    WAGNER, J.G., NOVAK, E., LESLIE, L.G. & METZLER, C.M. (1967).
    Absorption, distribution and elimination of spectinomycin
    hydrochloride in man.  Internat. Zeitschrift Klin. Pharmakol.
    Therap. Toxikol., 1: 261-285.

    WEAVER, R.N. & GRAY, J.E. (1975). Comparison of intramuscular
    irritancy of 3 lots of spectinomycin. Unpublished report
    No.7254/75/7262/001. Submitted to WHO by Upjohn Company, Kalamazoo,
    MI, USA.

    WEDIG, J.H. (1990). 28-day oral toxicity evaluation of
    spectinomycin in rats. Unpublished report # 396C-102-020-89.
    Submitted to WHO by Sanofi Sant Nutrition Animale, Libourne,
    France.

    WELTER, C.J. & JOHNSON, D.R. (1963). Subacute toxicity of
    spectinomycin (M-141) administered orally to baby pigs. Unpublished
    report. Submitted to WHO by Sanofi Sant Nutrition Animale,
    Libourne, France.

    WELTER, C.J. & WOODS, R. (1963). Subacute toxicity of spectinomycin
    administered intramuscularly to baby pigs. Unpublished report.
    Submitted to WHO by Sanofi Sant Nutrition Animale, Libourne,
    France.

    WILKES, L.C. (1990). Metabolism study of 3H-residues. Unpublished
    report project # 1090, 8 November, 1990. Submitted to WHO by Sanofi
    Sant Nutrition Animale, Libourne, France.

    ZIV, G. & SULMAN, F.G. (1973). Serum and milk concentrations of
    spectinomycin and tylosin in cows and ewes.  Am. J. Vet. Res.,
    34: 329-333.

    ZURENKO, G.E., YAGI, B.H., VAVRA, J.J. & WENTWORTH, B.B. (1988).
     In vitro antibacterial activity of trospectin (U063366F), a novel
    spectinomycin analog.  Antimicrob. Agents Chemother., 32:
    216-223.


    See Also:
       Toxicological Abbreviations
       SPECTINOMYCIN (JECFA Evaluation)