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    ENROFLOXACIN

    First draft prepared by
    Dr Louis T. Mulligan
    Center for Veterinary Medicine
    Food and Drug Administration, Rockville, Maryland, USA

    1.  EXPLANATION

         Enrofloxacin is a quinolone carboxylic acid derivative with
    antimicrobial action.  Enrofloxacin is most effective against gram-
    negative bacteria and is indicated for infections of the respiratory,
    gastrointestinal and urinary tracts in cattle, pigs and poultry. 
    Enrofloxacin is bactericidal through inhibition of DNA-gyrase.
    Enrofloxacin has not been previously evaluated by the Joint FAO/WHO
    Expert Committee on Food Additives.  The structure of enrofloxacin is
    shown in Figure 1.

    FIGURE 1

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

    2.1.1  Absorption, distribution, and excretion

         The following information was provided in a summary report of
    metabolism and residue data on enrofloxacin.  The full study reports
    were not provided.

    2.1.1.1  Rats

         Rats (number, species, strain not specified) were treated orally
    or intravenously with a single dose (5 mg/kg bw) of radiolabelled
    enrofloxacin.  The bioavailability was calculated to be approximately
    75%.  Enrofloxacin was rapidly absorbed and distributed to all
    tissues.  Highest concentrations were found in the liver and kidney,
    followed by muscle.  Fat did not contain appreciable amounts of
    radioactivity.  Elimination was rapid via urine and faeces.   Most of
    the radioactivity was excreted during the first 24 hours after
    administration.  About 40% of the radioactivity was excreted in bile. 
    The radioactivity in urine was attributed primarily to the unchanged
    parent drug, its de-ethylated metabolite, ciprofloxacin, and the
    glucuronide of enrofloxacin.  Bile contained mainly the unchanged
    parent molecule (Altreuther & Klostermann, 1994).

    2.1.1.2  Cattle, pigs, chickens, and turkeys

         Trials in all species showed that enrofloxacin is absorbed
    readily and distributes to all organs and tissues following oral or
    parenteral administration.  In pigs, when the same dose was
    administered by the oral or i.m. route, similar rates of absorption
    and subsequent concentrations of drug in tissues were observed. 
    Following parenteral administration, maximum serum concentrations in
    pigs and calves were reached within 1 to 2 hours.  The highest drug
    concentration initially occurred in the liver in all species. 
    Following a one-day withdrawal in poultry, highest drug concentrations
    were found in the skin.  In all species studied, elimination was
    primarily via the urine and bile/faeces (Altreuther & Klostermann,
    1994).

    2.1.2  Biotransformation

    2.1.2.1  Rats, cattle, pigs, and poultry

         Rats (number, species, strain not specified) were treated orally
    with 165 mg/kg bw of radiolabelled enrofloxacin for 3 consecutive
    days, then with 50 mg/kg bw on the fourth day.  Major urinary
    metabolites were enrofloxacin (30-36%), ciprofloxacin (26- 31%), and
    enrofloxacin glucuronide (19-29%).  Four other components were
    identified, each less than 2% of the total residue (Altreuther &
    Klostermann, 1994).

         In food animal species, ciprofloxacin was the main metabolite
    recovered.  The liver is considered the primary site of enrofloxacin
    metabolism in these species, forming ciprofloxacin through oxidative
    dealkylation. Additional metabolites occurred but comprised less than
    10% of the total residue (Altreuther & Klostermann, 1994).

    2.1.3  Effects on enzymes and other biochemical parameters

         The bactericidal in activity of quinolones, including
    enrofloxacin, is attributed  to their ability to inhibit DNA gyrase 
    (Mandell & Sande, 1990).

    2.2  Toxicological studies

    2.2.1  Acute toxicity studies

         The acute toxicity of enrofloxacin is summarized in Table 1.

    Table 1.  Acute toxicity studies on enrofloxacin
                                                                       
    Species      Sex         Route      LD50          Reference
                                        (mg/kg bw)
                                                                       

    Mouse        male        p.o.       > 5000        Schmidt, 1985
                 female                 4336

                 male        i.v.       225           Schmidt, 1985
                 female                 220

    Rat          male        p.o.       > 5000        Schmidt, 1985
                 female

    Rabbit       male        p.o.       500-800       Schmidt, 1985
                 female                               

                 male        topical    > 2000        Eigenberg,1987
                 female                               

    Dog          male        p.o.       n/a1          Schmidt, 1985
                 female

                                                                       

    1    Not determined due to vomiting of the drug.

         Animals were observed daily for 14 days post-exposure in these
    studies.  Clinical signs associated with enrofloxacin toxicosis
    included lethargy, trembling, tonic convulsions, dyspnea, prone and
    lateral decubitus, and ataxia.  Clinically affected animals that did
    not die recovered within 15 minutes to 7 days post-exposure.  Gross
    post-mortem lesions reported included pulmonary congestion and
    haemorrhage.

    2.2.2  Short-term toxicity studies

    2.2.2.1  Rats

         Groups of Charles River rats (15/sex/group) were administered
    diets containing 0, 500, 2000, or 7500 mg enrofloxacin/kg feed (equal
    to 36, 150, or 577 mg/kg bw/day for males and 45, 182, or 690 mg/kg
    bw/day for females, respectively) for 90 days.  No overt effects on
    appearance and behaviour were noted at any dose level.  Body-weight
    gain was reduced at the highest dose in both males (20%) and females
    (23%), while the actual diet consumption for males and females
    remained constant.

         Serum chemistry findings included a significant dose-related
    decrease in total plasma protein in the mid- and high-dose males and
    females at 6 and 13 weeks.  Total bilirubin and alanine aminotrans-
    ferase were decreased in the males at 6 weeks but were normal at 13
    weeks.  Aspartate aminotransferase was decreased in the high-dose
    males at 6 and 13 weeks.  Globulins were decreased in the high-dose
    males at 6 weeks and 13 weeks and high-dose females at 13 weeks.  A
    corresponding increase in the A/G ratio was seen in the high-dose
    males at 6 and 13 weeks.

         Haematology findings were unremarkable.

         Urinalyses showed a significant decrease in urine sodium output
    for males in the mid- and high-dose groups after 6 weeks and for
    females in the mid- and high-dose groups at 13 weeks.

         Treatment-related gross findings included swollen ears (2 males
    and 4 females in the mid-dose group, 4 males and 5 females in the
    high-dose group, and 1 female in the control group) and caecal
    distension (1 male in the mid-dose group and 3 males and 5 females in
    the high-dose group).

         Mean and relative prostate weights were statistically
    significantly reduced in the mid- and high-dose groups.  Mean heart
    weights were statistically significantly reduced in high-dose males
    and in mid- and high-dose females.  Mean liver weights were reduced in
    both male and female high-dose animals.  The reduction was
    statistically significant in females.

         Histological findings included auricular chondropathy which was
    present in all groups except low-dose males and appeared to be dose-
    related (1 control, 1 low dose, 6 mid dose, and 10 high dose).  In the
    testes of 12/15 rats from the high-dose group, dark, round or oval
    cells were distributed among the spermatozoa in the ducts of the
    epididymides.  These cells were occasionally observed in seminiferous
    tubules of 5/15 high-dose rats.  These findings were considered
    treatment-related.

         Based on decreased body-weight gain and microscopic changes
    observed in the ducts of the epididymides and testes in the high-dose
    group, and gross and microscopic changes indicating auricular
    chondropathy in the mid- and high-dose groups, the NOEL was 500 mg/kg
    feed, equal to 36 mg/kg bw/day (Kowalski  et al., 1985).

         A special study was performed in male rats to further assess the
    testicular toxicity seen in previous studies.  A 13-week recovery
    period was included in the study.  Thirty male Crl:CD Charles River
    rats per group were dosed with 0, 125, 500, or 7500 mg enrofloxacin/kg
    feed (equal to 10, 38, or 615 mg/kg bw/day) for 90 days.  Fifteen
    animals/group were killed on day 91 and the remaining 15 on day 181. 
    An apparent dose-related decrease in epididymal weights was observed
    in all dose groups at 91 and 181 days.  The difference achieved
    statistical significance (compared to controls) in the mid- and high-
    dose groups at both time points.   Relative mean testes weight was
    significantly decreased in the high-dose group after 91 days. 
    Bilateral testicular atrophy was seen in two high-dose rats at 181
    days.  Abnormal spermatozoa were seen at day 91 in the mid- and high-
    dose groups but not after the recovery period.  The NOEL for this
    parameter was 125 mg/kg feed, equal to 10 mg/kg bw/day (Bare  et al.,
    1988).

    2.2.2.2  Dogs

         Four groups (4/sex/group) of beagle dogs (3-4 months old, 2.6 to
    4.8 kg bw) were administered enrofloxacin in the diet at 0, 100, 320
    or 2500 mg/kg feed (equal to 3, 9.6, or 75 mg/kg bw/day, respectively)
    for 91 days.  

         No dogs died during the study.  Sporadic incidences of mild
    diarrhoea and vomiting were reported early in the study.  Vomiting
    occurred 5, 6, and nearly 24 hours after ingestion of the test
    article.  Severe hyperextension (upon manipulation) of carpal joints,
    hypoactivity, and abnormal gate or posture, were observed in all
    animals in the high-dose group during weeks 1 and 2.  Radiographic
    examination (8 dogs total) revealed several abnormalities including
    valgus deformity at the carpus, asymmetry of the distal ulnar physis,
    remodelling of the radial carpal bone, radius curvus, and increased
    width of the radial humeral joint.  The consulting radiologist
    concluded that only the radial carpal remodelling appeared to be dose-
    related, and neither bone growth nor density were significantly
    affected.

         Serum chemistry and haematologic findings were unremarkable. 
    However, two types of unidentified crystals in urine samples from dogs
    in the 2500 mg/kg feed group were considered treatment-related.

         Gross postmortem findings included an increase in mean absolute
    and relative testicular weights for treated animals when compared to

    control animals.  However, a clear dose-response relationship was not
    established and none of the differences were statistically significant
    when compared to controls. In 8/8 high-dose animals and 2/8 mid-dose
    animals joint lesions were observed grossly as superficial (0.2 to 0.4
    cm in diameter) erosions with dulling of the surfaces on the femoral
    head of the hip joint and/or the femoral condyles of the knee joint. 
    Histologically, joint lesions were characterized by splitting of the
    articular cartilage with disorganization of chondrocytes and formation
    of "brood capsules"  of cartilage cells.  Necrosis and disintegration
    of hyaline cartilage at the area of splitting was also noted.

         There was marked variation in the microscopic appearance of
    testes from animal to animal with respect to the stage of maturity,
    diameter of the lumen of seminiferous tubules, and vacuolar change in
    cells lining the tubules.  However, it was not clear whether these
    testicular changes were treatment-related because there was no dose-
    response relationship in incidence or severity.  These variations in
    testicular morphology could represent normal variation in the maturing
    process of this organ in this species.  Due to the uncertainty of the
    significance of the testicular findings in the low-dose males in this
    study, the Committee concluded that a no-effect level was not observed
    (Porter  et al., 1987).

         In another 90-day dietary study in beagle dogs, 4 groups
    (4/sex/group) of adult dogs (12-13 months old weighing 6.4 to 12.5 kg)
    received enrofloxacin at 0, 320, 800 or 2000 mg/kg diet (equal to 9.3,
    22, or 53 mg/kg bw/day for males, and 8.9, 23, or 51 mg/kg bw/day for
    females, respectively).  No joint or testicular lesions were reported
    in this study (Porter  et al., 1985).

         A special limited 90-day dietary study in males was performed.
    Five groups (4 dogs/group) of 3-month old beagle dogs (weighing 4.1 to
    5.7 kg) received enrofloxacin at 0, 10, 20, 40, or 3200 mg/kg diet
    (equal to 0, 0.3, 0.6, 1.2, or 92 mg/kg bw/day, respectively).  At
    termination of the study (day 92) testicular weights were determined
    and testes and epididymides collected for histopathological
    assessment.  No other tissues were collected.

         Histologically, the tissues examined contained wide variations in
    morphology attributable to differences in sexual maturation.  Sections
    of epididymides examined were considered normal.  Bilateral testicular
    degeneration characterized by multinucleated giant cells and cells
    with large cytoplasmic and nuclear volumes, sometimes in mitosis, were
    reported in the seminiferous tubules of one dog at the high dose. 
    Seminiferous tubules lined with single layers of spermatogonial cells
    and forming open lumens were present in 2/4 dogs in the 10 mg/kg feed
    group and 3/4 dogs in each of the 20, 40, and 3200 mg/kg feed groups. 
    This change was also reported in one control animal. Spermatocytic
    giant cells were reported in 0, 1, 2, 2 and 3 dogs from the 0, 10, 20,
    40 and 3,200 mg/kg feed groups, respectively.

         The author attributed the seminiferous tubule changes to normal
    variation in sexual maturity because similar morphology was reported
    in the testes of one control dog.  The author used this finding to
    support a NOEL of 100 mg/kg feed in the 90-day study reported above
    (Porter  et al., 1987).  The Committee concluded that a NOEL for
    testicular effects in this special, limited 90-day study could not be
    determined due to the inability to determine whether variations in
    testicular morphology were normal or due to treatment with the test
    article (Porter  et al., 1988a). 

         Three-month old male beagle dogs (4/group) were administered
    enrofloxacin at 0, 10, or 40 mg/kg diet (equal to 0.3 or 1.2 mg/kg
    bw/day) for 90 days, then maintained on control diets for an
    additional 91 days before being killed. The protocol was intended to
    evaluate the potential for enrofloxacin testicular toxicity to appear
    after animals reach sexual maturity, following exposure at an immature
    age (delayed testicular toxicity).

         No signs of clinical toxicity were observed nor was body-weight
    gain or food consumption affected.  Gross and microscopic examination
    of testes and epididymides showed no changes indicative of toxicity. 
    Testes and epididymides appeared mature in all treated animals and
    contained normal, mature spermatozoa.  The NOEL for delayed testicular
    toxicity was 40 mg/kg diet, equal to 1.2 mg/kg bw/day, the highest
    dose tested (Porter  et al., 1988b).

    2.2.3  Long-term toxicity/carcinogenicity studies

    2.2.3.1  Mice

         B6C3F1 mice (60/sex/group) received diets containing 0, 1000,
    3300, or 10 000 mg enrofloxacin/kg feed (equal to 323, 1100, or 3520
    mg/kg bw/day for males and 373, 1210, or 3700 mg/kg bw/day for
    females, respectively) for 24 months.  An interim sacrifice
    (10/sex/group) was performed after one year.  An additional dose group
    (10 mice/sex) was administered 20 000 mg enrofloxacin/kg feed (equal
    to 8030 mg/kg bw/day for males and 8010 mg/kg bw/day for females,
    respectively) and scheduled for interim sacrifice after one year.

         During the treatment phase of the study, general appearance and
    physical examination findings were within normal limits in all treated
    groups.  Treatment-related ophthalmological findings included a marked
    increase (relative to control animals) in the incidence of focal
    lenticular opacity in males and females at 10 000 mg/kg feed. 
    Histopathological examination of eyes revealed no treatment-related
    effects.  However, it was noted that focal lenticular changes are only
    verifiable to a limited extent with usual histolopathological methods.

         Clinical chemical and haematological evaluations were performed
    on 10 animals/sex/dose after 12 and 24 months on test.  Alkaline

    phosphatase levels were significantly lower in females at 3300 mg/kg
    feed at 12 months, and at 10 000 mg/kg feed at study termination. 
    Concurrent with these findings, alanine aminotransferase and aspartate
    transaminase values were within normal limits.  Total protein was
    decreased in males and females at all treatment levels as a result of
    decreased globulin fractions.

         Haematological analyses revealed a significant decrease in white
    blood cell counts in males at 10 000 mg/kg feed at 12 months and at
    3300 mg/kg feed at study termination.  In females, a significant
    decrease in white blood cell counts was noted at 10 000 mg/kg feed at
    study termination.  At 10 000 mg/kg feed, decreases were seen in
    haematocrit, MCV, and MCH values in both sexes, and in the haemoglobin
    value in males, at study termination.

         Gross necropsy findings included a dose-related incidence of
    caecal dilation in males at 1000, 3300, and 10 000 mg/kg feed and in
    females at 3300 and 10 000 mg/kg feed.  Histopathological examinations
    showed neither an increase in the incidence of, nor a decrease in the
    time of appearance to tumours in the dosed groups compared to the
    controls.  Bile duct hyperplasia was seen at 3300 mg/kg feed in males
    and 10 000 mg/kg feed in both sexes.  Focal papillary mucosal
    hyperplasia of the gall bladder was also present in males and females
    in these same dose groups.  There was no evidence of carcinogenicity
    in this study.  The NOEL was 1000 mg/kg feed, equal to 323 mg/kg
    bw/day (Bomhard  et al., 1991a).

    2.2.3.2  Rats

         A combined long-term toxicity (52 weeks) and carcinogenicity (104
    weeks) study of enrofloxacin was conducted in Wistar rats (BOR:WISW). 
    In the chronic study, 10 rats/sex/group received diets containing 0,
    770, 2000, 6000, or 10 000 mg enrofloxacin/kg feed (equal to 0, 41,
    103, 338, or 856 mg/kg bw/day for males and 0, 58, 146, 466, or 1000
    mg/kg bw/day for females, respectively).  In the carcinogenicity
    study, 50 rats/sex/group received diets containing 0, 770, 2000, or
    6000 mg enrofloxacin/kg feed (equal to 0, 41, 103, or 338 mg/kg bw/day
    for males and 0, 58, 146, or 466 mg/kg bw/day for females).

         Mortality rates, daily observations, and ophthalmologic findings
    in treated animals were comparable to controls.  Body-weight gain was
    decreased in males in the 6000 mg/kg feed group and in males and
    females at 10 000 mg/kg feed.  Feed and water intakes were increased
    in males and females at 10 000 mg/kg feed.  Water intake was also
    elevated at 6000 mg/kg feed.

         Serum chemistry evaluations were performed after 6, 12, 18, and
    24 months.  Notable findings included a significant decrease in total
    protein in males in all dose groups at all sampling periods.  Total
    protein was also significantly decreased in females in the high-dose

    group both at 6 months and at the end of 2 years, and at 2000 and 10
    000 mg/kg feed after 1 year.  The  albumin value was increased in
    males at 10 000 mg/kg feed after 1 year, at 6000 mg/kg feed after 18
    months, and in the two highest-dose groups (2000 and 6000 mg/kg feed)
    at the end of 2 years.  Bilirubin was significantly decreased in
    females in all dose groups at the 6-month sampling time only.

         Protein electrophoresis performed after 12, 18, and 24 months
    showed a decrease in gamma-globulin in males and females in all dose
    groups.  The author noted that this finding is not unexpected in
    animals receiving antimicrobials, as they lower the background
    incidence of common pathogens, resulting in a decrease in antigenic
    stimulation.

         Haematology evaluations were performed after 6, 12, 18, and 24
    months.  At doses of 2000 mg/kg feed and above, there were
    statistically significant and sometimes dose-related decreases in RBC
    counts in males and haemoglobin and haematocrit values in both sexes
    at various sampling times.  However, the values for these parameters
    in both sexes in all dose groups were comparable to controls at the
    terminal sampling period.  After 6 months leucocyte counts in both
    sexes were decreased compared to controls at all dose levels. In most
    instances, these differences were statistically significant.  A trend
    toward decreased leucocyte counts in the treatment groups was also
    discernible in the subsequent investigations. The author noted that
    due to the pharmaco-logical action of antimicrobial compounds,
    decreased leucocyte counts are a common finding.

         On gross postmortem examination, a decrease in testicular size
    (small with altered texture) was noted at 2000 mg/kg feed and above. 
    Histologically, marked testicular atrophy, decreased spermatogenesis,
    and a significant increase in the amount of mineralized concretion in
    the testes were noted in these same dose groups.  Normal age-related
    degenerative changes occurred with greater frequency in treated
    animals than in controls.  Caecal dilation was reported in both sexes
    of rats in the high-dose group and in the males at 2000 mg/kg feed.

         Organ weights recorded at both the interim and terminal kill
    revealed a decrease in absolute and relative liver weights in males at
    2000 mg/kg feed and above.  The same changes were seen in females in
    these groups at the interim necropsy but not at study termination.  At
    the interim and terminal kills, absolute weights of the brain, testes
    and adrenals were significantly decreased in the 6000 mg/kg feed
    males.  However, the relative weights of these organs were comparable
    to controls.

         Histopathological evaluation revealed a dose-related increase in
    incidence of hepatic cysts at 24 months, bile duct hyperplasia with
    sclerosis at 12 and 24 months, and cystic bile duct hyperplasia at 24
    months in both sexes and in all treatment groups.  Spinal cord

    demyelination/degeneration was reported in all treatment groups. 
    Because of the high incidence of this finding in controls and without
    further definition of lesions into degeneration versus demyelination,
    the biological significance of this finding is uncertain.  There was
    also a marked increase in degenerative changes in the sciatic nerve.

         A marked increase in the number of sarcolemmal nuclei in skeletal
    muscle cells of animals in the 6000 mg/kg feed group was noted.  This
    finding is generally associated with degenerative changes in muscle
    fibres.

         A marked increase in the incidence of cardiomyopathy  was
    observed  in males at 6000 mg/kg feed and in females in all dose
    groups.  Incidences at 0, 770, 2000, and 6000 mg/kg feed were 10/48,
    8/50, 13/50, and 24/50 in males and 8/50, 16/50, 17/50, and 25/50 in
    females, respectively.  Endocardial neoplasms and Schwann cell-like
    hyperplasia were seen in the hearts of some of the animals.  These
    findings were evaluated by a Pathology Working Group which concluded
    that these lesions were not related to treatment with the test
    article. Under the conditions of this study there was no evidence of
    a carcinogenic effect of the test substance.  A NOEL could not be
    determined because of the occurrence of bile duct changes and
    cardiomyopathy in the low-dose group (Bomhard  et al., 1991b; Hall,
    1992).

         A limited long-term study was performed with Wistar (Bor:WISW)
    rats (60/sex/group).  Diets containing 0, 100, or 500 mg
    enrofloxacin/kg feed (equal to 0, 5.3, or 26 mg/kg bw/day for males
    and 0, 7.2, or 36 mg/kg bw/day for females, respectively) were
    administered for 24 months.  An interim kill of 10 rats/sex/group was
    performed at 12 months.

         Morbidity, moribundity, and mortality in treated groups were
    comparable to controls.  General appearance, clinical observations,
    and the results of physical and ophthalmoscopic examinations were all
    comparable with normal animals of this species and age.  Exposure to
    enrofloxacin produced no biologically significant alterations in food
    or water intake, body weight, clinical chemical parameters or
    haematological parameters.

         At interim sacrifice, no abnormalities were noted in males or
    females on postmortem examination.  At terminal sacrifice, an
    increased number of males had swollen livers (3/50 [controls], 10/50,
    [100 mg/kg feed], and 8/50 [500 mg/kg feed]).  However, liver weights
    and histopathological findings were within normal limits.

         No treatment-related abnormalities were noted in the clinical
    chemistry parameters that were evaluated.  However, as in the long-
    term study summarized above at higher dose levels, the gamma globulin
    value in treated animals was consistently lower than in controls.

         On histological evaluation, sclerotic bile duct hyperplasia was
    more common in both males and females treated with enrofloxacin than
    in control animals.  The incidence was statistically significantly
    increased in the 100 and 500 mg/kg feed groups after 52 weeks of
    treatment, and in males and females at 500 mg/kg feed after 104 weeks
    of treatment. The total number of females affected was markedly less
    than the number of males. Although the incidence of bile duct
    hyperplasia at 104 weeks at 100 mg/kg feed was not statistically
    significantly different from the control values, the significant
    findings in males in both dose groups at 52 weeks suggests that
    administration of enrofloxacin accelerates the development of bile
    duct sclerosis in male rats.

         No evidence of carcinogenicity was reported in this study.
    However, the heart and liver were the only two tissues examined
    histologically.  A NOEL could not be determined in this study (Leser,
    1992).

         A consulting pathologist conducted a second histopathologic
    evaluation of liver slides of male rats from both the interim and
    terminal kills in the above study.  The consultant's conclusions were
    as follows:  "There was an increase over controls in the incidence of
    bile duct hyperplasia in both dose groups at the interim kill,
    although this was probably a spurious finding.  At the terminal kill,
    an increased incidence occurred only at the 500 ppm level.  No clear
    effect on lesion severity was noted in any group.  The 100 ppm dose
    (5.3 mg/kg bw/day) was a no-effect level in this study." (Squire,
    1992).

         A second limited long-term study was performed on Wistar
    (Bor:WISW) rats (60/sex/group), administered enrofloxacin in the diet
    at 0, 10, or 50 mg/kg feed (equal to 0, 0.6, or 2.9 mg/kg bw/day for
    males and 0, 0.7, or 3.5 mg/kg bw/day for females, respectively) for
    24 months.  An interim kill of 10 animals/sex/group was performed at
    12 months.  The purpose of this study was to establish a NOEL for the
    treatment-related bile duct hyperplasia observed in previous chronic
    studies.

         No treatment-related alterations were seen in physical
    examinations, ophthalmologic evaluations, feed or water consumption,
    body-weight gain, clinical chemistries, urinanalysis, or haematology
    at the termination of the study.  Postmortem examinations, including
    gross observations, organ weights and histopathological examinations
    were conducted at 12 and 24 months.  Portions of the right and left
    anterior liver lobes were collected and prepared for histological
    evaluation  Only one section per lobe was examined from these hepatic
    samples.  No treatment-related effects were reported in any of the
    parameters monitored during the study.  The incidence and severity of
    bile duct hyperplasia in the exposed female and male rats were
    comparable with the controls.  The NOEL was 50 ppm (equal to 2.9 mg/kg
    bw/day) (Leser, 1993).

    2.2.4  Reproductive toxicity studies

    2.2.4.1  Rats

         A two-generation reproductive toxicity study in rats was
    performed with enrofloxacin administered in the feed to groups of 30
    Crl: CD(SD)Br rats at doses of 0, 500, 2000, or 7500 mg/kg feed.  F0
    males received the diet for approximately 70 days and the F0 females
    for approximately 2 weeks prior to mating.  Reproductive performance
    of F0 and F1 generations was evaluated, as well as pup parameters. 
    A gross necropsy was performed on every animal and histopathologic
    evaluation was conducted on reproductive organs.

         Administration of the test article caused decreased body weights
    at 7500 mg/kg feed (equal to 630 mg/kg bw/day) in the F0 and F1
    generations.  This effect was not accompanied by a reduction in food
    consumption.  Reproductive performance of the same animals was
    significantly affected by the treatment at the high dose, which
    included increased gestation length, reductions in the number of
    litters, total pups, litter size and number of implants in the F0 and
    F1 generations.  Survival and growth rates were significantly
    decreased in the progeny of these animals.  Spermatic morphologic
    alterations were noted in the high-dose males in both generations,
    which were considered the primary cause for the adverse effects on
    fertility.  The NOEL was 2000 mg/kg feed, equal to 165 mg/kg bw/day
    (Clemens  et al., 1986).

         A two-generation reproductive toxicity study in rats was
    performed with enrofloxacin administered in the feed to groups of 30
    Crl:CD (SD)Br rats at doses of 0, 125, 300, or 2000 mg/kg feed
    (equivalent to 0, 6.2, 15, or 100 mg/kg bw/day).  This study was
    intended to evaluate the effect(s) of enrofloxacin on gonadal function
    and mating behaviour in treated males, reproductive parameters in
    females, and growth and development in the F1 and F2 offspring.  F0
    males and females received the test compound for 70 and 14 days,
    respectively, before mating.  A gross necropsy was performed on every
    animal and histopathologic evaluation was conducted on testes and
    epididymides from each F0 and F1 male.

         Administration of the test article caused a reduction in mean
    epididymal weights at the highest dose, and alterations in sperm
    morphology at 300 and 2000 mg/kg feed.  No effects on fertility or
    reproductive performance were noted.  The NOEL was 125 mg/kg feed,
    equivalent to 6.2 mg/kg bw/day (Kowalski  et al., 1989).

         A specialized male fertility study was performed with
    enrofloxacin to determine the timing of the onset of spermatic
    dysmorphogenesis and to ascertain whether functional fertility was
    restored during a 90-day recovery phase.  Diets containing 0 or 7500
    mg/kg feed (equivalent to 375 mg/kg bw/day) were administered to

    sexually mature Crl:CD BR male rats (60/group) for 90 days.  Interim
    kills were performed at 3, 6, 9 and 13 weeks, with 15 males from each
    group retained to mate with untreated females to assess male
    fertility.  The first mating was performed after 11 weeks on trial. 
    From day 91, all males were fed control diet and matings were again
    performed on weeks 3, 7, and 11 of recovery.  Females were killed on
    day 20 of gestation.

         Enrofloxacin administered at this dose caused significant
    decreases in male fertility, food consumption and body-weight gains.
    Testes weights were increased at all interim  kills, but were less
    than control values at the end of the study.  Treatment-related
    spermatic dysmorphogenic changes were seen by week 3 on trial.  These
    changes were partially reversible as functional fertility returned to
    13 of 15 previously treated males.  Varying grades of seminiferous
    tubular atrophy and other degenerative alterations were observed in
    40% of these animals.  Complete infertility was diagnosed in the
    remaining males (Clemens  et al., 1987).

    2.2.5  Special studies on teratogenicity/embryotoxicity

    2.2.5.1  Rats

         A teratogenicity (Segment II) study in the rat was performed in
    which enrofloxacin as a 5% suspension with carboxymethylcellulose and
    polysorbate 80 was administered by gavage to groups of 28 inseminated
    COBS CD female rats at 0, 50, 210, or 875 mg/kg bw/day.  Dosing was
    performed on days 6-15 of gestation.  On day 20, all dams were killed
    and maternal and fetal parameters were evaluated.

         Administration of the test article was maternally toxic at 210
    and 875 mg/kg bw/day.  Food consumption was higher in high-dose
    animals, but there was a significant reduction in mean maternal weight
    gain in these animals.  In the high-dose litters, fetal weights and
    litter size were significantly decreased and fetal resorption and
    post-implantation losses were increased.  Fetal weights were
    significantly decreased in the mid-dose group.  Skeletal examination
    of the mid- and high-dose groups showed delayed skeletal ossification. 
    Neither embryotoxicity nor fetotoxicity was seen.  No teratogenic
    effects were observed.  The NOEL was 50 mg/kg bw/day (Clemens &
    Hartnagel, 1985).

    2.2.5.2  Rabbits

         An embryotoxicity (including teratogenicity) study was performed
    with enrofloxacin administered by gavage to groups of 16 mated female
    chinchilla rabbits at doses of 0, 1, 5, or 25 mg/kg bw/day admixed in
    distilled water with 0.5% Tylose.  Dosing was performed on days 6-18
    of gestation.  On day 28, all dams were killed.  Because no maternal

    effects were seen at doses up to 25 mg/kg bw/day, a supplementary
    group of 16 females (with corresponding control group) was added and
    administered enrofloxacin at 75 mg/kg bw/day.

         Administration of the test article caused decreased food
    consumption and lower body weights at 75 mg/kg bw/day.  Increased
    post-implantation losses were also noted in this group.  All other
    dose groups showed only incidental findings.  The NOEL was 25 mg/kg
    bw/day (Becker  et al., 1987).

    2.2.6  Special studies on genotoxicity

         The results of genotoxicity studies with enrofloxacin are
    summarized in Table 2.

    2.2.7  Special studies on the human gastrointestinal flora

         No  in vivo studies were available.   In vitro studies of
     Escherichia coli (24 strains),  Staphylococcus aureus (24
    strains) and  Enterococcus spp. (24 strains) of human origin showed
    the following MIC values for enrofloxacin (E) and ciprofloxacin (C).
    Only summary tables were given.

         The results of these studies are summarized in Table 3 (Scheer,
    1993).

         Data on  in vitro susceptibility to ciprofloxacin for several
    strains of bacteria obtained from "clinical isolates" or "bite wounds"
    from humans were also available (Goldstein & Citron, 1988; Wise
     et al., 1988).

         The results of these studies are summarized in Table 4.

    2.3  Observations in humans

         Enrofloxacin has been developed specifically for use in
    veterinary medicine; therefore, no human data were available. 
    Ciprofloxacin, the major metabolite of enrofloxacin, is a human drug
    and has been used extensively.  Clinical data in humans has produced
    no evidence of nephrotoxicity or significant drug-related ocular
    changes.  Since the drug is not recommended for children or pregnant
    women, little evidence has been collected to assess the occurrence of
    articular or developmental changes in young patients (Schluter, 1987).


        Table 2.  Genotoxicity assays with enrofloxacin
                                                                                                 
    Test system         Test object         Concentration  Results          Reference
                                                                                                 
     In vitro

    Unscheduled         Rat primary         1-200 mg/ml    Negative         Cifone & Myhr, 1985
    DNA synthesis       hepatocytes

    Bacterial reverse    S. typhimurium     0.004 & 40     Inappropriate    Herbold, 1985a
    mutation1           TA98, TA100,        ng/plate2      & deficient3
                        TA1535,TA15                        
                        TA1537                             

    Mammalian cell      CHO/HGPRT           0.25-1.25      Equivocal        Den Boer & Hoorn,
    forward                                 mg/ml (-S9)4                    1987
    mutation1                               0.375 - 1.25
                                            mg/ml (+S9)5

    Mammalian cell      CHO/WBI             25-250 mg/ml   Positive         Taalman & Hoom,
    chromosomal                             (-S9)6                          1988
    aberration1                             0.1-1 mg/ml
                                            (+S9)7       

     In vivo

    Bone marrow         Bor:NMRI mice       1-2 g/kg bw    Negative         Herbold, 1985b  
    micronucleus

    Bone marrow         CD rat              0.04-1 g/kg    Negative         Bootman  et al. ,
    chromosomal                             bw8                             1987
    aberration

    Sister chromatid    Chinese             2-8 g/kg bw    Negative         Herbold, 1988
    exchange            hamster bone
                        marrow
                                                                                                 

    Table 2 (continued)

    1    Both with and without rat liver S9 fraction
    2    Positive controls:  2-Aminoanthracene, endoxan (TA100, TA1535), 
         and trypaflavine (TA98, TA1537).
    3    Inappropriate due to substantial bacteriotoxicity; deficient due
         to failed positive controls.
    4    5-Bromodeoxyuridine as positive control.
    5    3-Methylcholanthrene as positive control.
    6    Mitomycin C as positive control.
    7    Cyclophosphamide as positive control.
    8    Low dose previous LD50 studies showed an oral dose tolerance of
         >5 g/kg bw but in the present study, 6/30 animals administered 1 g/kg bw 
         had to be killed in extremis shortly after being dosed.

    Table 3. Summary of MIC-values for bacterial species of human origin 
                                                                                       
    Bacteria                   MIC range                MIC50              MIC90
                                 g/ml                   g/ml               g/ml
                                                                                       
                            E              C          E         C         E         C
                                                                                       
     E. coli             0.015-0.03     0.015-0.03    0.015     0.015     0.03      0.015

     Staphylococcus      0.06-128       0.125-64      0.125     0.25      4.0      32.0
     aureus

     Enterococcus        0.25-1.0       0.25-2.0      0.5       1.0       1.0       2.0
    spp.
                                                                                       
    

    Table 4.  In vitro susceptibility of bacteria to ciprofloxacin 

                                                                       

    Bacteria                       Number of strains       MIC range
                                                           g/ml
                                                                       

     Bacteroides fragilis 1                 15               4-16

     Bacteroides spp. 2                     17               0.06-32

     Clostridium spp. 1                     17               0.012-8

     E. coli 1                              66               0.015-1

     Enterobacter spp. 1                    51               0.015-2

     Enterococci 1                          10               1-2

     Flavobacterium 2                       18               0.5-1

     Fusobacterium spp. 2                   18               0.25-32

     Peptostreptococcus spp. 1              10               0.25-2

     Peptostreptococcus spp. 2              16               0.03-8
                                                                       

    1    Clinical isolate.
    2    Isolated from bite wounds.

    3.  COMMENTS

         The toxicological data available to the Committee were derived
    from acute, short-term, long-term, and carcinogenicity studies;
    reproductive and developmental studies; mutagenicity studies;
    metabolism and residue studies; antimicrobial activity and
    observations in humans following treatment with ciprofloxacin, the
    major metabolite of enrofloxacin.

         In rats orally dosed with 5 mg/kg bw of radiolabelled
    enrofloxacin, the bioavailability of the dose was 75%.  Enrofloxacin
    was rapidly absorbed and distributed to all tissues, with the highest
    concentration in the liver and kidney.  Enrofloxacin was rapidly
    excreted via urine and bile.  Radioactivity in the urine was mainly
    unchanged parent drug and the de-ethylated compound, ciprofloxacin. 
    Bile contained primarily unchanged enrofloxacin.  Similar results were
    obtained with all species of animals tested.

         Enrofloxacin is a relatively stable molecule.  Metabolism takes
    place mainly in the liver, with the main metabolite in all species
    being ciprofloxacin, probably formed by an oxidative dealkylation.  In
    rats four other components were identified, each comprising less than
    2% of the total residue.

         Single oral or topical doses of enrofloxacin were slightly toxic
    to experimental animals (LD50 = 500-5000 mg/kg bw).  In mice, single
    intravenous doses were moderately toxic (LD50 = approximately 220
    mg/kg bw).

         Following 90-day oral administration of enrofloxacin to rats,
    chronic degenerative changes in the auricular cartilage were seen at
    doses equal to 150 and 577 mg/kg bw/day.  Treatment-related
    morphological changes in the spermatozoa and testicular tubular
    atrophy were seen at 577 mg/kg bw/day.  These effects were not seen at
    a dose equal to 36 mg/kg bw/day.

         A special study was performed to further assess the morphological
    changes in the male reproductive tract seen in rats in previous
    studies.  Male rats were administered enrofloxacin in the feed at
    doses equal to 10, 38 or 615 mg/kg bw/day followed by a 90-day
    recovery period.  Statistically significant decreases in epididymal
    weights were seen at 91 days in the 38 and 615 mg/kg bw/day groups. 
    At 615 mg/kg bw/day, the testis/body-weight ratio was significantly
    increased, while the epididymides/body-weight ratio was significantly
    decreased.  Bilateral testicular atrophy was seen in two rats at 615
    mg/kg bw/day after the 90-day recovery period.  Abnormal spermatozoa
    were seen at 615 mg/kg bw/day at days 14 and 91, but not at the end of
    the 90-day recovery period.  The NOEL for testicular toxicity in this
    study was 10 mg/kg bw/day.

         To assess effects on testicular toxicity and articular cartilage
    in young dogs, a 90-day oral study in three- and four-month old dogs
    was performed.  Enrofloxacin was administered at dose levels
    equivalent to 0, 3, 9.6 or 75 mg/kg bw/day.  All treated animals
    except those dosed at 3 mg/kg bw/day showed degeneration of the
    articular cartilage.  The testes/body-weight ratio for all treated
    animals was consistently higher than for control animals, but the
    difference was not statistically significant.  In 4 high-dose and 1
    low-dose animals, marked dilatation of the seminiferous tubules, and
    focal areas of single layer spermatogonial cells or vacuolated
    epithelium in the tubules were considered beyond normal limits.  It
    could not be determined whether testicular changes observed in the
    low-dose group were treatment-related or due to the fact that the
    animals were not fully mature.  Therefore, a NOEL could not be
    determined.  The testicular effects seen in this study were not seen
    in 12-13-month old dogs treated orally with enrofloxacin up to 52
    mg/kg bw/day for 90 days.

         A 90-day study was performed in male dogs dosed with enrofloxacin
    at dose levels equal to 0.3, 0.6, 1.2, or 92 mg/kg bw/day to determine
    a NOEL for the testicular effects of enrofloxacin observed in the
    earlier study with 3- to 4-month old dogs.  At termination of the
    study, testicular weights were determined and testes and epididymides
    collected for histopathological assessment.  No other tissues were
    collected.  Testicular weights and testes/body-weight ratios were
    elevated over controls at 0.3, 0.6, and 1.2 mg/kg bw/day.  In
    addition, lameness was seen at 92 mg/kg bw/day following 2-3 days of
    enrofloxacin administ-ration.  This effect was not seen at 1.2 mg/kg
    bw/day.  One dog in the 92 mg/kg bw/day group also had bilateral
    testicular degenerative changes.  The NOEL was 1.2 mg/kg bw/day in
    this study.

         A 90-day oral study in 3-month old dogs with a 90-day recovery
    period was conducted with 0, 0.3, or 1.2 mg/kg bw/day of enrofloxacin
    to assure the continued absence of testicular effects after the
    animals reached sexual maturity.  After the recovery period, gross and
    microscopic examination of testes and epididymides showed no changes
    indicative of toxicity.  Testes and epididymides appeared mature and
    contained normal mature spermatozoa.  There was no evidence of delayed
    testicular toxicity in this study at levels up to and including 1.2
    mg/kg bw/day.

         Enrofloxacin was not carcinogenic in mice orally dosed at levels
    equal to 323, 1100, or 3520 mg/kg bw/day in a 2-year long-term
    toxicity/carcinogenicity study.  Bile duct hyperplasia was seen in
    males in the mid-dose group and at the high dose in both sexes.  The
    NOEL was 323 mg/kg bw/day.

         In a long-term toxicity/carcinogenicity oral study in rats at
    doses equal to 41, 103, 338 or 856 mg/kg bw/day, the Committee
    concluded that enrofloxacin was not carcinogenic in this species. 

    However, a NOEL could not be determined for the bile duct hyperplasia
    seen in this study.  The NOEL for bile duct hyperplasia in further
    limited chronic studies with enrofloxacin in rats was 2.9 mg/kg
    bw/day.

         A two-generation reproductive toxicity study in rats was
    performed with enrofloxacin administered in the feed to groups of rats
    up to a dose equivalent to 630 mg/kg bw/day.  Increased gestation
    length, reductions in the number of litters, total pups, litter size
    and number of implants for the F0 and F1 generations were seen at
    630 mg/kg bw/day.  Survival and growth rates were significantly
    decreased in the progeny of these animals.  Spermatic morphologic
    alterations were noted in the high-dose males in both generations and
    were considered the primary cause for the adverse effects on
    fertility.  The NOEL for reproductive performance was 165 mg/kg
    bw/day.

         An additional two-generation reproduction study in rats was
    performed with enrofloxacin administered in the feed to groups of rats
    at 0, 125, 300, or 2000 mg/kg feed to determine whether the test
    compound affected gonadal function and mating behaviour in treated
    males or reproductive parameters in females, as well as, to monitor
    growth and development in the F1 and F2 offspring.  Administration
    of the test article caused a reduction in mean epididymal weights at
    the highest dose and alterations in sperm morphology at 15 and 100 mg/kg
    bw/day.  No effects on fertility or reproductive performance were
    noted.  The NOEL was 125 mg/kg feed, equal to 10 mg/kg bw/day.

         A special fertility study was performed in sexually mature male
    rats fed enrofloxacin in the diet at doses equivalent to 0 or 375
    mg/kg bw/day for 90 days.  The purpose of the study was to determine
    the timing of the onset of spermatic dysmorphogenesis and to ascertain
    whether functional fertility was restored during a 90-day recovery
    phase.  Administration of the test article caused a significant
    decrease in male fertility, food consumption and body-weight gain. 
    Testes weights were increased at all interim kills, but were lower
    than in the control animals at the end of the study.  Treatment-
    related spermatic dysmorphogenic changes were seen by week 3 and these
    changes were partially reversible as functional fertility returned to
    13 of 15 previously treated males.  Forty percent of these animals
    demonstrated varying grades of seminiferous tubular atrophy and other
    degenerative alterations.  The remaining males were infertile.

         A teratogenicity study was performed in which enrofloxacin was
    administered to rats by gavage at 0, 50, 210, or 875 mg/kg bw/day. 
    Dosing was performed between days 6-15 of gestation.  Maternal
    toxicity was observed at 210 and 875 mg/kg bw/day.  Food consumption
    was higher in high-dose animals, but there was a significant reduction
    in mean maternal weight gain in these animals.  Fetal weights and
    litter sizes were significantly decreased and fetal resorption and

    post-implantation losses were increased in high-dose litters.  Fetal
    weights were significantly decreased in the mid-dose group.  Skeletal
    examination of the mid- and high-dose fetuses revealed delayed
    skeletal ossification, which correlated with the decreased fetal
    weights.  No teratogenic effects were observed in this study.  The
    NOEL was 50 mg/kg bw/day.

         In  in vitro mutagenicity testing, enrofloxacin gave equivocal
    results in a test for forward mutations in mammalian cells and
    positive results in chromosomal aberration tests.  Negative results
    were obtained in  in vivo bone marrow micronucleus, sister chromatid
    exchange and bone marrow chromosomal aberration tests.  The Committee
    concluded that enrofloxacin is not genotoxic.

         The potential for adverse effects on the human gastrointestinal
    flora was considered from summary data.   In vitro MIC data for
    ciprofloxacin covering representatives of the human gut flora were
    submitted for assessment.   Escherichia coli was found to be the
    most sensitive bacterium having an MIC50 value of 0.015 g/ml.

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

    
                         Concentration without 
                         effect on human gut                 x  Daily faecal bolus (g)
    Upper limit of       flora (g/ml)a
    temporary ADI  =                                                                   
    (g/kg bw)           Fraction of 
                         oral dose     x  Safety factorc   x  Weight of human (60 kg)
                         bioavailableb

                         (0.015 x 20) x 150
                    =                     
                         0.12 x 10 x 60

                    =    0.6 g/kg bw


    a    Since the MIC value was determined using only 105 bacteria/ml a 
         factor of 20 was used to account for the higher inoculum density 
         representative of the human intestine.  For example, 
          Enterobacteriaceae and  Pseudomonas aeruginosa MIC values 
         increased 8 to 32-fold when the inoculum size was increased to 
         107 bacteria/ml.

    b    The fraction of the dose available to the intestinal microflora 
         was derived from studies of ciprofloxacin in humans.  In human 
         volunteers given 2 x 50 mg ciprofloxacin the faecal concentration 
         was found to be 80 mg/kg.  In 150 g faeces, this corresponds to 
         12% of the administered

    c    A safety factor of 10 was used to account for the possible 
         variation in absorption between ciprofloxacin and enrofloxacin, an 
         uncertainty in the biliary excretion of enrofloxacin, and the 
         variability between individuals.
    
    4.  EVALUATION

         In view of the absence of information on the effects of
    enrofloxacin on microorganisms obtained from the human intestine, the
    Committee established a temporary ADI of 0-0.6 g/kg bw based on the
    results of the limited summary data of microbiology testing of
    enrofloxacin/ciprofloxacin.

         The temporary ADI of 0.6 g/kg bw calculated from the  in vitro 
    antimicrobial activity data represents an adequate margin of safety
    when compared to the NOEL derived from the toxicology endpoint of 1.2
    mg/kg bw/day for testicular toxicity.

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    See Also:
       Toxicological Abbreviations
       Enrofloxacin (WHO Food Additives Series 39)
       ENROFLOXACIN (JECFA Evaluation)