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    THIAMPHENICOL

    First draft prepared by
    Dr R. Fuchs,
    Department of Experimental Toxicology and Ecotoxicology,
    Institute for Medical Research and Occupational Health,
    Zagreb, Croatia

    1.   Explanation

    2.   Biological data
         2.1   Biochemical aspects
               2.1.1   Absorption, distribution and excretion
         2.2   Toxicological studies
               2.2.1   Acute toxicity studies
               2.2.2   Short-term toxicity studies
               2.2.3   Long-term toxicity/carcinogenicity study
               2.2.4   Reproductive toxicity studies
               2.2.5   Special studies on embryotoxicity and
                       teratogenicity
               2.2.6   Special studies on genotoxicity
               2.2.7   Special studies on immune responses
               2.2.8   Special studies on microbiological effects
         2.3   Observations in humans

    3.   Comments

    4.   Evaluation

    5.   References

    1.  EXPLANATION

         Thiamphenicol is a broad-spectrum antimicrobial agent,
    structurally similar to chloramphenicol, used orally to control
    infections in humans, pigs, poultry and non-ruminating cattle. It is
    bacteriostatic for both Gram-positive and Gram-negative aerobes and
    for some anaerobes. It has not been previously evaluated by the
    Committee.

         The molecular structure of thiamphenicol is shown below.

    CHEMICAL STRUCTURE 5

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

    2.1.1  Absorption, distribution and excretion

    2.1.1.1  Rats

         After i.v. administration in rats the half-life of thiamphenicol
    was 46.3 minutes, compared to 21.5 minutes for chloramphenicol
    (Ferrari & Della Bella, 1974).

         Pretreatment of rats with phenobarbital increased thiamphenicol
    half-life slightly from 46.3 to 55.2 minutes, whereas the
    chloramphenicol half-life was reduced from 21.5 minutes to 9.3 minutes
    (Della Bella  et al., 1968a).

         Following administration of 30 mg/kg to rats, thiamphenicol was
    eliminated in the urine almost entirely in the unchanged form: 62%
    following oral administration and 47% after i.m. administration (both
    at 48 hours). No significant glucuro-conjugation products were found.
    In the bile, 3.4% of the administered dose appeared unchanged and
    10-12% appeared as conjugated products after 4 hours. Of the
    administered dose, 36% was eliminated in faeces after 75 hours, almost
    entirely as unchanged thiamphenicol. Distribution studies showed that
    levels in the kidney and liver were higher than in plasma, while brain
    concentrations were negligible (Gazzaniga, 1974).

    2.1.1.2  Rabbits

         The amount of metabolites recovered in urine and bile within 7
    hours after i.v. administration was about 73% for thiamphenicol and
    60% for chloramphenicol, and the percentage of glucuronide to total
    amount recovered was 8% for thiamphenicol and 66% for chloramphenicol.
    The recovery of thiamphenicol into the bile was only 1%, mostly in
    unchanged form. About 3% of administered chloramphenicol was excreted
    into the bile and two-thirds of this consisted of metabolites
    (Uesugi  et al., 1974).

    2.1.1.3  Dogs

         Following intraduodenal administration of 70 mg/kg thiamphenicol
    or chloramphenicol, 30% of the thiamphenicol dose was found unchanged
    in urine within 8 hours, whereas only 8.3% of chloramphenicol was
    eliminated in the active form. After i.m. injection, the urinary
    elimination of active antibiotics within 8 hours was 24.2% for
    thiamphenicol but only 1.76% for chloramphenicol (Laplassote, 1962).

    2.1.1.4  Pigs

         To determine plasma and tissue concentrations of thiamphenicol in
    pigs following dietary treatment, 16 male pigs, approximately 7 weeks
    old, were fed thiamphenicol in the diet at a concentration of
    900 mg/kg (equivalent to 30 mg/kg bw), twice daily for a period of 5
    days. Three pigs were maintained as controls and fed basal diet only.
    Venous blood samples were taken prior to treatment and at various
    time-points during the study. The animals were killed at 4, 6, 8 and
    10 days after treatment and samples of kidney, liver, muscle, fat and
    lung taken. Concentrations of thiamphenicol in plasma were measured
    following solvent extraction, using HPLC. On the second day of the
    dosing period, scouring and swelling or redness of the anus/perineal
    area were noted in all treated animals. The signs resolved within 4-10
    days. The maximum mean plasma level of thiamphenicol (1.28 mg/litre)
    was demonstrated 8 hours after the first dose. Mean levels were in the
    range of 0.22-0.80 mg/litre during the dosing period and declined over
    the withdrawal period to give concentrations below or close to the
    limit of detection (0.01-0.08 mg/litre) from 4 hours to 5 days after
    the end of treatment. The results of the analysis of tissue samples
    were not reported (Redgrave  et al., 1991).

    2.1.1.5  Humans

         After a 500 mg oral dose of each of thiamphenicol and
    chloramphenicol, the plasma levels appear to be similar. A high level
    of active thiamphenicol and a low level of chloramphenicol were found
    in the urine (53.1% and 9.2%, respectively, after 24 hours). The
    half-life of thiamphenicol is significantly increased in renal
    insufficiency, but is almost unaffected by liver cirrhosis
    (Azzolini  et al., 1972).

    2.2  Toxicological studies

    2.2.1  Acute toxicity studies

         The acute toxicity of thiamphenicol and thiamphenicol-glycinate
    is given in Table 1.

         The predominant clinical signs in the animal species tested were
    sedation and piloerection after oral dosing, and dyspnoea, cyanosis,
    motility disorders and respiratory arrest after parenteral
    administration.

    2.2.2  Short-term toxicity studies

    2.2.2.1  Rats

         The oral toxicity of thiamphenicol, when administered as an
    aqueous suspension in 0.5% methocel for 13 week, has been investigated
    in four groups of rats (Sprague-Dawley 30/sex/group). Thiamphenicol
    was administered by oral gavage at dose levels of 30, 45, 65 or
    100 mg/kg bw per day, while a fifth control group received 0.5%
    methocel only. The first 15 animals of each group were killed on
    completion of the treatment period, and the remaining 15 after a
    recovery period of 8 weeks. Mortality during the treatment period was
    elevated among animals of both sexes receiving 100 mg/kg bw per day,
    and during the recovery period mortality was similar in all groups. At
    levels of 65 and 100 mg/kg bw per day, pallor, hair loss, prostration,
    hunched posture and flaccid musculature were seen. After the recovery
    phase the incidence and the severity of symptoms were similar in all
    groups including controls. Body weight stasis or loss was seen in
    animals receiving 65 and 100 mg/kg bw per day, and after 8 weeks
    recovery body weight was similar in all groups. Food intake was
    reduced at dose levels of 45, 65 and 100 mg/kg bw per day, with
    immediate improvement after cessation of treatment.

        Table 1.  Acute toxicity of thiamphenicol (TAP) and thiamphenicol-glycinate (TAP-G)
                                                                                              

    Species      Sex          Route       LD50 (mg/kg bw)         Reference
                                                           
                                          TAP         TAP-G
                                                                                              

    Mouse        M & F        oral        > 5000                  Bonanomi, 1978
                 M & F        i.p.        > 3000      1550        Bonanomi, 1978
                 M & F        i.v.                    450         Bonanomi, 1978

    Rat          M & F        oral        > 5000                  Bonanomi, 1978
                 M & F        i.p.        > 3000      1750        Bonanomi, 1978
                 M & F        i.v.                    470         Bonanomi, 1978
                                                                                              
    
         In all treated animals there were changes in erythrocyte
    parameters, differential and total leukocyte counts and clotting
    parameters, all of which were dose-related. After the recovery period
    erythrocyte and leukocyte counts were still low in males treated with
    65 and 100 mg/kg bw per day. Plasma levels of urea, triglycerides and
    total protein were altered from week 7 in animals treated with

    45 mg/kg bw per day and after the end of treatment also in males
    receiving 30 mg/kg bw per day. Parameters associated with liver and
    kidney function were affected at the two higher doses. After 8 weeks
    full recovery was considered to have occurred. The weights of all the
    main organs were reduced at dose levels of 65 and 100 mg/kg bw per
    day, but after the recovery period only the testis weight was still
    reduced. Postmortem examination revealed effects on the gastro-
    intestinal tract and spleen in both sexes and in the liver, thymus and
    testis of males at the highest dose level only. After 8 weeks only the
    testis weights were still reduced. The erythroid/myeloid cell ratio
    was increased in both sexes at doses of 65 or 100 mg/kg bw per day,
    and after 8 weeks was still slightly higher than usual.

         Treatment-related changes were seen in tissues with high cell
    turnover rates; most of them recovered after a period of respite from
    treatment. Animals in the groups treated with 30 and 45 mg/kg per day
    showed no histopathological findings except hepatocytic reduced
    basophilia (male, 45 mg/kg bw per day) and increased splenic extramed-
    ullary haematopoiesis (female 45 mg/kg bw per day). Testicular
    germinal epithelial deficit was present at doses above 45 mg/kg, and
    caecal oedema and adnexal atrophy were present after the recovery
    period at the highest dose level. The NOEL was 30 mg/kg bw per day
    (Marubini  et al., 1991).

         In a 6-month toxicity study in the rat, thiamphenicol was
    administered as an aqueous suspension in 2% gum arabic by stomach tube
    6 days/week to 180 Wistar rats (30/sex/group) at dose levels of 0, 40
    or 120 mg/kg bw per day. Body weight and food intake were recorded
    twice weekly in the first 4 weeks of treatment, and thereafter only
    once a week. At the end of weeks 4, 8, 16 and 24, ten animals from
    each group were killed following collection of 2-hour urine sample.
    Haematology, clinical chemistry assays and urinanalysis were performed
    on all tested animals. Histological examinations were carried out on
    the lungs, spermatozoa, blood and bone marrow smears and samples of
    main organs. There was a decrease in food intake at a dose level of
    120 mg/kg bw per day and a dose- and time-related decrease in body
    weight gain in females. No effect was observed on erythropoiesis or on
    hepatic or renal function. Urinanalysis showed the presence of albumin
    and haemoglobin in the high-dose rats. No gross pathological
    variations in organ weights were observed, but irritative changes in
    the gastrointestinal mucosa and high incidence of monolateral
    spontaneous hydronephrosis were seen both in treated and control
    animals. Histopathological examination performed on control and
    high-dose rats revealed a slight effect on the morphology of
    spermatozoa in the high-dose group at the 8th, 16th and 24th week of
    treatment (Della Bella  et al., 1968b).

    2.2.2.2  Rabbits

         Thiamphenicol-glycinate was administered subcutaneously to groups
    of rabbits ("Fauve de Bourgogne" seven/sex/group) at dose levels of
    0, 25, 50 or 100 mg/kg bw per day, 6 days/week for 12 weeks. Animals
    were weighed weekly and submitted to haematological (erythrocyte and
    leukocyte counts with differentials) and biochemical (urea, reducing
    sugars, chlorides) examinations before treatment, after 6 weeks and at
    the end of the treatment period. After macroscopic examination of the
    viscera, the various organs were examined histologically. During the
    treatment two control animals and three in the high-dose group died
    (no autopsies were carried out). A reduction in polymorphonuclear
    neutrophils in male rabbits in all treated groups and a slight fall in
    erythrocyte levels in high-dose females were observed. Anatomical and
    pathological examination provided no evidence of damage attributable
    to thiamphenicol-glycinate administration (Brunaud, 1965).

    2.2.2.3  Dogs

         In a 7-week study in beagle dogs (four/sex/group), thiamphenicol
    was administered orally in gelatin capsules at dose levels of 0, 40 or
    80 mg/kg bw per day. Two males and two female dogs were killed at the
    end of the 7-week treatment, and the remaining animals were kept for
    further 12 weeks without treatment before being killed. Behaviour and
    body weights were recorded, haematology and clinical chemistry
    examinations and urinanalysis were conducted on all animals pretest
    and at various intervals during the study. Complete gross postmortem
    examination, organ weighing and histopathological evaluation were
    conducted on all animals. The animals in the two treated groups
    developed diarrhoea soon after the beginning of treatment, which
    spontaneously regressed in the low-dose group but persisted in the
    high-dose group. At 80 mg/kg bw per day reduced food consumption with
    loss of weight and muscular asthenia occurred, and vomiting was
    observed in some cases. Four of these dogs were killed at the end of
    the 4th week. Slight loss of weight was observed in two dogs in the
    low-dose group.

         Decreases in haematocrit, haemoglobin concentration and
    erythrocyte count were seen in both treated groups, but did not appear
    to be dose-related, and returned to normal on withdrawal of treatment.
    Slight increase in proteinuria was observed in the last few weeks of
    treatment. At 40 mg/kg bw per day superficial erosion of the gall
    bladder mucosa and at 80 mg/kg bw per day haemorrhagic ulcers in the
    gall bladder, diffuse muco-membranous enteritis and thymic involution
    were seen in dogs killed at the end of treatment period. In dogs
    killed after the 12-week recovery period no differences were observed
    between treated and control animals. Histological examination after 7
    weeks revealed in the high-dose group severe cholecystitis, chronic
    sclerosing pancreatitis, enteritis, severe depletion of haematopoietic

    marrow and lymphoid thymus depletion. Two dogs in the low-dose group
    showed depletion of germinal epithelium in the testes and multinuc-
    leated cells in seminiferous tubules, which were not seen in the high-
    dose group. None of the changes observed at 7 weeks were detectable
    in the animals kept for 12 weeks after cessation of treatment
    (Bonanomi  et al., 1978).

         Thiamphenicol was administered orally in gelatin capsules to 24
    beagle dogs (four/sex/group) at dose levels of 30, 60 or 120 mg/kg bw
    per day for a period of 4 weeks. Physical observations, ophthalmo-
    scopic examinations, and body weight and food consumption measurements
    were performed before treatment and over selected intervals during the
    treatment. Haematology, clinical chemistry and urinanalysis were
    conducted on all animals pretest and at study termination. Complete
    gross postmortem examinations, organ weight and histopathological
    evaluation were conducted on all animals. The body weights of the
    high-dose animals were slightly lower than those of controls at week 3
    in both sexes, and at week 4 in males only. At 60 and 120 mg/kg bw per
    day absolute and relative liver weights in male dogs were greater than
    in controls, and relative liver weights were also increased in
    females. Microscopically, hepatocellular hypertrophy was present in
    the liver of mid- and high-dose animals, which correlated with the
    increase in liver weights in these groups. No other parameter
    evaluated showed evidence of adverse treatment-related effects. The
    NOEL was 30 mg/kg bw per day (Kelly & Daly, 1990).

         Thiamphenicol was administered orally in gelatin capsules to 56
    beagle dogs (seven/sex/group) at dose levels of 15, 30 or 60 mg/kg bw
    per day. After 6 months of treatment four animals/sex/group were
    sacrificed, and the remaining three animals/sex/group were kept for a
    2-month recovery period. Physical observations, ophthalmoscopic
    examinations, body weight, food consumption, haematology and clinical
    chemistry examinations and urinanalysis were conducted on all animals
    pretest and on all surviving animals at selected intervals during the
    treatment and recovery period. Complete gross postmortem examinations,
    organ weight and histopathological evaluation were conducted on all
    animals. One control male was found dead during the study. One male
    and one female dog in the highest dose group were moribund and had to
    be killed. Clinical signs prior to death included lethargy, poor food
    consumption, emaciation, tremors and dehydration. Physical findings
    related to thiamphenicol administration were tremors, lethargy,
    irregular gait and excessive licking or chewing in the high-dose
    group. Tremors were also present in the mid-dose animals. These signs
    were seen during the last two months of the study and were not present
    at the end of the recovery period. Body weights of the high-dose males
    during the study were 4 to 18% lower than those of controls. Decreased
    erythrocyte counts and mean haematocrit values were seen in high-dose
    males at weeks 6 and 13 and at termination of the study, and in high-
    and mid-dose females at week 13 and at termination of the study. After

    the recovery period no differences were observed in the haematological
    parameters between control and treated animals. No treatment-related
    effects were seen in the bone marrow smear examinations. Mean serum
    cholesterol and phospholipid levels of the mid-and high-dose males at
    week 6 and 13 and at termination of the study were greater than
    control values. The same parameters were elevated in high-dose females
    at the end of the study. Mean serum glucose levels of males at
    60 mg/kg bw per day and females at 30 and 60 mg/kg bw per day were
    significantly increased. Mean fibrinogen values of high-dose females
    were elevated at the end of the study. Relative liver weights were
    increased at mid- and high-dose levels. Pathological lesions related
    to treatment were seen in sections of the thymus (exacerbation of
    involution), bone marrow (decreased cellularity), liver (centrilobular
    necrosis and pigment deposition), testes (focal and diffuse tubular
    atrophy) and oesophagus (ulceration) from high-dose animals of both
    sexes, mostly occurring in animals killed in a moribund condition. No
    alterations were noted in any of the tissues examined microscopically
    from animals that were allowed to recover after treatment. The NOEL
    was 15 mg/kg bw per day (Kelly & Daly, 1991).

    2.2.2.4  Pigs

         A study designed to determine tolerance in pigs to treatment with
    thiamphenicol at three times the recommended dose for 5 days and at
    the normal recommended dose for 15 days was conducted with 16 weaned
    large white hybrid pigs (two pigs/sex/group). Thiamphenicol was
    administered in the diet at dose levels of 30 or 90 mg/kg bw per day
    for 5 days or 30 mg/kg bw per day for 15 days. The control group of
    animals was fed basal diet only. Clinical signs, body weight and food
    consumption were recorded. Blood, urine and faecal samples were
    obtained before dosing and at various time-points during the study. No
    significant treatment-related clinical abnormalities were noted. Body
    weight changes and food consumption were within normal limits. No
    consistent treatment-related differences in haematological and
    biochemical parameters or in urinanalysis values were observed. The
    authors concluded that treatment with thiamphenicol had no significant
    adverse effects on general health, body weight, food consumption or
    standard clinical pathology parameters (Roberts  et al., 1989).

         In a 4-week toxicity study, groups of pigs (Large White hybrid,
    four/sex/group) were fed 25, 50 or 100 mg thiamphenicol/kg bw per day.
    The control group of animals was fed basal diet only. Clinical signs,
    body weight and food consumption were recorded. Blood, urine and
    faecal samples were obtained before dosing and during week 4 for
    clinical pathological investigations. At the end of the 4-week dosing
    period, pigs were killed, and selected tissues were processed for
    histological examination. In all groups treated with thiamphenicol,
    swelling and erythema of the anus, vulva/testes and perineal area,
    tail and hocks were observed on the second day of the dosing period.

    These effects were consistent with scouring and irritancy, e.g., as a
    result of disruption of normal gastrointestinal flora activity, and
    disappeared within 1 to 13 days. All pigs remained in good health
    thereafter. Slight reductions in body weight gain and food consumption
    were noted at 50 and 100 mg/kg bw per day. At week 4 there was a
    slight reduction in mean PCV, haemoglobin concentration and
    erythrocyte counts in animals receiving 100 mg/kg bw per day and a
    treatment-related reduction of urinary pH in all groups dosed with
    thiamphenicol. At the end of the study, increases in liver and kidney
    weights in pigs fed 50 and 100 mg/kg bw per day were observed. On
    histological examination, treatment-related changes were found in the
    highest dose group only: an increase in vacuolation and fat in renal
    tubular epithelium and, in some animals, minimal diffuse hepatocyte
    vacuolation and hepatocyte fat (Cameron  et al., 1990).

    2.2.3  Long-term toxicity/carcinogenicity study

    2.2.3.1  Rats

         As a range-finding study for the dose selection in a 2-year
    carcinogenicity study, four groups of F-344 rats (10/sex/group)
    were given drinking-water containing 0, 125, 250 or 500 mg/litre
    thiamphenicol (equal to 9, 17 or 36 mg/kg bw per day for males and 12,
    29 or 39 mg/kg bw per day for females) for 13 weeks. The examinations
    at the end of the study covered clinical observations, water
    consumption, body weight changes, haematological parameters, serum
    biochemistry, organ weights and gross and microscopic appearance. In
    haematological examinations anaemic changes were observed in males
    treated with 250 mg/litre or more and high-dose females. Similar
    changes, such as increased MCV and increased related counts, were
    observed in males of the 125 mg/litre group and females of the 250 and
    125 mg/litre groups. At autopsy, enlargement of the caecum was seen in
    treated groups of both sexes. Histologically, the highest dose animals
    showed decreased haematopoiesis of the bone marrow, decreased spermato-
    genesis of the testis and sperm granulomas of the epididymis. Sperm
    granulomas in the epididymis were also seen in some of the animals in
    the 250 mg/litre group. Based on the results of this pilot study, a
    2-year carcinogenicity study of thiamphenicol was performed in rats.
    Three groups of F-344 rats (50/sex/group) were given drinking-water
    containing 0, 125 or 250 mg thiamphenicol/litre (equal to 8 or 16
    mg/kg bw per day for males and 9.7 or 19 mg/kg bw per day for females)
    for 104 weeks. All surviving animals subjected to 4-week withdrawal of
    the test chemical after the end of the treatment were killed for full
    histopathological examinations. The high-dose animals showed decreased
    body weight gain, but the incidence of rumours in treated groups was
    not significantly higher than that of controls (Maekawa, 1996; summary
    report only was available).

    2.2.4  Reproductive toxicity studies

    2.2.4.1  Rats

         In a fertility study on male Wistar rats, oral treatment with
    thiamphenicol for 2 or 3 months (30 animals per dose level, 10 per
    treatment time), at dose levels of 120, 180 or 240 mg/kg bw per day,
    resulted in reduction in the number of tubular germinal cells, which
    was more marked at the highest dose level. Ten animals of each group
    were treated for 4 weeks, ten for 8 weeks and the last ten for 12
    weeks. At the end of each test period 5 animals of each dose group
    were killed and necropsied, while the remaining 5 rats were mated with
    normal females. At 240 mg/kg bw per day extensive testicular
    hypotrophy, together with severe depletion of the germinal epithelium
    21 days after withdrawal of treatment, was seen. Histological changes
    coincided with a reduction of the fertility index, which gradually
    recovered within 50 days. Litters from matings between treated males
    and normal females were normal in number and weight, and no morpho-
    logical abnormalities were observed. The concentration ratio of
    thiamphenicol between testes and plasma after administration of
    240 mg/kg bw per day thiamphenicol was 1, indicating the absence of
    accumulation in testes (Della Bella  et al., 1967).

         Groups of 21 Sprague-Dawley rats were given thiamphenicol orally
    (30, 60 or 120 mg/kg bw per day daily) from day 15 of gestation to day
    21 postpartum. In groups receiving 60 and 120 mg/kg bw per day a
    higher post-implantation loss, slight weight reduction at birth and
    increased rate of perinatal mortality were observed. No malformations
    were observed. Development of pups was inhibited during the lactation
    period with a consistent dose-dependent relationship. From day 30
    postpartum a good recovery was observed in all groups. Sexual
    behaviour and fertility of F1 animals were normal, and the F2
    generation showed no signs of abnormal development (Bonanomi  et
     al., 1980).

    2.2.5  Special studies on embryotoxicity and teratogenicity

    2.2.5.1  Rats

         Teratogenicity studies were carried out on 195 mature female
    Wistar rats (15/group) given thiamphenicol orally at dose levels of
    40, 80 or 160 mg/kg bw per day from days 1 to 21 of pregnancy and 80
    or 960 mg/kg bw per day from days 1 to 7, 7 to 14 or 14 to 21 of
    gestation. Thiamphenicol did not induce any teratogenic effects in any
    of the four studies carried out. When the treatment period was 1-21
    days, a dose-related increase in resorptions was noted, and newborns
    had a high mortality rate in the second and third week of life,
    particularly in the 40 mg/kg bw per day group. In rats treated on days
    1-7 of gestation, a non-dose-related increase in resorptions and an

    increased mortality in newborns in the third week after birth were
    observed. When the treatment period was from 7 to 14 days, complete
    resorption of fetuses occurred at 160 mg/kg bw per day. The mean
    number of newborns per litter was reduced at 80 mg/kg bw per day and
    there was a high mortality of newborns in the first week. An increased
    mortality among newborns of the group treated with 80 mg/kg bw per day
    during days 14-21 of gestation was observed (Bonanomi & De Paoli,
    1969).

         When the inhibition of mitochondrial functions induced by
    thiamphenicol was compared with the inhibition of overall embryonic
    development, it appeared that mitochondrial respiration was the
    rate-limiting step for the embryotoxic effects of thiamphenicol.
    Because of the lack of specificity of these effects, prenatal
    mortality rather than teratogenic effects was seen (Bass  et al.,
    1978).

    2.2.5.2  Rabbits

         A teratogenicity study was performed with 50 New Zealand white
    rabbits administered thiamphenicol orally at dose levels of 5, 30, 60
    or 80 mg/kg bw per day from the 8th to the 16th day of pregnancy. The
    highest dose resulted in a complete resorption of implantation due to
    the toxic effects on the mothers. Data obtained in all treated groups
    showed moderate fetal toxicity with a dose-related increase in
    abortion rate and resorption. No skeletal malformations were found in
    fetuses (Bonanomi  et al., 1974).

         Thiamphenicol in 0.5% Methocel K15M was administered daily by
    oral gavage to female rabbits (16/group) from day 6 to day 18 of
    gestation at doses of 1.25, 2.5 or 5.0 mg/kg bw per day. Control
    animals received the vehicle alone. The females were killed on
    gestation day 29 and subjected to postmortem examination. All fetuses
    were examined for external and internal abnormalities and skeletal
    changes. No clinical signs attributable to treatment were observed.
    Mild signs of maternal toxicity were observed in mid- and high-dose
    animals, indicated by reduction in body weight changes during the
    treatment period.

         Necropsy findings in females on gestation day 29 were incidental,
    with no relation to treatment. Litter parameters and sex ratios did
    not show any significant difference between groups. Mean fetal weight
    was decreased in the high-dose group. Two fetuses in the mid-dose
    group and one in the control group were malformed, with cleft palate,
    abnormally shaped head, extra digits and incomplete flexure of the
    hind limbs. The number of small fetuses in the high-dose group was
    higher than in the control group. The few anomalies seen during the
    internal examination were not considered to be treatment-related.
    Skeletal examination revealed no differences between high-dose fetuses
    and controls. The authors concluded that thiamphenicol administered by

    oral gavage at concentrations of 1.25, 2.5 and 5 mg/kg per day had no
    effects on pregnancy or embryo-fetal development. However, the
    Committee concluded that the NOEL for embryotoxicity under the
    conditions of this experiment was 1.25 mg/kg per day (Sisti, 1994).

    2.2.6  Special studies on genotoxicity

         The results of genotoxicity assays on thiamphenicol are given in
    Table 2.

        Table 2.  Genotoxicity assays on thiamphenicol
                                                                                              

    Test system         Test object         Concentration       Results        Reference
                                                                                              

    Ames test1          S. typhimurium      0.5-50              Negative       Pinasi
                        TA98, TA100,        µg/plate2                          et al., 1990a
                        TA1535, TA1537,
                        TA1538

    Gene conversion     Saccharomyces       2.8-140.3 mM3       Negative       Marca &
      and mitotic       cerevisiae                                             Bonanomi,
      crossing over1                                                           1979

    Gene mutation       Chinese hamster     50-5000             Negative       Pinasi
      assay1            V79 cells           µg/ml4                             et al., 1990b

    Chromosomal         Cultured human      700-3250            Negative       Mosesso &
      aberrations1      lymphocytes         µg/ml5                             Driedger, 1989

    DNA repair          Primary rat         500 and 1000        Negative       Bichet, 1985
      test              hepatocytes         µg/kg6

    In vivo             Mouse bone          2500 and 5000       Negative       Pinasi
      micronucleus      marrow              mg/kg7                             et al., 1990c
      assay
                                                                                              

    1    Both with and without rat liver S9 fraction
    2    Methyl methanesulfonate and cyclophosphamide were used as positive controls
    3    2-Nitrofluorene, 9-aminoacridine, sodium azide and 2-aminoanthracene were used
         as positive controls
    4    Ethyl ethanesulfonate and N-dimethylnitrosoamine were used as positive controls
    5    Mitomycin-C and cyclophosphamide were used as positive controls
    6    2-Aminofluorene was used as positive control
    7    Cyclophosphamide was used as positive control
    
    2.2.7  Special studies on immune responses

         The effects on spontaneous nephritis in NZB × OUW hybrid mice
    (32-39 males/group) were investigated in a study involving lifetime
    administration of thiamphenicol in feed at dose levels of 25, 50 and
    250 mg/kg bw per day. Body weight, urinary protein, limited
    haematology, organ weights and histopathology investigations were
    reported. The prolonged treatment with thiamphenicol at dose rates of
    > 50 mg/kg reduced the severity of the spontaneous renal disease and
    significantly extended lifespan, compared to untreated controls. The
    immunosuppressive effect of thiamphenicol was demonstrated
    histologically by a reduction in immune-complex deposition in the
    glomeruli. No evidence of malignancy or premalignant signs was seen
    (Simpson  et al., 1979).

    2.2.8  Special studies on microbiological effects

    2.2.8.1  In vivo

         In a study of thiamphenicol-induced changes in mouse intestinal
    microflora, 100 female albino mice were divided into 10 subgroups, and
    five of these groups were treated with thiamphenicol at concentrations
    of 40 µg/kg diet for 35 days. Samples of intestinal content were taken
    from the caecum for bacteriological analysis before the treatment and
    after 7, 14, 28 and 35 days. Microorganisms were isolated by preparing
    serial dilutions of intestinal content, and the most representative
    bacteria of the mouse intestinal microflora were cultured on specific
    media. Their sensitivity to thiamphenicol was assessed by calculating
    the minimal inhibitory concentration (MIC) of the drug. The results
    show that the mean counts of various microorganisms did not differ
    significantly between control mice and those fed with thiamphenicol.
    The numbers of the bacterial populations did vary at the different
    sampling times, and in some cases the difference from pre-treatment
    results was significant, but confidence limits were the same in
    treated and control mice killed at the same time. The investigation
    shows that there were no appreciable differences in the type or amount
    of bacterial flora related to thiamphenicol administration.
    Differences in the distribution of genera such as  Diplococcus sp.
    and  Escherichia sp. were similar to those in controls. The
    thiamphenicol MIC values for the numerous strains tested indicate that
    addition to feed at concentrations corresponding to the proposed MRL
    of 40 µg/kg feed does not select for drug-resistant strains and has no
    effect on the qualitative or quantitative composition of the
    intestinal microflora. The MIC remained unchanged throughout the 35
    days of the study (Poli, 1994).

    2.2.8.2  In vitro

          In vitro antibacterial activity of thiamphenicol against 489
    bacterial isolates from infected animals was determined by the agar
    dilution method. In the case of mycoplasmas, however, MICs were
    determined by the broth dilution method. Depending on bacterial
    strains tested estimations were made under aerobic or anaerobic
    conditions. The results are presented in Table 3 (Albini, 1989).

         Data on the sensitivity of normal components of human intestinal
    microflora are presented in Table 4 (Sutter & Finegold, 1976;
    Schioppacassi, 1992).

        Table 3.  Antibacterial activity of thiamphenicol against 489 animal pathogens
                                                                                              

    Organisms                Number of      MIC (µg/ml)          Range
                                            isolates
                                            MIC50     MIC90
                                                                                              

    Bacteroides spp.         11             2         16         1 - 128
    Bordetella spp.          9              32        32         16 - 32
    Campylobacter spp.       17             8         16         4 - 16
    Clostridium spp.         37             2         4          0.25 - 16
    Corynebacterium spp.     10             2         16         2 - 16
    Escherichia coli         61             128       >128       16 - > 128
    Haemophilus
      pleuropneumoniae       7              0.5       1          0.5 - 1
    Micrococcus spp.         6              0.5       0.5        0.5 - 8
    Mycoplasma spp.          9              1         2          0.125 - 4
    Pasteurella spp.         71             1         2          0.25 - 128
    Salmonella spp.          34             32        32         8 - > 128
    Staphylococcus spp.      94             8         32         4 - > 128
    Streptococcus spp.       123            2         4          0.5 - > 128
                                                                                              
    
    2.3  Observations in humans

         Reversible dose-related bone marrow suppression is seen after
    thiamphenicol treatment and is attributed to its inhibitory effect on
    mitochondrial protein synthesis (Nijhof & Kroon, 1974). Reversible
    inhibition of myeloid and erythroid colony growth by thiamphenicol,
    resulting from an inhibition of mitochondrial protein synthesis, is
    consistent with the reversible bone marrow suppression induced by this
    drug (Yunis & Gross, 1975).

         A study of clinical reports on the use of thiamphenicol in 16 631
    cases from 1968 to 1977 in Japan revealed that blood disorders
    occurred in 41 (0.46%) out of 8848 patients receiving thiamphenicol
    glycinate therapy and 28 (0.36%) out of 7783 patients receiving
    thiamphenicol. The disorders were dose-dependent, occurring mainly in
    erythrocytes, and disappeared spontaneously on discontinuation of the
    drug (Tomoeda & Yamamoto, 1981).

         The  para-nitro group of chloramphenicol has been shown to have
    a central role in the pathogenesis of aplastic anaemia, probably as a
    result of its reduction to the highly toxic nitroso metabolite, which
    is a potent inhibitor of DNA synthesis. Thiamphenicol does not show
    this activity and the absence of the  para-nitro group is therefore
    advanced as evidence that thiamphenicol cannot induce aplastic anaemia
    (Murray  et al., 1983).

         Thiamphenicol has been used extensively in human medicine
    for over 25 years. Total human exposure to thiamphenicol up to
    1987 has been estimated at 130-650 million exposures, assuming an
    average course of therapy of 7.5-15 g (Personal communication from
    Dr S. Biressi, Zambon Group SpA, Italy to Dr R.D. Agostino,
    Farmaquest Co.; submitted to WHO by Zambon Group SpA, Italy).

         Epidemiological studies have not established any causal
    association between thiamphenicol treatment and irreversible aplastic
    anaemia (TAP Pharmaceuticals Inc., 1987). Statistical analysis of
    data obtained in these studies support the argument that the risk of
    aplastic anaemia from exposure to thiamphenicol is similar to the
    background risk of idiopathic aplastic anaemia (from 1 in 200 000 to 1
    in 800 000) (Kelly & Kaufman, 1989).

        Table 4.  Antibacterial activity of thiamphenicol against 261 strains of anaerobic bacteria isolated from humans
              (From: Sutter & Finegold, 1976)
                                                                                                                                    

    Bacteria                 No. of         Cumulative % susceptible to indicated concentration (µg/ml)
                             strains
                             tested                                                                                                 

                                            <0.1    0.5     1.0     2.0     4.0     8.0     16.0    32.0    64.0    128.0
                                                                                                                                    

    Bacteroides fragilis     42                                     5       21      71      100

    Bacteroides              59             9       24      51      90      100
      melaninogenicus

    Other Bacteroides        21                     19      24      57      76      86      91      95      100
      and Selenomonas

    Fusobacterium            8                      100
      nucleatum

    Other Fusobacterium      12                     42      92      100

    Peptococcus and          17                             35      71      100
      Gaffkya

    Peptostreptococcus       15                     33      47      93      100
                                                                                                                                    

    Table 4.  (cont'd).
                                                                                                                                    

    Bacteria                 No. of         Cumulative % susceptible to indicated concentration (µg/ml)
                             strains
                             tested                                                                                                 

                                            <0.1    0.5     1.0     2.0     4.0     8.0     16.0    32.0    64.0    128.0
                                                                                                                                    

    Anaerobic and            6                                      50      83              100
      microaerophilic
      streptococci

    Gram-negative cocci      7                      43      86      100

    Eubacterium              7                                      43      57      100

    Arachnia propionica      2                              50      100

    Propionibacterium        4                      50      75                      100

    Actinomyces              16                     25      56      94                      100

    Lactobacillus            10                     10      30      50      90                      100

    Clostridium              8                                              100
       perfringens

    Other Clostridium        27                             4       22      63      78      96              100
                                                                                                                                    
        3.  COMMENTS

         Studies on thiamphenicol available for evaluation included data
    on pharmacokinetics, acute toxicity, short-term toxicity, reproductive
    toxicity, developmental toxicology, genotoxicity, and limited
    information on long-term toxicity. Studies on microbiological effects
    of thiamphenicol and epidemiological data on humans were also
    considered by the Committee. The Committee noted that many of the
    studies were conducted utilizing protocols that would not meet
    contemporary standards, and therefore the substance was evaluated
    under the procedures developed for drugs with a long history of use
    (Annex 1, reference 104).

         The pharmacokinetic data showed that the drug is rapidly absorbed
    when administered by oral or parenteral routes. After intravenous
    administration in rats, the half-life was estimated to be 46 minutes.
    The main route of excretion in humans and animals is in the urine;
    approximately 60% of an oral dose of 30 mg/kg bw was excreted
    unchanged in the urine over a 24-hour period.

         Single oral doses of thiamphenicol were of low toxicity to mice
    and rats (LD50 > 3000 mg/kg bw).

         Short-term oral toxicity studies with thiamphenicol were
    performed in rats, dogs and pigs, the results are described in the
    following paragraphs.

         In a 13-week study in rats at dose levels of 30, 45, 65 or
    100 mg/kg bw per day, increased mortality was observed among animals
    given 100 mg/kg bw per day. In a 6-month study in rats, where the
    highest dose used was 120 mg/kg bw per day, increased mortality was
    not reported. In both studies, decrease in body weight gain during
    treatment occurred at doses of > 65 mg/kg bw per day. Dose-related
    decreases in red blood cell parameters, differential and total white
    blood cell counts, and clotting parameters were observed in the
    13-week study, but the same effects were not reported in the 6-month
    study. Testicular germinal epithelial cell depletion was seen at doses
    above 45 mg/kg bw per day in the 13-week study, and a dose of 30 mg/kg
    bw per day was considered to be the NOEL.

         Dogs were given 40 or 80 mg thiamphenicol/kg bw per day for 7
    weeks. At both dose levels decreases in body weight were observed, as
    well as reversible decreases in haematocrit, haemoglobin concentration
    and erythrocyte count. At 40 mg/kg bw per day, superficial erosion of
    the gall bladder mucosa was observed. The higher dose level resulted
    in haemorrhagic ulcers in the gall bladder, diffuse mucomembranous
    enteritis and early thymic involution. Two dogs in the low-dose group
    had testicular germinal epithelial cell depletion and multinucleated
    cells in the seminiferous tubules.

         When thiamphenicol was given to dogs at doses of 30, 60 or
    120 mg/kg bw per day for 4 weeks, the body weights of the high-dose
    animals were slightly lower than those of controls. In the mid- and
    high-dose groups, increases in absolute and relative liver weights
    were observed. Hepatocellular hypertrophy was present in the liver of
    dogs given 60 or 120 mg/kg bw per day.

         In a 6-month study dogs were given thiamphenicol at doses of 15,
    30 or 60 mg/kg bw per day. The body weights of high-dose males during
    the study were up to 18% lower than those of controls. The main
    haematological findings were decreases in red blood cell parameters at
    the highest dose level. Increases were noted in mean serum cholesterol
    level and phospholipid concentrations in males (30 and 60 mg/kg bw per
    day groups) and females (60 mg/kg bw per day group), and in the mean
    serum glucose concentration of males (60 mg/kg bw per day group) and
    females (30 and 60 mg/kg bw per day groups). The relative liver
    weights at the mid- and high-dose levels were increased. Histopatho-
    logical lesions related to treatment were seen in the thymus (early
    involution), bone marrow (decreased cellularity), testes (focal and
    diffuse tubular atrophy) and oesophagus (ulceration) of high-dose
    animals. The NOEL was 15 mg/kg bw per day.

        In a 4-week study, pigs were treated with 25, 50 or 100 mg
    thiamphenicol/kg bw per day. In the highest-dose group, slight
    reduction in body weight gain, as well as reductions in mean packed
    cell volume, haemoglobin concentration and erythrocyte counts, were
    observed, and histological examination showed vacuolation in renal
    tubular epithelial cells and mild diffuse hepatocyte vacuolation. In
    all treated groups treatment-related reduction in urine pH was
    observed.

         A summary report of a two-year carcinogenicity study in rats,
    including a range-finding study, was available to the Committee. Rats
    were given 125 or 250 mg/kg thiamphenicol in drinking-water (equal to
    8 or 16 mg/kg bw per day for males and 10 or 19 mg/kg bw per day for
    females) for 104 weeks. The highest-dose animals showed a decrease in
    body weight gain, but there was no significant increase in the
    incidence of tumours in treated groups compared to control animals.

         In a long-term study in mice (32-39 males/group), which was
    designed primarily to investigate the effects of thiamphenicol on
    immune responses, thiamphenicol was administered orally at doses of
    25, 50 or 250 mg/kg bw per day. No evidence of neoplastic or
    preneoplastic changes was observed.

         In a study to determine the effect of thiamphenicol on fertility
    in rats, the drug was administered orally at doses of 120, 180 or
    240 mg/kg bw per day for 2 or 3 months. Thirty male rats were used per
    dose level (10 per treatment period). From each treatment-period
    group, half of the animals were killed for histopathological
    examination at the given time intervals, while the remaining males
    were mated with untreated females. Reductions in the number of
    germinal epithelial cells in testes of all treated animals were
    observed. These changes were present up to 21 days after termination
    of treatment, and full recovery was observed by 50 days. Histological
    changes correlated with the fertility index. Litters from matings
    between treated males and non-treated females were normal in number
    and no physical abnormalities were reported.

         Thiamphenicol was given orally to rats from day 15 of gestation
    to day 21 post-partum at doses of 30, 60 or 120 mg/kg bw per day. In
    the mid-and high-dose groups, there were higher post-implantation
    losses and increased rates of perinatal mortality. Physical develop-
    ment of pups was inhibited during the lactation period in a dose-
    dependent manner. Sexual behaviour and fertility of F1 animals
    were normal, and animals in the F2 generation showed no
    abnormalities.

         In four teratogenicity studies in rats, thiamphenicol was
    administered orally at dosages of 40, 80 or 160 mg/kg bw per day from
    days 1 to 21 of pregnancy or of 80 or 960 mg/kg bw per day over
    critical days of gestation (either 1-7, 1-21, 7-14 or 14-21). No
    teratogenic effects were observed. In all animals treated from days 1
    to 21, a dose-related increase in resorption was noted and newborn
    pups had an elevated mortality rate.

         A teratogenicity study was performed in rabbits using oral doses
    of 5, 30, 60 or 80 mg/kg bw per day from days 8 to 16 of gestation.
    Complete resorption of embryos occurred at 80 mg/kg bw per day. In
    other treated groups, moderate fetal toxicity and dose-related
    increases in abortion rate and resorption were reported. No
    malformations were found in fetuses.

         In another teratogenicity study, rabbits received oral doses of
    thiamphenicol at doses of 1.25, 2.5 or 5 mg/kg bw per day from days 6
    to 18 of gestation. Mild maternal toxicity was observed in mid- and
    high-dose animals in the form of depressed body weights during the
    treatment. No effects were observed on embryo-fetal development. The
    NOEL was 1.25 mg/kg bw per day.

         Thiamphenicol gave negative results in five  in vitro
    genotoxicity tests and in an  in vivo micronucleus assay using mouse
    bone marrow.

         The Committee considered data from human epidemiological studies
    and concluded that there was no evidence that thiamphenicol can induce
    aplastic anaemia, in contrast to the structurally related compound,
    chloramphenicol.

         The Committee considered data from several  in vitro studies on
    the minimum inhibitory concentration (MIC) of thiamphenicol for a wide
    range of animal and human pathogens as well as genera representative
    of the human gut flora. The modal MIC50 value (minimum inhibitory
    concentration of thiamphenicol giving complete inhibition of growth of
    50% of cultures) was 1.68 µg/ml for 261 bacterial strains isolated
    from humans. The following species were found to be the most
    sensitive:  Bacteroides, Fusobacteria, Propionibacteria and
     Actinomyces. The Committee also noted that 40 µg thiamphenicol/kg
    food given to mice over 35 days did not alter the intestinal
    microflora in this species.

         The Committee calculated a microbiological ADI for thiamphenicol
    using the following formula:

    Upper limit of      MIC50 (µg/g) × mass of colonic content (g)
    microbiological =                                                 
    ADI                 fraction of oral   ×   safety    ×   human body
                        dose available         factor        weight (kg)

                         1.68 × 220
                    =              
                        0.4 × 1 × 60

                    =   15 µg/kg bw

         In calculating a microbiological ADI the Committee took the
    following factors into consideration:

    *    Concentration: 1.68 µg/ml was the modal MIC50 for micro-
         biological effects on human intestinal microflora (the density
         was assumed to be 1 g/ml).

    *    Availability: the Committee calculated the available portion of
         thiamphenicol as follows:

         100% ingested  -  60% excreted via  =  40% bioavailable
                           urine within         in the intestinal
                           24 hours             tract

         1 - 0.6 = 0.4

    *    Safety factor: the Committee concluded that the data deriving
         from the microbiological studies (substantial amount of MIC data
         covering a variety of microorganisms and  in vivo data from
         animal studies) provided sufficient information on microbio-
         logical effects of thiamphenicol. It therefore adopted a safety
         factor of 1 in the calculation.

    4.  EVALUATION

         Taking into account the available toxicological and antimicrobial
    data and the ADI based on antimicrobial activity, the Committee
    concluded that the toxicological data provided the most appropriate
    end-point for the evaluation of thiamphenicol. The Committee
    established a temporary ADI of 0-6 µg/kg bw for thiamphenicol, based
    on the NOEL of 1.25 mg/kg bw per day for maternal toxicity in the
    teratogenicity study in rabbits and a safety factor of 200. The ADI
    was designated "temporary" because only a summary report of the
    carcinogenicity study in rats was available. Detailed reports of the
    carcinogenicity study and the range-finding study used to establish
    dose levels in that study are required for evaluation in 1999
    (see Annex 4).

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    Azzolini, F., Gazzaniga, A., Lodola, E., & Natangelo, R. (1972).
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    See Also:
       Toxicological Abbreviations
       THIAMPHENICOL (JECFA Evaluation)