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    QUININE HYDROCHLORIDE

    1.  EXPLANATION

         This substance had not been evaluated previously by the Joint
    FAO/WHO Expert Committee on Food Additives.

         Quinine, as quinine salts or extracts from cinchona bark, is used
    as a bittering agent in tonic type drinks, usually at a concentration
    of approximately 80 mg of quinine hydrochloride per liter.  Such
    drinks are popular and have been widely consumed for almost 200 years. 
    Quinine rapidly breaks down when exposed to sunlight.  Thus it is also
    appropriate to consider the toxicity of these breakdown products,
    particularly deoxyquinine.

         Quinine and its derivatives are widely used therapeutically for
    treatment of protozoal infections such as malaria and treatment of
    nocturnal leg cramps.  There is an extensive literature on the
    pharmacokinetics and toxicity of quinine at high doses, well above
    that ingested through the consumption of tonic waters (e.g. Bateman &
    Dyson, 1986; Webster, 1985; Bacon  et al., 1988; White, 1987; White
     et al., 1982; Orme, 1987).

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

    2.1.1  Absorption, distribution and excretion

         Quinine is readily and completely absorbed from the small
    intestine when given orally.  Quinine is a potent local irritant and
    is not generally administered by either intramuscular or subcutaneous
    injection.  Peak plasma concentration is reached within one to three
    hours following a single oral dose.  Therapeutic doses of 1 g/day of
    quinine for several days result in an average plasma quinine
    concentration of approximately 7 µg/ml with a plasma half-life of
    about 12 hours.  Approximately 70% of plasma quinine is bound to
    proteins.  Quinine is extensively metabolized in the liver with less
    than 5% excreted unaltered in the urine (Webster, 1985; White, 1987). 
    The pharmacokinetics of quinine are variable (clearance 0.9-1.8
    ml/kg/min., half-life 8.4-18.2 hours).  Quinine readily crosses the
    placenta (Webster, 1985; White, 1987).

    2.1.2  Biotransformation

         Most metabolites, identified as hydroxy derivatives, are excreted
    in the urine (Webster, 1985; White, 1987).

    2.2  Toxicology studies

    2.2.1  Acute studies

         No data available.

    2.2.2  Short term studies

    2.2.2.1  Rats

         Five groups of 5 male and 5 female rats (Sprague-Dawley, Charles
    River, CD) were fed a diet containing the equivalent of 0.25, 100, 200
    and 250 mg/kg bw/day of quinine hydrochloride for 4 weeks.  There were
    reductions in the food consumption and body weight gains of the two
    high dose groups.  There were no treatment-related clinical or
    histopathological findings.  On the basis of this study, the authors
    concluded that dose levels of up to 200 mg/kg bw/day of quinine
    hydrochloride would be appropriate for a 13-week toxicity study
    (Colley  et al., 1982a).

         Diets containing the equivalent of 0, 1, 10, 40, 100 or 200 mg/kg
    bw/day of quinine hydrochloride were fed to 6 groups of 40 Sprague-
    Dawley (Charles River, CD) rats (20 male and 20 female per group) for
    13 weeks.  Following this exposure 5 male and 5 female rats from each
    group were placed on the control diet for an additional 6 weeks.  Rats
    in the two highest dose groups consumed less food and gained less

    weight than the controls.  Results from hematology, blood
    biochemistry, urinalysis and histopathology examinations were within
    normal ranges except for a decrease in total serum protein and
    globulin levels, increased urea nitrogen levels and depletion of
    periportal glycogen in the livers of rats in the two highest dose
    groups.  No toxicity was observed on ophthalmoscopic observation and
    hearing function (pinna reflex) tests.  During the withdrawal period,
    food intake increased in the group (males and females) that previously
    received 200 mg/kg bw/day and in males that previously received 100
    mg/kg bw/day.  There was also increased weight gain in male and female
    rats previously receiving 100 and 200 mg/kg bw/day.  Blood chemistry
    values measured during the final week of the withdrawal period were
    not different from the controls.  The authors concluded that 40 mg/kg
    bw/day of quinine hydrochloride was a no-effect level (Colley
     et al., 1982b).  A subsequent histopathologic examination of the
    optic nerve of the 200 mg/kg bw/day group revealed no treatment-
    related effects (Warren  et al., 1984).

         In a 13 week diet study, 4 groups of 20 male and 20 female
    Sprague-Dawley rats were exposed to the equivalent of 0, 60, 85 or 120
    mg/kg bw/day of quinine hydrochloride.  Following this exposure 5 male
    and 5 female rats from each group were placed on the control diet for
    a 6 week withdrawal period.  Reduced food consumption, decreased body
    weight gains, and decreased kidney weights were observed in the 85 and
    120 mg/kg bw/day dose groups.  A treatment-related loss of fur was
    noted in the 120 mg/kg bw/day dose group.  During the withdrawal
    period, food consumption was slightly lower in the 85 and 120 mg/kg
    bw/day group, but there were no differences in body weight gain,
    compared to controls.  The authors concluded that 60 mg/kg bw/day was
    a no-effect level (Watson  et al., 1983; Warren  et al., 1984).

    2.2.3  Long-term/carcinogenicity studies

         No data available.

    2.2.4  Reproduction studies

         No data available.

    2.2.5  Special studies on gentoxicity

         The vast majority of tests indicate that quinine hydrochloride is
    not mutagenic (Table 1).


        Table 1:  Results of genotoxicity assays of quinine hydrochloride

                                                                                                 
                                           Concentration
                                           of quinine
    Test System        Test Object         hydrochloride       Results        Reference
                                                                                                 

    Ames test1         S.typhimurium       0.1-2000 µg/        Negative       BIBRA, 1979
                       TA1535, TA1537      plate
                       TA1538, TA98
                       TA100

    Ames test1         S.typhimurium       1-1000 µg/          Negative       BIBRA, 1979
                       TA98, TA100         plate

    Ames test1         S.typhimurium       50-5000 µg/         Negative       Münzer &
                       TA1535, TA1537      plate                              Renner, 1983
                       TA1538, TA100
                       TA98

    Ames test2         S.typhimurium       1-50 µg/plate       Negative       BIBRA, 1979
                       TA98

    Ames test2         S.typhimurium       5-20 µg/plate       Positive       King  et al.,
                       TA98                (quinine                           1979
                                           dihydrochloride)

    DNA-repair         Human fibroblasts   0-400 µg/ml         Negative       BIBRA, 1979

    Cell               Syrian hamster      12.5-200 µg/ml      Negative       BIBRA, 1979
    transformation     kidney cells
                       (BHK 21 C13)
                                                                                                 

    Table 1 (contd).

                                                                                                 
                                           Concentration
                                           of quinine
    Test System        Test Object         hydrochloride       Results        Reference
                                                                                                 

    Cell               BHK 21 C13          6.5-100 µg/ml       Negative       Richold,  et al.,
    transformation     cells                                                  1981a

    Cell               BHK 21 C13          12.5-200 µg/ml      Negative       Richold,  et al.,
    transformation     cells                                                  1981a

    Sister chromatid   Chinese             55-110 mg/kg bw     Negative       Münzner &
    exchange           hamster                                                Renner, 1983

    Sister             Mice (NMRI          110 mg/kg bw        Positive       Münzner &
    chromatid          C3H)                                                   Renner, 1983
    exchange

    Sister             Mice (C57BL)        55-110 mg/kg bw     Positive       Münzner &
    chromatid                                                                 Renner, 1983
    exchange

    Micronucleus       Chinese             110 mg/kg bw        Negative       Münzner &
    test               hamster                                                Renner, 1983

    Micronucleus       Mice (NMRI          110 mg/kg bw        Negative       Münzner &
    test               C3H)                                                   Renner, 1983

    Chromosome         Chinese             110 mg/kg bw        Negative       Münzner &
    aberration         Hamster                                                Renner, 1983
    test
                                                                                                 

    Table 1 (contd).

                                                                                                 
                                           Concentration
                                           of quinine
    Test System        Test Object         hydrochloride       Results        Reference
                                                                                                 

    Chromosome         Mice (NMRI)         110 mg/kg bw        Negative       Münzner &
    aberration                                                                Renner, 1983
    test

    Chromosome         Mice (C3H)          110 mg/kg bw        Negative       Münzner &
    aberration                                                                Renner, 1983
    test
                                                                                                 

    1    Both with and without rat liver S-9 fraction
    2    With rat liver S-9 fraction.
    

    2.2.6  Special studies on genotoxicity of derivatives

         Studies on the genotoxicity of derivatives of quinine
    hydrochloride were negative (Table 1).

    2.2.7  Special studies on teratology

    2.2.7.1  Rats

         Four groups of 25 pregnant specific pathogen free rats (CRL: COBS
    CD (SD) BR strain) from Charles River UK were dosed by gavage on day
    6 to day 15 of gestation with either 0, 50, 100 or 200 mg/kg bw/day of
    quinine hydrochloride.  Rats in the two highest dose groups gained
    less weight than controls, but only the highest dose group consumed
    less food.  These findings are consistent with those in the 13 week
    feeding study which showed minimal toxic effects at 100 mg/kg bw/day
    (section 2.2.2.1).  Litter and mean fetal weights were significantly
    reduced in the 200 mg/kg bw/day dose group. There was a significant
    increase in total variant sternebrae in the 200 mg/kg bw/day dose
    group and a slight increase in the 100 mg/kg bw/day dose group
    compared to controls.  There were no differences in pregnancy data,
    total resorptions, litter size, sex ratio or major malformations
    between dose groups.  The authors concluded that the 100 mg/kg bw/day
    group showed no adverse effects on embryo or fetal development
    (Edwards  et al., 1984).

         Two groups of 5 female Sprague-Dawley rats were exposed to either
    0 or 0.25 mg/ml of quinine in their drinking water, starting two weeks
    prior to pregnancy and continuing throughout pregnancy and lactation. 
    The treated dams were mated with untreated males.  The quinine treated
    group showed some decrease in fluid consumption but no change in food
    intake or weight gain.  Pups from the quinine treated dams weighed
    significantly less at birth than those from the controls, had
    significantly delayed eye opening and teeth eruption and one neonate
    each was observed with syndactylia in the right forelimb or
    anopthalmia of the right eye.  Assuming that the female rat drinks
    approximately 30 ml/day and weighs approximately 200 g, the treated
    rats received a dose that is equivalent to approximately 40 mg/kg
    bw/day.  This report suffers from low numbers of animals and other
    deficiencies that make the significance of the reported results
    difficult to evaluate, e.g., it could not be determined if the terata
    that were reported are from the same litter or if the culling of pups
    from an average litter size of 13.6 to 8 was random (Lapointe & Nosal,
    1979).


        Table 2:  Results of genotoxicity assays of derivatives of quinine hydrochloride

                                                                                                 

                                           Concentration
    Test System        Test Object         (compound)          Results        Reference
                                                                                                 

    Ames test1         S.typhimurium       0-3000 µg/          Negative       Richold &
                       TA1537,TA98,        plate                              Jones, 1980
                                           (deoxyquinine)

    Ames test1         S.typhimurium       0-3000 µg/          Negative       Richold  et al.,
                       TA1535, TA1537      plate                              1981b
                       TA1538, TA98        (QCA/644)2
                       TA100

    Ames test1         S.typhimurium       0-3000 µg/          Negative       Richold  et al.,
                       TA1535, TA1537      plate                              1981c
                       TA1538,TA908,       (DQCA/678)3
                       TA100

    Micronucleus       Swiss Mice          70 mg/kg bw         Negative       Allen  et al.,
    test               Specific            (desoxyquinine)                    1984
                       Pathogen
                       Free CD-1
                                                                                                 

    1    Both with and without rat liver S-9 fraction
    2    QCA/644 is 2-(1', 3'-Dicarboxy-2'-hydroyprop-2'-quinine)
    3    DCQA/678 is 2-(1', 3'-Dicarboxy-2'-hydroxyprop-2'yl)desoxyquinine.
    

    2.2.8  Special study on teratology of deoxyquinine

    2.2.8.1  Rats

         Four groups of 30 specific pathogen free rats (CRL: cobs cd (SD)
    BR strain) from Charles River UK were dosed by oral gavage with either
    0, 6.67, 20 or 60 mg/kg bw/day of deoxyquinine during days 6 to 15 of
    gestation.  Twenty rats of each group were killed and the fetuses
    examined, with the remaining rats allowed to litter and undergo
    developmental assessment.  The mean litter sizes in the 6.67 and 60
    mg/kg bw/day groups were decreased, which was attributed to
    pre-implantation losses and not to treatment.  There was an increased
    percentage of fetuses with 14 ribs in the 60 mg/kg bw/day group. 
    There were no treatment-related developmental effects as assessed by
    surface righting reflex, pinna unfolding, incisor eruption, startle
    response, eye opening, air righting reflex, pupil reflex or startle
    response.  The authors concluded that there were no significant
    adverse treatment-related effects at the levels of deoxyquinine used
    in this study (Cozens  et al., 1981).

    2.2.8.2  Rabbits

         Four groups of 15 female New Zealand white rabbits were bred with
    untreated males and then dosed by gavage with either 0, 20, 40 or 80
    mg/kg bw/day of deoxyquinine during days 6-18 inclusive of gestation. 
    Prior to this study a preliminary study indicated that 135 mg/kg
    bw/day of deoxyquinine caused weight loss and death in rabbits.  In
    the teratology study, 3 animals of the 80 mg/kg bw/day group died
    shortly after dosing and in the other animals in this group there was
    reduced weight gain from days 10-23 of gestation compared to the
    controls.  There was no significant treatment-related developmental
    toxicity (Edwards  et al., 1982).

    2.2.9  Special study of ototoxicity

    2.2.9.1  Rats

         Diets containing the equivalent of either 0, 85 or 200 mg/kg
    bw/day of quinine hydrochloride were fed to 3 groups of 10
    cesarian-derived Sprague-Dawley (Charles River, CD) rats (5 of each
    sex) for 13 weeks.  There was a dose-related reduction in food
    consumption for females, some food reduction noted for the males and
    a dose-related reduction in body weight gain for all treated groups. 
    Auditory function was tested by pre-stimulus startle test at a
    frequency of 10 KHz and sound pressure level of 50 db, which revealed
    no group-related differences.  Electrocochleography tests showed some
    treatment and sex-related effects.  Detailed cochlear
    histopathological examinations were negative.  The authors concluded
    that exposure to quinine hydrochloride at the levels used in this
    study did not result in any permanent ototoxic effects (Colley
     et al., 1985).

    2.3  Observations in man

         Since quinine has a long history of drug use for the treatment of
    malaria, there are numerous reports on its toxicity in humans.  These
    reports are usually associated with overdoses of quinine (Brintin
     et al., 1980; Dyson  et al., 1985; Webster, 1985; Bateman & Dyson,
    1986; White, 1987, Orme, 1987; Bacon,  et al., 1988).  A fatal oral
    dose for adults is approximately 8 g, or 140 mg/kg bw.  At high (in
    the range of 1 g/day) repeated therapeutic doses, quinine produces a
    range of effects termed cinchonism which include auditory and visual
    disturbances, headache and nausea.  The auditory effects range from
    tinnitus to deafness, but milder symptoms usually resolve when intake
    of quinine is stopped.  Visual disturbances range from blurred vision
    to blindness and milder symptoms also generally resolve following
    cessation of intake of quinine. However, an acute overdose of quinine
    can result in permanent visual damage.  The recommended therapeutic
    administration of quinine is up to 650 mg three times per day
    (Webster, 1985).  There appear to be no reports of chronic toxicity
    resulting from normal therapeutic usage (Bateman & Dyson, 1986).

         Twenty normal adult volunteers (6 males and 14 females) consumed
    1.25 liters of tonic water containing 80 mg quinine hydrochloride/l,
    daily for 14 days (there were no controls).  Seven subjects complained
    of blurring of vision, five subjects complained of poor focussing and
    14 reported headaches.  There were significant changes in Goldman
    perimeter fields of vision which returned to pre-test condition upon
    re-examination 4 months after the end of the study.  There were no
    changes in visual acuity, audiometric records or blood chemistry
    values.  The mean plasma quinine levels on days 7 and 24 were 0.47 ±
    0.14 and 0.51 ± 0.16 µg/ml, respectively.  The authors concluded that
    "there were no auditory, visual or other effects that could be
    regarded as significant or irreversible" (Cantab Group and Medical
    Science Research, 1985).

         In a subsequent study, 2 groups of 5 subjects (adults of both
    sexes) consumed either 120 mg of quinine hydrochloride in tonic water
    or aerated drink free of quinine hydrochloride daily for 14 days.  No
    treatment-related complaints or adverse effects were reported.  The
    authors concluded that under the conditions of this study, 120 mg of
    quinine hydrochloride/day produced no adverse effects (Cantab Group
    and Medical Science Research, 1985).

         In a study designed to assess the correlation of low-dose quinine
    exposure to changes in electronystagmographic (ENG) recording,
    seventeen human subjects (4 control, 9 low dose, 4 high dose) were
    exposed to either 0, 52.5 or 105 mg of quinine per day from
    commercially prepared tonic water for two weeks. The authors reported
    that three of the four high dose subjects showed positional
    abnormalities on at least one ENG tracing while there were no effects
    in the low dose subjects (Zajtchuk  et al., 1984).

    3.  COMMENTS

         Biochemical studies, short-term studies in rats, teratology
    studies in rats, and mutagenicity studies were reviewed.  In these
    studies, no-effect levels ranged from 40 mg per kg bw per day to 100
    mg per kg bw per day.  Mutagenicity studies were negative.

         Varied complaints including headaches and transient visual
    problems were reported in human volunteer studies using doses of 100
    mg of quinine hydrochloride per person per day.  These findings were
    not confirmed in a second, controlled study using 120 mg per person
    per day.  A third study showed electronystagmographic changes in
    stressed subjects for which a no effect level of 52.5 mg quinine per
    person per day was determined.

         The Committee concluded that a Temporary ADI could be established
    on the basis of the human data.  In view of the fact that the toxicity
    of concern was acute and reversible in nature and that there is
    extensive experience of human consumption without reports of acute
    toxicity except very rarely in individuals with hypersensitivity, the
    Committee saw no need to require a margin of safety.

    4.  EVALUATION

         Level causing no toxicological effect
         Rats: 4O mg quinine hydrochloride/kg bw/day
         Humans:  0.9 quinine mg/kg bw/day.

         Estimate of temporary acceptable daily intake
         0-0.9 mg quinine/kg bw/day.

    5.  REFERENCES

    ALLEN, J.A., PROUDLOCK, R.J. & PUGH, L.C. (1984). Micronucleus test on
    desoxyquinine. Unpublished Report No. CBL/40A/84727 from Huntingdon
    Research Centre, Huntingdon, Cambridgeshire, England. Submitted to WHO
    by Cadbury Schweppes, Group Research, Reading, England.

    BIBRA (1979). An assessment of the carcinogenic and mutagenic
    potential of quinine hydrochloride by three short-term tests.
    Unpublished Report No. 259/l/79 from the British Industrial Biological
    Research Association, Carshalton, Surrey, England. Submitted to WHO by
    Cadbury Schweppes, Group Research, Reading, England.

    BACON, P., SPLATON, D.J. & SMITH, S.E. (1988). Blindness from quinine
    toxicity.  Br.J.Ophthalmol., 72, 219-224.

    BATEMAN, D.N. & DYSON, E.H. (1986). Quinine toxicity.  Adv. Drug
     React. Ac.Pois.Rev., 4, 215-233.

    BRINTIN, G.S., NORTON, E.W.D., ZAHN, J.R. & KINGHTON, R.W. (1980).
    Ocular quinine toxicity.  Am.J.Ophthalmol., 90, 403-410.

    CANTAB GROUP AND MEDICAL SCIENCE RESEARCH (1985). Report on the daily
    consumption for 14 days by normal subjects of tonic water containing
    quinine hydrochloride. Unpublished Nos. CS/1 and CS/Q/85/1 from Cantab
    Group, Cambridge Science Park, Cambridge, England, and Medical Science
    Research, Beaconsfield, Bucks, England. Submitted to WHO by Cadbury
    Schweppes, Group Research, Reading, England.

    COLLEY, J., EDMONDSON, J., HEYWOOD, R., & PRENTICE, D.E. (1982a).
    Quinine hydrochloride preliminary assessment of toxicity to rats by
    dietary administration for 4 weeks. Unpublished Report No.
    CBL/34/811063, from Huntingdon Research Centre, Huntingdon,
    Cambridgeshire, England. Submitted to WHO by Cadbury Schweppes, Group
    Research, Reading, England.

    COLLEY, J., EDMONDSON, J., HEYWOOD, R., STREET, A.E., PRENTICE, D.E.,
    SINGH, H., OFFER, J.M., GIBSON, W.A. & ANDERSON, A. (1982b). Quinine
    hydrochloride toxicity to rats in dietary administration over 13 weeks
    followed by a 6-week withdrawal period. Unpublished Report No.
    CBL/36/82740, from Huntingdon Research Centre, Huntingdon,
    Cambridgeshire, England. Submitted to WHO by Cadbury Schweppes, Group
    Research, Reading, England.

    COLLEY, J., PURSER, D., HEYWOOD, R., GOPINATH, C., ANDERSON, A. &
    CHANTER, D.O. (1985). Quinine hydrochloride: A study to assess
    ototoxicity to rats following dietary administration of 13 weeks.
    Unpublished Report No. CBL 39/8582, from Huntingdon Research Centre,
    Huntingdon, Cambridgeshire, England. Submitted to WHO by Cadbury
    Schweppes, Group Research, Reading, England.

    COZENS, D.D., EDWARDS, J.A., HUGHES, E.W. & OFLER, J.M. (1981). Effect
    of deoxyquinine on pregnancy of the rat. Unpublished Report No.
    CBL/22/81404 from Huntingdon Research Centre, Huntingdon,
    Cambridgeshire, England. Submitted to WHO by Cadbury Schweppes, Group
    Research, Reading, England.

    DYSON, E.H., PROUDFOOT, A.T., PRESCOTT, L.F. & HEYWORTH, R. (1985).
    Death and blindness due to overdose of quinine.  Br.Med.J., 291,
    31-33.

    EDWARDS, J.A., HUGHES, E.W. & CLARK, R. (1982). Effect of deoxyquinine
    on pregnancy of the New Zealand white rabbit. Unpublished Report No.
    CBL/25/26/8229 from Huntingdon Research Centre, Huntingdon,
    Cambridgeshire, England. Submitted to WHO by Cadbury Schweppes, Group
    Research, Reading, England.

    EDWARDS, J.A., LEEMING, N.M. & CLARK, R. (1984). Effect of quinine
    hydrochloride on pregnancy of the rat. Unpublished Report No. CBL
    39/83872, from Huntingdon Research Centre, Huntingdon, Cambridgeshire,
    England. Submitted to WHO by Cadbury Schweppes, Group Research,
    Reading, England.

    KING, M.T., BELKIRCH, H., ECKHARDT, K., GOCKE, E. & WILD, D. (1979).
    Mutagenicity studies with x-ray contrast media, analgesics,
    antipyretics, antirheumatics and some other pharmaceutical drugs in
    bacterial, Drosophila, and mammalian test systems.  Mut. Research,
    66, 33-43.

    LAPOINTE, G. & NOSAL, G. (1979). Saccharin- or quinine-induced changes
    in the rat pups following prolonged ingestion by the dam.
     Biol.neonate, 3, 273-276.

    MUNZNER, R. & RENNER, H.W. (1983). Mutagenicity testing of quinine
    with submammalian and mammalian systems.  Toxicology, 26, 273/178.

    ORME, M.L. (1987). Side effects of quinine and derivatives.  Acta
     Leidensia, 55, 77-86.

    RICHOLD, M. & JONES, E. (1980). Ames metabolic activation test to
    assess the potential mutagenic effect of deoxzquinine. Unpublished
    Report No. CBL 17/80313 from Huntingdon Research Centre, Huntingdon,
    Cambridgeshire, England. Submitted to WHO by Cadbury Schweppes, Group
    Research, Reading, England.

    RICHOLD, M., ALLEN, J.A., WILLIAMS, A. & RANSOME. S.J. (1981a). Cell
    transformation test for carcinogenicity of quinine hydrochloride.
    Unpublished Report No, CBL 19/80810 from Huntingdon Research Centre,
    Huntingdon, Cambridgeshire, England. Submitted to WHO by Cadbury
    Schweppes, Group Research, Reading, England.

    RICHOLD, M., JONES, E. & FLEMING, P.M. (1981b). Ames metabolic
    activation test to assess the potential mutagenic effect QCA/644.
    Unpublished Report No. CBL/24/81604 from Huntingdon Research Centre,
    Huntingdon, Cambridgeshire, England. Submitted to WHO by Cadbury
    Schweppes, Group Research, Reading, England.

    RICHOLD, M., JONES, E. & FLEMING, P.M. (1981c). Ames metabolic
    activation test to assess the potential mutagenic effect of DQCA/678.
    Unpublished Report No. CBL/28/82653 from Huntingdon Research Centre,
    Huntingdon, Cambridgeshire, England. Submitted to WHO by Cadbury
    Schweppes, Group Research, Reading, England.

    WARREN, S., HEYWOOD, R. GOPINATH, C. & BEGG, S.E. (1984). Quinine
    hydrochloride toxicity to rats in dietary administration over 13 weeks
    followed by a 6-week withdrawal period (addendum to Watson  et al.,
    1983). Unpublished Report No. CBL 37/84264, addendum to CBL 37/83629,
    from Huntingdon Research Centre, Huntingdon, Cambridgeshire, England.
    Submitted to WHO by Cadbury Schweppes, Group Research, Reading,
    England.

    WATSON, M., WARREN, S., HEYWOOD, R., STREET, A.E., GOPINATH, C.,
    ANDERSON, A. (1983). Quinine hydrochloride toxicity to rats in dietary
    administration over 13 weeks followed by a 6-week withdrawal period.
    Unpublished Report No. CBL 37/83629, from Huntingdon Research Centre,
    Huntingdon, Cambridgeshire, England. Submitted to WHO by Cadbury
    Schweppes, Group Research, Reading, England.

    WEBSTER, L.T., Jr. (1985). Drugs used in the chemotherapy of protozoal
    infections. In: A.G. Gilman, L.S. Goodman and A. Gilman (eds.). The
    Pharmacological Basis of Therapeutics, 6th ed. MacMillan, New York,
    pp. 1029-1048.

    WHITE, N.J. (1987). The pharmacokinetics of quinine and quinidine in
    malaria.  Acta Leidensia, 55, 65-76.

    WHITE, N.J., LOOAREESUWAN, S., WARRELL, D.A., WARRELL, M.J., BUNNAG,
    D. & HARINASUTA, T. (1982). Quinine pharmacokinetics and toxicity in
    cerebral and uncomplicated flaciparum malaria.  Am.J.Med., 73,
    564-572.

    ZAJTCHUK, J.E., MIHAIL, R., JEWELL, J.S., DUNNE, J.J. & CHADWICK, S.G.
    (1984). Electronystagmographic findings in long-term low-dose quinine
    ingestion.  Arch.Otolaryngol., 11, 788-791.


    See Also:
       Toxicological Abbreviations
       QUININE HYDROCHLORIDE (JECFA Evaluation)