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    CHLORPROMAZINE

    First Draft prepared by
    Dr. Radovan Fuchs, Institute for Medical Research
    and Occupational Health, University of Zagreb, Yugoslavia

    1.  EXPLANATION

           Chloropromazine belongs to the group of phenothiazine
    derivatives. It is widely used in human medicine in the therapy of
    schizophrenia, organic psychoses and the manic phase of
    manic-depressive illness. In veterinary medicine it is used as a
    tranquillizer and antiemetic agent. This compound has not been
    previously evaluated by the Joint FAO/WHO Expert Committee on Food
    Additives.

    CHEMICAL STRUCTURE

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

    2.1.1  Absorption, distribution and excretion

           Intestinal absorption of chlorpromazine is complete but it is
    variably metabolized during its passage through the intestinal wall.
    More than 90% of the drug in plasma is bound to proteins. It is
    metabolized mainly in liver, and there is an indication that it may
    accelerate its own hepatic metabolism or conjugation; in humans,
    after several weeks of treatment, the concentration of
    chlorpromazine in blood is lower with level dosage. After being
    absorbed the drug is widely distributed in the body and its
    lipophilicity allows it to achieve sufficient intra-membrane
    concentration to influence the stability or fluidity of the cell
    membrane (Baldessarini, 1975).

           The major metabolic pathways of chlorpromazine are
    hydroxylation and conjugation with glucuronic acid. Oxidative
    processes, as well, play a very important role in biotransformation
    of the drug, and the sulfoxide form possesses about one-eighth the
    sedative action of the parent drug in dogs (Booth, 1988). Among 10
    to 12 metabolites occurring in man (Baldessarini, 1975) N-oxide
    metabolites undergo significant reduction back to the parent
    compound in a number of species including man (Jaworski et al.,
    1990).

           The biological half-life of chlorpromazine is about 6 hours in
    dogs. After intravenous administration of 2.5 mg/kg b.w. of
    chlorpromazine to the goat the plasma elimination half-life is 1.51
     0.48 hours (Nawaz, 1981). In the goat, the concentration of the
    drug is higher in milk than in plasma (Nawaz & Rasmussen 1979). 
    After the drug was administered intravenously or orally to horses
    its metabolites were detected in urine for up to 96 hours. Only 10%
    or 27% of the dose, respectively, is recovered in the urine of
    horses following an intravenous or oral administration (Booth,
    1988).

    2.2  Toxicological studies

    2.2.1  Acute studies
        Table 1.  Acute toxicity of chlorpromazine
                                                                                            

    Species     Sex       Vehicle       Route          LD50          Reference
                                                     (mg/kg b.w.)
                                                                                            

    Mouse        *          *           p.o.           135           Nagai et al., 1976
                 *          *           i.p.           136           Fujimori & Cobb,
                                                                     1965
                 *          *           i.p.           115           Herr et al., 1985
                 *          *           i.v.            51           Domenjoz &
                                                                     Theobald, 1959
                M&F         *           i.v.            20           Casagrande et al.,
                                                                     1971

    Rat          *          *           p.o.           210           Irwin et al., 1959
                 *          *           i.p.            71
                 *          *           i.v.            49           Domenjoz &
                                                                     Theobald, 1959
                 *          *           i.v.            23           Irwin et al. 1959

    Rabbit       *          *           i.v.            16           Domenjoz &
                                                                     Theobald, 1959

    Dog          *          *           i.v.            30           Irwin et al. 1959
                                                                                            
    *   Details not reported
    
    2.2.2  Short-term studies

    2.2.2.1  Guinea pigs

           Groups of 8 male and female guinea pigs were injected
    intraperitioneally with chlorpromazine dissolved in physiological
    saline at a dose of 30 mg/kg b.w./day for 7 consecutive days. The
    animals were killed by decapitation on the 8th day after first
    dosing. Necropsies were performed and tissue samples were taken from
    ileum, colon and caecum only.

           In 7 out of 8 animals numerous delicate fibrous adhesions at
    the peritoneal surface were seen. Focal areas of haemorrhage were
    found on the peritoneal surface of the caecum. Histopathologically,
    occasional fibrous adhesions without other changes were observed in
    ileum and colon. In 4 out of 8 animals the caecum showed marked
    submucosal oedema. In some areas inflammatory changes and
    haemorrhages were observed (Szanto et al., 1988).

    2.2.3  Long-term/carcinogenicity studies

           Data not available.

    2.2.4  Reproduction studies

    2.2.4.1  Mice

           Chlorpromazine was given orally at a dose of 16 mg/kg b.w./day
    throughout the pregnancy period of C57BL10 mice. A decreased number
    of pregnancies, increase in days between mating and birth and
    reduced weight gain throughout pregnancy were noted. Maternal brain
    weight, liver glycogen and serum cholesterol were reported to be
    changed after chlorpromazine treatment. Statistically significant
    differences were observed in mean litter weights, brain, liver,
    heart, organ to body weight ratios, and serum and organ biochemistry
    of offspring between chlorpromazine-treated and control groups. The
    details were not given in the report (Rolsten, 1967).

           Forty-four newborn LACA strain mice were injected
    subcutaneously with a single dose of 20 mg/kg b.w. chlorpromazine
    disolved in distilled water on days 4, 6, 7, 8, 9, and 10 after
    birth. The animals were killed at 30 days of age. Testes and seminal
    vesicles were removed, weighed and examined histopathologically. A
    group of 7 untreated mice was used as control. A general increase in
    the proportion of tubules which contained spermatids, spermatozoa,
    and luminal spermatozoa was observed. The most prominent effect was
    seen in animals injected at day 7. In this group of animals a
    greater testis weight and seminal vesicle weight was noticed as
    well. Generally it was shown that the single injection of
    chlorpromazine at a dose of 20 mg/kg b.w., when administered up to
    the 10th day of life, accelerated sexual maturation of male mice
    (Hogarth & Chalmers, 1973).

           Two groups of 20 female inbred C5BL/10 mice received orally 4
    or 16 mg/kg b.w./day of chlorpromazine throughout the period of
    pregnancy. Control groups consisting of the corresponding number of
    animals were treated with the same volume of placebo. The treatment
    with chlorpromazine started on the 6th day after mating. All the
    animals were tested daily in the open field test for exploration and
    activity level. Effects of the drug on delays between mating and
    birth, drug-induced changes in maternal weight, and litter size and
    weight were recorded.

           There was no statistically significant difference in body
    weight of dams among the groups at the time of birth. No difference
    was observed in behaviour between the animals of the 4 mg/kg
    b.w./day group compared to the controls. In the 16 mg/kg b.w./day

    group frequent sedation lasting 1 to 5 hours was noticed after
    treatment. In the high-dose group, animals showed a statistically
    significant delay between mating and birth, and treated animals had
    a significantly lower number of offspring. When the two dose levels
    were combined, the mean litter weights were also significantly lower
    than the mean weight of litters from control dams (Orday et al.,
    1963).

    2.2.4.2  Rats

           A group of 24 male albino rats  (Rattus norvegicus) was given
    chlorpromazine i.m. at a dose of 1 mg/animal/day, equivalent to
    5 mg/kg b.w./day (calculated on a rat weight of 200 g), for 7 or 15
    consecutive days.  Groups consisting of 12 rats served as controls.
    On day 8 or 16 animals were killed and necropsied. Testes, caput and
    cauda epididymis were excised, blotted free of blood, weighed and
    used for biochemical studies.

           Significant decreases in the weight of testes, caput and cauda
    epididymides were observed as well as altered activity of some
    androgen dependent enzymes. An overall decrease in the level of free
    ascorbic acid, succinate  dehydrogenase, alkaline phosphatase and
    increases of acid phosphatase and cholesterol level in testis and
    epididymides were seen (Clinoy & Seethalakshmi, 1977).

           Chlorpromazine was given i.m. to female rats on the 4th day of
    pregnancy at a dose of 20 mg/kg b.w. It was found that the drug
    disturbed the late stage of pregnancy. Details were not reported
    (Bovet-Natti & Bovet, 1959).

           A separate study testing sexual behaviour was performed on
    twelve 150-day-old Sprague-Dawley male rats. Chlorpromazine was
    injected intraperitoneally at a single dose of 2.5 mg/kg b.w. 
    Placebo consisted of equivalent volume of distilled water injected
    to twelve control animals. It was found that treatment with
    chlorpromazine reduced the number of copulations preceding
    ejaculation. The number of copulations/minute, or rate of
    copulations, was significantly reduced (Gillett, 1960).

    2.2.5  Special studies on genotoxicity

        Table 2.  Results of genotoxicity assays on chlorpromazine
                                                                                               

    Test system       Test object          Concentration     Result       Reference
                                                                                               

    Chromosomal       Human                0.24-2.0 g/ml    positive     Jin-fu et al.
    aberration        lymphocytes                                         1988
    assay

    SRCE              Human                0.25-2.0 g/ml    positive     Jin-fu et al.
                      lymphocytes                                         1988

    Ames test1        S. typhimurium       5-10 g/ml        positive     Obaseiki-Ebor
                      TA97 his, TA                                        & Akerele,
                      102 his, EE97,                                      1988
                      EE102
                      transconjugates)

    Fluctuation       E. coli              2-4 g/ml         positive     Obaseiki-Ebor
    test                                                                  & Akerele,
                                                                          1988
                                                                                               

    1.   With rat liver S9 fraction
    
    2.2.6  Special studies on embryotoxicity and teratogenicity

    2.2.6.1  Mice

           Groups of 10 pregnant 3-month-old mice were given
    chlorpromazine at a dose of 1.8 and 9.2 mg/kg b.w./day. The drug was
    injected intraperitoneally once daily from the 6th to the 16th day
    of gestation. The mice were killed 2 or 3 days before parturition.
    The average growth weight, increased body weight and fetal
    malformations were recorded. A negative control group receiving
    0.3 ml saline and a positive control group receiving 0.3 ml of
    cod-liver oil containing vitamins A and D were injected with
    corresponding solutions in the same way and at the same gestation
    days as drug-treated groups.


           Incidence of abnormal mouse fetuses  was significantly higher
    in treated groups and positive controls when compared to the
    negative control group. Mean body weight of fetuses from treated
    dams was lower. The percentage of malformed fetuses was 38.5% in the
    low-dose and 42.9% in the high-dose group, 0% in the negative
    control and 28.6% in the positive control group. A description of
    the malformations was not given (Jin-fu et al., 1988).

    2.2.6.2  Rats

           Female CF rats were given chlorpromazine intraperitoneally at a
    single dose of 100 mg/kg b.w. on the 14th day of gestation. The
    controls were injected with a corresponding volume of physiologic
    saline. The number of treated animals was not given. Between the
    16th and the 20th day of gestation the fetuses were collected by
    uterotomy. Only living fetuses and intact preparations were used in
    this study.

           It was found that ossification was delayed by 1 to 3 days in
    the long bones of the extremities, by 1 day in scapulae and by 2 to
    3 days in the ileum. Ischium and pubis remained unossified until the
    20th day of gestation. Ossification of the skull bones was also
    delayed. The sternebrae were found to be most affected (Singh &
    Padmanabhan, 1979).

           Six compounds have been studied for teratogenic potential on
    Wistar/H-Riop pregnant rats. Groups of 5 pregnant rats were given
    single oral equimolar doses of 3.7 x 10-4M/kg b.w. of perphenzine;
    chlorpromazine; chlorcyclizine; thenalidine; haloanisone and
    haloperidol. The dose of chlorpromazine coresponded to 0.585 mg/kg
    b.w. The drugs were given to the animals on the 13th, 14th or 15th
    day of gestation respectively. Mothers were killed on the 21st day
    of pregnancy. Resorption, living and dead fetuses, fetal weight and
    external malformations were recorded.

           Higher fetal mortality (P<0.01) was observed in the
    chlorpromazine treated group compared to controls. The weight of
    fetuses was significantly lower (P<0.01) as well. The data indicate
    an embryotoxic effect of the drug in rats (Druga et al., 1980).

           Groups composed of 19-20 pregnant CAW; CFE (SD) rats were
    treated with chlorpromazine from day 6 through day 15 of gestation.
    Tablets of the drug were pulverized and administered to the animals
    orally in 2.5% aqueous Tween solution. The dose was adjusted so that
    each group received 5, 25 or 35 mg/kg b.w./day chlorpromazine. On
    day 21 of pregnancy the dams were killed and the offspring removed.
    The numbers of live fetuses, resorptions and nidations, sex and
    weight of each live fetus were recorded.

           The average litter size in the high-dose group was
    significantly lower (P<0.05), and the percentage of resorption in
    the intermediate and high-dose groups was higher (P<0.01), than in
    controls. Compared to the controls the body weight of pups was found
    to be lower than of low- and intermediate-dose groups (P<0.01), 
    but not of the high-dose group. In one pup of the low-dose group
    malformations were recognized: absence of tail, and 3 posterior
    lumbar vertebrae, and disturbance in ossification of vertebrae
    (Beall, 1972).

           Groups of Charles River CD female rats consisting of 20 mated
    rats each were given 1, 3 or 9 mg/kg b.w./day chlorpromazine orally
    by gavage from day 6 through 15 of gestation. Two identical groups
    receiving 0.5% aqueous methylcellulose served as control. One half
    of the animals were killed on day 21 of gestation and fetuses were
    examined for external abnormalities. Remaining females were allowed
    to deliver. Two male and two female pups in each litter were
    randomly selected for evaluation of physical development, behaviour
    and reproduction performance. The remaining animals were autopsied
    at 15 or 16 weeks of age.

           In females dosed with 9 mg/kg b.w./day decreased activity was
    observed 2 to 4 hours postdosing. There were no changes in
    reproductive status of females at caesarian section, or in average
    fetal weight. No teratogenic effects were observed. In females which
    were allowed to deliver no alterations were observed in the length
    of gestation and number of live and dead pups per litter on day 1
    postpartum. Statistically significant decreases were found in
    average pup weight of 3 and 9 mg/kg b.w./day groups but no
    dose-response relationship was observed. There was no
    treatment-related change in the postnatal development of pups. 
    Average organ weights of F1 offspring were comparable among the
    groups including controls. No effect on mating performance,
    reproductive status of females at term, number of live offspring and
    average pup weight was reported. Significantly increased activity in
    an open field test was observed in the 9 mg/kg b.w./day group in
    week 7 postpartum. The same was observed in the 3 mg/kg b.w./day
    group in the 13th week postpartum. There was a significant decrease
    in latency time in intermediate and high-dose groups in weeks 3 and
    13 postpartum. No histopathological changes were observed in the
    brains of treated rats. The NOEL for teratogenicity in this study
    was 9 mg/kg b.w./day (Robertson et al., 1980).

           Sprague-Dawley pregnant rats were given orally 20 mg/kg
    b.w./day of chlorpromazine hydrochloride from day 6 to day 20 of
    gestation. Control group animals received the same amount of vehicle
    (saline) in the same manner. Dams were weighed on day 0 and every 3
    days from day 6 of gestation to day 21 of gestation. Data concerning
    length of gestation, litter size, sex distribution, weight and
    number of dead or malformed offspring were recorded. Behavioural
    testing was performed on all offspring.

           No significant effect was observed on maternal weight,
    gestation length, litter size, sex distribution within litters, or
    offspring mortality. External examination did not reveal any
    malformations of offspring. There were no significant differences
    between the treated and control group in the measurements of
    physical parameters. The chlorpromazine treated group showed
    significant enhancement at day 6 in the righting reflex (P<0.01).
    Swimming angle development was improved in the treated group on days
    6 (P<0.05) and 8 (P<0.01). In the negative geotaxis test no
    significant effect was observed. Ambulation in chlorpromazine
    treated females was increased (P<0.05) on postnatal day 35. On day
    22 the rotorod performance of males was significantly lower
    (P<0.05) but not that of females. No difference was observed among
    the groups in water maze, pupil contraction and auditory startle
    responses. Among the animals from the treated group, when compared
    to controls, significantly lower nocturnal activity (P<0.01) was
    seen. Biochemical results revealed no differences in noradrenalin or
    dopamine contents, but there was a significant reduction in whole
    brain DNA concentration. Histopathologically, no changes in the
    brains of treated rats were reported (Saillenfait & Vannier, 1988).

           Eleven pregnant Sprague-Dawley rats were injected with
    chlorpromazine subcutaneously on days 4 through 7 of gestation. The
    drug was dissolved in distilled water and injected three times a day
    at a total daily dose of 6 mg/kg b.w./day. A control group of 11
    animals received distilled water only. No significant differences in
    litter size were seen. In the chlorpromazine-treated group
    significantly more deaths occurred compared to controls. Offspring
    from treated animals showed decreased motor activity and increased
    audiogenic seizure. No histomorphological changes in brains of
    animals were observed (Jewett & Norton, 1966).

    2.2.7  Special studies on immune responses

           A group of male Wistar rats was preimmunized using
    chlorpromazine-haemocyanin conjugate, precipitated with 2% aluminium
    hydroxide gel, injected at a dose of 3 mg into the Payer's patches
    of the small intestine. Two to seven days after injection the
    animals were fed diet containing chlorpromazine hydro-chloride at
    25 mg/kg b.w./day. A second group of nonimmunized rats received the
    same diet and the control group the diet without chlorpromazine. All
    rats were fed the chlorpromazine diet for 65, 75, or 90 days and
    were returned to a normal diet 3 days before killing. Blood, bile,
    liver and in some cases other organs were collected and analyzed.

           Elevated IgA antibodies in bile were found in 7 out of 10
    immunized animals. Anti-chlorpromazine antibodies were also found in
    serum but the class of antibodies was not determined. No significant

    gross pathology was observed. Histopathologically in the livers of
    some animals fed chlorpromazine diet periportal loss of glycogen,
    focal fatty changes and increased cellularity were seen (Mullock et
    al., 1983).

    2.3  Observations in man

           Therapeutic doses of chloropromazine may cause orthostatic
    hypotension in humans which may result in syncope. Obstructive type
    of jaundice was observed, at an incidence of 2-4%. Biopsies showed
    centrolobular cholestasis, with mild inflammatory response.
    Eosinophilia and eosinophilic infiltrations of the liver were
    frequently observed. During the chlorpromazine treatment
    leukocytosis and leukopenia have been observed, but in not more than
    1 out of 10 000 patients. This complication was more frequently
    observed during the first 6 weeks of treatment and more often in
    older women than in men.

           In patients receiving chlorpromazine therapy dermatological
    reactions were frequently observed. Urticaria or dermatitis was
    detected in about 5% of patients and 3 types of skin disorders were
    generally observed: hypersensitivity reaction, contact dermatitis
    and photosensitivity. Hypersensitivity reaction that may be
    urticarial, maculopopular, petechial and oedematous occurred usually
    between the first and eighth weeks of treatment. Contact dermatitis
    could be seen in personnel handling chlorpromazine but there is a
    possibility of cross-sensitivity to other phenothiazines. During
    long-term therapy of schizoprenic patients chlorpromazine can induce
    abnormal pigmentation of the skin which is manifested as gray-blue
    pigmentation in regions exposed to sunlight. Epithelial keratopathy
    and opacities in the cornea and in the lens of the eye were also
    noted (reviewed in Baldessarini, 1975; Davies, 1985).

           During chlorpromazine therapy interference of the drug with
    human female pituitary-gonadal function as evidence by development
    of lactorrhea and amenorrhea was reported as well. 

           This effect was associated primarily with the use of large 
    doses of chlorpromazine (Rudel & Kind, 1966).

    3.  COMMENTS

           Chlorpromazine has a broad spectrum of pharmacological
    activity. It produces behavioural changes and blocks many cell
    membrane receptors, notably those for dopamine and norpinephrine. 
    Besides its tranquillizing and sedative actions, it has a number of
    other pharmacological effects and shows synergism with other classes
    of central nervous system depressants. Chlorpromazine appears to be
    variably absorbed but is metabolized in the gut as well as in the
    liver, where it can accelerate its own metabolism or conjugation. 
    After being absorbed, the drug is widely distributed in the body and
    its lipophilicity allows it to achieve a high enough intra-membrane 
    concentration to influence the stability or fluidity of cell
    membranes. In the blood, more than 90% of the drug is bound to
    plasma proteins. It is metabolized by oxidation, demethylation, and
    hydroxylation, together with conjugation with glucuronic acid,
    leading to the formation of a sulfoxide, which was found to possess
    about one-eighth of the sedative action of the parent drug in the
    dog. N-Oxide metabolites on the other hand, undergo significant
    reduction in a number of species including humans to produce the
    parent compound again. In humans, chlorpromazine and its metabolites
    can be detected in urine for 6-18 months after termination of
    treatment.

           Although the drug was introduced into clinical use in the
    1950s, and a number of papers on it have been published since, there
    was a general lack of relevant toxicological data for evaluation.

           The intravenous LD50 (median lethal dose) of chlorpromazine
    was 20, 23, 16, and 30 mg/kg b.w. in mice, rats, rabbits and dogs
    respectively.

           Data from short-term, long-term, and carcinogenicity studies
    were not available to the Committee. Limited recent studies suggest
    that chlorpromazine may be genotoxic, as shown by microbial
    genotoxicity tests and by tests in human lymphocytes in culture. In
    addition, it has been established that certain reactive metabolic
    intermediates are capable of binding to macromolecules, including
    DNA.

           The Committee noted that there were a number of published
    reports, often containing contradictory results, on the effects of
    chlorpromazine on reproduction and fetal development in experimental
    animals, and on its behavioural effects on pups whose mothers had
    been treated during fetal development. While the design of most of
    these studies makes them inappropriate for evaluation, the concerns
    to which they give rise cannot be ignored.

           Since chlorpromazine has been in use for such a long period of
    time a number of published reports are available on the toxicity and
    side-effects of the drug in humans. Therapeutic doses may cause a
    number of side-effects in the circulatory and nervous systems, and
    adverse effects on blood cells, the skin, and the eye. Interference
    with human pituitary and gonadal function results in galactorrhoea
    and amenorrhoea.

    4.  EVALUATION

           In view of the lack of relevant toxicological data, the
    long-term persistence of chlorpromazine in humans, the spectrum of
    additional effects of the drug, and the probability that even small
    doses can cause behavioural change, the Committee was unable to
    establish an ADI. Furthermore the Committee suggested that
    chlorpromazine should not be used in food producing animals.

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    See Also:
       Toxicological Abbreviations
       CHLORPROMAZINE (JECFA Evaluation)
       Chlorpromazine (PIM 125)