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    CHLOROPROPANOLS

    First draft prepared by
    Dr P.  Olsen
    Institute of Toxicology, National Food Agency of Denmark
    Ministry of Health, Soborg, Denmark

    1.  EXPLANATION

          Certain chlorinated propanols occur as contaminants in
    hydrolyzed vegetable proteins.  The two substances considered by the
    Committee at its present meeting were 3-chloro-1,2-propanediol and
    1,3-dichloro-2-propanol, neither of which has previously been
    evaluated by the Committee.  Processing of defatted vegetable
    proteins by traditional hydrochloric acid hydrolysis leads to the
    formation of significant amounts of 3-chloro-1,2-propanediol and
    1,3-dichloro-2-propanol.  However, manufacturing techniques have
    been improved, enabling the reduction of the level of 3-chloro-1,2-
    propanediol to less than 2 mg/kg and that of 1,3-dichloro-2-propanol
    to less than 0.02 mg/kg in hydrolyzed vegetable proteins.

          Because this monograph covers the data considered by the
    Committee on both 3-chloro-1,2-propanediol and 1,3-dichloro-2-
    propanol, a modified form of the general monograph format has been
    used, presenting separately the biological data for each.

    3-CHLORO-1,2-PROPANEDIOL

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

    2.1.1  Absorption, distribution, and excretion

          3-chloro-1,2-propanediol was able to cross the blood-testis
    barrier, blood-brain barrier and was distributed widely in body
    fluids (Edwards  et al. 1975).  Accumulation of 3-chloro-1,2-
    propanediol was seen in the cauda epididymis of rats and to a lesser
    extent in mice through autoradiography (Crabo & Appelgren, 1972). 
    This finding was disputed by Jones  et al., (1978), who did not
    observe any tissue-specific retention of radioactivity in rats
    injected intraperitoneally with 100 mg/kg bw 36C-labelled
    3-chloro-1,2-propanediol.  Neither 3-chloro-1,2-propanediol nor the
    metabolite ▀-chlorolactate was accumulated in the tissue (Jones
     et al., 1978).

          A single intraperitoneal injection of 100 mg/kg bw of
    14C-labelled 3-chloro-1,2-propanediol was given to male Wistar
    rats.  After 24-hours 30% of the dose was exhaled as 14CO2 and
    8.5% was excreted unchanged in the urine (Jones, 1978).  In another
    study in rats which were injected intraperitoneally with a single
    dose of 100 mg/kg bw 36C-labelled 3-chloro-1,2-propanediol, 23% of
    the radioactivity was recovered in the urine as ▀-chlorolactate
    (Jones  et al., 1978).

    2.1.2  Biotransformation

          3-chloro-1,2-propanediol is detoxified by conjugation with
    glutathione yielding S-(2,3-dihydroxypropyl)cysteine and the
    corresponding mercapturic acid, N-acetyl-S-(2,3-dihydroxypropyl)
    cysteine (Jones, 1975).  3-chloro-1,2-propanediol undergoes
    oxidation to ▀-chlorolactic acid and further to oxalic acid (Jones
    and Murcott, 1976).  Formation of an intermediate metabolite,
    ▀-chlorolactaldehyde may also take place as traces of this substance
    have been determined in the urine in rats (Jones  et al., 1978). 
    The intermediate formation of an epoxide has been postulated, but
    not proven (Jones, 1975).

    2.1.3  Effects on enzymes and other biochemical parameters

          The activity of all glycolytic enzymes in the epididymal and
    testicular tissue was reduced in rats given daily subcutaneous
    injection of 6.5 mg/kg bw/dy 3-chloro-1,2-propanediol for 9 days
    (Kaur & Guraya, 1981a).

          Ram sperm incubated with 3-chloro-1,2-propanediol has shown
    that 3-chloro-1,2-propanediol inhibits the glycolysis of spermatozoa
     in vitro (Brown-Woodman  et al., 1975), possibly a result of
    indirect inhibition of glyceraldehyde-3-phosphate dehydrogenase

    (Suter  et al., 1975; Mohri  et al., 1975).  Decrease in the
    spermatozoa glycolytic enzymes was suggested to be a result of
    altered epididymal milieu (Kuar & Guraya, 1981b).

          Rats receiving daily doses of 6.5 mg/kg bw 3-chloro-1,2-
    propanediol for a period of 9 days showed significantly decreased
    (p<0.05) levels of RNA and protein in the testis and epididymis and
    the observations were closely related to a parallel increase in the
    concentration of proteinase and ribonuclease.  The DNA content was
    unchanged (Kaur & Guraya, 1981c).

    2.2  Toxicological studies

    2.2.1  Acute toxicity studies

          The oral LD50 of 3-chloro-1,2-propanediol was reported to be
    152 mg/kg bw in rats (Ericsson & Baker, 1970).

    2.2.2  Short-term toxicity studies

    2.2.2.1  Rats

          Groups of 8 male Fisher 344 rats were treated with a single
    subcutaneous injection of 75 mg/kg bw 3-chloro-1,2-propanediol and
    killed after 24 hours, 3, 8, 25, and 75 days, respectively.  A
    slight but significant (p<0.05) increase in liver weight was
    observed after 24 hours while this finding was not found at later
    sacrifices.  Histologically the hepatocytes showed mild to moderate
    cytoplasmatic swelling in the periportal area (Kluwe  et al.,
    1983).

          Intraperitoneal injection of a single dose of 100 mg/kg bw
    3-chloro-1,2-propanediol caused a increased diuresis for up to 15
    days in male Sprague-Dawley rats.  Higher doses (figure not
    reported) caused anuresis and death, and histological examination of
    the kidney showed acute glomerular nephritis.  The type of kidney
    lesions was characteristic of oxalic acid poisoning and crystals
    characteristic of calcium oxalate were seen by microscopical
    examination of the urine.  Oral treatment with 10 mg/kg bw/dy
    3-chloro-1,2-propanediol for five consecutive days did not cause any
    increased diuresis in rats (Jones  et al., 1978).

          Another study showed that intraperitoneal injection of 100 and
    120 mg/kg bw 3-chloro-1,2-propanediol caused severe proteinuria and
    glucosuria in male Wistar rats.  Oliguria and anuria were observed
    and 4/9 animals died.  The 5 surviving animals showed decreased
    appetite and body weight, proteinuria, dose-related diuresis and
    increased water intake (Morris and Williams, 1980).

          Testing of (R)- and (S)-isomers of 3-chloro-1,2-propanediol,
    synthesized under laboratory condition, has shown that only the
    (R)-isomer induced a period of diuresis and glucosuria in rats
    (Porter and Jones, 1982).

          Oxalic acid, a metabolite of 3-chloro-1,2-propanediol, appeared
    to play a important role in the development of kidney damage (Jones
     et al., 1979).  Birefringent crystals characteristic of calcium
    oxalate present in tubules at the cortico-medullary junction were
    early (1 day) morphological changes seen in rats treated with a
    single subcutaneous injection of 75 mg/kg bw 3-chloro-1,2-
    propanediol.  On day 75 focal tubular necrosis, regeneration, and
    tubular dilatation were observed in the kidney (Kluwe  et al.,
    1983).

          Groups of 20 Sprague-Dawley rats of each sex were given 0, 30,
    or 60 mg/kg bw/dy 3-chloro-1,2-propanediol by gavage 4 x 5 days over
    a period of 4 weeks.  10 animals/group and sex were sacrificed on
    day 2 and examined for clinical chemical parameters in the blood. 
    On day 2, rats of the high-dose group showed elevated activity of
    serum glutamate-pyruvate-transaminase (males, p<0.05; females,
    p<0.001), and elevated levels of creatinine (females, p<0.001),
    urea and glucose (females, p<0.05).  On day 25, treated rats
    exhibited elevated activity of glutamate-pyruvate-transaminase
    (males high-dose, p<0.001; females low and high-dose, p<0.001),
    and elevated serum urea in high-dose males (p<0.001) and females
    (p<0.05).  Statistically significant (p<0.05 or lower) decreased
    values of haemoglobin and haematocrit of treated male and female
    rats were observed.  Female rats in the high-dose group had
    decreased erythrocyte count (p<0.001).  Treated rats showed lowered
    body weight gain, which at termination of the study was
    statistically significant (statistics not reported).  After 2 days
    of treatment the relative organ weights of the kidney were elevated
    (p<0.001), (males high-dose; females low and high-dose).  On day 25
    treated rats had significantly elevated relative weights of the
    kidney, liver, and testis (males high-dose) (p<0.01 or 0.001). 
    Histopathological examination revealed chronic progressive
    nephropathy of 8 females in the high-dose group, mild tubular
    dilatation in the testis of 3 males in the low-dose group and 7 in
    the high-dose group.  One male in the high-dose group had severe
    atrophy of both testes (Marchesini and Stalder, 1983).

          Groups of 20 Fisher 344 rats of each sex were administered
    3-chloro-1,2-propanediol in their drinking water at concentrations
    of 0, 100, 300, or 500 mg/l over a period of 90 days.  The exposure
    corresponded to average daily intake levels of 9, 27 and 43 mg/kg bw
    3-chloro-1,2-propanediol in males and 11, 31, and 46 mg/kg bw
    3-chloro-1,2-propanediol in female rats.  Ten animals of each
    sex/group were sacrificed (interim sacrifice) after 30 days of
    treatment.  Clinical chemical and haematological parameters were

    determined.  Histopathological examinations were carried out on the
    high-dose and control groups.

          A slight anaemia (p<0.05 or 0.001) was evident in the middle-
    and high-dose females after 30 days and in rats of both sexes after
    90 days of treatment (p<0.05 or 0.01).  However, no morphological
    evidence of impaired haematopoiesis nor increased degradation of
    erythrocytes were observed.  A dose-dependent decrease (p<0.01) in
    plasma creatinine of both sexes (middle and high-dose groups) was
    seen after 30 days of treatment and at terminal sacrifice in all
    treated groups (p<0.05 or 0.01).  Serum phosphate levels in
    high-dose male rats were increased at interim (p<0.01) and terminal
    sacrifice (p<0.05).  A statistically significant (p<0.01)
    dose-dependent increase in relative organ weights was found for the
    kidney and liver, and the increase of the relative kidney weight was
    significant at the lowest dose level.  Histopathological examination
    of the high-dose and control groups revealed a lower incidence of
    crystalline precipitations in the kidneys of treated animals
    compared to the controls.  In the livers of dosed rats, single
    hepatocytes with 2-3 nuclei were noted in about half of the males
    after 90 days of treatment.  In the epididymis an increased number
    of exfoliated spermatozoids of treated male rats was observed
    (Marchesini  et al., 1989).

    2.2.2.2  Monkeys

          Three out of 6 monkeys given 30 mg/kg bw 3-chloro-1,2-
    propanediol perorally/day for 6 weeks showed haematological
    abnormalities: anaemia, leukopenia and severe thrombocytopenia
    (Kirton  et al., 1970).

    2.2.3  Long-term toxicity/carcinogenicity studies

    2.2.3.1  Mice

          A group of 50 female mice (CHR/Ha Swiss) was injected
    subcutaneously with 1 mg 3-chloro-1,2-propanediol/mouse/week over a
    period of 580 days.  A second group of 50 mice was treated 3x/wk
    with 2 mg 3-chloro-1,2-propanediol (dissolved in acetone)/mouse by
    topical application.  No changes were observed in the group treated
    by dermal application.  After subcutaneous application, local
    sarcomas were found at the site of application in one dosed and one
    control mouse (Van Duuren  et al., 1974).

    2.2.3.2  Rats

          Three groups of 26 male and female Charles River CD rats
    received 0, 30, or 60 mg 3-chloro-1,2-propanediol by gavage twice
    weekly.  After 10 weeks the doses were increased to 35 and 70 mg/kg
    bw.  The animals were treated for 72 weeks and the study was
    terminated after 2 years.  Three parathyroid adenomas were found in

    male rats at the high-dose level.  However, this finding was not
    statistically significant when compared with the control group.  The
    authors did not find the result conclusive indication that
    3-chloro-1,2-propanediol is a parathyroid carcinogen.  While the
    females showed no signs of toxicity, dosed male rats showed a higher
    mortality.  All male rats at both dose levels showed severe
    testicular degeneration and atrophy (Weisburger  et al., 1981).

          Four groups of Fisher F344 rats (50 animals/sex/group, SPF
    quality, 5-6 weeks old at start of the study, 11 days
    acclimatization period prior to study initiation) received either 0,
    20, 100, or 500 ppm 3-chloro-1,2-propanediol (equivalent to a mean
    daily intake of 0, 1.1, 5.2, 28 mg/kg bw/day for males and 0, 1.4,
    7.0, or 35 mg/kg bw/day for females) in their drinking water (tap
    water) for a period of 104 weeks.  Feed and tap water were provided
     ad libitum.  Feed was certified laboratory chow, feed contaminants
    were within acceptable range according to EPA, USA.  Test substance
    was 3-chloro-1,2-propanediol, 98% pure, one batch used for the
    entire study.  Stability: more than 4 days in water, test solution
    was prepared twice a week and tested once per group per week.  Tap
    water contaminants: a mean concentration of 2.7 ppm 3-chloro-1,2-
    propanediol was determined (tested once/week).  The report does not
    comment on presence of 3-chloro-1,2-propanediol in provided water.

          Experimental animals were examined daily for signs of ill
    health or behavioural changes.  Food consumption and body weight
    were recorded weekly from start to week 19 (feed consumption) and
    week 20 (body weight) of the study and thereafter monthly.  From
    week 88 to the end of the study, the body weight was recorded
    weekly.  Water consumption was recorded weekly from start to week 20
    of the study, and thereafter fortnightly.  Ophthalmological
    examination was performed regularly.  Haematological examination and
    blood chemistry were performed on blood samples taken at day 722 to
    737 from all surviving animals.  All animals found dead or animals
    killed "in extremis", as well as those killed at the end of the
    experiment, were subjected to complete necropsies and
    histopathological examination.  The liver, spleen, pancreas, heart,
    adrenals, testis, epididymides and brain were weighed.

          The body weights were significantly (P<0.05) reduced in
    high-dose male and female rats following the first week of
    treatment.  At termination the body weights were significantly
    reduced (P<0.05 or lower) in intermediate-, and high-dose animals
    showing a reduction in body weights of 33% (males) and 35% (females)
    in high-dose rats.  However, the mortality was unaffected by
    treatment, and at terminal sacrifice more than 42% of the group
    survived.  The food and water intake were significantly (P<0.05)
    reduced in high-dose male and female rats.  No treatment-related
    clinical signs were noted.  The results of the haematological and
    blood clinical chemical parameters varied considerably within the
    groups, however no consistent significant dose-related effects were

    observed.  The reduced body weight in intermediate-, and high-dose
    rats made it difficult to interpret a possible effect of treatment
    on organ weights.  However, the body weights were unaffected in
    low-dose rats, of which the males showed significant (P<0.05)
    increased kidney weight (absolute only).

          Dose-related increased (or decreased) incidence of
    hyperplasia/tumours were observed in the control, low- intermediate-
    and high-dose groups in the following organs: Kidney: tubular
    adenoma, males 0/50, 1/50, 1/50, 5/50, females 0/50, 1/50, 0/50,
    9/50 (P<0.05).  Tubular hyperplasia, males 3/50, 6/50, 15/50, 34/50
    (P<0.05 in intermediate-, and high-dose when tubular adenoma and
    tubular hyperplasia were combined), females 2/50, 4/50, 20/50, 31/50
    (P<0.05).  Testes: Leydig cell adenoma, 38/50, 43/50, 50/50
    (P<0.001), 47/50 (P<0.05).  Leydig cell adenocarcinoma, 0/50,
    0/50, 0/50, 3/50 (P<0.05).  Nodular Leydig cell hyperplasia was
    present in a high proportion of controls and the incidence decreased
    significantly in a dose-dependent pattern.  The incidence was 39/50,
    27/50, 4/50, 0/50.  When nodular Leydig cell hyperplasias, adenomas
    and carcinomas were combined for statistical analysis, there were no
    significant difference between groups.  Mammary gland (males):
    fibroadenoma 0/50, 0/50, 2/50, 10/50 (P<0.01).  Adenoma 0/50, 0/50,
    1/50, 1/50.  Adenocarcinoma 0/50, 0/50, 1/50, 1/50.  Preputial
    gland: adenoma 1/50, 2/50, 6/50 (P<0.05), 5/50.  Carcinoma 0/50,
    0/50, 1/50, 2/50 (P<0.05).  When adenomas and carcinomas were
    combined for statistical analysis, the resulting increased incidence
    was significant for both intermediate-, and high-dose groups. 
    Pancreas: There was a treatment-related decrease in the incidence of
    islet-cell hyperplasias, adenomas, and carcinomas in male rats.  The
    incidences were for islet-cell hyperplasia 14/50, 8/50, 5/50, 1/50. 
    Islet-cell adenoma 16/50, 9/50, 7/50, 0/50.  Islet-cell carcinoma
    8/50, 0/50, 2/50, 0/50.  When hyperplasias and neoplastic lesions
    were combined for statistical analysis, the decrease in incidence
    was significant at all dose levels (P<0.05 or lower).  Chronic
    progressive nephropathy occurred in both sexes in all groups and the
    incidence increased with dose being significant at the
    intermediate-, and high-dose level (P<0.05 or lower).  Female rats
    were more severely affected than males.  The figures were 36/50,
    40/50, 45/50, 49/50 (males) and 24/50, 23/50, 42/50, 48/50
    (females).  Correlations (P<0.001) between the severity of the
    nephropathy and the kidney tubular hyperplasia and kidney adenoma
    were found to be significant (P<0.01).

          A dose-dependent increase in epithelial single cell
    degeneration was observed in the epididymis.  The incidence was
    significant at intermediate-, and high-dose level (P<0.001).

          The report concludes that treatment with 3-chloro-1,2-
    propanediol caused increases in renal and testicular Leydig cell
    tumours.  Renal tumours developed in a dose-dependent fashion in
    both sexes and were considered secondary to the 3-chloro-1,2-

    propanediol treatment-related increase in chronic progressive
    nephropathy.  The treatment-related increase and acceleration of
    Leydig cell tumours may be considered as hormone-mediated promotion. 
    3-chloro-1,2-propanediol treatment caused a dose-related increase in
    mammary and preputial gland tumours in the males.  This effect may
    be considered as secondary to hormonal activity of large Leydig cell
    tumours (Sunahare  et al, 1993).

    2.2.4  Reproduction studies

          3-Chloro-1,2-propanediol has been reported to exert an
    inhibitory activity on male fertility (Gunn  et al., 1969; Helal,
    1982) and the effect is reversible (Ericsson & Youngdale, 1970;
    Jones, 1983).  The mechanism of the antifertility activity of
    3-chloro-1,2-propanediol is not known in detail.  However, it has
    been shown that the metabolites of 3-chloro-1,2-propanediol have an
    inhibitory activity on enzymes in spermatozoa glycolysis, resulting
    in a reduced motility of the spermatozoa (Jones, 1983).  Inhibition
    of spermatozoa motility was suggested partly to be due to alkylation
    of spermatozoa cysteine by 3-chloro-1,2-propanediol (Kalla & Bansal,
    1977).  3-Chloro-1,2-propanediol also affects several enzymes of
    epithelial cells in the testis and caput epididymis, resulting in
    decreased glycolysis (Gill & Guraya, 1980).  It is suggested that
    only the 3-chloro-1,2-propanediol (S)-isomer, synthesized under
    laboratory condition, possesses a specific inhibitory action on
    glycolysis in boar sperm (Stevenson and Jones, 1984).

          3-Chloro-1,2-propanediol has two specific effects on the
    reproductive tract of the male rat.  These effects were dose-
    dependent and have been classified as the high-dose effect and the
    low-dose effect.  The high-dose effect followed a single
    intraperitoneal injection of 75 mg/kg bw 3-chloro-1,2-propanediol. 
    Bilateral retention cysts or spermatocele of the caput epididymis
    developed 5 to 7 days after treatment (Cooper & Jackson, 1973). 
    Studies using electron microscopy have shown, that 3-chloro-1,2-
    propanediol, given by gavage at a level of 140 mg/kg bw,
    specifically affected the epithelia localized in the initial segment
    of epididymis in male rats 2 hours later.  The cellular lesions were
    characterised by sloughing of the epithelium, which led to
    obstruction of the epididymal tract (Hoffer  et al., 1973).  The
    back-pressure of the testicular fluid caused oedema, inhibition of
    spermatogenesis and atrophy of the testis (Jones, 1983). 
    Histological examination of testes from rats treated with daily
    injection of 40 mg/kg bw 3-chloro-1,2-propanediol for 20 days
    revealed total inhibition of the spermiogenesis by presence of
    degeneration and disappearance of the spermiogonia from the tubules. 
    Proliferation of the epithelial cells of the ducts in the cauda
    epididymis was observed and several blood vessels showed thickened
    walls (Samojlik and Chang 1970).

          The low-dose effect was directed towards mature sperm contained
    in the cauda epididymis.  The effect, which was evident after a few
    days following oral treatment of rats with levels of 5-10 mg/kg bw
    3-chloro-1,2-propanediol/dy, rendered the spermatozoa incapable of
    fertilization without causing any visible changes in their
    morphology (Jones 1983).  Male rats treated with daily subcutaneous
    injections of 15 or 40 mg/kg bw 3-chloro-1,2-propanediol showed
    infertility 6 and 3 days after commencement of treatment,
    respectively.  If the treatment with 15 mg/kg bw 3-chloro-1,2-
    propanediol was continued for 30 days recovery of fertility was
    observed 18 days after cessation of the treatment (Samojlik and
    Chang, 1970).  The lowest doses shown to cause infertility of male
    rats, determined by mating studies, were observed at the following
    daily orally treatment of male rats with 3-chloro-1,2-propanediol:
    6.5 mg/kg bw for 10 days (Gunn  et al., 1969); 5 mg/kg bw for 14
    days (Coppola, 1969); 2.5 mg/kg bw at "continuous" treatment
    (Erickson & Bennett, 1971); (subcutaneous injection): 8 mg/kg bw for
    3 days (Black  et al., 1975); 8 mg/kg bw for 4 days (Turner, 1971).

          Groups of 5 albino male rats treated perorally for 10 to 12
    days with either 0.5, 1.0, 2.0, 4.0, or 6.0 mg/kg bw 3-chloro-1,2-
    propanediol showed 2.5%, 20%, 45%, 85% and 100% sterility (sterility
    was based upon histological degree of spermiogenesis), respectively
    (Helal, 1982).

          The following abstract has been compiled from a summary report:
    groups of 5 Wistar male rats were dosed with 0 (distilled water),
    0.1, 0.5, 1, 2, 3, 4, 5, or 10 mg/kg bw/dy 3-chloro-1,2-propanediol
    by gavage for 7 days prior to, and during mating.  Each male rat was
    mated with a total of 5 virgin females which were sacrificed on day
    14 of gestation and examined for pregnancy status.  3-Chloro-1,2-
    propanediol induced no adverse effect on male fertility at a dose
    level of 3 mg/kg bw/dy and lower as shown by the pregnancy rate,
    total implantations and number of live embryos.  However, the
    pre-implantation loss was significantly greater (p=0.05) for female
    rats mated with males given 3 mg/kg bw/dy 3-chloro-1,2-propanediol
    when compared to controls.  The NOEL was 2 mg/kg bw/dy (Parish,
    1989).

          Antifertility activity of 3-chloro-1,2-propanediol in other
    species than rat has been reported in males of hamster, gerbil,
    guinea pig, dog, ram and rhesus monkey in vivo (Jones, 1983). 
    3-chloro-1,2-propanediol was reported to have no antifertility
    activity in the mouse, quail or rabbit (Jones, 1978).

          Groups of 10 female rats were injected subcutaneously with 0 or
    10 mg 3-chloro-1,2-propanediol (approx. 25 mg/kg bw) every second
    day for a period of 30 days.  Significant (p<0.01) decrease was
    noted in the relative organ weights of the ovary, uterus and vagina
    of treated females compared to the controls.  Histological
    examination revealed the following changes of the treated female

    rats: the ovary appeared small in size and showed wide spread
    follicular atresia and degeneration of corpora lutea; in the uterus
    the gland was regressed and the lumen was lined with columnar
    epithelium; atrophic changes were observed in the vaginal
    epithelium.  The protein and RNA content in the uterus and vagina
    were significantly (p<0.01) reduced in the treated females compared
    to controls.  The authors suggested a luteolytic and possibly
    antioestrogenic effect of 3-chloro-1,2-propanediol in female rats
    (Lohika and Arya, 1979).

    2.2.8  Special studies on genotoxicity

          The results of genotoxicity studies with 3-chloro-1,2-
    propanediol are summarized in Table 1.

    2.3  Observations in humans

          A synergistic effect of 3-chloro-1,2-propanediol and copper
    ions in decreasing the motility of human spermatozoa was observed
     in vitro (Kalla & Singh, 1981).  When 3-chloro-1,2-propanediol was
    incubated with ejaculated human sperm the motility of the
    spermatozoa was inhibited and their metabolic activity was reduced,
    as measured by glucose, oxygen uptake and lactate production
    (Homonnai  et al., 1975).


        Table 1.  Results of genotoxicity tests on 3-chloro-1,2-propanediol

                                                                                                                               

    Test system                  Test object              Concentration of             +/-      Reference
                                                          3-chloro-1,2-propanediol
                                                                                                                               

    In vitro bacterial           S.typhimurium TA1535,    2-200 Ámol/plate             + (2)    Silhankova  et al., 1982
    mutagenicity assay (1)       TA1537, TA1538, TA98

                                 S.typhimurium TA100      10-1 000Ámol/plate           +        Stolzenberg & Hine, 1980

                                 E.coli TM930             2-200 Ámol/plate             -        Silhankova  et al., 1982

    Forward-mutation             Schizosaccharomyces      100-300 mM                   +        Rossi  et al., 1983
    assay on yeast(1)            plombe

    Mammalian cell mutation      Mouse lymphoma TK        2-9 mg/ml                    + (5)    Henderson  et al., 1987
    assay (1)                    locus assay

    Mammalian cell mutation      HeLa cell                (6)                          -        Painter & Howard, 1982
    assay (1)

    Mammalian cell mutation      Mouse fibroblast         0.1-2 mg/ml                  +        Piasecki  et al., 1990
    assay                        M2-clone

    Sister chromatid exchange    Chinese hamster          700-2800 Ág/ml               +        May, 1991
    assay(1)                     V79 cells

    Mammalian cell HPRT-test     Chinese hamster          0.3-70mM                     ? (4)    G÷rlitz, 1991
    (1)                          V79 cells
                                                                                                                               

    Table 1 (contd).

                                                                                                                               

    Test system                  Test object              Concentration of             +/-      Reference
                                                          3-chloro-1,2-propanediol
                                                                                                                               

    In vivo dominant lethal      ICR/Ha Swiss mice        (3)                          -        Epstein  et al., 1972
    assay

    Micronucleus test            OF1 mice                 40-120 mg/kg bw              -        Jaccaud & Aeschbacher, 1989
                                                                                                                               

    (1) with and without metabolic activation
    (2) no frame shift mutations in strains TA1537, TA1538 or TA98
    (3) single intraperitoneal injection of 125 mg/kg bw 3-chloro-1,2-propanediol or peroral treatment of 20 mg/kg bw
        3-chloro-1,2-propanediol for five days
    (4) weak mutagenic effect only at toxic dose level (50mM)
    (5) positive only after metabolic activation
    (6) not reported
    

    1,3-DICHLORO-2-PROPANOL

    2.  Biological data

    2.1  Biochemical aspects

    2.1.1  Absorption, distribution, and excretion

          No information was available.

    2.1.2  Biotransformation

          ▀-Chlorolactate (approx. 5% of dose), N,N'-bis-acetyl-S,S'-
    (1,3-bis-cysteinyl)propan-2-ol (approx. 1% of dose), and N-acetyl-S-
    (2,3-dihydroxypropyl)cysteine  were identified in the urine of rats
    treated orally with 50 mg/kg bw/dy 1,3-dichloro-2-propanol for 5
    days.  The authors proposed that epoxy-halopropane ( epi-
    chlorohydrin) is formed as an intermediate, which may either undergo
    conjugation with glutathione to form mercapturic acid or be
    hydrolyzed to 3-chloro-1,2-propanediol.  The latter undergoes
    oxidation to ▀-chlorolactate which is further oxidized to oxalic
    acid.  Formation of other epoxides was postulated.  However, the
    formation of epoxides from alpha-chlorohydrins only takes place at
    high pH-values and is unlikely to occur under physiological
    conditions (Jones and Fakhouri, 1979).

    2.2  Toxicological studies

    2.2.1  Acute toxicity studies

          The oral LD50 of 1,3-dichloro-2-propanol was reported to be
    122 mg/kg bw in rats, while by intraperitoneal application the LD50
    was 106 mg/kg bw (Pallade  et al., 1963).  In rabbits the LD50 was
    800 mg/kg bw following dermal application (Smyth  et al., 1962). 
    In mice the LC50 over a period of 1-15 days was 1.7-3.2 mg/l air
    (Pallade  et al., 1963).  When tested on rabbit eyes 1,3-dichloro-
    2-propanol caused irritation and moderately severe damage (Grant,
    1974).

    2.2.2  Short-term toxicity studies

    2.2.2.1  Rats

          The following summary was written from an abstract cited in
     The Toxicologist.  A critical evaluation of the findings from this
    abstract has not been possible.  1,3-dichloro-2-propanol was
    evaluated for subchronic toxicity in Sprague-Dawley rats
    (10/sex/dose group) treated with dose levels of 0, 0.1, 1, 10, or
    100 mg/kg bw/dy 1,3-dichloro-2-propanol by gavage in distilled water
    5 days/week for 13 weeks.  Decreases in bw gain, feed consumption
    and haematologic parameters, increases in liver and kidney weights,

    alterations in serum chemistry and urinary parameters, gross
    pathologic changes in the stomach and histopathologic changes in the
    stomach, kidney, liver and nasal tissue were observed at 100
    mg/kg/day in males and females.  The changes in serum chemistry were
    considered secondary to renal and hepatic changes observed in high-
    dose animals.  At 10 mg/kg, increased liver weights in males and
    females and histopathologic changes in the stomach, kidneys and
    liver in males were observed.  The treatment related-effects
    observed at 10 mg/kg were less frequent and/or less severe than the
    effects observed at 100 mg/kg.  No effects were observed at 0.1 or 1
    mg/kg in males or females (Jersey  et al., 1991).

    2.2.3  Long-term toxicity/carcinogenicity studies

    2.2.3.1  Rats

          In a combined long-term toxicity/carcinogenicity study, 4
    groups of 80 male and 80 female rats (Wistar KFM/Han, initial age of
    4 weeks; 10 days acclimatization prior to test), received
    1,3-dichloro-2-propanol [purity: 99%; stability confirmed by sponsor
    at six-month intervals] in their drinking water over a period of up
    to 104 weeks.  1,3-dichloro-2-propanol concentrations in the
    drinking water (daily preparation of 1,3-dichloro-2-propanol/water
    mixture, regular determination of 1,3-dichloro-2-propanol stability,
    concentration and homogeneity) were 0, 27, 80, or 240 mg/l
    corresponding to intakes of 0, 2.1, 6.3, and 19.3 mg/kg bw/day for
    male rats and 0, 3.4, 9.6, and 30 mg/kg bw/day for female rats.  The
    diet [pelleted; regular determination of contaminants showed
    presence of low, biologically insignificant levels of aflatoxin,
    estrogen, pesticides and heavy metals] was provided  ad libitum. 
    Interim kill was performed on 10 rats of each sex and group after
    26, 52, and 78 weeks of treatment.

          Haematologically, female rats in the high-dose group, in
    particular, showed statistically significantly (p<0.05) decreased
    haemoglobin concentration and haematocrit (26 and 104 weeks), and
    red blood cell count (104 weeks).  Clinical biochemical and urine
    analysis findings suggested hepatotoxicity primarily in high-dose
    females.  Statistically significant (p<0.05) increased activity of
    aspartate- and alanine aminotransferase (78 and 104 weeks), alkaline
    phosphatase (104 weeks), and gamma-glutamyltransferase (104 weeks)
    were observed in female rats.  Statistically significant (p<0.05)
    increases in urinary levels of protein and amylase were noted in
    high-dose female rats after 52, 78, and 104 weeks of treatment. 
    Increased mortality was observed in high-dose males (32/50) and
    females (27/50) compared to that in the controls (males 18/50;
    females 13/50), (statistics not reported).  The mortality of the
    low-dose group was: 11/50 (males), 9/50 (females); of the
    intermediate-dose group was: 16/50 (males), 14/50 (females).

          There were no treatment-related signs of toxicity nor changes
    in food and water consumption.  However, statistically significant
    (p<0.05 or lower) reductions in mean body weights were observed in
    high-dose males after 74 weeks and in high-dose females after 78
    weeks.  A dose-related increase in the relative organ weights was
    observed in a number of organs, in particular, the liver and kidney. 
    After 26 weeks: liver of males and females in all treated groups
    (p<0.05); kidney of males at intermediate- and high-dose (p<0.05),
    and females at high-dose (p<0.05).  After 52 weeks: livers of males
    and females in intermediate- and high-dose groups (p<0.05); kidney
    of females at high-dose (p<0.05).  After 78 weeks: liver and kidney
    of males and females at high-dose (p<0.01).  After 104 weeks:
    liver, kidney and brain of males and females at high-dose (p<0.01). 
    Histopathological examination revealed occurrence of several tumours
    in various organs.  Among these tumours dose-related neoplastic
    lesions in middle- and high-dose male and female rats were seen. 
    Statistically significant positive trends were found for
    hepatocellular adenoma (females, p<0.001); hepatocellular carcinoma
    (males and females, p<0.001); hepatic hemangiosarcoma (males,
    p<0.01 and females, p<0.05); renal tubular adenoma (males,
    p<0.001); renal tubular carcinoma (males, p<0.05); lingual
    papilloma (males and females, p<0.001); lingual papillary carcinoma
    (males, p<0.001 and females, p<0.01); thyroid follicular adenoma
    (females, p<0.05); thyroid follicular carcinoma (males, p<0.01). 
    These neoplastic lesions occurred in treated animals after 26 weeks
    (hepatocellular adenoma), 52 weeks (hepatocellular adenoma and
    carcinoma, lingual papilloma and carcinoma), and 78 weeks
    (hepatocellular carcinoma, renal tubular adenoma, lingual papilloma
    and carcinoma, thyroid follicular adenoma).  In addition to the
    above-mentioned tumours, one stomach papilloma was found in one
    high-dose female rat after 78 weeks and at terminal sacrifice one
    stomach carcinoma (low-dose, female), carcinomas in the oral cavity
    [intermediate-dose (one, female) and high-dose (two, males)].

          The incidence of the above-mentioned neoplastic lesions in
    control rats was: two hepatocellular adenomas (male and female) and
    one thyroid follicular adenoma (female).  Among non-neoplastic
    lesions the liver showed dose-dependent increase in incidence of
    fatty change, eosinophilic foci, glycogen free foci, Kupffer cell
    haemosiderin storage, and peliosis.  Follicular hyperplasia was
    evident in thyroid glands of high-dose males.  These results
    strongly suggest an oncogenic effect of 1,3-dichloro-2-propanol on
    liver, kidney, oral epithelia/tongue and thyroid gland in rats at
    the intermediate- and high-dose level.  The significance of the
    sinusoidal peliosis observed in all treated groups was not clear. 
    However, peliosis has been suggested to represent a pre-neoplastic
    stage of vascular hepatic neoplasia (Wayss  et al., 1979).

          The increased incidence of hepatic fatty change and
    haemosiderin-storing Kupffer cells in the liver in animals in the
    intermediate- and high-dose groups were suggested to reflect a

    metabolic disturbance of the liver caused by 1,3-dichloro-2-propanol
    (RCC, 1986).

    2.2.4  Reproduction studies

    2.2.4.1  Rats

          The following summary has been obtained from an abstract cited
    in Hazardous Substances Data Base.  A critical evaluation of
    material from this abstract has not been possible: Groups of 20, 10
    or 10 male Wistar rats were dosed with either water (controls), 15,
    or 60 mg/kg bw/dy 1,3-dichloro-2-propanol by gavage for 14 days,
    respectively.  Treated rats showed appearance of spermatocele or
    sperm granuloma formation in the epididymides (Tunstall
    Laboratories, 1979).

          Investigations on the genotoxic mechanisms of 1,3-dichloro-2-
    propanol (Hahn  et al., 1991), indicate that the genotoxic effect
    of 1,3-dichloro-2-propanol depends on the chemical formation of
    epichlorohydrin, which has mutagenic activity (Rossi  et al.,
    1983).

        2.2.8  Special studies on genotoxicity

    Table 2.  Results of genotoxicity tests on 1,3-dichloro-2-propanol

                                                                                                                               

    Test system                  Test object              Concentration                +/-      Reference
                                                          1,3-dichloro-2-propanol
                                                                                                                               

    In vitro Bacterial           S.typhimurium TA1535,    2-200 Ámol/plate             + (2)    Silhankova,  et al., 1982
    mutagenicity assay (1)       TA1537, TA1538, TA98

                                 S.typhimurium TA100      0.1-10Ámol/plate             +        Stolzenberg & Hine, 1980

                                 S.typhimurium TA100,     3-300Ámol/plate              +        Nakamura  et al., 1979
                                 TA1535

                                 E.coli, TM930            2-200Ámol/plate              + (3)    Silhankova  et al., 1982

    Mammalian cell mutation      Mouse lymphoma TK        2-9 mg/ml                    +        Henderson  et al., 1987
    assay(1)                     locus assay

    Sister chromatid exchange    Chinese hamster V79      0.12-3.3 mM                  + (5)    Von der Hude  et al., 1987
    assay(1)                     cells

    Mammalian cell mutation      HeLa cell                2.5x103 M (4)                +        Painter & Howard, 1982
    assay(6)

    Mammalian cell mutation      Mouse fibroblast         0.1-1 mg/ml                  +        Piasecki  et al., 1990
    assay                        M2-clone
                                                                                                                               
    (1) with and without metabolic activation
    (2) no frame shift mutations in strains TA1537, TA1538 or TA98
    (3) only positive after metabolic activation
    (4) effective concentration
    (5) almost inactivated with metabolic activation
    (6) only tested with metabolic activation
    
    2.3  Observations in humans

          Severe irritation of the throat and stomach has been described
    as a likely effect after ingestion of 1,3-dichloro-2-propanol
    (Gosselin  et al., 1976).

    3.  COMMENTS

    3-Chloro-1,2-propanediol

          3-Chloro-1,2-propanediol has been shown to increase the
    relative kidney weights of rats treated for 4 weeks (30 mg/kg bw/dy
    by gavage), or 3 months (9 mg/kg bw/dy in the drinking water) and
    absolute kidney weights when treated for 104 weeks (1.1 mg/kg bw/dy
    in the drinking water).  A single subcutaneous injection of 75 mg
    3-chloro-1,2-propanediol/kg bw to rats caused renal tubular necrosis
    and dilatation.  A no-effect level  for the effect on the kidney was
    not observed.

          In monkeys 3-chloro-1,2-propanediol induced anaemia,
    leucopenia, and thrombocytopenia following ingestion of 30 mg/kg
    bw/dy for 6 weeks.

          Data presented to the Committee clearly demonstrated that
    3-chloro-1,2-propanediol possesses an inhibitory effect on male
    fertility in rats and that the effect is reversible.  This effect is
    caused by an inhibition of glycolytic enzymes in the epididymis,
    testicular tissue, and in spermatozoa, resulting in reduced motility
    of the spermatozoa.  No visible morphological changes of the
    spermatozoa or epididymis were seen at dose levels of 5-10 mg
    3-chloro-1,2-propanediol/kg bw/dy, while a single intraperitoneal
    injection of 75 mg/kg bw caused development of retention cysts or
    spermatocele of the caput epididymis in rats.  In a reproduction
    study the NOEL for male rat fertility was 2 mg/kg bw/dy when the
    rats were treated orally with 3-chloro-1,2-propanediol for 7 days
    and during the mating period.

          3-Chloro-1,2-propanediol was genotoxic in most  in vitro
    assays, while it was negative in  in vivo assays.  In addition,
    3-chloro-1,2-propanediol induced malignant transformation of mouse
    M2-fibroblasts in culture.

          The results of a recently-completed long-term
    toxicity/carcinogenicity study in rats treated at dose levels of
    1.1, 5.2 or 28 mg 3-chloro-1,2-propanediol/kg bw/dy in drinking-
    water for 104 weeks indicated a carcinogenic effect.  Occurrence of
    treatment-related increased incidences of tumours in the kidneys of
    both sexes and testis, mammary and preputial gland of male rats were
    reported.  Although it has been suggested that the occurrence of
    these tumours might be secondary to either a sustained organ
    toxicity (kidney) or hormonal disturbances (testis and mammary
    gland), information was not available to the Committee to support
    this assumption.  The Committee noted that the drinking-water of the
    control animals contained low levels of 3-chloro-1,2-propanediol. 
    The presence of 3-chloro-1,2-propanediol in the drinking-water may
    have confounded the quantitative evaluation of the dose-response

    relationships for carcinogenicity.  In addition, significantly
    increased kidney weights were observed in male rats at the lowest
    dose level.

    1,3-dichloro-2-propanol.

          The Committee reviewed studies on biotransformation, acute
    toxicity and long-term toxicity/carcinogenicity in rats, and
     in vitro genotoxicity of 1,3-dichloro-2-propanol.

          The results of a long-term toxicity/carcinogenicity study in
    rats treated at dose levels of 2.1, 6.3, or 19 mg 1,3-dichloro-2-
    propanol/kg bw/dy in the drinking-water for 104 weeks indicated a
    carcinogenic effect of 1,3-dichloro-2-propanol.  Induction of benign
    and malignant tumours of the liver, kidney, thyroid gland, and oral
    epithelia/tongue was observed in rats at the mid- and high-dose
    levels.

          1,3-Dichloro-2-propanol was active in a range of genotoxicity
    screening assays, including tests for chromosomal effects in
    mammalian cells in culture and tests for gene mutations in bacteria. 
    In addition, 3-chloro-1,2-propanediol induced malignant
    transformation of mouse M2-fibroblasts in culture.

          The Committee was not presented with results from studies on
    absorption, distribution or excretion of 1,3-dichloro-2-propanol.

          The Committee noted that different rat strains were used in the
    long-term toxicity/carcinogenicity studies on 3-chloro-1,2-
    propanediol and on 1,3-dichloro-2-propanol, which precluded a direct
    comparison between these two compounds in regard to their
    carcinogenicity.

    4.  EVALUATION

          The Committee concluded that 3-chloro-1,2-propanediol and
    1,3-dichloro-2-propanol are undesirable contaminants in food and
    expressed the opinion that their levels in hydrolyzed vegetable
    proteins should be reduced to the lowest technologically achievable.

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    See Also:
       Toxicological Abbreviations