IPCS INCHEM Home



    PESTICIDE RESIDUES IN FOOD - 1980


    Sponsored jointly by FAO and WHO






    EVALUATIONS 1980





    Joint meeting of the
    FAO Panel of Experts on Pesticide Residues
    in Food and the Environment
    and the
    WHO Expert Group on Pesticide Residues
    Rome, 6-15 October 1980




    CHLORDIMEFORM

    Explanation

    Chlordimeform was reviewed and evaluated for an Acceptable Daily
    Intake in 1971, 1975, 1978, and 1979 (FAO/WHO, 1972, 1976; FAO, 1979,
    1980).  In 1971, a temporary ADI was allocated. In 1976, as a result
    of long-term studies in mice, which showed a potential carcinogenic
    response characterised histologically as hemangioendothelioma, the
    distribution of chlordimeform was voluntarily and temporarily
    suspended.  In 1978, an extensive series of short-term, high-level,
    and long-term, low-level studies in both rats and mice were reviewed.
    Results of long-term studies demonstrated that chlordimeform and its
    principal metabolites, N-formyl 4-chloro-o-toluidine, and
    4-chloro-o-toluidine, were carcinogenic in the mouse, producing a
    dose-related malignant hemangioendothelioma in various tissues.
    Carcinogenicity studies with these compounds in rats, predominantly
    negative, were somewhat conflicting.  Chlordimeform itself was not
    mutagenic to bacteria but the 4-chloro-o-toluidine, the major
    metabolite, was mutagenic.  The temporary ADI was maintained at a
    reduced level in the light of the new information and with the
    consideration that further long-term studies were in progress.  In
    1979, complete results of long-term studies in rats and mice with
    4-chloro-o-toluidine and in rats with chlordimeform were submitted
    in detail to the Meeting and were reviewed.  Interim reports of
    chronic toxicity studies in rats administered 4-chloro-o-toluidine
    and N-formyl-4-chloro-o-toluidine were reviewed.  Additionally,
    pharmacokinetic data and mutagenicity studies were reviewed.  In these
    studies, there was no evidence for bioaccumulation or unusual
    metabolite formation.  The data further suggested a lack of mutagenic
    potential in mammalian systems.  A complete review of the data was not
    performed in anticipation of submission of completed studies in time
    for the 1980 Meeting.

    Complete results of the two-year studies with chlordimeform and its
    two principal metabolites in rats have been submitted in detail.  In
    addition, short-term, high-level dietary studies in rats and mice
    administered chlordimeform or the N-formyl metabolite were made
    available and reviewed.  This monograph addendum includes that new
    information received and does not constitute a full review of the
    toxicology of chlordimeform.

    DATA CONSIDERED FOR DERIVATION OF ACCEPTABLE DAILY
    INTAKE

    TOXICOLOGICAL STUDIES

    Short-term studies

    Rats

    Groups of rats (30 males and 30 females/group), housed under SPF
    conditions, were fed chlordimeform in the diet at dosage levels of O,
    750, 1,500, 3,000 or 6,000 mg/kg for 60 days.  These dosage levels
    corresponded to dietary intakes of O, 84, 137, 222, or 462 mg/kg
    bw/day for males and 0, 71, 121, 231 or 464 mg/kg bw/day for females.

    Groups of 10 males and 10 females were sacrificed at 60 days for
    complete haematological, clinical chemistry, and urinalysis
    examinations.  At the end of the study, 10 males and 10 females from
    each group were subjected to gross and microscopic pathological
    examination as well all animals that died over the course of the
    study.

    Food intake and growth were reduced over the course of the study, at
    all dose levels.  Slight mortality was observed at the highest
    concentration.  Clinical signs of toxicity or adverse behaviour were
    not noted at any dose level.  Slight changes in several haematological
    parameters were noted at the two highest dose levels.  Methaemoglobin
    levels were increased in a dose-related manner at all treatment
    levels.  Heinz bodies were noted in haematologic examination at 1,500
    mg/kg and above.  Slight changes were noted in several clinical
    chemistry parameters including: decreased glucose concentration,
    increased alkaline phosphatase activity, and increased gamma-glutamyl
    transpeptidase activity, predominantly at the three highest dose
    levels.  Urinalyses showed slight changes at the two highest dose
    levels including a reduced urine volume, reduced protein
    concentration, and reduced electrolyte (potassium) level,
    predominantly at the highest dietary levels.

    Terminal body weights of all animals administered chlorodimeform were
    significantly reduced in a dose-related fashion.  Substantial changes
    in growth and relative organ weights were noted in both males and
    females at all dietary levels.  Reductions in the weight of such
    organs as the brain, heart, liver, kidneys, adrenals, and thymus were
    reported for both males and females.  In males, reduced testes weight
    was noted only at the highest dose level while reduced ovarian weights
    were noted at all dose levels.

    Other than excessive emaciation at the highest dose level, no gross
    anatomical changes were noted in the animals sacrificed for
    pathological examination.  In most rats of the highest dose groups,
    haemosiderosis in the spleen was observed.  Reduced spermatogenesis
    was noted at the highest concentration.  Focal hyperplasia of small
    biliary ducts and of the transitional epithelium and increased

    vascularisation in the mucous membrane of the bladder was observed in
    the highest dose group.  In addition, the highest dose group showed
    thymic atrophy in several of the animals examined.  No
    compound-related histopathological changes were noted in rats treated
    with 1,500 mg/kg or below (Sachsse et al., 1979a).

    Groups of rats (30 males and 30 females/group), housed under SPF
    conditions, were fed N-formyl-4-chloro-o-toluidine in the diet at
    dosage levels of 0, 750, 1,500, 3,000 or 6,000 mg/kg for 60 days. 
    These dosage levels corresponded to dietary intakes of 0, 91, 176, 347
    or 875 mg/kg bw/day for males and of 87, 165, 329 or 719 mg/kg bw/day
    for females.  Groups of 10 males and 10 females were sacrificed at the
    conclusion of the study for complete haematological clinical
    chemistry, urinalysis examinations, and gross and microscopic
    pathological examinations of tissues and organs.

    Extensive mortality was observed at the high dose level within the
    first few weeks of the experiment.  At the end of the third week of
    treatment, the highest dose level was terminated.  There was no
    substantial mortality at dose levels of 3,000 mg/kg and below.  Food
    intake and growth were reduced over the course of the study in a
    dose-dependent fashion in all dose groups.  Other than mortality noted
    at the high dose level, no clinical signs of toxicity or adverse
    behaviour were observed.  Auditory and ophthalmological examinations
    showed no evidence of loss of these functions in any of the animals
    examined.

    The results of the haematologic examination suggested a toxic
    haemolytic anemia in both sexes of all treatment groups; characterised
    by reduction of haemoglobin concentration, erythrocyte count, packed
    cell volume and an increase in methaemoglobin.  Heinz bodies were
    observed at 3,000 mg/kg.  In addition, at 1,500 mg/kg and above there
    was a slight reticulocytosis and reduced partial thromboplastin time
    in these dose groups.  Changes in the clinical chemistry parameters
    were noted at both 1,500 and 3,000 mg/kg.

    Gross examination of certain tissues and organs showed changes in
    absolute weights and relative weight ratios at all dosage levels.
    These reductions appeared to follow a dose-dependent relationship.
    Animals administered 6,000 mg/kg showed atrophy of the thymus and
    spleen within the first three weeks of the test.  Liver changes were
    noted in all dose groups characterised as hyperplasia of the bile duct
    epithelium and changes in the distribution of lipid.  At the highest
    dose group, hyperplasia of the urinary bladder epithelium and testes
    was noted.  About half the animals of both sexes in the 6,000 mg/kg
    group showed an increase in the mitotic incidence in hepatocytes
    (Sachsse et al., 1980a).

    Mice

    Groups of mice (30 male and 30 female mice/group), housed under SPF
    conditions, were fed chlordimeform in the diet at dosage levels of O,
    750, 1,500, 3,000, or 6,000 mg/kg for 60 days.  These dosage levels

    corresponded to dietary intakes of 0, 107, 194, 616, or 1,525 mg/kg
    bw/day for females and 0, 119, 200, 669, or 1,519 mg/kg bw/day for
    males.  At the end of the 60-day interval, all animals were examined
    for haematologic, blood chemistry, and urinalysis parameters.  At the
    conclusion of the study, groups of 10 male and 10 female animals from
    the control and the lower three dose groups, maintained for 60 days,
    were subjected to gross and microscopic examination of tissues and
    organs.

    Mortality was observed in the two highest dose groups over the course
    of the study.  The 6,000 mg/kg dose group was terminated after two
    weeks because of a general poor condition.  Growth, as evidenced by
    body weight gain, was reduced in all dietary groups.  Food consumption
    was reduced in females only over the course of the study at all
    dietary levels.  No clinical signs of toxicity were noted.
    Ophthalmologic and auditory examinations were normal.  The results of
    haematological investigations showed a toxic haemolytic anemia
    observed in both sexes of all treated groups which was characterised
    as a reduction in haemoglobin concentration, red blood cell count, and
    packed cell volume which was apparently associated in a dose-related
    manner with an increased methaemoglobin concentration and an
    observable increase in Heinz body formation.  At 3,000 mg/kg there was
    a slight reticulocytosis noted in both sexes.  This was accompanied in
    females by a shift in the differential leucocyte count noted as an
    increase in the percentage of polymorphonuclear neutrophils and a
    decrease in the percentage of lymphocytes.  Small changes were
    observed at the highest dose level in alkaline phosphatase activity,
    which was slightly increased in male mice.  At the same dose level,
    total protein concentration was slightly reduced in female mice. 
    There were no abnormal results in the urinalyses.

    In the animals that died or were sacrificed within the first two week
    period, all were found to be emaciated and in poor general condition.
    In all treated animals dying during the test period, congestion of the
    organs, especially of the liver, was observed.  At the highest
    concentrations, atrophy of thymic tissue was observed.  There was an
    increased haemosiderosis at the two highest dose levels.  There were
    no other pathological findings associated with the occurrence of
    chlordimeform in the diet (Sachsse, 1979b).

    Groups of mice (30 males and 30 females/group), housed under SPF
    conditions, were fed N-formyl-4-chloro-o-toluidine in the diet at
    dosage levels of 0, 750, 1,500, 3,000 or 6,000 mg/kg for 60 days. 
    These dosage levels corresponded to dietary intakes of 0, 138, 379,
    1,203, or 3,153 mg/kg bw/day for females and 0, 140, 349, 1,023, 2,549
    mg/kg bw/day for males.  All animals were subjected to a complete
    haematological, clinical chemistry, and urinalysis examination at the
    end of the 60-day experimental period.  Groups of 10 males and 10
    females from each group were examined for gross and microscopic
    pathological changes at the conclusion of the study.

    Mortality was observed predominantly at the high dose level over the
    course of the study.  There were no clinical signs of poisoning
    although food consumption and growth were depressed.  Growth was
    significantly depressed at 1,500 mg/kg and above in both males and
    females over the course of the study.  Ophthalmologic and auditory
    examinations showed no effect of the presence of the chlordimeform
    metabolite in the diet.

    Significant haematological abnormalities were observed at all dose
    levels at the conclusion of the study.  Toxic haemolytic anemia in
    both males and females was characterised as a reduction in haemoglobin
    concentration, erythrocyte count, packed cell volume and
    methaemoglobinaemia accompanied by an increased number of Heinz
    bodies.  Additionally, both males and females in all treated groups
    showed a significant reticulocytosis, thrombocythemia, and
    leucocytosis.  At higher concentrations in both males and females, the
    leucocytosis was accompanied by a shift in the differential leucocyte
    count.

    Slight changes were noted with respect to several blood chemistry
    parameters reflective of hepatic function (an increased activity of
    SCOT, SGPT, and SAP).  Urinalysis revealed a somewhat lower specific
    gravity and the presence of bile pigment in animals treated with the
    two highest dietary concentrations.

    Microscopic examination of tissues and organs revealed cytomegaly and
    hyperplasia of the bile duct epithelium and kupffer cells in some
    animals at 750 mg/kg and in most animals at the higher dose levels.
    Nuclear inclusion bodies were also evident in all treated animals and
    at the highest dose level, moderate centrolobular fatty changes were
    observed.  Additionally at the high level, atrophy of thymic lymphoid
    tissue and of splenic white pulp was observed.  Substantial
    hyperplasia of the epithelium of the urinary bladder was observed in
    most animals at the highest dose level and sporadically throughout the
    treated groups. (This hyperplasia was associated with apoptosis, a
    form of cell death characterised by condensation and fragmentation of
    the cell into discrete membrane-bound bodies which are either shed
    from epithelial surfaces or ingested by other cells and degraded)
    (Sachsse et al., 1980b).

    Long-term studies

    [In three basically identical studies, chlordimeform and its two
    principal metabolites, N-formyl-4-chloro-o-toluidine and
    4-chloro-o-toluidine, were tested in rats using a standard protocol
    to define carcinogenic hazards from long-term, dietary administration.
    Preliminary results of these studies were previously reported and the
    following is a complete evaluation of the final reports.]

    Rats

    Groups of rats (90 males and 90 females/group), Tif:RAIf strain,
    maintained under SPF conditions were fed chlordimeform in the diet for

    24 months at dosage levels of 0, 2, 20, 100 or 500 mg/kg.  These
    dietary levels based upon food consumption data were equivalent to
    dosage levels of 0, 0.1, 1.0, 5.0 and 24 mg/kg bw/day for males and 0,
    0.1, 1.2, 6.0, and 28 mg/kg bw/day for females.  At the conclusion of
    the dietary feeding study, all remaining rats were fed control diets
    for a period of time until a survival rate of 20% per sex (10 rats)
    per group was attained, at which time the animals were sacrificed and
    examined.

    Groups of 20 male and 20 female rats per group were examined
    periodically (4, 13, 26, 52, 78 and 104 weeks) for clinical laboratory
    investigations including haematology, blood chemistry and urinalyses.

    Groups of 10 animals/sex/group were sacrificed at 27 and 52 weeks for
    gross and microscopic examinations of tissues and organs.  Note: it
    appears that at 106 weeks, all the remaining animals were killed and
    examined for gross changes (organ weight and ratio data) and tumour
    pathology.  A complete terminal microscopic pathology was performed on
    10 rats sacrificed at the end of the experiment.  Additionally all
    rats dying between 12-24 months are reported.  There is no specific
    106-week microscopic pathology and while the report is not usual in
    some respects it is very complete and totally acceptable.  At the
    conclusion of the study, all animals sacrificed (also those that died
    prior to the termination) were examined for gross and microscopic
    pathology.

    Excessive mortality was not observed over the course of the study.
    Growth and body weight were maintained in all groups with the
    exception of the 500 mg/kg level where growth in both sexes was
    slightly retarded.  There were no clinical signs of poisoning or
    abnormal behaviour.  Survival with respect to the extended duration of
    the study (beyond 24 months) was not affected by chlordimeform.
    Sacrifice of each group of rats was made when mortality reached 20%
    (10 rats surviving).  Each sacrifice date was unrelated to the dietary
    dosage, indicating that chlordimeform did not affect the longevity of
    the exposed rats.  Pathology examination made at the conclusion of the
    study (either 24 months for gross or terminal for microscopic) did not
    indicate adverse effects of chlordimeform exposure.  Ophthalmologic
    and auditory examinations, performed at periodic intervals, revealed
    no adverse effects attributable to chlordimeform.  Methaemoglobinaemia
    was observed at dose levels of 20 mg/kg and above.  At week 4, both
    males and females showed a slight, but statistically significant,
    increase in methaemoglobin content.  At weeks 13 and 26, this
    condition abated but returned at the end of one year and was
    significant in both sexes at the highest dose group for the remainder
    of the study.  Changes in several other blood chemistry parameters
    were observed at the highest dose level.  Heinz body formation
    generally associated with methaemoglobinaemia was not observed at week
    4 but at the end of one year and thereafter, Heinz bodies were
    observed at the highest dose level.  A slight but significant
    reduction in blood glucose concentration was noted at the highest dose
    level throughout the majority of the study.  Slight changes in the
    urinalysis were observed in the highest dose group.  This was

    manifested as a slightly reduced urinary volume and a slightly higher
    specific gravity observed in the youngest animals.  Ketonuria and
    proteinuria were observed in the youngest animals fed 500 mg/kg.  This
    was noted only at the earliest examination periods and urinalysis
    performed at 13 weeks and thereafter for the remainder of the study
    did not reveal these occurrences.

    Gross pathology and organ weight data (provided for 27, 52 and
    106-week sacrifice intervals) did not show any significant
    dose-related responses.  While several organ weight and organ to body
    weight or brain weight ratios showed statistically significant
    differences from control animals, the findings were not dose related
    and the biological significance of these random occurrences is
    doubtful.  Microscopic histopathologic analyses of tissues and organs
    (performed at weeks 27 and 52 and at the termination of the study)
    indicated no significant changes attributable to chlordimeform in the
    diet.  Although numerous benign and malignant tumours were observed in
    both treated and control animals, the frequency and type of neoplasms,
    reported at 12 and 24 months with pathology analyses, were not
    dose-related nor were they attributable to chlordimeform.  Several
    congenital, degenerative, or inflammatory changes were attributed to
    disease, common in older animals.

    Based on the haematologic occurrence of methaemoglobinaemia in young
    rats, the no-effect level of chlordimeform for rats is 2 mg/kg in the
    diet, corresponding to an intake of 0.1 mg/kg bw/day.  Over the course
    of the study, there was no indication of carcinogenic potential to
    rats as a result of the presence of chlordimeform in the diet (Sachsse
    et al., 1980c).

    Groups of rats (90 males and 90 females/group), housed under SPF
    conditions, were fed N-formyl-4chloro-o-toluidine in the diet at
    dosage levels of 0, 2, 20, 100, or 500 mg/kg for two years.  These
    dosage levels were estimated to correspond to dietary intakes of 0,
    0.1, 1.0, 5 or 30 mg/kg/day for females and 0, 0.1, 1.0, 4.0 or 24
    mg/kg for males.  Groups of 10 males and 10 females were sacrificed at
    periodic intervals (26 and 52 weeks) for gross and microscopic
    pathology examinations.  Complete haematological, clinical chemistry,
    and urinalysis examinations were performed at 4, 13, 26, 52 and 78
    weeks on 20 males and 20 females of each group.  At 24 months, 20
    males and 20 females were sacrificed and examined for clinical
    laboratory parameters and gross pathology.  The remaining animals were
    fed control diets for additional periods of time until a survival rate
    of 20% per sex per group was attained.  At that time the remaining
    animals were sacrificed and examined microscopically for pathological
    changes.  All animals were examined for pathological events,
    especially neoplastic and non-neoplastic lesions.

    In the high dose group food intake and growth were affected over the
    course of the study and slight growth retardation was observed.
    Clinical signs of toxicity or adverse behaviour were not observed.
    There was no mortality in the study attributable to the presence of
    N-formyl-4-chloro-o-toluidine.  Sacrifice of each group of males and

    females was made when mortality reached 20%, and each sacrifice date
    was not related to dietary dosage.  This chemical did not affect the
    longevity of the exposed animals.  Tissue pathology did not show
    adverse effects of dietary treatment.  During the course of the study,
    no adverse clinical signs of poisoning were observed.  Ophthalmologic
    examinations and auditory tests were normal.  The results of the
    haematological investigation showed haemoglobin concentration to be
    slightly, but significantly, below that of the controls in both male
    and female rats at the two highest dosage levels.  In addition, slight
    but significant decreases in the erythrocyte count and packed cell
    volume, a slight increase in reticulocytes and somewhat higher
    methaemoglobin values were also seen in both male and female rats at
    500 mg/kg.

    With the exception of lower body weights of the animals at the highest
    concentration, the most obvious change was a significant increase in
    absolute and relative liver weights seen in both sexes, but more
    pronounced in females, in the 500 mg/kg group.

    A significantly increased incidence of hyperplasia of small biliary
    ducts was seen in the liver of rats of the 500 mg/kg concentration
    group.  In rats of the 500 mg/kg group, which were sacrificed after 2
    years or died after 12 months, a marked increase in frequency of
    multiloculated cholangiogenic biliary cysts in the liver was noted.
    Both of these findings were more pronounced and more frequent in
    female that in male animals.  The incidence of biliary lesions in rats
    fed dietary concentrations of 100 mg/kg or below was not significantly
    higher than that noted in the controls.

    Numerous benign and malignant tumours were observed in both control
    and treated rats.  The frequency and types of neoplasms occurring in
    these animals were not influenced by the N-formyl metabolite in the
    diet.  All gross and histopathological lesions and changes seen in
    both control and test animals were described as congenital,
    degenerative, or inflammatory in origin and were attributed to
    naturally occurring diseases common in aged rats.  There was no
    oncogenic potential in this species with
    N-formyl-4-chloro-o-toluidine, the chlordimeform metabolite.  A
    no-effect level in this study is 20 mg/kg in the diet (Sachsse et
    al., 1980e).

    Groups of rats (90 males and 90 females/group), housed under SPF
    conditions, were fed 4-chloro-o-toluidine in the diet at dosage
    levels of 0, 2, 20, 100 or 500 mg/kg for two years. These dosage
    levels corresponded to dietary intakes of 0, 0.1, 1.0, 5, or 28 mg/kg/
    day for females and 0, 0.1, 1.0, 4.6 or 24.6 mg/kg/day for males. 
    Groups of 10 males and 10 females were sacrificed at periodic
    intervals (27 and 54 weeks) for gross and microscopic pathology
    examinations. Complete haematological, clinical chemistry and
    urinalysis examinations were performed at 4, 13, 26, 52 and 78 weeks
    on 20 females and 20 males of each group.  At 24 months, 20 males and
    20 females were sacrificed and examined for clinical laboratory

    parameters.  Several animals were examined for gross pathology.  The
    remaining animals were fed control diets for additional periods of
    time until a survival rate of 20% per group was attained.  At that
    time, the remaining animals were sacrificed and examined for
    microscopic pathology and oncogenic response.  A complete microscopic
    analysis was made on at least 10 rats of each sex of each group at the
    termination of the experiment.  All rats dying during the course of
    one study were examined for tumours or neoplasms.

    In the high dose group of females food intake and growth were affected
    over the course of the study and slight growth retardation was
    observed.  There was no effect on male growth at any dose level.
    Clinical signs of toxicity or adverse behaviour were not observed.
    There was no mortality in the study attributable to the presence of
    the chlordimeform metabolite.  As noted with chlordimeform and the
    N-formyl metabolite, the extended duration of the study beyond the
    24-month-sacrifice date was not affected by 4-chloro-o-toluidine in
    the diet.  Sacrifice of each group of males and females, made when
    mortality reached 20%, was made at random dates not reflective of a
    dietary dose-response.  Again, this metabolite did not affect
    longevity of the exposed animals and tissue pathology was uneventful.
    Ophthalmologic examinations and auditory tests did not reveal changes
    that were related to the administration of 4-chloro-o-toluidine.

    The results of the haematological investigation, blood chemistry data,
    and the urine analysis were similar for both treated and control rats.
    Periodically, the haemoglobin concentration was slightly but
    significantly below that of the controls in the female rats at 100
    mg/kg and above.  Slight, but significant decreases were observed in
    the erythrocyte count and packed cell volume in the female rats at 500
    mg/kg.  Marginal reticulocytosis was also found to occur at 500 mg/kg
    in the female rats at week 13 and in both sexes at week 26.  In both
    male and female rats at 500 mg/kg, the methaemoglobin level was found
    to be slightly, though significantly, increased when compared to
    controls.  Periodically, this change was observed in the females of
    the 100 mg/kg dosage group and, occasionally, Heinz bodies were also
    observed in female rats.

    Organ weights, organ to body weight ratios, and organ to brain weight
    ratios revealed some statistically significant differences between
    treated and control animals.  With the exception of the absolute and
    relative liver weights at the conclusion of the study, these findings
    were not dose-related.

    In rats from the 500 mg/kg dosage group, a slightly but significantly
    increased incidence of multilocular cholangiogenic cysts was observed
    in the liver.  These biliary cysts were seen in 10/89 female and in
    3/90 male rats from the 500 mg/kg group, but only in 4/89 female and
    in none of the male control animals (9/90).  The incidence of
    cholangiogenic cysts in rats at the lower dosage groups was similar to
    that in the controls.

    Numerous benign and malignant tumours were observed in both control
    and treated rats. The frequency and types of the neoplasms occurring
    in these animals were not influenced by the presence of
    4-chloro-o-toluidine in the diet.  Gross and histopathological
    lesions and changes seen in both control and test animals were
    described as congenital, degenerative, or inflammatory in origin and
    were attributed to naturally occurring diseases, common in aged rats. 
    Based on these data, there was no evidence of carcinogenic potential.
    A no-effect level in this study is 20% mg/kg in the diet (Sachsse et
    al., 1980d).


    OBSERVATIONS IN MAN

    The 1979 Meeting (FAO, 1980) requested that future Meetings be
    informed of results of occupational exposure surveillance programs.
    Such data have been made available in summary form concerning the
    agricultural situation with chlordimeform in nine countries.  Surveys
    of aerial pesticide applications to cotton entailed the monitoring of
    about 600 airstrips in 1979 in the nine countries.  Over 28,000 urine
    samples were analysed from workers in all phases of the application
    situation.  The urine was monitored and residue data expressed as
    chlordimeform equivalents.

    Only 1% of the assays showed substantial chlordimeform urinary
    residues indicating a significant occupational exposure. Over 75% of
    the samples were at or below the lowest level of the analytical
    capability.  In general, the conditions in two countries, the USA and
    Australia, were indicative of a favourable working relationship where
    only about 1% of the samples contained a residue level indicating a
    higher than desired level of exposure.  Working conditions in some of
    the other countries (i.e., Colombia, El Salvador, Guatemala, and
    Honduras) were less favourable.  There was an improvement made in
    these areas but, because of limitations in acceptable equipment and
    educated people, the exposure picture was less than optimal.  However,
    in some areas where flagmen were (had to be) intentionally exposed,
    the urinary residue samples were low, indicating that with precautions
    exposure can be limited.  In all cases, even with the highest exposure
    of individuals, there were no cases of haematuria.  The monitoring of
    exposure and education of agricultural operators in the appropriate
    use of chlordimeform to minimize exposure in continuing (Kossmann,
    1980).


    EVALUATION

    COMMENTS

    Chlordimeform, an insecticide and acaracide, was reviewed in 1971,
    1975, 1978, and 1979 (FAO/WHO, 1972b, 1976b, 1979b, 1980b).  In 1978,
    it was reported that chlordimeform and its principal metabolites were
    carcinogenic in the mouse, producing a dose-related malignancy,
    histologically characterized as haemangioendothelioma.

    Carcinogenicity studies with rats produced conflicting results and
    were repeated.  Several short-term bioassay systems had demonstrated
    mutagenicity with the chlordimeform metabolite 4-chloro-o-toluidine.
    In 1979, two studies confirmed the carcinogenicity of
    4-chloro-o-toluidine in mice and the lack of it in rats.

    Information requested by previous meetings was reviewed.  Extensive
    long-term carcinogenicity studies in rats with chlordimeform and its
    two major metabolites confirmed the lack of a carcinogenic response in
    this species.  Based on toxicological and clinical data, no-effect
    dietary levels were estimated for chlordirneform and its metabolites
    in the rat and dog.

    Monitoring agricultural workers has showed that whilst minimal
    exposure can occur in controlled situations under less well controlled
    conditions, occupational exposure can be a significant problem and
    control of exposure is recommended.

    No further data have been submitted on the incidence of a haemorrhagic
    cystitis. This occurrence has not been reported again.

    In consideration of all of the available data on metabolism,
    teratogenicity, mutagenicity, carcinogenicity and toxicity as well as
    the current uses of chlordimeform in agriculture the meeting
    re-affirmed the temporary AD1 and required a review of the
    epidemiology programme.

    Level causing no toxicological effect

    Rat: 2 mg/kg in the diet equivalent to 0.1 mg/kg bw/day.
    Dog: 250 mg/kg in the diet equivalent to 6.25 mg/kg bw/day.

    Estimate of temporary acceptable daily intake for man

    0-0.0001 mg/kg bw/day.

    FURTHER WORK OR INFORMATION

    Required (by 1985)

    Report on continued surveillance and epidemiological studies of
    occupationally exposed workers in both industry and agriculture.

    Desirable

    Confirmatory long-term animal bioassay using a third species for
    evaluation of the potential carcinogenic hazard.

    REFERENCES

    Kossmann, Summary Report on 1979 Chlordimeform Monitoring Programmes.
    (1980) Unpublished report submitted to the World Health Organization
    by Schering, A.G.

    Sachsse, K., Suter, P., Leutkemeier, H., Zak, F. and Hose, R.
    Chlordimeform-HC 1 - 60-Day Feeding Study in the Rat - Final Report.
    (1979a) Unpublished report from Ciba-Geigy, Ltd., submitted to the
    World Health Organization by Ciba-Geigy, Ltd.

    Sachsse, K., Suter, P., Leutkemeier, H., Zak, F. and Hose, R..
    Chlordimeform-HC1 - 60-Day Feeding Study in Mice - Final Report.
    (1979b) Unpublished report from Ciba-Geigy, Ltd. submitted to the
    World Health Organization by Ciba-Geigy, Ltd.

    Sachsse, K., Suter, P., Leutkemeier, H., Zak, F. and Hose, R.
    N-formyl-4-chloro-o-toluidine - 60-Day Feeding Study in the Rat -
    Final Report. (1980a) Unpublished report from Ciba-Geigy, Ltd.,
    submitted to the World Health Organization by Ciba-Geigy, Ltd.

    Sachsse, K., Suter, P., Leutkemeier, H., Zak, F. and Hose, R.
    N-formyl-4-chloro-o-toluidine - 60-Day Feeding Study in Mice - Final
    Report. (1980b) Unpublished report from Ciba-Geigy, Ltd., submitted to
    the World Health Organization by Ciba-Geigy, Ltd.

    Sachsse, K., Suter, P., Leutkemeier, H., Zak, F. and Hose, R.
    Chlordimeform-HC1 - Lifespan (Chronic Toxicity and Carcinogenicity)
    Feeding Study in Rats - Final Report. (1980c) Unpublished report from
    Ciba-Geigy, Ltd., submitted to the World Health Organization by
    Ciba-Geigy, Ltd.

    Sachsse, K., Suter, P., Leutkemeier, H., Zak, F. and Hose, R.
    4-chloro-o-toluidine.HC1 - Lifespan (Chronic Toxicity and
    Carcinogenicity) Feeding Study in Rats - Final Report. (1980d)
    Unpublished report from Ciba-Geigy, Ltd., submitted to the World
    Health Organization by Ciba-Geigy, Ltd.

    Sachsse, K., Suter, P.. Leutkemeier, H., Zak, F. and Hose, R.
    N-formyl-4-chloro-o-toluidine - Lifespan (Chronic Toxicity and
    Carcinogenicity) Feeding Study in Rats - Final Report. (1980e)
    Unpublished report from Ciba-Geigy, Ltd., submitted to the World
    Health Organization by Ciba-Geigy, Ltd.

    


    See Also:
       Toxicological Abbreviations
       Chlordimeform (EHC 199, 1998)
       Chlordimeform (ICSC)
       Chlordimeform (WHO Pesticide Residues Series 1)
       Chlordimeform (WHO Pesticide Residues Series 5)
       Chlordimeform (Pesticide residues in food: 1978 evaluations)
       Chlordimeform (Pesticide residues in food: 1979 evaluations)
       Chlordimeform (Pesticide residues in food: 1985 evaluations Part II Toxicology)
       Chlordimeform (Pesticide residues in food: 1987 evaluations Part II Toxicology)
       Chlordimeform (IARC Summary & Evaluation, Volume 30, 1983)