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)