CHLORDIMEFORM JMPR 1975
Explanation
This pesticide was evaluated for acceptable daily intake by the
1971 Joint Meeting of the FAO Committee on Pesticides in Agriculture
and the WHO Expert Committee on Pesticide Residues (FAO/WHO, 1972). A
temporary ADI for man was estimated to be 0-0.01 mg/kg body weight. It
was considered that a further long-term study in rats would be
appropriate to obtain precise information on the incidence and nature
of the histopathological changes in the liver and bile duct of rats
exposed to levels above and below 100 ppm in the diet. In addition,
the meeting requested further investigations of the nature of the
hepatic lesions observed on the dog; metabolic studies in several
animal species, including man; data on the nature and levels of
residues in animal tissues after use in cattle sprays and dips; data
on residues in milk after use in cattle sprays and dips; data on the
residue levels in commercial butter and cheese. The present monograph
addendum summarizes further relevant studies that have become
available.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOCHEMICAL ASPECTS
Effects on enzymes and other biochemical parameters
Several studies have been reported to further define the
mechanism of action following acute poisoning. Based on in vitro
studies, Aziz and Knowles (1973) and Beeman and Matsumura (1973, 1974)
suggested that inhibition of Monoamine oxidase through an accumulation
of toxic biogenic amines could ultimately result in toxic signs
following acute poisoning. However, Maitre and Gfeller (1975) and
Robinson et al. (1975) demonstrated in acute studies that this
mechanism does not play a significant role in the acute toxicity in
rats. Groups of rats were administered chlordimeform by a single
intraperitoneal injection or by four injections (each at a level of 10
mg/kg) at 24 hour intervals. Monoamino oxidase activity in brain and
liver using tyramine and serotonin as a substrate was not affected. No
signs of acute intoxication were noted in the study.
In one study following acute intoxication, there was an
accumulation of serotonin and norepinephrine. Chlordimeform was found
to antagonize the effects of reserpine (Beeman and Matsumura, 1973).
Thus, while MAO inhibition may have a role in the toxic action of
chlordimeform, there may be synergistic effect in combination with
accumulated biogenic anines that may be more significant than the MAO
inhibition.
Chlordimeform has been shown to be ineffective in inhibiting
Na/K-ATPase and cholinesterase (Dittrich, 1966; Beeman and Matsumura,
1974) and has no effect on the acetycholine receptor of the isolated
frog rectus abdominus muscle (Beeman and Matsumura, 1974). Uncoupling
of oxidative phosphoxylation by chlordimeform and the desmethyl
metabolite has been shown by Abo-Khatwa (1972, 1973). At high
concentrations, RNA synthesis has been inhibited (Murakami and Fukami,
1974).
TOXICOLOGICAL STUDIES
Special studies on pharmacological effects
In vitro studies on the effect of chlordimeform on the isolated
heart preparation of guinea pigs were performed in an effort to
evaluate previously reported results indicating an effect on
contractile force of rabbit heart. Isolated guinea pig atria and
perfused heart preparations were treated with chlordimeform at doses
varying from 0.1 to 100 µg/ml. At 1 µg and below contractile force was
not affected, while at higher concentrations the heart rate and
contractile force was decreased. The effects of noradrenalin in
response to the effect of chlordimeform were examined. Under
continuous perfusion with chlordimeform, noradrenalin caused the same
qualitative changes and slight changes noted were believed to be due
to the initial effects of chlordimeform. It was thus suggested that
while chlordimeform has direct effects on heart rate and contractile
force, the effect of noradrenalin was negligible (Meier, 1975).
Long-term studies
Rat
Groups of rats (25 males and 25 female,/group) were fed
chlordimeform in the diet at dose levels of 0, 50, 75, 100, 250 and
500 ppm for one year. Growth and behaviour, as evidenced by food
consumption and weight gain data, were recorded. Terminal organ
weights and gross and microscopic examinations of tissues and organs
were the only other parameters reported.
The 500 ppm group was terminated at 37 weeks after 10 males and 8
females had died. At the conclusion of the study there was
considerable mortality noted in all groups. Food consumption was
decreased at 500 ppm in both sexes and was slightly reduced at 100 ppm
and above in males only. This reduced food consumption was not
significantly reflected in the growth curves of males or females.
Gross examination did not show any compound related abnormalities.
Organ weights and organ/body weight or organ/brain weight ratios did
not differ from control values.
Histological examinations of liver and spleen were performed on
all animals. There were no significant differences from control values
with respect to fatty changes and inflammatory changes in the liver.
Slight proliferation of the bile duct was more frequent in female rats
treated with 500 ppm than in the rats of other treated groups or the
control group. Results of examinations of the spleen for
haemosiderosis suggested that while this condition was more pronounced
in females there were no significant differences from control values
(Zak et al., 1973).
Observations in man
Thirteen persons concerned with the packaging of chlordimeform
developed gross haematuria with symptoms of bladder irritation in
eight cases, asymptomatic microscopic haematuria in three cases and
urinary symptoms in two cases. The most prevalent symptoms suggesting
bladder and urethral inflammation included: urinary urgency, increased
urine frequency, dysuria, nocturia, penile discharge and abdominal
pain. There was also an incidence of sleepiness and a case of striking
heat intolerance. Six patients reported a rash which typically
involved the face and arms. No cyanosis, dyspnoea or photosensitivity
was reported (Armstrong et al., 1975). Eleven cases of haematuria have
been reported in workers exposed to 5-chloro-o-toluidine (Currie,
1933).
COMMENTS
Chlordimeform was evaluated in 1971 and a no-effect level was
estimated based on two year rat and dog studies. However, because of
concern over observed effects on the liver and bile duct, a temporary
ADI was estimated. In addition information was requested because of
possible potentiating effects of chlordimeform and tyramine on the
pharmacological effects on the heart and circulation and on the
leucocyte count in rats.
New studies on the mode of action of chlordimeform following
acute poisoning suggest that the principal lesion is not MAO
inhibition. The acute mode of action, however, remains undefined. A
new one year study in rats did not show unusual liver or bile duct
abnormalities. The study did not confirm the suggestion that
chlordimeform enhanced the ageing process. While some of the concerns
expressed by the previous meeting were alleviated, the present studies
were not of sufficient duration to allow the Meeting to change the
temporary ADI. In addition a preliminary report on haemorrhagic
cystitis in occupationally exposed people was of concern to the
Meeting.
TOXICOLOGICAL EVALUATION
Level causing no toxicological effect
Rat: 100 ppm in the diet equivalent to 5 mg/kg body weight.
Dog: 250 ppm in the diet equivalent to 6.25 mg/kg body weight.
ESTIMATE OF TEMPORARY ACCEPTABLE DAILY INTAKE FOR MAN
0 - 0.01 mg/kg body weight.
RESIDUES IN FOOD AND THEIR EVALUATION
USE PATTERN
The uses of chlordimeform have been extended since 1971 and now
include, in addition to those reported previously, use on rice to
control stemborers in irrigated rice, on cotton to control
lepidopterous larvae and on cabbage and tomatoes to control a wide
range of lepidopterous larvae.
Details of use patterns reported since 1971 are included in Table
1.
TABLE 1. Registered use patterns for chlordimeform
Pre-harvest
Country Crop Rate interval
Japan Rice 0.6-0.8 kg/ha 30
Rice 0.1% 30
Cabbage 0.05% -
Peppers 0.02-0.03% -
Tea 0.06% -
Japanese pear 0.06% 7
Persimmons 0.06% 7
TABLE 1. (Cont'd.)
Pre-harvest
Country Crop Rate interval
USA Apple 0.05% 14
Pear 0.05% 0
Peach, nectarine 0.05% 21
Cole crops 0.05 kg/ha
Cherries 0.05% 21
Walnuts 0.05% 21
Plums, prunes 0.05% 21
Alfalfa 0.8 kg/ha For seed
Mexico Tomatoes 0.25-0.5 kg/ha 2 days
See also FAO/WHO 1972 and list of national tolerances.
The control of stemborers in irrigated rice is one of the most
important uses of chlordimeform. The excellent results obtained are
based on a threefold activity. The compound:
(1) kills eggs and young larvae;
(2) suppresses feeding by larvae; and
(3) interferes with moth flight resulting in irregular egg
laying.
Part of the active material is taken up by the rice plant from
the irrigation water and translocated to the aerial plant parts. This
results in an enhanced residual activity since not only the
chlordimeform on the plant surface, but also that stored within the
plant, is effective.
Various formulations including emulsifiable concentrates, dusts,
granules and water soluble granules are used depending upon the size
of the plots and the method of irrigation.
Considerable success has recently been obtained using
chlordimeform in combination with other insecticides. When using such
combinations the amount of active ingredient can be reduced
considerably.
In the case of cotton, chlordimeform has become one of the most
important substitutes for DDT and other organochlorine insecticides,
particularly when used in combination with such materials as
parathion. Depending upon the spectrum of the pests, it is often
combined with camphechlor and more recently with Baccilus
thuringiensis, where a definite synergism has been demonstrated.
The use of chlordimeform with its essentially ovicidal activity
to control lepidopterous pests, necessitates a new approach to control
techniques. The control of the pests at their egg stage prevents crop
injury. On the other hand, treatments must start earlier than usual,
that is as soon as egg laying has begun.
For the control of lepidopterous insects on vegetables including
tomatoes, it is likewise essential to treat at egg laying and to
repeat treatments as further egg laying occurs. Combinations with
Baccilus thuringiensis appear as important in vegetable culture as
in cotton.
Post-harvest treatment
No recommendations have yet been made for any post-harvest use of
chlordimeform.
Non-crop uses
Chlordimeform has no significant usage in non-crop situations
other than on ornamentals.
RESIDUES RESULTING FROM SUPERVISED TRIALS
Several of the maximum residue limits for chlordimeform proposed
by the 1971 Joint Meeting were considered by member countries of the
Codex Committee on Pesticide Residues to be rather high in the light
of the data available from the 1971 Monograph (FAO/WHO 1972).
Additional supporting data for the tolerances previously recommended
are presented in Table 2 of this monograph.
Residues in apples
Extensive new data were available from supervised residue trials
carried out in several countries. These are summarized in Table 2.
Attention is drawn to the relative stability of residues and the fact
that there is no significant decline in residue levels over the period
2-30 days after application.
These new data support the temporary tolerance recommended in
1971.
Residues in grapes
Further data from residue trials indicate that the residue level
on grapes declines hardly at all during the interval 1-30 days after
application.
Because of the wide range of grape varieties and the varying
conditions under which they are grown, the Meeting considered that the
maximum residue limit previously recommended should not be lowered.
Residues in citrus
Likewise, in the case of citrus many new data available to the
Meeting indicate the comparative stability of the residue and the
range of residue levels that can occur in different citrus varieties.
The Meeting considered that the maximum residue limits previously
recommended were necessary to cover good agricultural practices in
many countries.
Residues in peaches
Results from a number of supervised residue trials are summarized
in Table 2 and indicate that, while the residue levels appear to
decline during the 30 days after application, the rate of decline
during the first 21 days is relatively slow. The initial uptake by
peaches appears to be somewhat higher than by other crops, possibly
due to the skin texture, so that an interval of 21 days was required
before the residue levels declined to the maximum residue level
recommended.
Residue in pears
Data from extensive supervised residue trials carried out on
pears in the USA have been summarized in Table 2. These indicate that
approximately 10 mg/kg of chlordimeform is to be found on fruit
treated at the recommended rate with either the base or hydrochloride
formulation. The residue level at 14-18 days post-application is at or
above 5 mg/kg. Even after 35-40 days residue levels of 4 mg/kg or
above are not uncommon. In the light of these new data, the Committee
agreed to revise the recommended maximum residue limit.
Residues in tomatoes
Since 1971 there has been considerable interest in the use of
chlordimeform for the control of lepidopterous pests of tomatoes
largely as a replacement for DDT and other organochlorine
insecticides. Results from many supervised residue trials in Mexico,
USA and Switzerland were submitted to the Meeting and are summarized
in Table 2.
TABLE 2. Residues of chlordimeform resulting from supervised trials
Residue, mg/kg, after interval (days)
Concentration, No. of
Commodity Origin Year % sprays Formulation 0-1 2-4 5-9 10-19 20-30 31-60
Apples USA 1969 0.06 3 EC 1.5 1.0 0.8
USA 1969 0.06 2 EC 3.3 2.2 1.2 0.4
USA 1969 0.06 2 EC 8.8 3.4 2.8 2.4 1.4
USA 1969 0.12 3 EC 5.1 1.5 1.4 1.0
Australia 1965 0.05 1 EC 0.7 1.0 0.5 0.4 0.5
Germany 1969 0.07 1 SP 1.4 1.5 1.3 1.0
Italy 1965 0.05 1 EC 1.1 0.8 0.4 0.5
Grapes USA 1969 0.12 2 SP 3.5 3.2 2.6 2.5 2.2
Italy 1965 0.05 1 EC 1.8 2.0 2.1 2.2 2.9 2.3
Lemons Italy 1967 0.05 2 EC 2.0 0.1
Mandarins Japan 1966 0.05 1 EC 0.4
Oranges whole Italy 1968 0.034 1 SP 0.7 0.6 0.4 0.7 0.3 0.3
pulp Italy 1968 0.034 1 SP 0.08 0.1 0.1 0.2 0.05 0.06
Peaches USA 1968 0.04 1 SP 6.7 2.6 1.5 0.6
USA 1967 0.06 1 EC 10.4 8.6 5.6 0.7
USA 1973 0.06 1 SP 13.5 8.4 3.9 3.1
Australia 1970 0.07 1 SP 0.9 1.2 0.4 1.67 0.62 0.53
Pears USA 1969 0.12 2 SP 17.3 11.3 8.0 6.2
USA 1969 0.12 2 EC 8.3 5.3 4.7 3.4
Italy 1965 0.05 1 EC 1.1 1.2 1.0 1.0 0.9 0.5
USA 1973 0.06 3 SP 7.7 5.7 4.3 4.0 3.1
USA 1973 0.06 3 EC 7.9 5.0 4.3 3.3 3.2
USA 1973 0.06 3 SP 6.5 6.3 4.7 3.6 2.7
TABLE 2. (continued)
Residue, mg/kg, after interval (days)
Concentration, No. of
Commodity Origin Year % sprays Formulation 0-1 2-4 5-9 10-19 20-30 31-60
Pears (cont'd) USA 1973 0.06 3 EC 7.3 6.1 5.0 4.6 3.7
USA 1973 0.06 3 SP 10.4 9.7 6.1 4.7 4.3
USA 1973 0.06 3 EC 9.3 7.6 4.9 4.3 4.0
Tomatoes Mexico 1970 1.0 1 SP 0.19
Mexico 1973 1.0 8 SP 0.13 <0.05 <0.05
Mexico 1973 0.2 10 SP 0.11 0.6 0.1 <0.05
USA 1970 0.06 7 EC 0.3 0.36 0.45 0.29 0.1
USA 1971 0.06 6 EC 0.45 0.5 0.18 0.12
USA 1970 0.12 7 EC 0.67 0.9 0.6 0.46 0.75
Switzerland 1972 0.05 3 EC 0.37 0.33 0.37 0.26 0.31
USA 1973 0.12 5 SP 0.5 0.4 0.31 0.28 0.3
Hops (green) Germany 1970 0.05 3 EC 12.5
Strawberries Australia 1971 0.04 1 SP 2.17 1.41 1.07 0.75
Australia 1971 0.08 1 SP 3.5 2.53 2.19 1.32
New Zealand 1968 0.07 1 SP 0.8
It is interesting to note that notwithstanding repeated
applications of both the hydrochloride and base formulation, the
uptake of chlordimeform by tomatoes is considerably below that of
pears, peaches or apples. The level of residues found in fruit treated
three weeks before harvest is substantially the same as on the day of
application.
FATE OF RESIDUES
General comments
Extensive information on the nature and fate of chlordimeform
residues was considered at the 1971 Meeting and a review of this
information is contained in the monographs (FAO/WHO 1972). Since then
only limited information has been received on the general fate of
chlordimeform residues.
In plants
An abstract of the thesis by Witkonton, 1974, indicates that
radio tracer studies of apples treated with chlordimeform revealed a
rapid disappearance of the chemical from the surface of the treated
fruit. Less than 1% of the applied chemical remained on the surface at
harvest 60 days after application. However, 25% of the applied
chemical was recovered in apple peel and pulp. This mainly comprised
the parent compound and N-formyl-4-chloro-o-toluidine.
Studies on tomatoes grown in Mexico revealed that little of the
chlordimeform residue was removed by simple washing. Field treated
tomatoes picked two days after application were found to contain 0.19
mg/kg of chlordimeform (range 0.17 to 0.20). Following a simple
washing process, these same tomatoes contained 0.12 mg/kg
chlordimeform (range 0.07 to 0.17).
In cooking and processing
In solution, chlordimeform. is susceptible to hydrolysis but not
to oxidative processes, provided that enzyme systems from living
organisms are not present. The rate of hydrolysis depends on the Ph
value of the medium. Chlordimeform is stable under strongly acid
conditions (in the region of Ph 2). Considerable instability occurs in
neutral medium with a half-life of 42 hours at 30°C in a buffer of pH
7 containing 5% of methanol (Kosmann et al., 1971).
Hydrolysis of chlordimeform in neutral medium yields
N-formyl-4-chloro-o-toluidine. Further hydrolysis to
4-chloro-o-toluidine is very slow under these conditions. It is,
however, much more rapid in extremely acid or alkaline solutions.
Chlordimeform residues in crops decrease during cooking processes
through hydrolysis of the parent compound, but volatilization in steam
is not an important contributing factor. It has been demonstrated that
the rate of disappearance of chlordimeform is a function of pH since
the loss is much more rapid in weakly acid or neutral material such as
cauliflower than in strongly acid fruit like apples. This finding is
in agreement with the known chemical properties of the compound.
Cooking processes do not reduce substantially the total residue
which can be estimated by the method which determines the total
4-chloro-o-toluidine moiety. In the light of these results, which
were derived from detailed studies with different crops (apples,
grapes, tomatoes, cauliflowers, beans, sugar beet foliage) (Kossmann,
1971), it can be concluded that cooking procedures reduce the
proportion of parent compound while at the same time increasing the
proportion of the hydrolysis product N-formyl-4-chloro-o-toluidine.
This change is not large except in the case of neutral or alkaline
conditions and in any event is not likely to be detected when making
analyses by the accepted method. Results of studies using analytical
methods specific for the parent compound are set out in Tables 3-5.
Further studies on the fate of chlordimeform residues in cooking
and processing have been reported. These include studies on the
following commodities.
Tea
The total residues of chlordimeform in three different tea leaf
samples were determined to be 30.4, 12.3 and 3.7 ppm respectively. Tea
prepared from these samples (1 g per 100 ml of boiling water)
contained total residues of 0.18, 0.07 and 0.02 ppm. These results
indicate that more than 50% of the total residues present in the dried
tea are extractable under the conditions of infusion and will thus
move into the beverage (CIBA-GEIGY, 1972a).
Apple juice
Apple juice was prepared using a pneumatically operated press to
yield 80% juice and 20% wet pomace. Whole apples containing 5 mg/kg
total chlordimeform residue yielded juice containing 2 mg/kg
(CIBA-GEIGY, 1972b). The wet pomace on the other hand contained 9.2
mg/kg chlordimeform. Upon drying, the dry pomace yielded 35.7 mg/kg.
The level of residues in the juice is only half what would be
expected had the residue been distributed homogeneously between the
pulp and the juice. Earlier studies (Schering, 1967a,b) had shown that
apples containing 1.9% total chlordimeform only contain 0.2 ppm in the
flesh but 9.2 ppm in the skin and outer layer, which represents 20% of
the total weight of the apple.
Grape juice and wine
Grape berries containing 1.4 mg/kg of total chlordimeform when
pressed, yielded juice containing 0.9 mg/kg (CIBA-GEIGY, 1972c). This
is in agreement with earlier studies (Schering, 1967a,b) which showed
that depending upon the interval between spraying and harvest, the
grape skins contained from 60 to 76% of the residues found in the
whole grapes. The skins, on the other hand, only represented 17% of
the total weight of fruit pressed.
TABLE 3. Effect of cooking on chlordimeform residuesa in crops
Residue found Residue found
before cooking Cooking after cooking
Crop period
(variety) Code mg/kg % pH min. mg/kg %
Apples 73/70 0.76 100 2.5 15 0.61 80
(Ontario) 74/70 0.73 100 2.5 15 0.57 78
73/70 0.76 100 2.5 60 0.55 72
74/70 0.73 100 2.5 60 0.46 63
Grapes 89/70 2.35 100 2.5 15 2.30 98
(Riesling) 2.35 100 2.5 60 2.05 87
Grapes 94/70 1.95 100 2.5 15 2.20 113
(Muller-Thurgau) 1.95 100 2.5 60 1.48 76
Sugar beet 119/70 4.10 100 6 15 0.70 17
foliage 120/70 7.95 100 6 15 1.05 13
119/70 4.10 100 6 60 0.24 6
120/70 7.95 100 6 60 0.17 2
a Residues were determined by means of a method specific for chlordimeform
parent compound.
TABLE 4. Effect of cooking on chlordimeform contenta of samples
spiked with chlordimeform
Chlordimeform
Cooking recovered
Chlordimeform period
Crop added mg/kg pH min. mg/kg %
Apples 2.0 2.5 15 1.60 80
(deep freeze) 2.0 2.5 60 1.85 92
Tomatoes 2.0 3 15 2.00 100
(fresh) 2.0 3 60 1.75 88
Green beans 2.0 5 15 0.76 38
(fresh) 2.0 5 60 0.23 11
Cauliflower 2.0 6 15 0.45 22
(fresh) 2.0 6 60 <0.02 <1
a Chlordimeform content determined by means of a method specific
for chlordimeform parent compound.
TABLE 5. Effect of cooking on total chlordimeform, contentb
of samples spiked with chlordimeform
Chlordimeform
Cooking recoveredc
Chlordimeform period
Crop added mg/kg pH min. mg/kg %
Tomatoes 2.0 3 60 1.94 97
(fresh)
Green beans 2.0 5 15 1.68 84
(fresh) 2.0 5 60 1.80 90
Cauliflower 2.0 6 15 2.06 103
(fresh) 2.0 6 60 1.78 89
b Total chlordimeform content determined by a procedure that
accounts for the active ingredient and its hydrolysis products
N-formyl-4-chloro-o-toluidine and 4-chloro-o-toluidine.
c Average of three determinations.
Fermentation of the grape juice over a period of 72 days yielded
a wine still containing about 1 mg/kg of chlordimeform, (CIBA-GEIGY,
1972d). This result indicates that the fermentation process for wine
production does not significantly lower the total chlordimeform
residues found in the raw grape juice.
Beer
Green hop cones containing 12.5 mg/kg chlordimeform were used to
prepare beer. Residues in the beer prepared from the treated cones
were found to be below the limit of detection as calculated
statistically from the control and analytical values (CIBA-GEIGY,
1971). The limit of determination was 0.03 mg/kg.
Milk and butter
Extensive studies carried out in Australia and reported by Bull
(1971a,b) indicate that when chlordimeform is used on cows as a dip or
spray for the control of cattle ticks, the maximum concentration of
chlordimeform occurs in the milk of the first milking after treatment.
The maximum concentration found in a number of trials was 0.04 mg/kg
(just above the limit of determination). Butter prepared from this
milk, which contained 3.8 to 4.0% butterfat, was found to contain 0.26
to 0.34 mg/kg chlordimeform.
Butter prepared from milk collected 12 hours later contained only
0.08 mg/kg chlordimeform. Thereafter the residue level declined
rapidly, being below the limit of determination in butter on the
fourth day after treatment. These studies indicate that only about one
third of the total chlordimeform excreted in the milk is located in
the butterfat and finds its way into butter.
Further studies using chlordimeform at 0.05% concentration (four
times the label recommendation), showed that residues in whole milk
collected six hours after treatment contained up to 0.3 mg/kg
chlordimeform. Butter prepared from this milk contained up to 1.75
mg/kg. Residues in milk did not decline below the limit of
determination for 72 hours following such treatment but, even at this
stage, the butter was found to contain 0.1 mg/kg chlordimeform. These
studies further indicate that chlordimeform is only partly partitioned
into the lipid portion of milk.
RESIDUES IN FOOD IN COMMERCE OR AT CONSUMPTION
Only one piece of information was submitted to show results of
monitoring for chlordimeform residues in food moving in commerce. The
Australian Department of Agriculture reported that during the
continuous survey of raw agricultural commodities for a wide range of
residues, 152 samples of beef fat collected at abbatoirs within the
cattle tick zone were analysed for chlordimeform residues. None of the
samples were found to contain residues at or above the limit of
determination (0.05 ppm).
METHODS OF RESIDUE ANALYSIS
No significant developments appear to have been made since the
available data were reviewed in 1971. Voss et al. (1973) have
published a detailed review of the available methods and have
confirmed the techniques suitable for research and regulatory purposes
including automated modifications. The methods most suitable for
regulatory residue analysis appear to be those involving the
determination of chlordimeform and metabolites hydrolyzable to
4-chloro-o-toluidine using gas chromatography following iodination
of the diazotised aromatic amine (Baunok and Geissbuhler, 1968;
Geissbuhler et al., 1971).
At the present time there are a number of other formamidine
compounds being developed as insecticides and acaricides for the
treatment of cattle. Same of these also contain the
4-chloro-o-toluidine moiety and would be determined quantitatively
by the same procedure. A means of distinguishing such residues will be
required if and when both classes of compounds are available
concurrently.
NATIONAL TOLERANCES REPORTED TO THE MEETING
The following are examples of national tolerances and withholding
periods that have been established.
Withholding
period (days)
Tolerance (pre-harvest
Country Crop mg/kg interval)
Argentine Apples, pears - 28
Australia Apples, grapes 3 7
Citrus, cole crops 2 7
Cotton seed 2 2
Pears, stone fruit 5 7
Strawberries 3 2
Tomatoes 1 1
Fat of meat and edible offal of cattle 1 3
Milk and milk products (fat basis) 0.5 -
Edible vegetable oil 0.05 -
Canada Apples 3 14
Broccoli 2 7
Brussels sprouts 3 14
Cabbage 0.5 7
Cauliflower 3 7
Peaches 4 28
Pears 5 28
Plums and prunes 4 21
Turnip roots (Brassica) <0.05 7
(Continued)
Withholding
period (days)
Tolerance (pre-harvest
Country Crop mg/kg interval)
Federal Fruits 3 14
Republic Vegetables 2 14
of Germany Sugar beets 0.2 42
France Not specified - 15
Italy Not specified 1 -
Japan Citrus 2 30
Fruits 2 7
Grapes - 45
Rice 0.1 30
Strawberries - 7
Tea 0.6 -
Vegetables 0.6 -
New Zealand Fruits - 14
Peru Cotton (seed) - 15
South Africa Apples, pears 1 -
Citrus - 14
Spain Fruits, cotton - 21
Switzerland Pome fruits, grapes 1 42
USA Apples 3 14
Pears 12 0
Dried apple pomace 25 -
Cherries 5 21
Peaches 5 21
Nectarines 5 21
Plums 4 21
Dried prunes 15 21
Walnuts 0.1 21
Broccoli 2 14
Brussels sprouts 2 14
Cabbage 2 14
Cauliflower 2 14
Tomatoes 1 -
Cotton seeds 5 21
Cotton seed hulls 10 -
Meat, fat, meat byproducts 0.25 -
Eggs, milk 0.25 -
Venezuela Fruits, citrus 2 -
APPRAISAL
The 1971 Joint Meeting, having reviewed the available information
on chlordimeform, specified that further work or information was
required on the nature and level of residues in animal tissues,
residues in milk, residues in butter and cheese, further data on
disappearance of residues during storage, processing and cooking, and
data on residue levels in commodities moving in commerce.
The Meeting received considerable information on all these
questions with the exception of residues in commodities moving in
commerce. There was additional information on new uses, including
application to irrigated rice. Residue studies to indicate the
incidence and level of residues resulting from the use of
chlordimeform on rice were not available.
Additional information was received on supervised residue trials
carried out in several countries on apples, grapes, citrus, peaches,
pears, tomatoes and strawberries. These data indicate that in the case
of apples, grapes, citrus and peaches, the information reviewed
confirmed the recommendations made in 1971 and the Meeting agreed that
the maximum residue limits then recommended could not be lowered. Data
from extensive supervised residue trials carried out on pears in the
USA indicate that approximately 10 ppm of chlordimeform is to be found
on fruit treated at the recommended rate with either the base or
hydrochloride formulation. The residue level at 14 to 18 days
post-application is at or above 5 mg/kg. Even at 35 to 40 days after
application, residue levels of 4 mg/kg are not uncommon. In the light
of these new data, the Meeting agreed to revise the recommended
maximum residue limit.
The need to use chlordimeform for the control of lepidopterous
pests of tomatoes has resulted in the generation of extensive residue
data on the basis of which the Meeting has proposed a maximum residue
limit.
Only limited new information has been received on the general
fate of chlordimeform residues but in view of the extensive
information reviewed in 1971, this is not surprising. It is, however,
clear that little of the residue will be removed by a simple washing
process but the bulk will be removed with the peel of such commodities
as apples, citrus, peaches and grapes.
Further studies on the fate of chlordimeform residues during
cooking and processing have shown that the cooking of acid fruits and
vegetables does not substantially reduce the residue of the active
ingredient. Any metabolites, including the terminal
4-chloro-o-toluidine, are not particularly volatile in steam and are
thus not lost during cooking.
In the preparation of fruit juices the bulk of the residues
remain in the pomace. Any residues which occur in the juice are
resistant to further processing, including the fermentation of wine.
In the case of residues in milk arising from the application of
chlordimeform to dairy cows for tick control, the residue levels
decline rapidly and are only of significance in butter made from such
milk from the first and second milkings following treatment. It has
been shown that only a portion of the chlordimeform residue is
partitioned into the lipid fraction of the milk. It is not yet clear
whether the residues in milk contain any of the parent compound or
whether they represent metabolites and terminal residues.
RECOMMENDATIONS
The following amended (pears) and new temporary maximum residue
limits are recommended:
Temporary maximum
Commodity residue limit, mg/kg
Pears 10
Tomatoes 1
Rice (hulled) 0.1
FURTHER WORK OR INFORMATION
Required before 30 June 1978
1. Long-term study to consider the occurrence of changes in liver
and bile duct of rats.
2. Further metabolic studies in several animal species including
observations in man.
3. Further studies to elucidate the mode of action.
4. Continued observations on the possible occurrence of haemorrhagic
cystitis in people exposed to chlordimeform.
5. Information to justify the short pre-harvest interval on pears in
the USA.
REFERENCES
Abo-Khatwa, N. and Hollingworth, R. M. (1972) Chlordimeform: the
relation of mitochondrial uncoupling to toxicity in the German
cockroach. Life Sciences II, 11:1181-90
Abo-Khatwa, N. and Hollingworth, R. M. (1973) Chlordimeform,
uncoupling activity against rat liver mitochondria, in vitro.
Pesticide Biochemistry and Physiology, 3:358-69
Armstrong, J., Graves, O., Lovejoy, G., Swiggart, R. and Kimbrough, R.
(1975) Insecticide induced acute haemorrhagic cystitis. Morbidity,
Mortality Weekly Report, US, CDC, Atlanta, Georgia. Vol. 24, No. 44,
p.374
Aziz, S. A. and Knowles, C. O. (1973) Inhibition of monoamine oxidase
by the pesticide chlordimeform and related compounds. Nature, 242:
417-18
Baunok, I. and Geissbuhler, H. (1968) Specific determination of urea
herbicide residues by EC gas chromatography after hydrolysis and
iodine derivative formation. Bull. Env. Contam & Toxicol, 3(1)7
Beeman, R. W. and Matsumura, F. (1973) Chlordimeform: a pesticide
acting upon amine regulatory mechanisms. Nature, 242:273-74
Beeman, R. W. and Matsumura, F. (1974) Studies on the action of
chlordimeform in cockroaches. Pesticide Biochemistry and Physiology,
4: 325-26
Bull, M. S. (1971b) Determination of chlordimeform residues in milk
and butter following treatment of cows with chlordimeform at label
recommended strength for plunge dipping and spraying. Ciba-Geigy
(Australia) Technical Report 71/10/354
Bull, M. S. (1971a) Determination of chlordimeform residues in milk
and butter following treatment of dairy cows with 0.05% chlordimeform.
Ciba-Geigy (Australia) Technical Report 71/8/348
CIBA-GEIGY (1971) Galecron residues - German hops and beer 1970.
Report by G. Voss RVA 42/71 (June 15, 1971)
CIBA-GEIGY (1972a) Galecron residues in Japanese tea. Report by W.
Blass, RVA 5/72 (January 11, 1972)
CIBA-GEIGY (1972b) Chlordimeform residues in McIntosh apples, cider
and wet and dry pomace. Research Report CF 10824
CIBA-GEIGY (1972c) Galecron residues in Swiss grapes. Report by W.
Blass, RVA 11/72 (January 17, 1972)
CIBA-GEIGY (1972d) Galecron residues in Swiss wine 1971. Report by W.
Blass, RVA 16/72 (February 4, 1972)
Currie, A. N. (1933) Chemical haematuria from handling
5-chloro-o-toluidine. J. Ind. Hyg., 15:
Dittrich, V. (1966) N-(2 methyl-4-chlorphenyl)-N',N'-dimethyl
Formamidine (C8514/Schering 36268) Evaluated as an acaricide. J. Econ.
Entomol., 59:889-93
Geissbuhler, H., Kossman, K., Baunok, I. and Boyd, V. F. (1971)
Determination of total residues of chlordimeform in plant and soil
material. J. Agr. Food Chem., 19:365
Kossman, K. (1971) Effect of cooking on chlordimeform residues in
apples, grapes, tomatoes, cauliflower, beans and sugar been foliage.
Schering AG report PC 29/64 (September 28, 1971)
Kossman, K., Geissbuhler, H. and Boyd, V. F. (1971) Specific
determination of chlordimeform and some potential metabolites in plant
materials by thin-layer and flame ionisation gas chromatography. J.
Agr. Food Chem., 19:360
Maitre, L. and Gfeller, W. (1975) Influence of Compound 8514
(chlordimeform) on the brain and liver monamino oxidase of rats.
Unpublished report from Ciba-Geigy Pharmaceutical Division submitted
to the World Health Organization by Ciba-Geigy Ltd., Basel,
Switzerland
Meier, M. (1975) Investigation of the effect of chlordimeform in
isolated heart preparations of the guinea pig. Unpublished report from
the Ciba-Geigy Pharmaceutical Division submitted to the World Health
Organization by Ciba-Geigy Ltd., Basel, Switzerland
Robinson, C. P., Smith, P. W., Zelenski, J. D. and Endecott, B. R.
(1975) Lack of an effect of interference with amine mechanisms on the
lethality of chlordimeform in the rat. Tox. Appl. Pharmacol.,
33:380-83
Schering AG (1967b) Ruckstandsuntersuchungen chlorphemidin (Schering
36268) IV Mitteilung 1968 -Lokalisation eines chlorphenamidin -
Ruckstandes auf Apfelen de Sorte Cox Orange. Report of Schering AG, Dr
Ko/So, 17.10.67
Schering AG (1967a) Ruckstandsuntersuchungen chlorphenamidine III
Mitteilung 1967. Erntegut: Weintrauben. Report of Schering AG, Dr
Ko/So, 13.10.67
Witkonton, S. (1974) Fate of the pesticide in fruit and soil and
toxicological properties of some of its conversion products. Diss.
Abstr. Int., 38(8) 3831 B (Thesis, Pennsylvania State University)
Voss, G., Kossmann, K. and Geissbuhler, H. (1973) Chlordimeform in
analytical methods for pesticides and plant growth regulators. Edited
by G. Zweig, Academic Press, New York, p.211-230
Zak, F., Sachsse, K., Bathe, R. and Hess, R. (1973) One-year feeding
study on the rat with Technical C-8514. Unpublished report from the
Toxicology/Pathology Division, Ciba-Geigy, submitted to the World
Health Organization by Ciba-Geigy Ltd., Basel, Switzerland