CHLORDIMEFORM
EXPLANATION
Chlordimeform was reviewed and evaluated for an acceptable daily
intake by the Joint Meetings in 1971, 1975, 1978, 1979 and 1980 (Annex
1, FAO/WHO, 1972a, 1976a, 1979a, 1980a and 1981a). A toxicological
monograph was prepared by the Joint Meeting in 1971 (Annex 1, FAO/WHO,
1972b) and monograph addenda were prepared in 1975, 1978, 1979, and
1980 (Annex 1, FAO/WHO, 1976b, 1979b, 1980b, and 1981b). A temporary
acceptable daily intake (TADI) of 0-0.01 mg/kg b.w. was established in
1971 and reduced to 0-0.0001 in 1978. Further evaluations carried out
in 1979 and 1980 did not modify the TADI. The 1980 Meeting required
for review at the present meeting a report on continued surveillance
and epidemiological studies of occupationally exposed workers in both
industry and agriculture. A confirmatory long-term animal bioassay
using a third species for evaluation of potential carcinogenic hazard
was considered desirable. A considerable amount of additional
information, not all relevant to the above requests, was evaluated by
the Meeting and is presented in this monograph addendum.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOLOGICAL DATA
Biochemical Aspects
Effects on enzymes and other biochemical parameters
In a study to investigate the effects of chlordimeform on hepatic
enzymes in rats and mice, groups of eight male and eight female
Tif:Magf (SPF) mice and Sprague-Dawley-derived Tif:RAI f (SPF) rats
were treated by gastric intubation with 0, 50, 100 and 150 mg/kg b.w.
chlordimeform in 0.9% saline solution (1 ml/100 g b.w.) for seven
consecutive days. The animals were then fasted for 24 hours before
sacrifice. The following parameters were investigated in hepatic
microsomal fractions: benzo(a)pyrene hydroxylase, ethoxycoumarin
O-de-ethylase ethylmorphine N-demethylase, cytochrome P-450 content,
NADPH cytochrome P-450 reductase, UDP-glucuronyl transferase, and
microsomal epoxide hydrolase. Glutathione S-transferase was measured
in 100,000xg supernatants.
Chlordimeform treatment induced several hepatic drug-metabolising
enzymes with some species and/or sex specificity. Relative liver
weights were increased in female rats and mice in a dose-dependent
manner. Cytochrome P-450 content was increased in all cases but
cytochrome P-450 reductase activity was increased only in the highest
dose in male rats and mice and in the lowest and highest doses only
in female mice. Ethylmorphine N-demethylase was induced in a dose-
dependent manner in male mice but only at the highest dose in female
mice. Ethoxycoumarin O-de-ethylase was induced in dose-dependent
manner in male and female rats but only at high doses in both sexes of
mice. Benzo(a)pyrene hydroxylase was increased in a dose-dependent
manner in female rats and mice but only at the mid-dose in male mice.
UDP-glucuronyl transferase was induced in rats of both sexes and
female mice in a dose-dependent manner but male mice exhibited no
induction.
Dose-dependent increases of expoxide hydrolase and glutathione
S-transferase occurred in male and female rats and female mice.
(Bentley et al., 1985a). The results of these investigations clearly
indicate that chlordimeform induces the activity of several hepatic
enzymes but reveal no clear distinctions between rats and mice.
The effect of acute and repeated chlordimeform treatment on rat
hepatic microsomal enzymes has been examined following acute or
repeated dosing. Groups of 6 male and 6 female Sprague-Dawley rats
received either a single intraperitoneal injection of chlordimeform
(100 mg/kg) 60 minutes prior to sacrifice or daily injections
(75 mg/kg) for 4 days. Control animals received equivolume injections
of normal saline (1 ml/kg). The duration of zoxazolamine-induced
paralysis (70 mg/kg i.p.) or pentobarbitone-induced hypnosis (40 mg/kg
i.p.) were assessed in the latter group.
Hepatic microsomal preparations were utilized to assay the
following enzymatic activities: ethylmorphine N-demethylase, aniline
hydroxylase, p-nitroanisole-O-demethylase and NADPH cytochrome C
reductase. Hepatic microsomal cytochrome P-450 content was estimated
and the spectral binding of chlordimeform (2.1 mM), aniline (20 mM)
and hexobarbital (10 mM) to hepatic microsomes was studied.
It was found that acute chlordimeform exposure prolonged
zoxazolamine paralysis and pentobarbitone hypnosis. However, after
repeated exposure, the duration of zoxazolamine paralysis was
significantly reduced whilst the duration of pentabarbitone hypnosis
remained unchanged.
Significant sex-related difference in hepatic metabolism were
found. In male rats, ethylmorphine N-demethylation was significantly
reduced in acutely treated animals and to a lesser extent in the
repeatedly exposed group. Repeated exposure caused a modest reduction
in aniline hydroxylation but did not affect the metabolism of
p-nitranisole. For female rats, however, either acute or repeated
chlordimeform treatment had little effect on ethylmorphine
N-demethylation and p-nitroanisole demethylation whilst aniline was
metabolised to a lesser extent following both treatment regimens.
These results suggest that the hepatic microsomal enzymes of male rats
are significantly more responsive to chlordimeform exposure than are
those of females.
In acutely-treated rats, hepatic microsomal NADPH cytochrome C
reductase activity, cytochrome P-450 content and the spectral binding
of hexobarbitone and aniline were significantly reduced. However, only
the spectral binding of hexobarbitone was significantly reduced in
rats repeatedly exposed to chlordimeform. Chlordimeform was found to
produce a characteristic Type I difference spectrum when added to rat
liver microsomes. The authors concluded that chlordimeform bound to
cytochrome P-450 at non-active sites, producing a change in protein
conformation (Budris et al., 1983).
Special studies on mutagenicity
Chlordimeform and its principal metabolites, 4-chloro-2-toluidine
and N-formyl-2-toluidine, were variably active in a range of
in vitro assays. In vivo, however, chlordimeform was inactive but
the metabolites were each positive in one assay. Results are
summarised in Table 1.
Special studies on macromolecular binding
Species difference in the DNA-binding of the metabolite
4-chloro-2-toluidine were investigated in rats and mice in vivo and
in vitro. l4C-Ring labelled metabolite was dosed daily at 25 mg/kg
to male Tif:MAG f (SPF) mice, and Sprague-Dawley derived Tif:RAI f
(SPF) rats, by gastric intubation. Animals were held for 20 hours
before sacrifice. The radioactivity bound to purified DNA isolated
from liver homogenates was found to increase with total dose in both
rats and mice. DNA binding in mice was about twice that in rats.
Covalent binding of 4-chloro-2-toluidine to calf thymus DNA was
studied in vitro after incubation with liver fractions from rats and
mice. Mouse liver fractions produced more metabolites which bound to
DNA than did those prepared from rat liver. Binding was catalysed
by active liver homogenates and microsomal fractions and was
NADPH-dpendent. Pretreatment with known inducers of cytochrome P-450
(phenobarbitone, 3-methylcholanthrene, and arochlor 1254) was without
effect.
The patterns of adducts produced in rat and mouse liver in vivo
and by incubation of calf thymus DNA in vitro with hepatic
subcellular fractions of each species were analysed
chromatographically. The patterns were qualitatively similar, the same
metabolites being formed in each case. Significant quantitative
differences occurred with two metabolites only (Bentley et al.,
1985b).
Species differences in the toxicity of 4-chloro-2-toluidine were
further investigated. 14C-4-Chloro-2-toluidine (25 mg/kg) was
administered in aqueous solution by gastric intubation to male Tif:MAG
f(SPF) mice and Sprague-Dawley derived Tif:RAI f (SPF) rats. Urinary
Table 1: Results of mutagenicity assays on chlordimeform and its metabolites
Test system Test Test substance Concentrations Results Reference
Object (purity) used
Studies on microorganisms
Salmonella typhimurium/ TA98 chlordimeform -S9: 0.1,1,10.100,1000 µg/0.1 ml - Arni & Müller,
microsome TA100 HCl* +S9: 0.1,1,10,100,1000,2000 - 1976a
TA1535 µg/0.1 ml -
TA1537 -
TA98 N-formyl-4- ±S9: 0.1,1,10,100,1000 µg/O.1 ml - Arni & Müller,
TA100 chloro-2- +(with S9 only) 1976b
TA1535 toluidine* -
TA1537 -
TA98 4-chloro-2- ±S9: 0.1,1,10,100,1000 µg/0.1 ml +(with S9 only) Arni & Müller,
TA100 toluidine +(with S9 only) 1976b
TA1535 HCl* -
TA1537 -
Salmonella typhimurium/ TA98 chlordimeform single oral dose of 50, 100, - Arni & Müller,
Intrasanguine host- TA100 HCl (99.9%) 200 mg/kg in mice - 1983a
mediated assay TA1535 -
TA98 4-chloro-2- single oral dose of 250,500, - Arni & Müller,
TAlO0 toluidine 1000 mg/kg in mice - 1983b
TA1535 HCl (99.9%) -
Table 1: (Con't)
Test system Test Test substance Concentrations Results Reference
Object (purity) used
Saccharomyces cerevisiae/ D7 chlordimeform ±S9: 80,400,2000,10000 µg/ml inhibition of Arni & Müller,
microsome HCl (99.9%) ±S9: 15,45,125,405 µg/ml growth above 1983c
400 µg/ml
D7 4-chloro-o- ±S9: 80,400,2000,10000 µg/ml inhibition of Arni & Müller,
toluidine HCl ±S9: 3.2,10,30,90 µg/ml growth at all 1983d
(99.9%) conc. +(at 30,
90 µg/ml)
Salmonella typhimurium/ TA98 chlordimeform* ±S9: 100 µg/ml - Konopka &
microsome TA100 - Heymann,
TA1535 - 1977
TA1537 -
TA1538 -
TA98 4-chloro-2- -S9: 500 µg/ml +(with S9 at 250 Konopka &
toluidine µg/ml) Heymann, 1977
TA100 +S9: 10,250,500 µg/ml +(with S9 at 10
µg/ml)
TA1535 -
TA1537 -
TA1538 -
TA98 2-chloro-N- -S9: 500 µg/ml - Konopka &
TA100 formyl-2- +S9: 100, 500 µg/ml +(with S9 at Heymann, 1977
toluidine* 100 µg/ml)
TA1535 -
TA1537 -
TA1538 -
Table 1: (Con't)
Test system Test Test substance Concentrations Results Reference
Object (purity) used
TA98 chlordimeform ±S9: 100,500,1000,2000 µg/plate - Meucke
TA100 HCl - et el., 1979
TA98 4-chloro-2- ±S9: 0.1,1,5,10,25,50,100,1000 +(with S9 only) Meucke
TA100 toluidine HCl 2000 µg/plate +(with S9 above et al., 1979
100 µg only)
TA100 N-formyl-4- ±S9: 0.1-2000 µg/plate - Meucke
chloro-2- et el., 1979
toluidine
TAl00 4-chloro-2- ±S9: 10-2000 µg/plate - Meucke
toluidyl-N,N- et el., 1979
dimethy
iormamide
Salmonella typhimurium/ TA100 4-chloro-2- ±S9: 10-2000 µg/plate - Meucke
microsome toluidyl-N,N- et al., 1979
methyl
formamide
TA100 4-chloro-2- ±S9: 10-2000 µg/plate - Meucke
toluidyl- et al., 1979
formamide
TA100 4-chloro-2- ±S9: 0.1-2000 µg/plate *(above 25 µg Meucke
methylphenyl- with S9) et al., 1979
hydroxylamine +(above 50 µg
without S9)
Table 1: (Con't)
Test system Test Test substance Concentrations Results Reference
Object (purity) used
TA100 5-chloro-2- ±S9: 0.1-2000 µg/plate *(above l0 µg Meucke
nitroso- with S9 only) et al., 1979
toluene
TA100 4-chloro-acetyl- ±S9: 0.1-2000 µg/plate - Meucke
2-toluidine et al., 1979
TA100 4-chloro-acetyl- ±S9: 0.1-2000 µg/plate - Meucke
N-hydroxy-o- et al., 1979
toluidine
TA100 4,4'-dichloro- ±S9: 0.1-2000 µg/plate - Meucke
2,2'-dimethyl- et al., 1979
azobenzene
TA100 4,4'-dichloro- ±S9: 0.1-2000 µg/plate - Meucke
2,2'-dimethyl- et al., 1979
azobenzene-
N-oxide
TA98 chlordimeform -S9: 1,5,25,125,625 µg/plate - Rashid
TA100 (analytical +S9: 5,10,50,250,1250 µg/plate - et al., 1984
TA1535 grade) -
TA1537 -
TA1538 -
TA98 4-chloro-N- -S9: 1,5,25,125,325 µg/plate - Rashid
TAlO0 formyl-2- - et al. 1984
TA1535 toluidine* +(325 µg/plate)
TA1537 -
TA1538 -
Table 1: (Con't)
Test system Test Test substance Concentrations Results Reference
Object (purity) used
TA98 4-chloro-2 -S9: 1,5,25,125,325 µg/plate - Rashid
TA100 toluidine - et al. 1984
TA1535 (99%) -
TA1537 -
TA1538 -
Eschericia coli/ WP2 chlordimefom ±S9: 250,500,1000, - Rashid
microsome WP2uvrA (analytical 2000 µg/plate - et al., 1984
WP67 grade) -
CM611 -
CM571 -
WP2 4-chloro-N- ±S9: 250,500,1000, - Rashid
WP2uvrA formyl-2- 2000 µg/plate - et al., 1984
WP67 toluidine* -
CM611 -
CM571 -
WP2 4-chloro-2- ±S9: 250,500,1000, - Rashid
WP2uvrA toluidine 2000 µg/plate - et al., 1984
WP67 (99%) -
CM611 -
CM571 -
Table 1: (Con't)
Test system Test Test substance Concentrations Results Reference
Object (purity) used
In vitro assays
Cell transformation BALB/ chlordimeform 0.063,0.125,0.25,0.5,1.0 µg/ml +(not dose- Beilstein &
assay 3T3 HCL (99.9%) related) Müller, 1983
Mouse lymphoma test L5178Y/ chlordimeform -S9: 42.5-1700 µg/ml -(cytotoxicity Beilstein &
TK+/- HCl* above 850 µg/ml) Müller, 1984a
+S9: 75-3000 µg/ml -(cytotoxicity
above 1800 µg/ml)
L5178Y/ 4-chloro-2- -S9: 37.5-600 µg/ml -(cytotoxicity Bellserin &
TK+/- toluidine HCl above 450 µg/ml) Müller, 1984b
* +S9: 31.3-500 µg/ml +
Cell transformation BALB/ 4-chloro-2- 2.25, 4.5, 9, 18, 36 µg/ml + Bellstein &
assay 3T3 toluidine HCl Müller, 1984c
(99.9%)
DNA repair test rat chlordimeform 5, 25, 125, 625 µg/ml - Puri & Müller,
hepatocytes HCl (99.9%) 1983a
rat 4-chloro-2- 0.61, 3.1, 15.7, 78.5 µg/ml +(dose-related) Puri & Müller,
hepatocytes toluidine HCl 1983b
(99.9%)
DNA repair test CRL chlordimeform 2, 10, 50, 250 µg/ml - Puri & Müller,
human lymphocytes 1121 HCl (99-9%) 1983c
CRL 4-chloro-2- 1.25, 6.25, 31.25, 156.25 µg/ml - Puri & Müller,
1121 toluidine HCl 1983d
(99.9%)
Table 1: (Con't)
Test system Test Test substance Concentrations Results Reference
Object (purity) used
Mouse lymphoma cells/ L5178Y 4-chloro-2- single oral dose of 330 mg/kg - (no positive Strasser &
host-mediated toluidine HCl* in mice control) Müller, 1983a
assay
L5178Y N-formyl-4- single oral dose of 300 mg/kg - (no positive Strasser &
chloro-2- in mice control Müller, 1983b
toluidine*
Mouse lymphoma cells/ L5178Y 4-chloro-o- 111, 255 µg/ml + (no positive Strasser &
point mutation toluidine HCl* control) Müller, 1984a
L5178Y N-formyl-4- 213,640 µg/ml + (no positive Strasser &
chloro-2- control) Müller, 1984b
toluidine*
In vivo assays
Chromosomal/germinal spermatogonia N-formyl-4- 1 oral dose o£ 80, 160, or - Arni
epithelium chloro-2- 320 mg/kg in mice et al., 1983a
totuidine*
spermatocytes chlordimeform 5 oral doses of 18, 36, or - Arni
HCl* 72 mg/kg in mice et al., 1983b
spermatocytes N-formyl-4- 5 oral doses of 80, 160, or + (chromosomal Arni & Müller,
chloro-2- 320 mg/kg in mice aberration, not 1983e
toluidine* dose-related)
Table 1: (Con't)
Test system Test Test substance Concentrations Results Reference
Object (purity) used
Dominant lethal 4-chloro-2- single oral dose of - Fritz
toluidine HCl* 110 or 330 mg/kg in mice et al., 1978
chlordimeform * single oral dose of - Fritz, 1978a
22 or 66 mg/kg in mice
N-formyl-4- single oral dose of - Fritz, 1978b
chloro-2- 105 or 315 mg/kg in mice
toluidine *
Chromosomal/germinal spermatogonia chlordimeform 5 oral doses of 9, 18, 22, 36, - Hool
epithelium HCL* and 66 mg/kg in mice et al., 1983
Chromosomal/somatic bone N-formyl-4- 2 oral doses of 300, 600, and + (not seen in Hool & Arni,
cells marrow chloro-2- 1200 mg/kg in Chinese hamster repeat 1983a
toluidine* experiment)
bone 4-chloro-2- 2 oral doses of 100,200,237,356, + Hool & Arni,
marrow toluidine HCl* 533,800 mg/kg in Chinese hamster 1983b
Chromosomal/germinal spermatogonia 4-chloro-2- 5 oral doses of 85, 125, 170, - Hool & Arni,
epithelium toluidine HCI* 250, 340, 500 mg/kg in mice 1983c
spermatocytes 4-chloro-2- 5 oral doses of 85, 125, 170, - Hool & Arni,
toluidine HCl* 250, 340, 500 mg/kg in mice 1983d
Table 1: (Con't)
Test system Test Test substance Concentrations Results Reference
Object (purity) used
Sister chromatid bone chlordimeform single oral dose of 31, 62, 324 - Hool & Armi,
exchange marrow HCl (99.9%) mg/kg in Chinese hamster 1983e
bone 4-chloro-2- single oral dose of 100, 200, - Hool & Arni,
marrow toluidine HCl 400 mg/kg in Chinese hamsters 1983f
(99.9%)
Chromosomal/somatic bone chlordimeform 2 oral doses of 60, 120, 240 - Hool & Müller,
cells marrow HCl* mg/kg in Chinese hamster 1978
Heritable translocation male chlordimeform* 49 daily oral doses of 120 mg/kg - Lang & Adler,
mice 1982
male N-formyl-4- 49 daily oral doses of 100 mg/kg - Lang & Adler,
mice chloro-2- 1982
toluidine*
male 4-chloro-2- 49 daily oral doses of 200 mg/kg - Lang & Adler,
mice toluidine* 1982
Mammalian spot test C57BL/ chlordimeform 3 oral doses of 160 mg/kg - Lang, 1984
6J mice
genotype
a/a
b/+;cch N-formyl-4- 3 oral doses of 100 mg/kg - Lang, 1984
p/++; chloro-2-
dse/++; toluidine*
s/+
Table 1: (Con't)
Test system Test Test substance Concentrations Results Reference
Object (purity) used
4-chloro-2- 3 oral doses of 100 mg/kg +(spots of Lang, 1984
toluidine* genetic
relevance)
Nucleus anomaly/ bone chlordimeform 2 oral doses of 60, 120, 240 - Langauer &
somatic nuclei marrow HCI* mg/kg in Chinese hamsters Müller, 1977
bone N-formyl-4- 2 oral doses of 300, 600, 1200 - Langauer &
marrow chloro-2- mg/kg in Chinese hamsters Müller, 1978a
toluidine*
bone 4-chloro-2- 2 oral doses of 100, 200, 400 - Langauer &
marrow toluidine* mg/kg in Chinese hamsters Müller, 1978b
* Purity not specified
excretion of radioactivity was monitored daily until sacrifice.
Covalent binding of radioactivity to hepatic DNA, RNA and protein was
measured 6, 12, 20 and 68 hours after treatment. In each case, the
extent of binding to mouse DNA significantly exceeded that to rat DNA
but binding to mouse RNA and protein exceeded that to rat DNA and
protein.
The effect of 4-chloro-2-toluidine upon the incorporation of
3H-thymidine into capillary endothelial cells was also studied.
Male rats and mice were dosed orally with 4-chloro-2-toluidine
(25 mg/kg/day) and received subsequently 3H-thymidine by i.p.
administration at varying intervals. The incorporation of
radioactivity into blood capillary endothelial cell nuclei was studied
by autoradiography. Between 500 to 1500 nuclei per animal were
assessed. It was found that the incorporation of 3H-thymidine was not
elevated in treated animals when compared to controls (Bentley
et al., 1985c).
Observations in humans
Information was submitted on the results of monitoring the urine
of more than 100 workers engaged in chlorimeform production and
packaging in 1976. In more than 800 individual urine samples, total
urinary levels ranged from 0.05-50 ppm. Microscopic haematuria was not
detectable, suggesting that it may not occur at these levels of
excretion (Barnett, 1979). Information was also submitted on the
results of urinary monitoring of workers engaged in chlordimeform
application to cotton in seven countries (Limmer, 1985). As the
temporal relationship between exposure and urine sampling was not
established, it was not possible to relate this information to actual
levels of exposure.
In the period 1980-1984, four separate incidents resulting in 7
cases of frank haematuria following industrial exposure occurred in
the USA. Chemical cystitis, confirmed by cystoscopy and biopsy, was
diagnosed in one case while non-specific bladder mucosal lesions was
found in another. Six cases required hospitalisation but all resolved
after cessation of exposure (Barnett, 1985).
In the same period, no cases of chlordimeform-induced haematuria
occurred at manufacturing plants in Switzerland and West Germany or
formulation plants in Australia, Columbia, Central America, Mexico and
the USA. No cases of haematuria reportedly resulted from application
or use of chlordimeform in the field. (Reckefus and Kossman, 1985;
Pfister and Dubach, 1985).
Twenty-one cases of haemorrhagic cystitis have been reported in
workers exposed to chlordimeform wastes and in those drinking
contaminated water (Morgan and Gillen, 1982).
COMMENTS
Chlordimeform has been found to induce haemangiosarcomas in mice
but not in rats (JMPR, 1980; Annex 1, FAO/WHO, 1981a). 4-Chloro-2-
toluidine (previously termed 4-chloro-O-toluidine), a metabolite of
chlordimeform, also produces haemangiosarcomas in mice but not in rats
(IARC, 1983).
Data reviewed by the present meeting indicated that chlordimeform
induced the activity of several hepatic drug metabolising enzymes but
the observed biological differences could not be attributed to the
results of either in vivo or in vitro studies.
Studies of macromolecular binding of 4-chloro-2-toluidine to RNA
and DNA of rat and mouse tissues in vitro and in vivo also could
not explain the observed differences in response to this compound, nor
could a study of its effect on the incorporation of 3H-thymidine into
capillary endothelial cells.
Chlordimeform was without mutagenic activity in various cellular
systems but gave positive results in a cell transformation assay. The
metabolites 4-chloro-2-toluidine and N-formyl-4-chloro-2-toluidine
were positive in several reverse mutation assays but only with
metabolic activation; the former metabolite was also positive in mouse
lymphoma, cell transformation and DNA repair assays. Both produced
chromosomal anomalies in at least one in vivo assay.
Occupational studies indicate that haematuria and cystitis have
occurred following incidents of relatively high exposure. Exposed
workers readily absorb chlordimeform and the excretion of 4-chloro-2-
toluidine can be monitored.
Data were submitted on the results of extensive urinary
monitoring of chlordimeform applicators in seven countries. Results
were variable but could not be related to exposure adequately, as
information on the timing of exposure and sample collection was not
provided. It is of interest to note that a daily excretion of
1.5 litres of urine containing 0.5 mg/1 of 4-chloro-2-toluidine by a
60 kg individual approximates to absorption of 0.017 mg/kg body weight
of chlordimeform.
Epidemiological data were not submitted.
The Meeting was advised by the submitters of the data that
chlordimeform is used only on cotton and that no other uses are
anticipated. The Meeting recommended that the use of chlordimeform be
restricted to cotton production.
As the Meeting considered that the available information
partially met the requirement of the 1980 Joint Meeting, it decided to
extend the temporary ADI.
TOXICOLOGICAL EVALUATION
LEVEL CAUSING NO TOXICOLOGICAL EFFECT
Rat: 2 ppm in the diet, equivalent to 0.1 mg/kg b.w.
Dog: 250 ppm in the diet, equivalent to 6.25 mg/kg b.w.
ESTIMATE OF TEMPORARY ACCEPTABLE DAILY INTAKE FOR MAN
0.0001 mg/kg b.w.
REQUIRED (by 1987)
Interpretable epidemiological and urinary monitoring data on
occupationally-exposed workers.
DESIRED
1. Confirmatory long-term animal bioassay using a third species
for evaluating the potential carcinogenic hazard.
2. Further observations in man.
REFERENCES
Arni, P., Hool, G., & Müller, D. CGA 72'651: Chromosome studies in
(1983a) male germinal epithelium (mouse spermatogonia). Unpublished
report from Ciba-Geigy Ltd., Basel, Switzerland. Submitted
to WHO by Ciba-Geigy Ltd. and Schering Aktiengesellschaft.
Arni, P., Hool, G., & Müller, D. C8513: Chromosome studies in male
(1983b) germinal epithelium (mouse spermatogonia). Unpublished
report from Ciba-Geigy Ltd., Basel, Switzerland. Submitted
to WHO by Ciba-Geigy Ltd. and Schering Aktiengesellschaft.
Arni, P. & Müller, D. C8513: Salmonella/mammalian mutagenicity test.
(1976a) Unpublished report from Ciba-Geigy Ltd., Basel, Switzerland.
Submitted to WHO by Ciba-Geigy Ltd. and Schering
Aktiengesellschaft.
Arni, P. & Müller, D. CGA 72'651: Salmonella/mammalian-microsome
(1976b) mutagenicity test. Unpublished report from Ciba-Geigy Ltd.,
Basel, Switzerland. Submitted to WHO by Ciba-Geigy Ltd. and
Schering Aktiengesellschaft.
Arni, P. & Müller, D. CGA 72'647: Salmonella/mammalian-microsome
(1976c) mutagenicity test. Unpublished report from Ciba-Geigy Ltd.,
Basel, Switzerland. Submitted to WHO by Ciba-Geigy Ltd. and
Schering Aktiengesellschaft.
Arni, P. & Müller, D. C8513: Intrasanguine host-mediated assay with
(1983a) S. typhimurium. Unpublished report from Ciba-Geigy Ltd.,
Basel, Switzerland. Submitted to WHO by Ciba-Geigy Ltd. and
Schering Aktiengesellschaft.
Arni, P. & Müller, D. CGA 72'647: Intrasanguine host-mediated assay
(1983b) with S. typhimurium. Unpublished report from Ciba-Geigy
Ltd., Basel, Switzerland. Submitted to WHO by Ciba-Geigy
Ltd. and Schering Aktiengesellschaft.
Arni, P. & Müller, D. C8513: Saccharomyces cerevisiae D7/mammalian-
(1983c) microsome mutagenicity test in vitro. Unpublished report
from Ciba-Geigy Ltd., Basel, Switzerland. Submitted to WHO
by Ciba-Geigy Ltd. and Schering Aktiengesellschaft.
Arni, P. & Müller, D. CGA 72'647: Saccharomyces cerevisiae
(1983d) D7/mammalian-microsome mutagenicity test in vitro.
Unpublished report from Ciba-Geigy Ltd., Basel, Switzerland.
Submitted to WHO by Ciba-Geigy Ltd. and Schering
Aktiengesellschaft.
Arni, P. & Müller, D. CGA 72'651 pure: Chromosome studies in male
(1983e) germinal epithelium (mouse spermatocytes). Unpublished
report from Ciba-Geigy Ltd., Basel, Switzerland. Submitted
to WHO by Ciba-Geigy Ltd. and Schering Aktiengesellschaft.
Barnett, J.W. Letter to California Department of Food and Agriculture
(1979) from Ciba-Geigy Agricultural Div., Greenborough, NC, USA.
Submitted to WHO by Ciba-Geigy Ltd. and Schering
Aktiengesellschaft.
Barnett, J.W. Letter to Ciba-Geigy Ltd., Basel, Switzerland from Ciba
(1985) Geigy Agricultural Division, Greenborough, NC. Submitted to
WHO by Ciba-Geigy Ltd. and Schering Aktiengesellschaft.
Beilstein, P. & Müller, D. C8513; BALB/3T3 cell transformation assay.
(1983) Unpublished report from Ciba-Geigy Ltd., Basel, Switzerland.
Submitted to WHO by Ciba-Geigy Ltd. and Schering
Aktiengesellschaft.
Beilstein, P. & Müller, D. C8513; L1578Y/TK+/- mouse lymphoma
(1984a) mutagenicity test. Unpublished report from Ciba-Geigy Ltd.,
Basel, Switzerland. Submitted to WHO by Ciba-Geigy Ltd. and
Schering Aktiengesellschaft.
Beilstein, P. & Müller, D. CGA 72'647: L1578Y/TK+/- mouse lymphoma
(1984b) mutagenicity test. Unpublished report from Ciba-Geigy Ltd.,
Basel, Switzerland. Submitted to WHO by Ciba-Geigy Ltd. and
Schering Aktiengesellschaft.
Beilstein, P. & Müller, D. CGA 72'647: BALB/3T3 cell transformation
(1984c) assay. Unpublished report from Ciba-Geigy Ltd., Basel,
Switzerland. Submitted to WHO by Ciba-Geigy Ltd. and
Schering Aktiengesellschaft.
Bentley, P., Staubli, W., Bieri, F., Muecke, W., & Waechter, F.
(1985a) Induction of hepatic drug metabolising enzymes following
treatment of rats and mice with chlordimeform. Unpublished
report from Central Toxicology Unit and Agricultural
Division, Ciba-Geigy Ltd., Basel, Switzerland. Submitted to
WHO by Ciba-Geigy Ltd. and Schering Aktiengesellschaft.
Bentley, P., Bieri, F., Waechter, F., Staubli, W., & Muecke, W..
(1985b) Species differences in the toxicity of 4-chloro-o-toluidine
to rats and mice. Covalent binding to DNA assessed in vivo
and in vitro. Unpublished report from Central Toxicology
Unit and Agricultural Division, Ciba-Geigy Ltd., Basel,
Switzerland. Submitted to WHO by Ciba-Geigy Ltd. and
Schering Aktiengesellschaft.
Bentley, P., Bieri, F., Muecke, W., Waechter, F., & Staubli, W.
(1985c) Species differences in the toxicity of 4-chloro-o-toluidine
to rats and mice. Covalent binding to hepatic macromolecules
and hepatic non-parenchymal cell DNA and an investigation of
effects upon the incorporation of (3H)-thymidine into
capillary endothelial cells. Unpublished report from Central
Toxicology Unit and Agricultural Division, Ciba-Geigy Ltd.,
Basel, Switzerland. Submitted to WHO by Ciba-Geigy Ltd. and
Schering Aktiengesellschaft.
Budris, D.M., Yim, G.K.W., Carlson, G.P., & Schnell, R.C. Effect of
(1983) acute and repeated chlordimeform treatment on rat hepatic
microsomal drug metabolising enzymes. Toxicology Letters
18, 63-71.
Fritz, H., Becker, H., & Müller, D. CGA 72'647: Dominant lethal study
(1978) (mouse). Unpublished report from Ciba-Geigy Ltd., Basel,
Switzerland. Submitted to WHO by Ciba-Geigy Ltd. and
Schering Aktiengesellschaft.
Fritz, H. C8513: Dominant lethal study (mouse). Unpublished report
(1978a) from Ciba-Geigy Ltd., Basel, Switzerland. Submitted to WHO
by Ciba-Geigy Ltd. and Schering Aktiengesellschaft.
Fritz, H. CGA 72'651: Dominant lethal study (mouse). Unpublished
(1978b) report from Ciba-Geigy Ltd., Basel, Switzerland. Submitted
to WHO by Ciba-Geigy Ltd. and Schering Aktiengesellschaft.
Hool, G., Bulstein, P., & Arni, P. C8513: Chromosome studies in male
(1983) germinal epithelium mouse spermatogonia. Unpublished report
from Ciba-Geigy Ltd., Basel, Switzerland. Submitted to WHO
by Ciba-Geigy Ltd. and Schering Aktiengesellschaft.
Hool, G. & Arni, P. CGA 72'651: Chromosome studies in somatic cells
(1983a) (Chinese hamster). Unpublished report from Ciba-Geigy Ltd.,
Basel, Switzerland. Submitted to WHO by Ciba-Geigy Ltd. and
Schering Aktiengesellschaft.
Hool, G. & Arni, P. CGA 72'647: Chromosome studies in somatic cells
(1983b) (Chinese hamster). Unpublished report from Ciba-Geigy Ltd.,
Basel, Switzerland. Submitted to WHO by Ciba-Geigy Ltd. and
Schering Aktiengesellschaft.
Hool, G. & Arni, P. CGA 72'647: Chromosome studies in male germinal
(1983c) epithelium (mouse spermatogonia). Unpublished report from
Ciba-Geigy Ltd., Basel, Switzerland. Submitted to WHO by
Ciba-Geigy Ltd. and Schering Aktiengesellschaft.
Hool, G. & Arni, P. CGA 72'647: Chromosome studies in male germinal
(1983d) epithelium (mouse spermatocytes). Unpublished report from
Ciba-Geigy Ltd., Basel, Switzerland. Submitted to WHO by
Ciba-Geigy Ltd. and Schering Aktiengesellschaft.
Hool, G. & Arni, P. C8513: Sister chromatid exchange studies on
(1983e) somatic cells of Chinese hamster. Unpublished report from
Ciba-Geigy Ltd., Basel, Switzerland. Submitted to WHO by
Ciba-Geigy Ltd. and Schering Aktiengesellschaft.
Hool, G. & Arni, P. CGA 72'647: Sister chromatid exchange studies on
(1983f) somatic cells of Chinese hamster. Unpublished report from
Ciba-Geigy Ltd., Basel, Switzerland. Submitted to WHO by
Ciba-Geigy Ltd. and Schering Aktiengesellschaft.
Hool, G. & Müller, P. C8513: Chromosome studies on somatic cells
(1978) (Chinese hamster). Unpublished report from Ciba-Geigy Ltd.,
Basel, Switzerland. Submitted to WHO by Ciba-Geigy Ltd. and
Schering Aktiengesellschaft.
IARC. International Agency for Research on Cancer: Monographs on the
(1983) evaluation of the carcinogenic risk of chemicals to Humans,
30, 61-72.
Konopka, E.A. & Heymann, H. Salmonella/microsome mutagenicity test
(1977) with chlordimeform. Unpublished report from Ciba-Geigy Ltd.,
Basel, Switzerland. Submitted to WHO by Ciba-Geigy Ltd. and
Schering Aktiengesellschaft.
Lang, R. & Adler, I.D. Studies on the mutagenic potential of the
(1982) pesticide chlordimeform and its principal metabolites in the
mouse heritable translocation assay. Mutation Research 92,
243-248.
Lang, R. The mammalian spot test and its use for testing of mutagenic
(1984) and carcinogenic potential: experience with the pesticides
chlordimeform, its principal metabolites and the drug
lisuride hydrogen maleate. Mutation Research, 135,
219-224.
Langauer, M. & Müller, D. C8513: Nucleus anomaly test in somatic
(1977) interphase nuclei (Chinese hamster). Unpublished report from
Ciba-Geigy Ltd., Basel, Switzerland. Submitted to WHO by
Ciba-Geigy Ltd. and Schering Aktiengesellschaft.
Langauer, M. & Müller, D. CGA 72'651: Nucleus anomaly test in somatic
(1978a) interphase nuclei (Chinese hamster). Unpublished report from
Ciba-Geigy Ltd., Basel, Switzerland. Submitted to WHO by
Ciba-Geigy Ltd. and Schering Aktiengesellschaft.
Langauer, M. & Müller, D. CGA 72'647: Nucleus anomaly test in somatic
(1978b) interphase nuclei (Chinese hamster). Unpublished report from
Ciba-Geigy Ltd., Basel, Switzerland. Submitted to WHO by
Ciba-Geigy Ltd. and Schering Aktiengesellschaft.
Limmer, F.B. Ciba-Geigy and Schering world-wide exposure data summary
(1985) of personnel applying chlordimeform products covering the
period 1980-1984. Unpublished report from Ciba-Geigy Ltd.,
Basel, Switzerland. Submitted to WHO by Ciba-Geigy Ltd. and
Schering Aktiengesellschaft.
Meucke, W., Hamboeck, H., & Arnia, P. Metabolic and pharmacokinetic
(1979) aspects of chlordimeform in rats and mice. Unpublished
report from Ciba-Geigy Ltd., Basel, Switzerland. Submitted
to WHO by Ciba-Geigy Ltd. and Schering Aktiengesellschaft.
Morgan, L.R. & Gillen, L.E. Haemorrhagic cystitis produced by
(1982) chlordimeform. Federation Proceedings 41(4), 1312
(Abstract 6089).
Pfister, F.E. & Dubach, P. Statement by Ciba-Geigy Ltd., Agricultural
(1985) Division, Basel, Switzerland. Submitted to WHO by Ciba-Geigy
Ltd. and Schering Aktiengesellschaft.
Puri, E. & Müller, D. C8513: Autoradiographic DNA repair test on rat
(1983a) hepatocytes. Unpublished report from Ciba-Geigy Ltd., Basel,
Switzerland. Submitted to WHO by Ciba-Geigy Ltd. and
Schering Aktiengesellschaft.
Puri, E. & Müller, D. CGA 72'647: Autoradiographic DNA repair test on
(1983b) rat hepatocytes. Unpublished report from Ciba-Geigy Ltd.,
Basel, Switzerland. Submitted to WHO by Ciba-Geigy Ltd. and
Schering Aktiengesellschaft.
Puri, E. & Müller, D. C8513: Autoradiographic DNA repair test on human
(1983c) fibroblasts. Unpublished report from Ciba-Geigy Ltd., Basel,
Switzerland. Submitted to WHO by Ciba-Geigy Ltd. and
Schering Aktiengesellschaft.
Puri, E. & Müller, D. CGA 72'647: Autoradiographic DNA repair test on
(1983d) human fibroblasts. Unpublished report from Ciba-Geigy Ltd.,
Basel, Switzerland. Submitted to WHO by Ciba-Geigy Ltd. and
Schering Aktiengesellschaft.
Rashid, K.A., Ercegovich, C.D., & Mumma, R.O. Evaluation of
(1984) chlordimeform and degradation products for mutagenic and DNA
damaging activity in Salmonella typhimurium and
Escherichia coli. J. Environ. Sci. Health, B 19 (1),
95-110.
Reckefuss & Kossman. Statement by Schering Aktiengesellschaft
(1985) Agrochemical Division, Berlin. Submitted to WHO by
Ciba-Geigy Ltd. and Schering Aktiengesellschaft.
Strasser, F.F. & Müller, D. CGA 72'651: Point mutation assay with
(1983a) mouse lymphoma cells, host-mediated assay. Unpublished
report from Ciba-Geigy Ltd., Basel, Switzerland. Submitted
to WHO by Ciba-Geigy Ltd. and Schering Aktiengesellschaft.
Strasser, F.F. & Müller, D. CGA 72'647: Point mutation assay with
(1983b) mouse lymphoma cells, host-mediated assay. Unpublished
report from Ciba-Geigy Ltd., Basel, Switzerland. Submitted
to WHO by Ciba-Geigy Ltd. and Schering Aktiengesellschaft.
Strasser, F.F. & Müller, D. CGA 72'647: Point mutation assay with
(1984a) mouse lymphoma cells, host-mediated assay. Unpublished
report from Ciba-Geigy Ltd., Basel, Switzerland. Submitted
to WHO by Ciba-Geigy Ltd. and Schering Aktiengesellschaft.
Strasser, F.F. & !MHller, D. CGA 72'651: Point mutation assay with
(1984b) mouse lymphoma cells, host-mediated assay. Unpublished
report from Ciba-Geigy Ltd., Basel, Switzerland. Submitted
to WHO by Ciba-Geigy Ltd. and Schering Aktiengesellschaft.