PROPHAM
First draft prepared by J.-J. Larsen
National Food Agency, Ministry of Health
Soborg, Denmark
EXPLANATION
Propham, isopropyl carbanilate, is the active substance of
several products used as herbicides and potato sprout inhibitors. It
was previously evaluated by the JMPR in 1963 and 1965 (Annnex 1,
references 2 and 3) at which time the data available were considered
inadequate for allocating an ADI.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOLOGICAL DATA
Biochemical aspects
Absorption, distribution, and excretion
The tissue distribution and excretion of 14C-labelled propham
(purity > 99%, specific activity of chain-labelled molecule 4.9
mCi/mmol and of ring-labelled molecule 4.1 mCi/mmol) were
investigated in adult female Wistar rats (mean body-weight 270 g). A
single oral dose (2 animals per dose) of 0, 0.67, 19, 38, or 75
mg/kg bw 14C-labelled propham (5µCi in 1.0 ml of 20% aqueous
ethanol solution) was administered by intubation. Rats were housed
individually in glass metabolism cages; expired air was continuously
monitored for radioactivity for 72 h. The faeces and urine samples
were collected at 24, 48, and 72 h and analyzed for 14C by liquid
scintillation counting. The urine was analyzed by paper
chromatography and thin-layer chromatography. In a similar
experiment, single rats were killed at various times (1-24 h) after
administration of a single dose of 0.81 mg/kg bw 14C-labelled
propham/kg bw (5µCi in 1.0 ml of a 20% aqueous ethanol solution).
Tissue samples (kidneys, liver, blood, lungs, heart, spleen,
intestine, brain, muscle, and fat) were freeze-dried, and analyzed
for 14C by gas-flow G-M counter.
The average 3-day excretion of radioactivity in urine, faeces,
and CO2 was 80, 5, and 5%, respectively after chain-labelling of
propham, and 85, 5, and 0%, respectively after ring-labelling of
propham. There was no significant difference in the rate of
excretion or the route of elimination among rats receiving different
dosages. The radioactivity was distributed in all examined tissues
with the highest concentrations in the kidneys. The average
biological half-life of propham in most organs was short, ranging
between 3 and 8 h. However, in brain, fat, and muscle, the half-life
was about twice the value for other organs. Propham was metabolized
by hydrolytic and oxidative mechanisms and the resulting metabolites
were excreted either as free forms or as conjugates. Tentative
identification of the metabolites indicated the following substances
to be present in urine: (4-OH)-propham, 1-OH-2-propyl-propham, 1-
carboxyl-1-ethyl-propham, and (4-OH)-propham-sulphate (Fang et
al., 1974).
Biotransformation
The metabolic fate of propham was investigated in male Wistar
rats weighing approximately 250 g. The animals received a single
dose of 15 mg 14C-labelled propham (purity 98.8%)
intraperitoneally in 0.2 ml absolute ethanol (n=5) or orally as a
suspension in 1.0 ml syrup (n=6). Urine, faeces and carbon dioxide
were collected for up to 4 days after dosing, the respired gases
being trapped in 20% sodium hydroxide solution. For biliary studies,
bile was collected for 6 h after injection of 0.5 mg 14C-labelled
propham in 0.25 ml 40% aqueous ethanol into the femoral vein of rats
under urethane anaesthesia. Other rats received 50 mg neomycin
sulphate in 0.5 ml water orally 24 h before an oral dose of 14C-
labelled propham. The drinking-water provided for these animals
contained 1% neomycin sulphate. Radioactivity was measured by liquid
scintillation counting.
After both oral and intraperitoneal doses approximately 80% of
the administered radioactivity appeared in the urine over 4 days,
with much smaller amounts appearing in the faeces and respired air.
Of the urinary radioactivity about 80% was present as the sulphate
ester of isopropyl N-(4-hydroxyphenyl)carbamate. Little or no
isopropyl N-(2-hydroxyphenyl)-carbamate was formed. Neomycin feeding
studies suggested that the small amount of hydrolysis which occurred
was mediated by the animal rather than by its gut microflora.
Biliary elimination of 14C-labelled propham was also examined,
about 30% of an intravenous dose being excreted in the bile within
6 h (Bend et al., 1971).
The identification of propham metabolites was studied in six
male Sprague-Dawley rats, weighing 220-274 g, and a lactating goat
weighing 48 kg. Each animal was given a single dose by stomach tube
of 100 mg/kg bw 14C-ring-labelled propham (purity 99%, 6.8-8.6 µCi
in the rats and 37 µCi in the goat, specific activity not given).
Faeces and urine (plus milk from the goat) were collected separately
at 6, 24, and 48 h after dosing. The samples were analyzed together
with fractions from the liver, heart, kidneys, intestine, intestinal
content, and the remaining carcass for 14C by liquid scintillation
techniques.
Radioactivity was rapidly eliminated in the urine of both the
rat and goat during the first 6 h after dosing. The cumulative 48-h
excretion of radioactivity, in per cent of the dose given, in urine
was 96% and 90% in the rat and goat, respectively, and in faeces 2%
and 3% in rat and goat, respectively. Radioactivity in milk was
highest during the first 6 h after dosing. The cumulative 48-h milk
radioactivity was 0.45% of the dose. The content of radioactivity 48
h after dosing was highest in the liver. The relative content of
radioactivity of the heart, kidney, and intestine seemed to be quite
different in rat and goat. The data indicated that biliary excretion
of propham metabolites into the intestinal tract had occurred. The
metabolites in the rat included: glucuronic acid conjugate of
isopropyl 4-hydroxycarbanilate, sulphate ester of isopropyl 4-
hydroxycarbanilate, sulphate ester of 4-hydroxyacetanilide and
several other minor unidentified compounds. Goat urinary metabolites
included the sulphate ester of isopropyl 4-hydroxycarbanilate,
glucuronic acid conjugate of isopropyl 4-hydroxycarbanilate, another
conjugated form of isopropyl 4-hydroxycarbanilate, a conjugate of
isopropyl 3,4-dihydroxy-carbanilate, the sulphate ester of isopropyl
2-hydroxycarbanilate, a conjugate of 4-hydroxyaniline, the sulphate
ester of 2-hydroxyaniline, another conjugated form of 2-
hydroxyaniline, the glucuronic acid conjugate of 4-
hydroxyacetanilide, a conjugate of (2-hydroxyisopropyl)4-
hydroxycarbanilate and several other unidentified compounds (Paulson
et al., 1973).
Effects on enzymes and other biochemical parameters
No data available.
Toxicological studies
Acute toxicity studies
Studies of acute toxicity following oral (animals fasted 16 h
before dosing) or dermal administration or after inhalation of
propham were performed (purity 98.4%) in SPF-bred Wistar rats, Bor
strain: WISW (SPF Cpb) (body-weight 160-200 g) and acclimatized and
randomised before use (Mihail, 1984; Pauluhn, 1984).
Table 1. Acute toxicity of propaham
Species Strain Sex Route LD50 LC50 Reference
mg/kg bw mg/l
Rat Wistar M oral 4300 Mihail (1984)
Wistar F oral 8700
Rat Wistar M dermal > 5000 Mihail (1984)
Wistar F dermal > 5000
Rat Wistar M inhal. > 2.1 Pauluhn (1984)
Wistar F inhal. > 2.1
Short-term toxicity studies
Four groups of 10 Wistar rats (Bor strain, WISW/SPF Cpb)/sex, 4
to 5 weeks old were fed dietary concentrations of 0, 200, 1000 or
5000 ppm (equal to 0, 14, 70 or 384 mg/kg bw/day for males and 0,
21, 109 or 576 mg/kg bw/day for females) 99.3% purity propham for 13
weeks. Stability and homogeneity in the diet were based on parallel
studies (dietary concentrations, 100 and 15 000 ppm), which
indicated acceptable results (i.e. ±10% of nominal values). Body-
weight, food and water intake were monitored weekly. Haematology,
clinical biochemistry, gross pathological examinations and
histopathological examinations were performed.
Appearance, behaviour and mortality of the rats were unaffected
by dosages of up to 5000 ppm. Food intake of females was slightly
increased at all three dose levels, but the increase was not dose-
dependent. At 5000 ppm the body-weight gain in males was slightly
but statistically significantly reduced. A significant and dose-
dependent decrease was seen in the erythrocyte counts, haemoglobin,
haematocrit and mean cell haemoglobin concentration and an increase
was seen in the mean cell volume in males receiving 1000 and 5000
ppm and in females receiving 5000 ppm. Cholesterol concentrations
were increased in females at 5000 ppm. Males dosed with 1000 and
5000 ppm had a significantly increased relative adrenal weight and
at 5000 ppm increased relative liver and spleen weights. In females
a significant increase in relative liver weight was observed at 1000
ppm and a significant increase in relative kidney and liver weight
at 5000 ppm. At 1000 and 5000 ppm a treatment-related effect on
liver function (liver weight and ASAT activity) was seen in both
sexes. A dose-dependent increase in haemosiderin content in the
spleen was seen in both sexes at 1000 and 5000 ppm. Based on the
effects on the blood parameters a NOAEL of 200 ppm equal to 14 and
21 mg/kg bw/day in males and females, respectively, was determined
(Hahnemann & Vogel, 1984).
Four groups of 20 SPF Wistar rats (Bor strain, WISW/SPF
Cpb)/sex, 5 to 6 weeks old and weighing 68 to 124 g (males) or 84 to
116 g (females) were fed dietary concentrations (99.4% purity
propham) of 0, 10, 30 or 100 ppm equal to 0, 0.6, 1.8 or 5.8 mg/kg
bw/day for males and 0, 0.7, 2.4 or 7.8 mg/kg bw/day for females for
12 months. Homogeneity in the 10 and 100 ppm diet was within ±10%
and stability of diets stored under similar conditions to those in
the study were within ±3% of original concentrations. Body-weight,
food and water intake were monitored weekly up to week 13 and
biweekly thereafter. Haematology, clinical biochemistry, urinalysis,
and ophthalmoscopy were performed and gross pathological
examinations and histopathological examinations were carried out.
The body-weight was unaffected in both sexes at all dose levels as
were mortality and clinical signs. Haematological data indicated no
significant effects at 10 and 30 ppm. At certain times during the
treatment with 100 ppm statistically significantly reduced
erythrocyte counts, leucocyte cell counts, per cent lymphocytes in
differential blood count and haematocrit were observed.
Statistically significantly increased values for mean MCH and MCHC
compared to control values were noted. Haemosiderosis in spleen was
more severe in the propham-treated males compared to control
animals. A NOAEL of 100 ppm, equal to 5.8 or 7.8 mg/kg bw/day for
males and females respectively, was determined (Eiben, 1988a).
Long-term toxicity/carcinogenicity studies
Rats
Four groups of 20 SPF Wistar rats (Bor strain, WISW/SPF
Cpb)/sex, 4 to 5 weeks old, and weighing 72 to 110 g (males) or 73
to 107 g (females) were fed dietary concentrations (99.3% purity
propham) of 0, 100, 500 or 2500 ppm equal to 0, 5.7, 29 or 150 mg/kg
bw/day for males and 7.6, 37 or 200 mg/kg bw/day for females, for 24
months. Ten additional rats/sex/dose level were fed similar diets
and were sacrificed at 12 months. Homogeneity based on diet
containing 100 or 15 000 ppm was within ±10% and stability under
conditions of storage similar to those used in the present study
indicated 101 to 109% of initial concentrations. Body-weight, food
and water intake were monitored weekly up to week 13 and biweekly
thereafter. Haematology, clinical biochemistry, urinalysis, and
ophthalmoscopy were performed and gross pathological examinations
and histopathological examinations were carried out. No treatment-
related incidences of clinical signs and symptoms, changes in food
and water intake or mortality were observed up to the dosage of 2500
ppm. Body-weight gain was comparable to control rats up to 2500 ppm
(males) and 500 ppm (females). At 2500 ppm, weight gain was slightly
decreased in females during the second half of the study. No
evidence of any treatment-related adverse effects on the blood or
haematopoietic organs was found in the 100 ppm dosage group. At and
above 500 ppm, evidence of increased haemopoiesis was observed in
the spleen and liver. Reduced erythrocyte and haematocrit counts and
increased spleen weights were also recorded in the 2500 ppm groups.
At 2500 ppm mineralization in the kidneys and increased relative
kidney weights were observed most often in the females. No adverse
effects were noted for any other organ systems. Ophthalmological
investigations revealed age-related eye changes which were fairly
evenly distributed over all groups. No carcinogenic potential of
propham could be inferred from the type, frequency or time of onset
of benign or malignant tumours. Based on the effects on the blood
parameters, a NOAEL for propham of 100 ppm, equal to 5.7 and 7.6
mg/kg bw/day in males and females respectively was determined.
Carcinogenicity was not demonstrated (Eiben, 1989).
Hamsters
The Meeting determined that the data available in a published
carcinogenicity study on golden hamsters (Van Esch & Kroes, 1972)
were inadequate to permit evaluation. The authors concluded that
there was no indication of a carcinogenic effect of propham in
hamsters at a dose level of 200 mg/kg bw/day given daily for 33
months.
Reproduction studies
In a two-generation, two-litter per generation Wistar rat (Bor
strain, WISW/SPF Cpb) reproduction study, 4 groups of 25 rats/sex
(initial age 4 to 6 weeks, weighing 62-93 g) were fed diets
containing 0, 200, 1000 or 5000 ppm, 99.3-99.4% purity propham,
equal to 0, 20, 80 or 100 mg/kg bw/day in the F0 generation and 0,
20, 100 or 550 mg/kg bw/day in the F1 generation. Homogeneity and
stability were determined in parallel studies for dietary
concentrations of 100 and 15 000 ppm. Homogeneity was within ±10%
and stability data indicated 101 and 109% of nominal values. F0
animals were inspected daily for clinical signs and were weighed
weekly mating (after approximately 16 weeks on test for F0 animals
and at about 100 days of age for F1b parents) was determined by
vaginal smear. Lactation period was 4 weeks. F1a, F2a and F2b
pups were sacrificed at weaning and subject to gross and
histopathological examination.
At dietary concentrations up to 5000 ppm there were no effects
on appearance, behaviour, general condition, mortality, fertility,
insemination rate, gestation, viability, duration of pregnancy or
sex ratio. No malformations were observed and incidence of
stillbirths was unaffected. The lactation index and mean litter size
at birth were comparable to those of the controls up to 1000 ppm. At
5000 ppm, the lactation index was in some cases significantly
depressed and the litter size was reduced. Body-weight gain was not
retarded in the parent animals or in the pups up to 1000 ppm. The
body-weight of parents and pups in the 5000 ppm group increased more
slowly during the rearing period. Food intake was unaffected up to
1000 ppm. Following 5000 ppm F1b rats consumed less food. The
macroscopic examination of the dissected F1b and F2b pups
revealed no changes of organs related to the treatment. The
histopathological investigations revealed indications of increased
breakdown of the red blood cells from 200 ppm upwards in F0 and
F1b parents, which was identified by an increased incidence of
siderosis in the liver and/or spleen. At 5000 ppm increased
extramedullary haematopoiesis was frequently observed and increased
spleen weights were recorded. At 200 ppm and above (F1b) and from
1000 ppm and above (F0) spleens were commonly dark in colour. No
indications of organ damage were found in the other organs of parent
animals in the gross pathology examinations nor on the basis of the
organ weights or histopathological investigations. In all dosage
groups, therefore, signs of increased breakdown of erythrocytes were
found. The dose of 200 ppm of propham was therefore toxic to
parental animals. Based on effects on lactation index, food intake
and body-weight gain, a NOAEL for reproduction of 1000 ppm equal to
80 mg/kg bw/day, was determined. The NOAEL for maternal toxicity
(haematological effects) was < 200 ppm (equal to 20 mg/kg bw/day)
(Eiben, 1988b).
The effect of propham on the haematopoietic organs was
investigated in a 6-month reproduction study in rats, since a NOAEL
in this context had not been determined in the previous 2-generation
study. Propham (purity 99.1-99.4%) was administered at dietary
concentrations of 0, 20, 60 or 180 ppm to F0 males (25
animals/dosage group) and F0 females (25 animals/dosage group),
their F1 litters until weaning and for a further 6 months to 20
male and 20 female weaned F1 rats from these litters. The dosages
in the F1 generation were equal to 0, 1.8, 5.3, or 16 mg/kg bw/day
in the males and 0, 2.3, 6.7, or 21 mg/kg bw/day in the females.
SPF-bred Wistar rats, Bor strain: WISW (SPF Cpb), were acclimatized
before use. All animals were randomized in order to obtain
comparable groups. At the start of the study, the rats had an age of
11-16 weeks and a body-weight of 300-349 g (F0 males) and 189-217
g (F0 females). Test for homogeneity from a parallel study showed
a mean propham concentration of 97%, 90%, and 99% of nominal values
in feed containing 20, 100, and 15 000 ppm, respectively. Tests for
stability from a parallel study resulted in 105%, 101%, and 109% of
nominal values in feed containing 20, 100, and 15 000 ppm,
respectively. The animals were inspected daily for general clinical
signs and specific behaviours. The body-weight and food intake was
recorded weekly during study. Mating was determined by presence of
sperm in vaginal smears or by finding of vaginal plugs. The body-
weight of each of the F1 litter was determined weekly and each pup
underwent inspections for malformations. Blood samples were taken
from 10 animals per group for haematological examination. Organ
weights were determined and histopathological examinations were
carried out on selected tissues.
Dietary concentrations of 180 ppm propham were tolerated
without any adverse effect on general behaviour, mortality or any of
the reproduction parameters of the F0 generation (fertility,
gestation, viability, lactation, litter size and litter weight). No
malformations or increase in the number of still-births were
observed. Feed intake, appearance, behaviour, body-weight gain
(lactation period and 6 months treatment period) and mortality of
adult F1 rats remained unaffected at dosages up to 180 ppm.
Haematological investigations were negative. No findings were
obtained at autopsy which indicated any treatment-related organ
damage or changes in organ weights of liver, spleen or kidney.
During the histopathological examination of liver, spleen, kidneys
and bone marrow, no treatment-related pathological findings were
observed up to 180 ppm. Detection of ferruginous pigment in liver,
kidney and spleen was within the normal variability.
Administration of 180 ppm propham equal to 16 and 21 mg/kg
bw/day in males and females, respectively, was tolerated with no
adverse effects during the ante-natal development phase, the rearing
period and the following 6 months. NOAELs for reproduction and
maternal toxicity exceeded 180 ppm, equal to 16 mg/kg bw/day (Eiben,
1988c).
Special studies on genotoxicity
Data are shown in Table 2.
Table 2. Results of genotoxicity assays on propham
Test system Test object Concentration Purity Results Reference
of propham
In vitro
Ames test (with and Salmonella 300-4800 99.6% Negative Herbold
without metabolic typhimurium µg/plate (± S9) (1992)
activation)
Sister chromatid exchange Human lymphocytes 10-4, 10-5, n.g. Negative Lindahl-
(without metabolic 10-6 M Kiessling
activation) et al.
(1989)
Gene mutation S-49 1.1 - 2.2 M n.g. Negative Friedrich
(dexamethasone Mouse & Nass
resistance) (without lymphoma cells (1983)
metabolic activation)
In vivo
Micronucleus test Mouse (NMRI) 2 x 1000 mg/kg 99.9% Negative Machemer
bw and 2 x 2000 (1977)
mg/kg bw orally.
The two doses
were administered
with an interval
of 24 h
n.g. = not given
Special studies on teratogenicity.
Four groups of 25 pregnant Wistar rats (strain, Bor WISW/SPF
Cpb) were dosed orally with a 0.5% aqueous suspension of propham at
0, 30, 100 or 300 mg/kg bw/day on days 6-15 of pregnancy. Fetuses
were removed by caesarean section on day 20 of pregnancy.
The body weight, clinical signs and pregnancy rate of the dams
were unaffected by propham. There were no treatment-related
mortalities among the fetuses. Malformations occurred in three
fetuses of two dams in the 300 mg/kg bw group and in one fetus of a
dam in the 30 mg/kg bw/day group and in none of the control or 100
mg/kg bw/day group. One of the three fetuses had multiple skeletal
anomalies and two fetuses had exencephaly and some other
malformations The Meeting concluded that this study was inadequate
for evaluation (Renhof, 1984).
Special studies on skin-sensitizing effect
Propham was tested in female guinea-pigs for skin sensitizing
properties using Magnusson and Kligman's Maximization Test. SPF-bred
DHPW female guinea-pigs were used. The animals were acclimatized for
at least 7 days before start of treatment. At the start of treatment
the guinea-pigs were 4-7 weeks old and weighed 276-358 g. The
animals were observed daily throughout the study for clinical signs
and body-weights were recorded before and at the end of study.
Propham (purity 99.6%) was formulated in Cremophor EL (2% v/v) in
physiol-ogical NaCl solution. The stability of propham was
satisfactory. An analysis showed that 95-97% of the active substance
in the test solution was found after 24 h storage. The homogeneity
of test solutions was also satisfactory. The mean content of three
samples from each of two test solutions was 93-108% of the nominal
values. The test animal group consisted of 10 guinea-pigs, and two
control groups consisted of 10 animals each. The following propham
concentrations were used: intradermal induction: 2.5%, topical
induction: 25%, and challenge: 25%. Following shaving of the backs
and flanks of the guinea-pigs three intradermal injections
(injection volume 0.1 ml) with a distance of 1-2 cm were given in a
row per side to the left and right of the spinal column. Topical
induction with propham in cremophor/saline solution was performed
one week after intradermal induction. Challenge exposure (0.5 ml)
was performed three weeks after intradermal induction. A
hypoallergenic dressing soaked in the 25% test article formulation
was placed for 24 h on the left flank of propham animals and first
control group. A control dressing was placed on the right flank. The
criterion for sensitization was a higher incidence and intensity of
skin reaction in test animals compared to control animals. All
animals tolerated the treatment without signs of toxicity and no
skin reactions occurred among the test or control animals. There is
thus no indication of a skin sensitizing effect of propham (Diesing,
1989).
Observations in humans
No data available.
COMMENTS
Following oral administration to rats, propham was rapidly
eliminated via the urine (80-96%), faeces (5%), and expired air
(5%). Metabolism proceeds by hydrolysis and oxidation.
Propham had a low acute oral toxicity in rats. The World Health
Organization has classified propham as unlikely to present acute
hazard in normal use (WHO, 1992).
In short-term toxicity studies in rats at dietary
concentrations of 0, 200, 1000, or 5000 ppm for 13 weeks or of 0,
10, 30, or 100 ppm for 12 months, effects were observed on
haematological parameters, ASAT and relative weight of the adrenals,
liver and spleen. Increases in haemosiderin content in the spleen
were seen. On the basis of the haematological effects the NOAEL was
100 ppm, equal to 5.8 and 7.8 mg/kg bw/day in males and females,
respectively.
In a 2-year long-term toxicity/carcinogenicity study in rats at
dietary concentrations of 0, 100, 500, or 2500 ppm propham, effects
on haematological parameters and spleen weight were observed.
Increased haemopoiesis was seen in the spleen and liver. On the
basis of the effects on the haematological parameters the NOAEL was
100 ppm, equal to 5.7 and 7.6 mg/kg bw/day in males and females,
respectively. There was no evidence of carcinogenicity.
A 33-month study in hamsters was inadequate for evaluation.
In a two-generation reproduction study in rats at dietary
concentrations of 0, 200, 1000, or 5000 ppm propham, the NOAEL was
1000 ppm, equal to 80 mg/kg bw/day, on the basis of effects on
lactation index, food intake, and body-weight gain.
An oral teratogenicity study in rats was inadequate for
evaluation.
Although the data were not fully adequate, the Meeting
concluded that propham was not likely to be genotoxic.
The available toxicological data on propham were not adequate
to allocate an ADI.
Studies without which the determination of an ADI is impractible
1. A biotransformation study in rats.
2. Short-term toxicity study in a non-rodent species.
3. A test specifically for aneuploidy.
4. Teratogenicity study in two species.
5. Available observations in humans.
REFERENCES
Bend, J.R., Holder, G.M. & Ryan, A.J. (1971) Further studies on the
metabolism of isopropyl N-phenylcarbamate (propham) in the rat. Fd.
Cosmet. Toxicol., 9: 169-177.
Diesing, L. (1989) Studies on skin-sensitizing effect in guinea-
pigs. Unpublished report No. 17537 from Institute of Toxicology,
Agrochemicals, Department of Toxicology, Bayer AG, Friedrich-Ebert
Str. 217-333, D-5600 Wuppertal 1, Germany. Submitted to WHO by Bayer
AG, Wuppertal, Germany.
Eiben, R. (1988a) Chronic toxicity study in Wistar rats.
Supplementary study to investigate effects on the spleen.
Unpublished report No. 17170 from Institute of Toxicology for
Industrial Chemicals, Fachbereich Toxicology, Bayer AG, Friedrich-
Ebert Str. 217-333, D-5600 Wuppertal 1, Germany. Submitted to WHO by
Bayer AG, Friedrich-Ebert Str. 217-333, D-5600 Wuppertal 1, Germany.
Eiben, R. (1988b) Two-generation study in rats. Unpublished report
No. 16880 from Institute of Toxicology for Industrial Chemicals,
Fachbereich Toxicology, Bayer AG, Friedrich-Ebert Str. 217-333, D-
5600 Wuppertal 1, Germany. Submitted to WHO by Bayer AG, Friedrich-
Ebert Str. 217-333, D-5600 Wuppertal 1, Germany.
Eiben, R. (1988c) Six month feeding study after intrauterine
pretreatment (supplementary study to clarify haemotoxic effects).
Unpublished report No. 16877 from Institute of Toxicology for
Industrial Chemicals, Fachbereich Toxicology, Bayer AG, Friedrich-
Ebert Str. 217-333, D-5600 Wuppertal 1, Germany. Submitted to WHO by
Bayer AG, Friedrich-Ebert Str. 217-333, D-5600 Wuppertal 1, Germany.
Eiben, R. (1989) Chronic toxicity and carcinogenicity investigations
in Wistar rats. Unpublished report No. 17947 from Institute of
Toxicology for Industrial Chemicals, Fachbereich Toxicology, Bayer
AG, Friedrich-Ebert Str. 217-333, D-5600 Wuppertal 1, Germany.
Submitted to WHO by Bayer AG, Friedrich-Ebert Str. 217-333, D-5600
Wuppertal 1, Germany.
Fang, S.C., Fallin, E., Montgomery, M.L. & Freed, V.H. (1974)
Metabolic studies of 14C-labelled propham and chlorpropham in the
female rat. Pesticide Biochemistry and Physiology, 4: 1-11.
Friedrich, U. & Nass, G. (1983) Evaluation of a mutation test using
S49 mouse lymphoma cells and monitoring simultaneously the induction
of dexamethasone resistance, 6-thioguanine resistance and quabain
resistance. Mutation Research, 110: 147-167.
Hahnemann, S. & Vogel, O. (1984) Subchronic toxicity studies in rats
(13-week feeding study). Unpublished report No. 13083 from Institute
of Toxicology for Industrial Chemicals, Fachbereich Toxicology,
Bayer AG, Friedrich-Ebert Str. 217-333, D-5600 Wuppertal 1, Germany.
Submitted to WHO by Bayer AG, Friedrich-Ebert-Str. 217-333, D-5600
Wuppertal 1, Germany.
Herbold, B.A. (1992) Salmonella/microsome test. Unpublished report
No. 21469 from Institute of Toxicology for Industrial Chemicals,
Fachbereich Toxicology, Bayer AG, Friedrich-Ebert Str. 217-333, D-
5600 Wuppertal 1, Germany. Submitted to WHO by Bayer AG, Friedrich-
Ebert-Str. 217-333, D-5600 Wuppertal 1, Germany.
Lindahl-Kiessling, K. Karlberg, I. & Olofsson; A-M. (1989) Induction
of sister-chromatid exchanges by direct and indirect mutagens in
human lymphocytes, co-cultured with intact rat liver cells.
Mutation Research, 211: 77-87.
Machemer, L. (1977) Micronucleus test on the mouse for testing for
mutagenic effects. Unpublished report No. 7067 from Institute of
Toxicology for Industrial Chemicals, Fachbereich Toxicology, Bayer
AG, Friedrich-Ebert Str. 217-333, D-5600 Wuppertal 1, Germany.
Submitted to WHO by Bayer AG, Friedrich-Ebert-Str. 217-333, D-5600
Wuppertal 1, Germany.
Mihail, F. (1984) Study for acute oral and dermal toxicity.
Unpublished report No. 12577 from Institute of Toxicology for
Industrial Chemicals, Fachbereich Toxicology, Bayer AG, Friedrich-
Ebert Str. 217-333, D-5600 Wuppertal 1, Germany. Submitted to WHO by
Bayer AG, Friedrich-Ebert-Str. 217-333, D-5600 Wuppertal 1, Germany.
Pauluhn, J. (1984) Study for acute inhalation toxicity and
irritation/corrosion effect in the rabbit. Unpublished report No.
12633 from Institute of Toxicology for Industrial Chemicals,
Fachbereich Toxicology, Bayer AG, Friedrich-Ebert Str. 217-333, D-
5600 Wuppertal 1, Germany. Submitted to WHO by Bayer AG, Friedrich-
Ebert-Str. 217-333, D-5600 Wuppertal 1, Germany.
Paulson, G.D., Jacobsen, A.M., Zaylskie, R.G. & Feil, V.J. (1973)
Isolation and identification of propham (isopropyl carbanilate)
metabolites from the rat and the goat. J. Agr. Food Chem., 21:
804-811.
Renhof, M. (1984). Study for embryotoxic effect on the rat following
oral administration. Unpublished report No. 12655 from Institute of
Toxicology for Industrial Chemicals, Fachbereich Toxicology, Bayer
AG, Friedrich-Ebert Str. 217-333, D-5600 Wuppertal 1, Germany.
Submitted to WHO by Bayer AG, Friedrich-Ebert-Str. 217-333, D-5600
Wuppertal 1, Germany.
Van Esch, G.J. Van & Kroes, R. (1972). Long-term toxicity studies of
chlorpropham and propham in mice and hamsters. Fd. Cosmet.
Toxicol., 10: 373-381.
WHO (1992) The WHO recommended classification of pesticides by
hazard and guidelines to classification 1992-1993 (WHO/PCS/92.14).
Available from the International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland.