DITHIANON
First draft prepared by
J.E.M. van Koten-Vermeulen and E.M. Den Tonkelaar
National Institute of Public Health and Environmental Protection
Bilthoven, Netherlands
EXPLANATION
Dithianon is used as a multi-site protective fungicide which
inhibits spore germination. It is used on a range of fruits and
vegetables. Dithianon was considered for the first time by the
present Meeting.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOLOGICAL DATA
Biochemical aspects
Absorption, distribution, and excretion
Rats
Four male and 4 female rats were administered once daily 25 mg
14C-dithianon (dioxonaphtyl-labelled)/kg bw/day in dimethyl
sulfoxide for 7 days. Faeces and urine were collected at daily
intervals until 8 days after the last administration. After 24 h,
males eliminated 24.3% via urine and 37.1% via faeces and females
22.9% and 32.2%, respectively. Seventy-two hours after the last
treatment, 1.0% (males) and 1.8% (females) of the administered dose
was still found in faeces and urine. Total recovery was 69.1% and
68.0% in the faeces and 27.5% and 28.3% in urine of males and
females, respectively. The carcass contained 0.1% of the total
administered radioactivity (Schlüter, 1985).
Radioactivity in blood was measured in 5 rats/sex over a period
up to 6 days following a single oral dose of 25 mg 14C-
dithianon/kg bw. Plasma radioactivity levels 15 minutes after dosing
were 0.07 mg/l (males) and 0.15 mg/l (females) increasing to peak
levels of 1.2 mg/l (males) and 1.9 mg/l (females) 8 h after dosing.
Thereafter the values decreased rapidly to 0.07 mg/l after 144 h for
both sexes (Schlüter, 1985).
Rats (5/sex) were given a single oral dose of 25 mg 14C-
dithianon/kg bw/day for 7 days. Tissue distribution was measured
over 5 periods up to 7 days after the last treatment. Twenty-four
hours after the last treatment, most tissue levels of radioactivity
were below 0.01% of the administered dose except for liver (0.01-
0.02%) and stomach and intestine (0.3-2.2%). After 7 days, all
tissue residues were < 0.01% of the administered radioactivity
(Schlüter, 1985).
One rat/sex was given a single oral dose of 50 mg 14C-
dithianon (dioxonaphtyl-labelled)/kg bw. After 5 days, a total of
95.8% and 101.3% was excreted by the male and female rat,
respectively. Urinary excretion was almost complete within 48 h and
accounted for 33.5%-30.3% of the total radioactivity. Faecal
excretion was complete by 72 h and accounted for 62.1% and 70.9%. No
radioactivity was detected in the expired air during the 48 h after
dosing (Hawkins et al., 1989).
Groups of rats (5/sex/group) were administered a single oral
dose of 10 or 50 mg 14C-dithianon. Total recovery was about 97%
regardless of the dose. After 5 days most of the radioactivity was
excreted in the faeces (about 65%) while 31% was recovered in urine.
Elimination occurred predominantly during the first 24 h. Dithianon
was absorbed to approximately the same extent at the low- and high-
dose levels. Only a small proportion of the administered dose was
recovered in tissues. Highest amounts after the low-dose
administration were in kidneys (males 0.16 mg/kg and females 0.17
mg/kg), GIT (males and females 0.05 mg/kg) and whole-blood (males
0.04 mg/kg and females 0.05 mg/kg). After the administration of 50
mg the highest tissue residues were also found in kidneys (males
0.58 mg/kg and females: 0.66 mg/kg), GIT (males 0.15 mg/kg and
females 0.23 mg/kg) and whole-blood (males 0.28 mg/kg and females
0.36 mg/kg) (Hawkins et al., 1989).
The repeated administration of 14 daily non-labelled doses of
10 mg dithianon/kg bw/day followed by a single oral dose of 10 mg
14C-dithianon/kg bw had no significant effect on the absorption,
excretion and distribution of dithianon in rats (Hawkins et al.,
1989).
Two groups of 3 rats/sex with cannulated bile ducts received a
single oral dose of 10 or 50 mg 14C-dithianon/kg bw. Bile samples
were collected at 3-h intervals and urine and faeces were collected
at 24 h intervals. The rats were sacrificed 48 h after dosing. About
10 and 7% of the dose was recovered in the bile at the low and the
high dose, respectively (Hawkins, 1989).
After a single oral administration of 10 or 50 mg 14C-
dithianon/kg bw to rats radioactivity in plasma was measured at
various time intervals up to 240 h after dosing. Peak plasma levels
were reached in 6 h (males 0.99 mg/l and 3.9 mg/l and females 0.76
mg/l and 3.81 mg/l at the low- and high-dose, respectively). At 240
h all concentrations were below the detection limit. The terminal
half-lives were similar for both dose levels, 55.8 and 46.4 h for
males and 56.8 and 56.7 h for females, at 10 and 50 mg/kg bw,
respectively (Hawkins et al., 1989).
Hens
Groups of 5 laying hens were given capsules containing 0, 0.36
or 3.6 mg 14C-dithianon/day (purity 99.3%), orally for 5
consecutive days. These doses were equivalent to 3 or 30 ppm in the
feed, respectively. Excreta and eggs were collected twice daily.
Radioactivity was excreted very rapidly and at a constant rate.
Irrespective of the dose, 4 days after the last administration,
total recovery of 14C was about 94% of the dose with about 90%
recovered in the excreta and 3-5% in the GIT contents. Detectable
tissue residues were found in kidney and liver (0.03% and 0.02%,
respectively). The 14C recovered in eggs comprised less than 0.01%
of the total radioactive dose. The radioactivity in egg yolk was
higher than in egg white and was maximal at sacrifice (0.005 mg/kg
and 0.075 mg/kg at the low- and the high-dose, respectively) (Cheng,
1990a).
Goats
Two lactating goats were given 14C-dithianon in capsules
orally for 5 consecutive days at a dose level of 6 mg/day or 60
mg/day. These dose levels were equivalent to 3 or 30 ppm in the
feed, respectively. A control goat received placebo capsules. Body-
weight, food consumption and clinical signs were recorded. Daily
samples of urine, faeces and milk were collected. The goats were
sacrificed 5 h after the last dose. Excretion was rapid and constant
with the majority excreted in the faeces (50.2% to 53.7%) followed
by the urine (27.9% and 24.2%). Less than 0.1% of the total
radioactivity was recovered in the milk. Concentrations of
radioactivity in milk, muscle and fat were less than 0.003 and 0.03
mg/kg for the low- and high-dosed animal. The levels in liver (0.02
and 0.17 mg/kg) and kidneys (0.06 and 0.49 mg/kg) were higher.
Concentration in the bile was high, 0.3 and 2.9 mg/kg for the low-
and the high-dose, respectively. This points to biliary involvement
in the excretion also for the goat (Cheng, 1990b).
Biotransformation
After 7 daily treatments of 14C-dithianon (dioxonaphtyl-
labelled), urinary and faecal extracts were studied with thin-layer
chromatography. There was no difference between males and females.
The compound is quickly metabolized to a great number of polar
compounds. None of these compounds exceeded 5% of the administered
radioactivity. According to the authors this is due to the molecular
structure of the substance, having different functional groups (CO,
CN, S). Also cleavage of the molecule in various places is possible.
It is assumed that very reactive products are formed which are
immediately degraded further or react with endogeneous compounds in
the animal to form polar products which are rapidly excreted. Less
than 1% unchanged dithianon is found in the faeces (Schlüter, 1985).
In the study of Hawkins et al. (1989) extracts of urine and
faeces were examined by TLC. More than 14 components were detected
in the urine. The three major components had Rf values of 0.98, 0.55
and 0.36. The two more polar compounds (Rf 0.55 and 0.36) were
hydrolyzed with ß-glucuronidase or sulfatase giving rise to a higher
proportion of the component with Rf value of 0.98. In the faeces the
major components had the same chromatographic properties as those
found in urine extracts. No attempt was made to characterize any of
the metabolites.
Toxicological studies
Acute toxicity studies
The acute toxicity of dithianon to several animal species is
given in Table 1. Signs of toxicity following oral administration
included sedation, dyspnoea, abnormal appearance, changes in gait
and body posture, emaciation and diarrhoea.
The acute oral toxicity in Wistar rats of the formulation Delan
Liquid (25% dithianon) was 1325 mg/kg bw (Sommer & Frohberg, 1968a).
Short-term toxicity studies
Mice
In a range-finding study, groups of 6 Crl:CD-1(ICR)BR mice/sex
were fed diets containing 0, 100, 500 or 1000 ppm dithianon (purity
92%) for 4 weeks. Observation included clinical signs, body-weight,
food consumption, haematology and clinical chemistry. Macroscopical
examinations were performed on all mice, but weight and
histopathology of liver and kidney were examined in female mice
only. Body-weight gain was decreased at the highest dose. Hb, PCV
and RBC counts were slightly lower in male mice at 1000 ppm and in
female mice at 500 and 1000 ppm. T3 and T4 concentrations were
lower in treated mice (dose-related in females). Increased relative
liver and kidney weight were observed in mid- and high-dose females.
A dose-related increased deposition of pigment in Kupffer cells was
seen in 4/6 female livers at 500 ppm and in 6/6 female livers at
1000 ppm (Brown, 1987).
Rats
Groups of 10 rats/sex were fed diets containing 0, 30 or 180
ppm dithianon (purity 92%) equal to 0, 2.5 and 14.6 mg/kg bw/day for
males and 0, 2.97 and 16.3 mg/kg bw/day for females, respectively,
for 90 days. The high-dose group received 1080 ppm (equal to 86.7
mg/kg bw/day for males and 99.5 mg/kg bw/day for females) and
consisted of 20 rats/sex of which 10/sex were kept after the 90-day
dosing for a 4-week recovery period. Observations included clinical
signs, body-weight, food consumption, haematology, clinical
chemistry, urinalysis, ophthalmoscopy, auditory acuity and
dentition, macroscopy, organ weight and histopathology. Body-weight
gain was decreased in high-dose males and females; Hb and Ht and the
number of erythrocytes was significantly decreased and the number of
reticulocytes was increased. Male rats at all dose levels showed
significantly decreased T3 levels (not clearly dose-related) and
at the highest dose decreased T4 levels. TSH was slightly
decreased in males at low- and mid-dose and increased at the highest
Table 1. Acute toxicity of dithianon
LD50 LC50
Species Strain Sex Route mg/kg bw mg/m3 Reference
Mouse1 JCL.ICR M oral 492 Sakamoto et al. (1975)
F 528
M i.p 100
F 77
M&F dermal >3200
M&F s.c. >3200
Mouse NMRI M&F i.p. 49 Sommer & Frohberg (1969)
Rat2 KFM-Han M oral 720 Ullmann (1987a)
Wistar F 678
Rat3 KFM-HAN M&F inhal. 2089 Ullmann (1984)
wistar (4-hr
exp.)
Rat2 KFM-Han M&F dermal >2000 Ullmann (1986a)
wistar (24-hr
exp.)
1 the purity of dithianon was 95%
2 the purity of dithianon was 92%
3 technical dithianon of 94.7% purity was used.
dose. Blood urea was increased in high-dose males (statistically
significant) and females. Chloride was decreased in females at 1080
ppm as was total protein. Albumin and alpha1-globulin was
increased in males (statistically significant) and females.
Urinalysis showed that, in males at 1080 ppm, specific gravity was
decreased. Absolute and relative liver and kidney weight and
relative adrenal weight were slightly increased in both sexes at 108
ppm. In females a tendency to an increased absolute and relative
kidney weight was seen at 180 ppm. This is considered to be an
effect because the kidney in the female rat is the target organ.
After the recovery period, females still exhibited a slightly
depressed erythrocyte count and an increased kidney weight and in
males T4 levels were still depressed, all at the highest dose. No
histopathological lesions were found. The NOAEL in this study was 30
ppm, equal to 2.5 mg/kg bw/day, based on increased kidney weight in
females (Leuschner & Neumann, 1987).
Kidney slides of 10 control female rats and of 20 rats at 1080
ppm (including 10 from the recovery experiment) were re-evaluated.
The incidence of hydropic degeneration and tubular hyperplasia was
increased in treated rats at termination of the treatment period
(Grasso, 1991a).
Groups of rats (5/sex/group) were exposed to 0.11, 0.31 or 1.07
g dithianon/m3, 6 h/day, 5 days/week for 2 weeks (head/nose
exposure). One of the mid-dose groups was kept for a recovery period
of 14 days. Additionally, 2 groups of 5 rats/sex were exposed to
filtered air and the vehicle alone, respectively. No dose-related
effects were observed on clinical signs, body-weight, food
consumption, haematology, blood chemistry, urinalysis, organ weight,
macroscopy or histopathology. The NOAEL in this study was > 1.07
g/m3 (Bhide, undated).
Groups of Wistar rats (9/sex/group) were exposed to an aerosol
of 0 or 33.6 mg/m3 Delan WP (equal to 26 mg/m3 dithianon), 4
h/day, 6 days/week for a total of 13 exposures (head/nose exposure).
No effects were observed on clinical signs, body-weight, food
consumption, haematology, clinical chemistry, macroscopy or
histopathology. The NOAEL in this study was > 33.6 mg/m3 Delan
WP, equal to 26 mg/m3 dithianon (Sommer & Frohberg, 1971; Spicer,
1971a).
In a 5-day dermal range-finding study, 2000 mg dithianon/kg
bw/day was administered to 5 Crl:CD(SD)BR rats/sex for 6 h/day on 5
consecutive days. Brown staining was observed at the application
site and on surrounding hair with dermal erythema or fissuring.
Body-weight and food consumption were slightly reduced in treated
male rats (Lackenby, 1987).
In a dermal limit test, suspensions of dithianon (purity 92%)
in PEG 200 were applied to the skin of Crl:CD(SD)BR rats
(5/sex/group) at doses of 0 or 1000 mg/kg bw/day, 6 h/day on 22
consecutive days. Mortality, food consump-tion and blood
biochemistry showed no dose-related effects. Body-weight gain was
decreased in treated males. In treated females, Hb, RBC and PCV were
slightly lower and MCV was slightly higher. Adrenal and kidney
weights were increased in female rats. At histopathology slight
irritation was observed in the treated skin. The incidence of
basophilic tubules was increased in the kidneys of treated rats; in
some of the females, the lesion was associated with the presence of
occasional mitotic figures and eosinophilic material in the tubular
lumen (Brown, 1989).
Because of the effects seen at 1000 mg/kg bw/day, an additional
study was carried out according to the same protocol with 5
rats/sex/group administered 0, 40 or 200 mg dithianon/kg bw/day. At
both dose levels the same haematological changes were observed not
only in females but also in some treated males. Body weight was
decreased and adrenal, kidney and liver weights were increased in
treated rats. Skin damage (moderate to marked acanthosis, slight to
moderate hyperkeratosis, leucocyte infiltration in the stratum
corneum and the dermis and occasionally ulceration) was observed in
all treated rats. Most of the systemic effects may be secondary, due
to stress caused by the marked local irritation. A NOAEL was not
determined in this study (Brown, 1989).
Dogs
In a 4-week range-finding study, one beagle dog/sex was fed
1000 ppm dithianon (purity 92%) for 14 days. After 7 days off-dose,
they were treated for 7 days at 60 ppm. One dog/sex, used as control
dog for the initial 15 days, was given 1000 ppm dithianon in the
diet from days 15-21 and 1500 ppm from days 21-28. Food consumption
and body-weight were markedly reduced at 1500 ppm, while at 1000 ppm
only slight changes in food consumption were observed (Pickersgill,
1987).
Dithianon (purity 92%) was fed in the diet to groups of 4
beagle dogs/sex at dose levels of 0, 40, 200 or 1000 ppm (equal to
0, 0.6, 3.0 or 12.6 mg/kg bw/day for males and 0, 0.7, 3.0 or 12.6
mg/kg bw/day for females, respectively) for 90 days. No dose-related
effects were observed on mortality, clinical signs, haematology,
urinalysis, eye examination, hearing, dentition, macroscopy or
histopathology. Food consumption was decreased in females at 1000
ppm. Body-weight gain was lower at the highest dose. A marked
increase in ALP was observed in both sexes after 6 and 13 weeks at
1000 ppm. The absolute and relative weights of liver, spleen and
kidneys were increased in all high-dose dogs and absolute and
relative thymus weight was decreased at the highest dose. No
histopathological findings were observed. The NOAEL in this study
was 200 ppm, equal to 3 mg/kg bw/day, based on increased organ
weights at the high dose (Neumann & Leuschner, 1989).
Groups of beagle dogs (4/sex/group) were fed diets containing
0, 40, 200 or 1000 ppm dithianon (purity 92%) for 52 weeks.
Observations included clinical signs, food consumption,
ophthalmoscopy, haematology, clinical chemistry, urinalysis,
macroscopy, organ weight and histopathology. During the first 13
weeks, food consumption was decreased in high-dose males. Male body-
weight was lower during the whole study period. Hb, RBC and PCV were
decreased in all high-dose dogs and MCHC was decreased in high-dose
females throughout the study. At termination, platelet count was
increased in high-dose males. In 3/4 high-dose males and 3/4 high-
dose females erythrocytes in which deposition of cholesterol had
occurred were present. At the highest dose, ALP activity was
increased and BUN and creatinine were decreased. The incidence of
blood in urine was increased in females at the mid- and high-dose
level at week 26 and in high-dose females at termination. Absolute
and relative liver, kidney and thyroid weights (spleen not measured)
were increased at 1000 ppm. In females a tendency to an increased
liver weight was observed at 200 ppm. The incidence of
hepatocellular hypertrophy in the liver was increased in females at
200 and in both males and females at 1000 ppm. In the same groups
there was also an increase in tubular pigment in the kidney.
Intranuclear inclusions and foci of pigmented histiocytes in the
liver were observed in most high-dose dogs. The NOAEL in this study
was 40 ppm, equivalent to 1 mg/kg bw/day, based on increased liver
weight and histopathological changes at 200 ppm (Clay, 1991).
Groups of 4 beagle dogs/sex were administered 0, 40, 400 or
1000 ppm dithianon (purity 95.3%) in the diet for 2 years. No
effects were observed on clinical signs, mortality, body-weight,
urinalysis or ophthalmoscopy. Food consumption was slightly
depressed in high-dose dogs during the first 3 months of the study.
At the highest dose level, Hb, PCV and RBC were decreased throughout
the study and platelet counts tended to increase. At 1000 ppm,
activity of ALP and ASAT were increased, as were levels of total
protein and ß-globulin. At the end of the study, a decrease in
glucose 6-phosphatase activity in the liver was seen in all female
dogs and 1 male dog at 1000 ppm. Absolute and relative liver,
kidney, pituitary, pancreas, thyroid weights were increased in dogs
at 1000 ppm. Liver weight was also increased at 400 ppm. An
irregular appearance of the exterior and cut surface of the liver
was seen at 1000 ppm. At histopathology liver changes, consisting of
hepatocyte enlargement associated with the presence of Kupffer cells
which contained brown material, were observed at 1000 and sometimes
at 400 ppm, more marked in females than in males. In the kidney
tubular brown pigmentation was increased at 1000 ppm. The NOAEL in
this study was 40 ppm, equivalent to 1 mg/kg bw/day, based on
increased liver weight and histopathological changes at 400 ppm
(Noel et al., 1969)
Additionally, stains for iron were used on all liver sections
and bone marrow smears and sections were examined. The incidence and
degree of iron accumulation was increased at 1000 ppm, particularly
in females (Spicer, 1971b).
Long-term toxicity/carcinogenicity studies
Mice
Groups of Crl:CD-1 (ICR)BR mice (51/sex/group) were fed
concent-rations of 0, 20, 100 or 500 ppm dithianon (purity 92%) in
the diet for 80 weeks. Observations included clinical signs,
mortality body-weight, food and water consumption, haematology
(differential white cell count), macroscopy, organ weights (brain,
liver, thyroids, kidneys and testes of 20 mice/sex/group) and
histopathology (about 40 tissues from control and high-dose mice and
from mice that died or were killed in extremis, and tissues of
lungs, liver and kidneys of all mice in the mid- and low-dose
groups).
Mortality was increased in high-dose males during the second
part of the study. The incidence of fur staining in mice was
increased at 500 ppm. Male terminal body-weight was lower in high-
dose group. Relative kidney weight was increased in mice at 100 and
500 ppm and relative brain weight was decreased in high-dose males.
Histopathological kidney changes were observed in males at 500 ppm
and in females at 100 and 500 ppm. Tumour incidence was not
enhanced. The NOAEL in this study was 20 ppm, equal to 2.9 mg/kg
bw/day, based on increased kidney weight and an increased incidence
of chronic nephrosis (Brown, 1990).
Rats
Groups of Charles River CD rats (35/sex/group) were fed diets
containing 0, 20, 200 or 1000 ppm dithianon (purity 95%) for 2
years. High-dose rats received 500 ppm dithianon in their feed
during the first 4 weeks of the study. An interim kill was performed
on 5 rats/sex/group at weeks 26 and 52 for clinical and pathological
examinations. The remaining rats were sacrificed after 104 weeks
except for the high-dose group in which the surviving males and
females were killed at week 88 and 96, respectively, due to
declining general condition. Observations included mortality,
clinical signs, body-weight, food and water consumption, food
efficiency, haematology, blood chemistry, urinalysis, macroscopy,
organ weight and histopathology. Mid- and high-dose rats showed
yellow discoloration of the fur during the first part of the study.
Body-weight gain and food consumption were reduced in high-dose rats
and in females at 200 ppm and water consumption was increased at the
highest dose. PCV and Hb were decreased in rats at 1000 ppm
throughout the study and PCV was also decreased at week 78 and 103
in rats at 200 ppm. At the high-dose level, protein levels were
increased in males and females and polyurea and proteinuria were
occasionally found in this group towards the end of the study.
Relative liver and kidney weight were increased in males and females
at 1000 ppm and at 200 ppm in females. Relative thyroid weight was
increased in high-dose males. No dose-related histopathological
findings were observed. The NOAEL in this study was 20 ppm,
equivalent to 1 mg/kg bw/day, based on effects on body-weight, red
blood cells and liver and kidney at 200 ppm and higher (Wheldon et
al., 1969; Spicer & Benson, 1971).
Groups of Crl:CD(SD)BR rats (50/sex/group) were fed diets
containing 0, 20, 120 or 600 ppm dithianion (purity 92%) for 104
weeks. Observations included mortality, clinical signs, body-weight,
food and water consumption, ophthalmoscopy, macroscopy, organ weight
(adrenals, liver, ovaries, brain, kidneys and testes) and
histopathology (about 40 tissues from control and high-dose rats and
from rats that died or were killed in extremis, and tissues of
lungs, liver and kidneys of all mid- and low-dose rats). Satellite
groups (20/sex/group) were kept according to the same protocol but
observations also included haematology, clinical chemistry
(including thyroid hormone assays), urinalysis and thyroid weight.
The incidence of fur staining and rough haircoat was increased in
high-dose females. At high-dose, body-weight gain and food
consumption were decreased in males up to week 24 and in females
during the whole study. At 600 ppm and occasionally at 120 ppm, Hb,
RBC, PCV and MCV were decreased in both sexes. T3 levels were
decreased at the highest dose. At 120 and 600 ppm, glucose, BUN and
œ-GT were increased in both sexes. Throughout the study cholesterol
levels were decreased at the highest dose. No clear effects were
observed in urinalysis. Relative kidney and liver weights were
increased in both sexes at 600 ppm. The incidence of treatment-
related kidney lesions (glomerulonephropathy and tubular nephrosis)
was increased in both sexes at 600 ppm. In the kidneys of females at
this dose level, an increased incidence of proliferative tubules,
adenomas and carcinomas was observed. In females at 120 ppm,
glomerulonephropathy and tubular nephrosis showed an increased
incidence. The NOAEL in this study was 20 ppm, equivalent to 1 mg/kg
bw/day, based on non-neoplastic kidney lesions observed at 120 ppm
(Brown, 1991).
Grasso (1991b) re-evaluated the kidney sections from female
rats in the Brown, 1991 study. Similar changes were reported as in
the original evaluation, including proliferative tubular changes
(see Table 2). The incidence of kidney lesions was increased at 120
and 600 ppm. A comparison of the kidney tumours found by Brown
(1991) and Grasso (1991b) is given in Table 3. The re-evaluation
reduced the number of adenomas, but the number of adenocarcinomas
remained the same. In neither evaluation were tumours seen at doses
below 600 ppm.
Table 2. Incidence of proliferative and some non-proliferative
lesions in kidneys of female rats in a long-term/
carcinogenicity study (according to Grasso, 1991b)
Dose level (ppm)
0 20 120 600
Basophilic tubules 24 24 34 30
Eosinophilic inclusions 0 2 3 9
Atypical hyperplasia 0 0 4 10
Proliferative tubules 0 0 0 6
Adenoma 0 0 0 7
Adenocarcinoma 0 0 0 2
Table 3. Tumour incidence in female rats in a long-term/
carcinogenicity study according to Brown (1991) and a
re-evaluation by Grasso (1991b)
Dose level (ppm)
Pathologist 0 20 120 600
Brown adenoma 0 0 0 10*
carcinoma 0 0 0 2*
Grasso adenoma 0 0 0 7
carcinoma 0 0 0 2
* one animal had an adenoma and a carcinoma therefore 11 animals
had tumours.
Reproduction studies
Groups of 10 male and 20 female rats received 0, 20, 200 or 500
ppm dithianon (purity not specified) in the diet for 100 days before
the initial mating. The treatment was continued throughout 3
generations of 2 litters each. Observations were made on general
condition and behaviour, food consumption (F0 generation only) and
body-weight. Conception rate, gestation time, litter size, pup
mortality, litter and mean pup weights at birth as well as at
weaning (day 21) were studied. Autopsy, organ weight and
histopathological examinations of selected organs were performed on
all rats of the F3b generation. Grooming was impaired over the 3
generations at 500 ppm and, in the F2b generation, at 200 ppm. At
the highest dose, body-weight gain was depressed in all generations
and in the 200 ppm of the F2b generation. Litter size at birth was
not affected but throughout the study entire litters tended to be
lost completely before weaning so litter size at weaning was
generally lower in treated groups than in control groups (none dose-
related). In the F1b matings (both litters) the incidence of
litter loss was increased at 500 ppm. Over the three generations a
tendency to a lower mean pup weight at birth as well as at weaning
was observed at 500 ppm. Pup mortality was very variable in both
treated and control groups but at the highest dose pup mortality
seemed to be increased in the F1a, F2a and F2b litters. Liver
and kidney weights of F3b pups were increased in males and females
at 500 ppm. Kidney weight was also increased in 200 ppm males as was
adrenal weight in 500 ppm males. The NOAEL was 20 ppm, equivalent to
1 mg/kg bw/day, on the basis of decreased body-weight gain and
increased kidney weight (Palmer & Readshaw, 1969).
Groups of 28 Crl:CD(SD)BR rats/sex were fed diets containing 0,
35, 200 or 600 ppm dithianon (purity 91.6%). After 100 days of
treatment, animals (F0 generation) were mated to start a 2-
generation (1 litter/generation) study. F1 parents (24/sex/group)
selected from F1a offspring were mated after 100 days to produce
one litter. During the premating and mating period, body-weight gain
and food consumption were decreased in F0 and F1 males and
females at 600 ppm and in F0 females during gestation at the
highest dose. No treatment-related effects were observed on clinical
signs, mating and fertility indices in any of the parenteral rats,
gestational length, pup weight, sex ratio and pup viability,
physical and functional development and macroscopy of both parents
and pups. Histopathology and weights of liver and kidneys were not
available. The NOAEL in this study was 200 ppm, equivalent to 10
mg/kg bw/day, based on decreased body-weight gain and food
consumption at 600 ppm (Osterburg, 1991).
Special studies on embryotoxicity and/or teratogenicity
Mice
Groups of 24 pregnant NMRI mice were orally administered 0,
3.3, 10, 30, or 90 mg dithianon/kg bw/day suspended in MHEC from
days 6-15 of gestation. The dams were observed for clinical signs,
food consumption and body-weight and were killed at day 19 of
gestation. The number of implantations, resorptions, live and dead
fetuses were recorded. Fetuses were weighed, sexed and examined for
external and skeletal malformations. At 90 mg/kg bw/day, all dams
died, 4 by day 7, and the last dam at day 15 of gestation. At
autopsy pale parenchymatous organs were observed and the intestine
was filled with haemorrhagic fluid. Body-weight was decreased at 10
and 30 mg/kg bw/day and food consumption was decreased at 30 mg/kg
bw/day during treatment. Fetal and placental weights were decreased
at 30 mg/kg bw/day. Delayed ossification was observed at 10 and 30
mg/kg bw/day. No malformations were observed. The NOAEL in this
study for maternal and embryo-fetal toxicity was 3.3 mg/kg bw/day
(Leuschner, 1976a).
Rats
In a preliminary study, groups of 8 mated Crl:CD(SD)BR rats
were administered by gastric intubation 0, 20, 40 or 70 mg
dithianon/kg bw/day suspended in CMC from days 6-15 post-coitum. At
the end of the study, another 2 groups of 8 mated rats were treated
according to the same protocol with 0 or 100 mg dithianon/kg bw/day.
The dams were sacrificed on day 20 of gestation and the fetuses were
removed and examined for external/visceral malformations. Excessive
urination and increased water consumption was observed at 100 mg/kg
bw/day. Maternal body-weight was decreased during days 6-9 of
gestation and body-weight gain was depressed during treatment at 70
and 100 mg/kg bw/day. At 100 mg/kg bw/day, post-implantation loss
was increased and mean fetal weight was reduced. The incidence of
external malformations was not increased. The NOAEL for maternal
toxicity was 40 mg/kg bw/day and 70 mg/kg bw/day for embryotoxicity
(Müller, 1989a).
Groups of 25-32 mated female Crl:CD(SD)BR rats were dosed
orally by gavage with 0, 20, 70 or 100 mg dithianon/kg bw/day
(purity 91.6%) suspended in CMC from days 6-15 of gestation. Another
2 groups of 25 mated female rats received 0 or 50 mg dithianon/kg
bw/day and were treated according to the same protocol. On day 20
the dams were sacrificed and the fetuses were removed and examined.
Observations included mortality, clinical signs, body-weight, food
consumption, number of corpora lutea, number and position of
implantations, early and late resorptions, and live and dead
fetuses. Fetuses were weighed, sexed and examined for external,
skeletal or visceral abnormalities. At 100 mg/kg bw/day, 5/25 dams
died and at 70 mg/kg bw/day, 1/32 dams died. Body-weight gain and
food consumption were dose-relatedly reduced at 50, 70 and 100 mg/kg
bw/day. Dams at 70 and 100 mg/kg bw/day revealed an increased
incidence of abnormal findings in the stomach and large intestines
at necropsy. Post-implantation loss and intra-uterine deaths were
markedly and dose-relatedly increased at 50, 70 and 100 mg/kg
bw/day. Mean fetal weight was reduced at the highest dose. No
teratogenic effects were observed. The NOAEL for maternal and
embryo-fetal toxicity was 20 mg/kg bw/day (Müller, 1991).
Rabbits
Groups of 12 pregnant New Zeeland white rabbits were orally
dosed by gavage with 0, 3.3, 10, 30 or 90 mg dithianon/kg bw/day
suspended in MHEC from days 6-18 of pregnancy. The dams were killed
on day 29 of pregnancy and fetuses were removed and weighed, sexed
and examined for external and skeletal malformations. At the highest
dose, all dams died prematurely between days 8 and 12 of pregnancy.
At autopsy their parenchymatous organs appeared pale and the
intestine was filled with fluid. In dams at 30 mg/kg bw/day food
consumption was reduced during treatment and body-weight was
decreased. The resorption rate and the post-implantation loss were
increased at 30 mg/kg bw/day and placental weight was decreased.
Slightly retarded ossification was observed in fetuses at 30 mg/kg
bw/day. The NOAEL in this study for maternal and embryo-fetal
toxicity is 10 mg/kg bw/day (Leuschner, 1976b).
In a preliminary study, groups of 8-9 mated female New Zeeland
white rabbits received 0, 10, 20 or 40 mg dithianon/kg bw/day
(purity 91.6%) by oral gavage from days 6-18 of gestation. The dams
were sacrificed on day 28 and the ovaries and uteri were removed and
examined for number of corpora lutea, live and dead fetuses, early
and late resorptions. Fetuses were weighed, sexed and externally
examined. At the highest dose, two abortions were observed and one
female showed 100% intra-uterine deaths at necropsy. During
treatment, food and water consumption were reduced and body-weight
was decreased from days 6-9 post-coitum at 40 mg/kg bw/day. The mean
number of early resorptions and the post-implantation loss was
increased at the highest dose. No external malformations were
observed. The NOAEL for maternal and embryo-fetal toxicity is 20
mg/kg bw/day (Müller, 1989b).
Groups of 20 mated New Zeeland white rabbits were orally
administered by gavage 0, 10, 25, or 40 mg dithianon/kg bw/day
(purity 91.6%) in CMC from days 6-18 post-coitum. On day 28, the
dams were sacrificed and fetuses were delivered by caesarean
section. The number of corpora lutea, early and late resorptions and
live and dead fetuses were recorded. The fetuses were weighed, sexed
and examined for external, visceral or skeletal abnormalities.
Mortality of dams was 0, 4, 3 and 4 in the control, low-, mid- and
high-dose group, respectively. Three high-dose dams aborted; at
necropsy no relevant findings were observed. Body-weight gain and
food consumption were decreased at 25 and 40 mg/kg bw/day during
treatment. At 10 mg/kg bw/day food consumption was also slightly
decreased. An increased pre- and post-implantation loss was seen and
the number of fetuses was reduced at the highest dose. In this study
there were no indications for structural malformations associated
with treatment. The NOAEL for maternal toxicity was 10 mg/kg bw/day
and 25 mg/kg bw/day for embryo-fetal toxicity (Müller, 1990).
Special studies on genotoxicity
A number of genotoxicity tests had been carried out with
dithianon. The results are summarized in Table 3. The only positive
effect found was in the chromosomal aberration test in vitro.
However, an in vivo test having the same endpoint, was negative.
Special studies on nephrotoxicity
Groups of CrL:CD(SD)BR rats (15/sex/group) were administered 0,
120, 600 or 1080 ppm dithianon (purity 90%) in the diet for 7 days.
Interim kills were performed on 5 rats/sex/group at days 2 and 4,
the remaining animals were sacrificed at day 7. Food consumption was
measured during treatment and body and kidney weights were recorded.
Kidney and adrenal tissues as well as tissues from organs showing
visible abnormalities were histopathologically examined. Sections of
the cortex of the right kidney of all rats were examined by electron
microscopy. Kidney samples of the control and high-dose groups after
day 2 were not evaluated because of a technical problem. At both
interim kills and at final sacrifice, body-weight was decreased at
high dose and absolute and relative kidney weight were increased at
all dose levels in a dose-related way. The incidence of pale kidneys
was increased at the highest dose. After 7 days, kidneys showed
hydropic degeneration of the proximal tubular cells and basophilic
Table 3. Results of genotoxicity assays on dithianon
Concentration
Test system Test object of dithianon Purity Results Reference
In vitro
Ames test S. typhimurium 1-333.3 µg/pl 91.6% negativec Müller &
TA1535, TA1537 in DMSOa Miltenburger,
TA1538, TA98 33.3-3333.3 µg/pl negativec (1986)
TA100 in DMSOb
Ames test S. typhimurium 0.1-5 µg/pld 95% negativec Shirasu et al.
TA1535, TA100 (1977)
TA1538, TA98
TA1537
Ames test S. typhimurium 0.3-6.6 µg/pla 91.6% negativec Timm (1987)
TA 1537, TA98 10-2000 µg/plb negativec
TA 1538;
TA1535 0.1-20 µg/pla negativec
10-2000 µg/plb negativec
TA100 1.0-333.3 µg/pla negativec
10-3333.3 µg/plb negativec
Bacterial E. coli WP2 hcr 0.1-5µg/pld 95% negativec Shirasu et al.
mutation (1977)
assay
Rec assay B. subtilis 0.1-5 µg/pld 95% negativec Shirasu et al.
H17, M45 (1977)
Chromosome Chinese hamster 25-600 ng/ml 91.6% positivec Heidemann
aberration V79 cells in DMSOa (1988)
assay 500-5000 ng/ml
in DMSOb positivec
CHO/HGPRT Chinese hamster 20-200 ng/ml 94.7% negativec Miltenburger
mutation V 79 cells in DMSOa (1984)
assay 60-600 ng/ml negativec
in DMSOb
UDS assay Rat hepatocytes 0.1-20 µg/ml 91.6% negativec Timm (1986)
in 1% DMSO
Table 3 (Contd)
Concentration
Test system Test object of dithianon Purity Results Reference
In vivo
Micro nucleus NMRI (SPF) 1, 10 or 100 94.6% negativec Schultze
test and mice mg/kg orally Schencking, M.
in CMC & Unkelbach, H.
(1984)
Host-mediated S. typhimurium 100-400 mg/kg 95% negativec Shirasu et al.
assay G46 (1977)
in male ICR mice
Chromosomal Wistar rat 22.3, 106 and 91.6% negativec Volkner (1990)
aberration bone marrow 393.5 mg/kg bw
assay in PEG 400
a without metabolic activation
b with metabolic activation
c positive control(s) yielded expected positive results.
d with and without metabolic activation
tubules at 600 and 1080 ppm. In high-dose females the lesions were
more severe and persistent. To a lesser extent these effects were
already found after 4 days. Basophilic tubules represent tubular
degeneration and reflect the extensive loss of proximal tubular
cells through hydropic degeneration. From electron microscopical
examination it appeared that the mitochondriae were especially
involved. They were affected in a dose-related manner at most time
points or doses investigated (in females even after day 2 at 120
ppm). The mitochondria were swollen and had lost their cristae. The
lesions were most severe in female rats treated with 1080 ppm. In
addition, the proximal cells in female rats also showed inclusions
of osmophilic material within the lyosomes. This suggests that lipid
peroxidation had taken place (Price, 1991). A hypothesis was
proposed that because dithianon shows a toxic effect to the kidneys,
the increase in tumour incidence at a high toxic dose is most
probably due to a non-genotoxic mechanism. The toxic action may be
due to accumulation of a toxic glutathion conjugate in the kidneys,
similar to the mechanism of action for hexachloro 1:3-butadiene.
Special studies on skin and eye irritation
A dose of 500 mg dithianon (purity 91-94%) moistened with
distilled water was applied to the shaven intact and abraded skin of
New Zeeland white rabbits for 24 h. No skin irritation up to 7 days
after application was observed (Sommer & Frohberg, 1968b).
Dithianon (purity 92%) was tested for irritation to shaven
intact skin areas of 3 male and 3 female New Zeeland white rabbits
under occlusive conditions. No edema or erythema were observed 24,
48 and 72 h after a 4-h exposure (Ullmann, 1986b).
Delan liquid (formulation with 25% dithianon) produced marked
erythema and occasionally edema in 5 male and 5 female New Zeeland
white rabbits when applied under occlusive conditions to the shaven
intact and abraded skin for 24 hours. The effects were still present
72 h after application (Sommer & Frohberg, 1968a).
Nine New Zeeland white rabbits were given doses of 100 mg
dithianon (purity 91-94%) into the conjunctival sac of the left eye.
The eyes of 6/9 rabbits were washed, 3/9 after 2 seconds and the
remaining 3/9 after 4 seconds. In the unwashed eyes redness,
swelling and secretion of the conjunctiva, swelling of the iris,
iridic injection and distinct turbidity of the whole cornea were
observed. The pupils did not react to light. After 2 weeks, the
conjunctival irritation was still apparent (slight) in 1 rabbit and
the corneal changes were not reversible in 1/3 rabbits and only
partly in the other 2/9. When the eyes of the rabbits were washed no
signs of irritation were observed (Sommer & Frohberg, 1968b).
Two New Zeeland white rabbits received a single installation of
0.1 ml Delan liquid into the conjunctival sac of the left eye.
Slight erythema, swelling and secretion of the conjunctiva developed
in both eyes after 24 h. After a week, the conjunctiva still showed
slight erythema and swelling (Sommer & Frohberg, 1968a).
Application of 100 mg dithianon (purity 92%) into the left eyes
of 3 male and 3 female New Zeeland white rabbits caused corneal
opacity, iritis and inflammation of the conjunctivae. Severe corneal
opacity was still observed in 2/6 rabbit by day 21 (Ullmann, 1987b).
Special studies on skin sensitization
Dithianon (purity 94.7%) had slight sensitizing properties when
tested in Dunkin-Hartley albino guinea-pigs by the maximization test
(Ullmann, 1985). This weak sensitization was also observed when
dithianon (purity 91.6%) was tested by the open epicutaneous test
(OET) on Dunkin-Hartley guinea-pigs (Ullmann & Kups, 1989a). After a
re-challenge with 3 different dithianon impurities (D13, D14 or D25)
in the OET with dithianon-sensitized guinea-pigs at least one
impurity gave a positive result (Ullmann et al., 1990). Pure
dithianon (99.2%) failed to produce sensitization when also tested
in the open epicutaneous test (Ullmann & Kups, 1989b).
Dithianon was tested in albino guinea-pigs for photoallergenic
properties. In one test, the observed weak sensitizing potential was
enhanced by simultaneous UV-exposure (Heusener, 1986). This slight
photo-allergenic effect was not established by two additional tests
carried out with either dithianon technical (purity 91.6%) or
dithianon pure (purity 99.6%) (Ullmann et al., 1989d, 1989e).
COMMENTS
After oral administration to rats, goats and hens, dithianon
was rapidly absorbed, distributed and excreted. Five days after its
oral administration to rats almost all of the administered
radioactivity had been eliminated, 62-70% via faeces and 30-34% via
urine. Only a small proportion of the dose was recovered in tissue,
with highest levels in kidneys, the gastrointestinal tract and whole
blood. Up to 10% had been excreted in the bile after 48 h. Dithianon
was quickly metabolized to a number of polar metabolites, which have
defied identification due to their lability. Less than 1% unchanged
dithianon was found in the faeces.
The acute oral toxicity of dithianon was moderate in mice and
rats. WHO has classified dithianon as slightly hazardous (WHO,
1992).
Short-term toxicity studies with mice, rats and dogs indicated
that the kidney is the primary target organ. Increased kidney
weight, hydropic degeneration of the proximal tubular cells and
basophilic tubules were demonstrated in the rat.
In a 90-day study in rats, dithianon was administered at
dietary concentrations of 0, 30, 180, or 1080 ppm. At high
concentrations effects on red blood cells, an increase in liver and
kidney weight and histopathological changes in the kidney were
noted. The NOAEL was 30 ppm, equal to 2.5 mg/kg bw/day for males and
3 mg/kg bw/day for females based on increased kidney weight.
Three studies with dogs were reviewed. In a 90-day study,
dithianon was fed at dietary concentrations of 0, 40, 200, or 1000
ppm. The NOAEL was 200 ppm, equal to 3 mg/kg bw/day based on
increased organ weights in the high-dose group. In both the 52-week
(0, 40, 200 or 1000 ppm) and 2-year (0, 40, 400 or 1000 ppm) studies
dithianon caused effects on red blood cells increased liver and
kidney weights, hepatocellular hypertrophy and tubular pigmentation
in the kidney. In each study the NOAEL was 40 ppm, equivalent to 1
mg/kg bw/day, based on increased liver weight and histopathological
changes at 200 ppm and 400 ppm, respectively.
In an 80-week long-term feeding study in mice at dietary
concentrations of 0, 20, 100, or 500 ppm, the NOAEL was 20 ppm,
equal to 2.9 mg/kg bw/day, based on increased kidney weight and an
increased incidence of chronic nephrosis. Two 2-year rat studies at
dietary concentrations of 0, 20, 200, or 1000 ppm and 0, 20, 120, or
600 ppm, respectively, were conducted. In the first study, only
effects on body-weight, red blood cells and liver and kidney weight
were observed at 200 ppm and higher, equivalent to 10 mg/kg bw/day.
In the second study these effects were confirmed together with a
number of histo-pathological renal changes, especially in females at
600 ppm. At this level kidney adenomas and adenocarcinomas were also
found. The NOAEL was 20 ppm, equivalent to 1 mg/kg bw/day, based on
non-neoplastic kidney lesions observed at 120 ppm. The Meeting
concluded that dithianon induced kidney tumours in females rats at
600 ppm. It has been hypothesized that tumour induction is secondary
to other renal changes seen in rats.
Two reproduction studies in rats were reviewed. In the first
study at dietary concentrations of 0, 20, 200, or 500 ppm dithianon,
the body-weight gain of parents and pups was decreased, pup
mortality was increased and liver and kidney weight were increased.
The NOAEL was 20 ppm, equivalent to 1 mg/kg bw/day based on
decreased body-weight gain and increased kidney weight. In the
second study (dietary concentrations of 0, 35, 200, or 600 ppm) the
NOAEL was 200 ppm, equivalent to 10 mg/kg bw/day based on decreased
body-weight gain and food consumption at 600 ppm.
Teratogenicity studies were conducted with mice, rats, and
rabbits. In mice, maternal toxicity and delayed ossification were
observed. The NOAEL for both effects was 3.3 mg/kg bw/day. In rats,
maternal toxicity, post-implantation loss and reduced fetal weight
were observed at doses of 50-100 mg/kg bw/day. The NOAEL was 20
mg/kg bw/day. In a study in rabbits, 30 mg/kg bw/day caused maternal
toxicity, post-implantation loss and retarded ossification. The
NOAEL was 10 mg/kg bw/day. In a second study in rabbits, maternal
toxicity was observed at 25 and 40 mg/kg bw/day but not at 10 mg/kg
bw/day. The NOAEL for fetotoxicity was 25 mg/kg bw/day. Teratogenic
effects were not observed in any of the studies.
After reviewing the available genotoxicity data, the Meeting
concluded that dithianon was not genotoxic.
The Meeting concluded, after consideration of the long-term
toxicity studies and the genotoxicity data, that dithianon did not
pose a carcinogenic hazard for humans.
An ADI was allocated, based on NOAELs in two-year studies in
rats and dogs, using a 100-fold safety factor.
TOXICOLOGY EVALUATION
Level causing no toxicological effect
Mouse: 20 ppm in the diet, equal to 2.9 mg/kg bw/day (80-
week study)
Rat: 20 ppm in the diet, equivalent to 1 mg/kg bw/day (2-
year studies)
Dog: 40 ppm in the diet, equivalent to 1 mg/kg bw/day (one
and two-year studies).
Estimate of acceptable daily intake for humans
0-0.01 mg/kg bw
Studies which will provide information valuable in the continued
evaluation of the compound
1. Characterization of the metabolites of dithianon in mammals and
plants.
2. Clarification of the mechanism of nephrotoxicity and induction
of kidney tumours.
3. Observations in humans.
REFERENCES
Bhide, M.B. (undated) Subacute inhalation toxicity in rats (14 day)
of dithianon (technical) of E. Merck (India) Ltd., Bombay, Institute
of Toxicology. Submitted to WHO by Shell International Chemical
Company Ltd., Shell Centre, London, UK.
Brown, D. (1987) Dithianon, 4-week oral (dietary administration)
dose range-finding study in the mouse. Unpublished report No. 5478-
460/15 dated July 1987 from Hazleton UK. Otley Road, Harrogate,
England. Submitted to WHO by Shell International Chemical Company
Ltd., Shell Centre, London, UK.
Brown, D. (1989) Dithianon: 21-day dermal toxicity study in the rat.
Unpublished report 5774-460/19A from Hazleton UK, Otley Road,
Harrogate, England. Submitted to WHO by Shell International Chemical
Company Ltd., Shell Centre, London, UK.
Brown, D. (1990) Dithianon: 80-week oral (dietary administration)
carcinogenicity study in the mouse. Unpublished report No. 6096-
460/16 dated July 1990 from Hazleton UK, Otley Road, Harrogate,
England. Submitted to WHO by Shell International Chemical Company
Ltd., Shell Centre, London, UK.
Brown, D. (1991) Dithianon: 104 week oral (dietary administration)
carcinogenicity and toxicity study in the rats. Unpublished report
No. 6165-460/14 dated August 1991 from Hazleton UK, Otley Road,
Harrogate, England. Submitted to WHO by Shell International Chemical
Company Ltd., Shell Centre, London, UK.
Cheng, Th. (1990a) Five-day repeated dose of 14C-dithianon in
laying hens. Unpublished report 107AX-652-001, Lab. project
identification HLA 6160-122 dated October 17, 1990 from Hazleton
Laboratories America, Inc., Madison, WI 53707 USA. Submitted to WHO
by Shell International Chemical Company Ltd., Shell Centre, London,
UK.
Cheng, Th. (1990b) Five-day repeated dose of 14C-dithianon in
lactating goats. Unpublished report 107AX-652-002, Lab. project
identification HLA 6160-123 dated October 17, 1990 from Hazleton
Laboratories America, Inc., Madison, WI 53707 USA. Submitted to WHO
by Shell International Chemical Company Ltd., Shell Centre, London,
UK.
Clay, H. (1991) Dithianon: 52 week oral (dietary administration)
toxicity study in the beagle. Unpublished report No. 5939-460-20
dated August 1991 from Hazleton UK, Harrogate, North Yorkshire,
England. Submitted to WHO by Shell International Chemical Company
Ltd., Shell Centre, London, UK.
Grasso, P. (1991a) Summary report on short-term studies on dithianon
and results of slide reviews from a 90-day study. Unpublished report
dated October, 1991 from Toxicology Advisory Services (TAS) Hamilton
House, Sutton, Surrey, UK. Submitted to WHO by Shell International
Chemical Company Ltd., Shell Centre, London, UK.
Grasso, P. (1991b) Review of kidney histopathology in female rats
given dithianon in a carcinogenicity study. Unpublished report dated
October, 1991 from Toxicology Advisory Services (TAS) Hamilton
House, Sutton, Surrey, UK. Submitted to WHO by Shell International
Chemical Company Ltd., Shell Centre, London, UK.
Hawkins, D.R., Elsom, L.F., Thomson, J.K & Whitby, B.R.(1989) The
biokinetics and metabolism of 14C-dithianon in the rat.
Unpublished report No. HRC/CMK 23/88942 (Shell Agrar doc. No. 107AK-
651-004) from Huntingdon Research Centre, Huntingdon, England.
Submitted to WHO by Shell International Chemical Company Ltd., Shell
Centre, London, UK.
Heidemann, A. (1988) Chromosome aberration assay in Chinese hamster
V79 cells in vitro with dithianon technical. Unpublished report
CCR project 122106 dated August 08, 1988 from CCR Cytotest Cell
Research GmbH & Co.KG Darmstadt, Germany. Submitted to WHO by Shell
International Chemical Company Ltd., Shell Centre, London, UK.
Heusener, A. (1986) Investigation for photoallergenic potential in
albino guinea pigs. Unpublished report dated August, 25, 1986
Bericht nr. 4/56/86 from Merck, Darmstadt, Germany. Submitted to WHO
by Shell International Chemical Company Ltd., Shell Centre, London,
UK.
Lackenby, F. (1987) Dithianon: 5 day dermal range-finding study in
the rat. Unpublished report No. 5537-460/18 dated September 1987
from Hazleton UK, Harrogate, North Yorkshire, England. Submitted to
WHO by Shell International Chemical Company Ltd., Shell Centre,
London, UK.
Leuschner, F. (1976a) Influence of dithianon on the pregnant mouse
and foetus at oral administration. Unpublished report dated August
26, 1976 CelaMerck document No. 107AC-451-005 from Laboratorium für
Pharmakologie und Toxicologie, Hamburg. Submitted to WHO by Shell
International Chemical Company Ltd., Shell Centre, London, UK.
Leuschner, F. (1976b) Influence of dithianon technical lot 45 (1,2-
dithiaanthraquinone-2,3-dicarbonitrile) known for short as
"dithianone", on the pregnant mouse and the foetus at oral
administration. Unpublished report dated August, 26, 1976 CelaMerck
document No. 107AC-451-005 from Laboratorium für Pharmakologie und
Toxicologie, Hamburg. Submitted to WHO by Shell International
Chemical Company Ltd., Shell Centre, London, UK.
Leuschner, F. & Neumann, B.W. (1987) 90-day feeding study of
dithianon, batch 15C/86, in Sprague-Dawley rats. Unpublished report
No. 3836/86 from Laboratory of Pharmacology and Toxicology Hamburg,
Germany. Submitted to WHO by Shell International Chemical Company
Ltd., Shell Centre, London, UK.
Miltenburger, H.G. (1984) Mutations affecting the hypoxanthine-
guanine phosphoribosyl transferase locus in V79 cells. Unpublished
report dated December 12, 1984 from Laboratorium for Mutagenicity
Testing, Darmstadt Germany. Submitted to WHO by Shell International
Chemical Company Ltd., Shell Centre, London, UK.
Müller, W. (1989a) Dithianon preliminary oral (gavage)
embryotoxicity study in the rat. Unpublished final report No. 872-
460-042 dated November 9, 1989 from Hazleton Laboratories
Deutschland GmbH, Münster, Germany. Submitted to WHO by Shell
International Chemical Company Ltd., Shell Centre, London, UK.
Müller, W. (1989b) Dithianon preliminary oral (gavage)
embryotoxicity study in the rabbit. Unpublished final report No.
873-460-044 dated September 5, 1989 from Hazleton Laboratories
Deutschland GmbH, Münster, Germany. Submitted to WHO by Shell
International Chemical Company Ltd., Shell Centre, London, UK.
Müller, W. (1990) Dithianon oral (gavage) teratogenicity study in
the rabbit. Unpublished report No. 879-460-045 dated April 11, 1990
from Hazleton Laboratories Deutschland GmbH, Münster, Germany.
Submitted to WHO by Shell International Chemical Company Ltd., Shell
Centre, London, UK.
Müller, E.W. (1991) Dithianon oral (gavage) teratogenicity study in
the rat. Unpublished final report No. 878-460-043 dated 23 January
1991 from Hazleton, Laboratories Deutschland GmbH, Münster, Germany.
Submitted to WHO by Shell International Chemical Company Ltd., Shell
Centre, London, UK.
Müller, E.W. & Miltenburger, H.G. (1986) Induction of gene mutations
in mutant strains of Salmonella typhimurium (Ames test) without
and with metabolic activation. Unpublished test report of study LMP
200 A dated August 22, 1986, from Laboratorium for Mutagenicity
Testing, Darmstadt, Germany. Submitted to WHO by Shell International
Chemical Company Ltd., Shell Centre, London, UK.
Neumann, B.W. & Leuschner, F. (1989) 90-Day feeding study of
dithianon, batch No. 15C/86 in beagle dogs. Unpublished report No.
3837/86 from Laboratory of Pharmacology and Toxicology, Hamburg,
Germany. Submitted to WHO by Shell International Chemical Company
Ltd., Shell Centre, London, UK.
Noel, P.R.B., Mawdesley-Thomas, L.E., Chesterman, H., Squires, P.F.
& Street, A.E. (1969) Dithianon. Toxicity studies in pure-bred dogs
(initial studies and dietary intake for two years). Unpublished
report No. 2954/69/380 from Huntingdon Research Centre, Huntingdon,
England. Submitted to WHO by Shell International Chemical Company
Ltd., Shell Centre, London, UK.
Osterburg, J. (1991) Dithianon. Two-generation oral (dietary
administration) reproduction toxicity study in the rat (one litter
per generation). Unpublished final report No. 795-460-030 dated 13
February 1991 from Hazleton Laboratories Deutschland GmbH, Münster,
Germany. Submitted to WHO by Shell International Chemical Company
Ltd., Shell Centre, London, UK.
Palmer, A.K. & Readshaw, M.A. (1969) Effect of dithianon on
reproductive function of multiple generations in the rat.
Unpublished final report No. 2548/68/425 dated 18 April 1969 from
Huntingdon Research Centre, Huntingdon, England. Submitted to WHO by
Shell International Chemical Company Ltd., Shell Centre, London, UK.
Pickersgill, N. (1987) Dithianon: palatability study in the beagle.
Unpublished report No. 5610-460/21 dated November 1987 from
Hazleton, UK, Harrogate, North Yorkshire, England. Submitted to WHO
by Shell International Chemical Company Ltd., Shell Centre, London,
UK.
Price, S.C. (1991) Short-term study (7 day) on the nephrotoxicity of
dithianon on male and female Sprague-Dawley rats. Unpublished final
report No. R191/0306 from Robens, Institute of Health and Safety,
University of Surrey, Guildford, Surrey. Submitted to WHO by Shell
International Chemical Company Ltd., Shell Centre, London, UK.
Sakamoto, Y., Matsumoto, K. & Okami, H. (1975) Acute toxicological
studies of dithianon: oral, subcutaneous, dermal and intraperitoneal
administration in mice. Unpublished study dated 22-01-1975 from
Merck Japan Limited. Shell Agrar document No. 107AA-421-008.
Submitted to WHO by Shell International Chemical Company Ltd., Shell
Centre, London, UK.
Schlüter, H. (1985) Investigations into biokinetics and metabolism
of dithianon in the rat. Unpublished report No. 107AA-651-003 from
Celamerck GmbH, Ingelheim/Rhen, Germany. Submitted to WHO by Shell
International Chemical Company Ltd., Shell Centre, London, UK.
Schulze Schenking, M. & Unkelbach, H.D. (1984) Micronucleus test in
mice after oral administration. Unpublished report No. 4/45/84 from
Institut für Toxicologie Merck, Darmstadt, Germany. Submitted to WHO
by Shell International Chemical Company Ltd., Shell Centre, London,
UK.
Shirasu, Y., Moriya, M. & Kato, K. (1977) Mutagenicity testing on
dithianon in microbial systems. Unpublished report dated 21-7-1977
from the Institute of Environmental Toxicology, Japan. Submitted to
WHO by Shell International Chemical Company Ltd., Shell Centre,
London, UK.
Sommer, S. & Frohberg, H. (1968a) Test for acute toxicity after oral
administration and for primary irritation of the skin and mucous
membranes. Unpublished report dated January 1968 from Merck A.G.
Darmstadt, Germany. Submitted to WHO by Shell International Chemical
Company Ltd., Shell Centre, London, UK.
Sommer, S. & Frohberg, H. (1968b) Trial for primary irritation of
the skin and mucous membranes in rabbits. Unpublished report dated
September 1968 from Merck, AG, Darmstadt, Germany. Submitted to WHO
by Shell International Chemical Company Ltd., Shell Centre, London,
UK.
Sommer, S. & Frohberg, H. (1969) Trial for acute toxicity in mice
following intraperitoneal injection. Unpublished report dated
January 1969 from Merck AG, Darmstadt, Germany. Submitted to WHO by
Shell International Chemical Company Ltd., Shell Centre, London, UK.
Sommer, S & Frohberg, H. (1971) Delan Spritzpulver. Prüfung auf
subakute inhalations toxizität an der Ratte. Unpublished report
dated 31 August 1971 from Merck, Darmstadt, Germany. Submitted to
WHO by Shell International Chemical Company Ltd., Shell Centre,
London, UK.
Spicer, E.J.F. (1971a) Delan 75WP subacute inhalation toxicity in
rats. Histopathological findings. Unpublished report dated 3 June
1971 from Huntingdon Research Centre, England. Submitted to WHO by
Shell International Chemical Company Ltd., Shell Centre, London, UK.
Spicer, E.J.F. (1971b) Dithianon: toxicity study in pure-bred dogs
(dietary intake for two years). Addendum to HRC report 2954/69/380
from Huntingdon Research Centre, Huntingdon, England. Submitted to
WHO by Shell International Chemical Company Ltd., Shell Centre,
London, UK.
Spicer, E.J.F. & Benson, H.G. (1971) Dithianon: two year feeding
study in rats. Unpublished addendum dated 26 November 1971 to HRC
report 2631/69/57 from Huntingdon Research Centre, Huntingdon,
England. Submitted to WHO by Shell International Chemical Company
Ltd., Shell Centre, London, UK.
Timm, A. (1986) Dithianon technisch. Unscheduled DNA synthesis in
hepatocytes of male rats in vitro (UDS test). Unpublished test
report of study LMP 200 B dated September 1986 from Laboratorium für
Mutagenitätsprüfung, Technische Hochschule Darmstadt, Germany.
Submitted to WHO by Shell International Chemical Company Ltd., Shell
Centre, London, UK.
Timm, A. (1987) Dithianon technisch. Induction of gene mutations in
mutant strains of Salmonella typhimurium (Ames test) with and
without activation. Unpublished test report of study LMP 278 dated
May 08 1987 from Laboratorium für Mutagenitätsprüfung, Technische
Hochschule Darmstadt, Germany. Submitted to WHO by Shell
International Chemical Company Ltd., Shell Centre, London, UK.
Ullmann, L. (1984) Four-hour acute aerosol inhalation toxicity
(LC50) study with dithianon, technical in rats. Unpublished report
dated 14 December 1984 from RCC, Research & Consulting Company AG.,
Itingen, Switzerland. Submitted to WHO by Shell International
Chemical Company Ltd., Shell Centre, London, UK.
Ullmann, L. (1985) Test for delayed hypersensitivity in the albino
guinea-pig with dithianon technical (Guinea-pig maximization test)
Unpublished report No. 3742 dated 17 December 1984 from Research &
Consulting Company AG., Itingen Switzerland. Submitted to WHO by
Shell International Chemical Company Ltd., Shell Centre, London, UK.
Ullmann, L. (1986a) Acute dermal toxicity study with dithianon in
rats. Unpublished report dated December 1986 from RCC, Research &
Consulting Company AG., Itingen, Switzerland. Submitted to WHO by
Shell International Chemical Company Ltd., Shell Centre, London, UK.
Ullmann, L. (1986b) Primary skin irritation study with dithianon in
rabbits (4-hour occlusive application). Unpublished report project
nr.: 22 October 1986 from Research & Consulting Company AG.,
Itingen, Switzerland. Submitted to WHO by Shell International
Chemical Company Ltd., Shell Centre, London, UK.
Ullmann, L. (1987a) Acute oral toxicity study with dithianon in
rats. Unpublished report dated 13 January 1987 from RCC, Research &
Consulting Company AG., Itingen, Switzerland. Submitted to WHO by
Shell International Chemical Company Ltd., Shell Centre, London, UK.
Ullmann, L. (1987b) Primary eye irritation study with dithianon in
rabbits. Unpublished report project no.: 077242 d.d. 3 March 1987
from Research & Consulting Company AG, Itingen, Switzerland.
Submitted to WHO by Shell International Chemical Company Ltd., Shell
Centre, London, UK.
Ullmann, L. & Kups, A. (1989a) Determination of skin irritation and
capacity of allergenic sensitization by the open epicutaneous test
on guinea-pigs (OET) with Dithianon (15 C/86). Unpublished report
RCC project 219644 dated 29 March 1989 from Research & Consulting
Company AG, Itingen, Switzerland. Submitted to WHO by Shell
International Chemical Company Ltd., Shell Centre, London, UK.
Ullmann, L. & Kups, A. (1989b) Determiniation of skin irritation and
capacity of allergenic sensitization by the open epicutaneous test
on guinea-pigs (OET) with Dithianon (Gr I/42/43). Unpublished report
RCC project 219655 dated March 31, 1989 from Research & Consulting
Company AG, Itingen, Switzerland. Submitted to WHO by Shell
International Chemical Company Ltd., Shell Centre, London, UK.
Ullmann, L., Kups, A., Lucini, P. & Janiak, Th. (1989d)
Determination of photoallergenicity with dithianon (15C/86) in
albino guinea-pigs. Unpublished report project no.: 239040 d.d. 10
November 1989 from Research & Consulting Company AG, Itingen,
Switzerland. Submitted to WHO by Shell International Chemical
Company Ltd., Shell Centre, London, UK.
Ullmann, L., Kups, A., Lucini, P. & Janiak, Th. (1989e)
Determination of photoallergenicity with dithianon (GR 1/42/43) in
albino guinea-pigs. Unpublished report RCC project no.: 239051 dated
10 November 1989 from Research & Consulting Company AG, Itingen,
Switzerland. Submitted to WHO by Shell International Chemical
Company Ltd., Shell Centre, London, UK.
Ullmann, L., Krölig, C., Lucini, P. Janiak, Th. & Decker, U. (1990)
Determination of skin irritation and capacity of allergenic
sensitization by the open epicutaneous test (OET) on guinea-pigs
sensitized with dithianon technical and on naive control plus
appendix. Unpublished report No. 253124 dated 14 March 1990 from
Research & Consulting Company AG, Itingen, Switzerland. Submitted to
WHO by Shell International Chemical Company Ltd., Shell Centre,
London, UK.
Volkner, W. (1990) Chromosome aberration assay in bone marrow cells
of the rat with dithianon. Unpublished report CCR project No. 186107
dated 25 July 1990 from Cytotest Cell Research GMBH & CO. Rossdorf,
Germany. Submitted to WHO by Shell International Chemical Company
Ltd., Shell Centre, London, UK.
Wheldon, G.H., Cozens, D.D., Street, A.E. & Mawdesley-Thomas, L.E.
(1969) Dithianon: Two year feeding study in rats. Unpublished report
No.: 2631/69/57 dated 15 April 1969 from Huntingdon Research Centre,
Huntingdon, England. Submitted to WHO by Shell International
Chemical Company Ltd., Shell Centre, London, UK.
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.
See Also:
Toxicological Abbreviations