PROPINEB
EXPLANATION
The toxicology of propineb was previously reviewed by the Joint
Meeting in 1977, 1980, and in 1983 (Annex 1, FAO/WHO, 1978a, 1981a, &
1984). A toxicological monograph was prepared by the Joint Meeting in
1977 (Annex 1, FAO/WHO, 1978b) and a monograph addendum was prepared
in 1980 (Annex 1, FAO/WHO, 1981b). Because of concern of the meeting
in 1977 regarding the potential for thyrotoxicity and tumourigenicity
of propylene thiourea (PTU), a breakdown product of propineb, the
Meeting recommended a temporary ADI of 0.005 mg/kg b.w. Although no
new toxicity data were provided in 1980, the Meeting took into account
available data on ethylene thiourea (ETU), an analogous breakdown
product of the ethylenebisdithiocarbamates. Further evaluation of
propineb was postponed pending the submission of additional data.
After examining the available data in 1983, the Meeting concluded that
a complete evaluation was not possible. Adequate data for evaluation
was required by 1985. Meanwhile, the temporary ADI was extended an
additional 2 years to 1985.
Data submitted for evaluation in 1985 consisted of long-term
mouse and rat studies, mutagenicity studies, and a special study on
the effect of PTU on DNA. In addition, data previously submitted for
evaluation in 1983 were re-examined. These data included several
studies on propineb (acute and subacute toxicity studies, short-term
studies on thyroid function in rats, mutagenicity studies, and an
oncogenicity study on mice) and on PTU (pharmacokinetic studies on
rats and a long-term thyroid-function study on rats).
EVALUATION FOR ACCEPTABLE INTAKE
BIOLOGICAL DATA
Biochemical aspects
Absorption, distribution, and excretion of propylene thiourea
Radiolabeled 14C-propylene thiourea was orally administered to
groups of 5 male Sprague-Dawley rats at dosage levels of 0.5 to
50 mg/kg. Additional groups of rats were given i.v. doses of 5 or
10 mg/kg. Intraduodenal doses of 5 mg/kg were also administered to
rats with bile duct fistulas. Radioactivity in urine, faeces, exhaled
air, and bile was measured for up to 10 days. Radioactivity was also
monitored in body tissues/organs for up to 10 days. Whole-body
autoradiograms were prepared. Inasmuch as radioactivity was directly
measured, with no prior extraction procedures, all results were for
unchanged parent compound plus metabolites.
Total recoveries of radioactivity in experiments ranged from 86%
to 98%. More than 95% of orally-administered doses was absorbed.
Absorption and excretion of radioactivity were rapid. At 48 hours,
85-92% of orally- or i.v.-administered doses was recovered in the
urine, 7-14% in the faeces, < 0.2% in exhaled air, and only 1-2%
remained in the body. The elimination half-life for the first 48 hours
was about 6 hours. After 5 days, the elimination half-life was 2-2.5
days, which indicated a biphasic elimination pattern. Biliary
excretion was also observed, as was evidence for entero-hepatic
circulation. Two hours after oral doses of 5 mg/kg, radioactivity was
essentially uniformly distributed in body tissues/organs, with the
exception of the thyroid, which had a 12-fold higher level of
radioactivity. Thyroid levels of radioactivity reached a peak at 8
hours, which was about double that observed at 2 hours, and
radioactivity remained considerably higher than levels in other
tissues/organs for the remainder of the 10-day study. By 48 hours,
radioactivity levels in body tissues/organs, with the exception of the
thyroid, declined about 50-fold. Somewhat higher levels of
radioactivity were observed in the kidney and liver. Selective uptake
and accumulation of radioactivity in the thyroid was apparent
throughout the 10-day study (Weber et al., 1978).
Toxicological studies
Special study on carcinogenicity
Mouse
Technical grade propineb of 82.9% purity was administered in the
feed to NMRI mice for 104 weeks at dosage levels of 0, 50, 200, or
800 ppm. Each control and test group contained 50 mice of each sex.
The animals were observed daily for mortality, general appearance, and
signs of toxicity. Body weights were determined weekly for 6 weeks and
biweekly thereafter. Feed consumption was measured weekly. Clinical
laboratory examinations were performed on satellite groups of 10
mice/sex/group prior to initiation of dosing and at 6, 12, 18, and 24
months. Haematological examinations consisted of erythrocyte counts,
haemoglobin determinations, leukocyte counts, and differential
leukocyte counts. Clinical chemistries consisted of alkaline
phosphatase and glutamate-pyruvate transaminase activity
determinations. Urinalyses consisted of semiquantitative
determinations of protein, glucose, haemoglobin, urobilin-ogen, and
pH. Gross necropsies were performed on nearly all mice. At terminal
sacrifice, absolute organ weights and relative organ/body-weight
ratios were determined for brain, heart, lung, liver, spleen, kidneys,
adrenals, thyroids, and gonads. Approximately 36 organs or tissues
from each of 37 to 47 mice in each group were histopathologically
examined.
No meaningful differences in mortality were observed between male
and female control and test groups, respectively. The number of male
mice surviving to termination of the study were 19, 20, 19, and 25 for
the control, low-, mid-, and high-dose groups, respectively.
Comparable numbers for female mice were 5, 4, 13, and 7, respectively.
The causes of death of animals that died during the study were
attributed in numerous instances to pulmonary tumours, malignant
lymphomas, or amyloid nephrosis. Daily observations did not indicate
any differences between test and control mice. Mean feed consumption
was similar in male and female control and test groups, respectively.
No apparent differences in mean body weights were observed between
male and female control and test groups, respectively. Haematological,
clinical chemistry, and urinalysis examinations did not reveal any
effects attributable to the test material. Gross necropsies were
reported to be negative for lesions attributable to the test material,
but documentation was lacking. Organ weights and organ/body-weight
ratios did not reveal any differences that could be related to the
test material. Possibly increased mean thyroid weights and
thyroid/body-weight ratios in all treated female groups were noted,
but could not be related to the test material because too few female
mice survived to termination of the study.
Non-neoplastic lesions were not reported in the histopathological
evaluation; therefore, this study cannot be used as a chronic feeding
study. Percentages of female mice with tumours of any kind were 65,
66, 73, and 88 for the contol, low-, mid-, and high-dose groups,
respectively. A similar increase was not observed in treated male
mice. Frequently-observed neoplasms were pulmonary adenomas and
malignant lymphomas in male and female mice and benign granulosa cell
tumours in the ovaries of female mice.
Increased incidences of pulmonary adenomas were observed in the
treated female mice. Percentages were 19, 27, 30, and 50 for the
control, low-, mid-, and high-dose female groups, respectively.
Pulmonary carcinomas were not increased. The increase in adenomas in
the high-dose female group may possibly be related to treatment. A
similar increase was not observed in treated male mice.
Malignant lymphomas in male mice ranged from 26 to 28%, and in
female mice from 30 to 38%. Benign granulosa cell tumours in the
ovaries of female mice ranged from 14 to 32%, but their incidence was
not dose-related and could not be related to the test material. A
suggestive increase in pituitary adenomas was noted in the high-dose
female mice. Percentages were 3, 0, 2, and 10 for the control, low-,
mid-, and high-dose female groups, respectively. Thyroid or adrenal
tumours were not increased in treated male or female mice.
An increased incidence of hepatocellular adenomas was observed in
the high-dose male group. Percentages were 6, 7, 0, and 20 for the
control, low-, mid-, and high-dose male groups, respectively.
Hepatocellular carcinomas in male mice ranged from 0 to 4%, but their
incidence was not dose-related. Historical control data presented by
the testing laboratory for hepatocellular adenomas in NMRI mice ranged
from 4 to 12%. The increase in hepatocellular adenomas in the high-
dose male group may possibly be related to treatment with the test
material. Hepatocellular tumours were not increased in treated female
mice (Brune et al., 1980).
Special studies on mutagenicity
Propineb was tested in the mutagenicity studies listed in
Table 1.
Special studies on effect upon thyroid function
Rat
Propineb of unknown purity was administered in the feed for 62
days to 5 groups of 80 male Wistar TNO/W74 rats at dosage levels of 0,
2, 10, 50, or 250 ppm. The rats were 40-50 days old at the beginning
of the study and had a mean body weight of 113 grams. Ten rats per
group were sacrificed at 7 days and at 21 days. Gross necropsies,
organ-weight determinations, and clinical laboratory examinations were
performed on these animals. An additional 10 rats per group were also
sacrificed at 7, 21, and 62 days and given a "thyroid function test",
which was reported separately (see Weber & Dressier, 1980). The
remaining animals were sacrificed at 62 days. Animals were examined
daily. Body weights and feed consumption were determined weekly.
Clinical laboratory examinations consisted of lactate dehydrogenase,
creatinine phos-phokinase, total thyroxin, calcium, magnesium, and
inorganic phosphate-level determinations. Animals were necropsied and
organ weights were determined for thyroids, adrenals, and liver.
Histopathological examinations were performed on 30 control and 29
high-dose animals. Liver, adrenals, thyroid, para-thyroid, skeletal
muscle, and grossly-apparent lesions were examined.
Table 1. Mutagenicity assays with propineb
Study type Dosage level and/or Results Reference
conditions
Bacteria tests
Reverse mutation, Dosage levels up to 2.5 Negative Herbold, 1980a
S. typhimurium, mg/plate, w/o and with
strains TA1535, metabolic activation1
TA100, TA1537,
& TA98
Reverse mutation, Dosage levels up to Negative Hatano Institute,
S. typhimurium, 0.864 mg/plate, w/o 1978
strains TA1535, and with metabolic
TA100, TA1537, activation2
TA1538, & TA98.
E. coli, strain WP2.
Preferential toxicity, Dosage levels up to 0.864 Negative Hatano Institute
B. subtilis, mg (on filter disc)/plate, 1978
strains M45, H17 w/o metabolic activation2
In vivo study
Micronucleus test, 2 oral doses of 1000 or Negative Herbold, 1982
male and female mice 2000 mg/kg, 24h apart3
1 Purity of test material, 84.3%
2 Purity of test material, unknown
3 Purity of test material, 85.7%
No mortalities occurred during the study. Daily examinations
indicated no effects that could be attributed to the test material.
Mean body weights of animals in the 250-ppm group were slightly but
consistently lower than those of the control group throughout the
entire study. Feed consumption was unaffected. Lactate dehydrogenase
and creatinine phosphokinase levels were decreased in all treatment
groups at 7, 21, and 62 days when compared to the control group.
Calcium, magnesium, and inorganic phosphate levels were unaffected.
Total thyroxin was decreased in the 50- and 250-ppm groups at 21
and 62 days. Thyroid weights were decreased in the 250-ppm group at 7
days, but later increased in the 50- and 250-ppm groups at 62 days.
These findings suggest a reduction in thyroid function at 50 and 250
ppm, which initially resulted in lower thyroid weights, but later in
higher thyroid weights, possibly due to increased production of
pituitary thyrotropic hormone.
Gross necropsies were negative. Adrenal and liver weights were
unaffected. Histopathological examinations revealed no effects that
could be attributed to the test material (Krotlinger et al., 1980).
Ten male rats per group from the just-described study were each
tested at 7, 21, and 62 days. In addition, iodine accumulation in the
thyroid was assayed 24 hours after oral intubation of 0.2 µCi of
131I-NaI tracer by measuring radioactivity in excised and weighed
thyroid tissue. Concentrations of triiodothyronine (T3) and of
tetraiodothyronine (T4) in the serum were also determined by use of a
commercially-available 125iodine radioimmunoassay test system.
Mean thyroid weights were increased above control values in the
50-ppm group at 62 days (+25%), and in the 250-ppm group at 21 days
(+22%) and at 62 days (+27%). A decrease in mean thyroid weights was
observed in the 2-ppm group at 7 days (-14%). Mean iodine accumulation
in the thyroid, expressed as the amount of radioactive iodine per mg
of tissue, was decreased below control values in the 50-ppm group at
62 days (-20%) and in the 250-ppm group at 21 days (-32%) and at 62
days (-25%). Mean T3 concentrations were increased above control
values in the 2-ppm group at 7 days (+26%) and in the 10-ppm group at
7 days (+20%). A decrease in mean T3 was observed in the 250-ppm group
at 62 days (-25%). Mean T4 concentrations were decreased below control
values in the 250-ppm group at 7 days (-32%), at 21 days (-42%), and
at 62 days (-16%).
The study results indicate that propineb inhibits thyroid
function at all dosage levels tested. The effect appears to be dose-
related. At 50 ppm and 250 ppm, iodine accumulation in the thyroid was
reduced and at 250 ppm, T3- and T4 serum levels were also reduced. A
compensatory reaction occurred, however, at these dosage levels, as
evidenced by increased thyroid weights and a return toward control
values for several of the other parameters. Compensation was more
complete in animals in the 50-ppm group than in those in the 250-ppm
group. At 2 and 10 ppm, inhibition of thyroid function was indicated
by the increased levels at 7 days of T3, the more biologically-active
form of the thyroid hormone (Weber & Dressier, 1980).
Special studies on carcinogenicity of propylene thiourea
Mouse
Propylene thiourea of 99.3% purity was administered in the diet
to groups of CF1/W74 mice at dosage levels of 0, 1, 10, or 100 ppm for
24 months. An additional group of mice received 1000 ppm in the diet,
which was regularly alternated on a weekly basis with control diet.
The latter group was referred to as the 1000-ppm group. Sixty male and
60 female mice were treated at each dosage level. Mice were 5 to 6
weeks old at the start of the study. The mean starting body weight for
male mice was 22 grams and for female mice it was 23 grams. Powdered
feed and tap water were available ad libitum. At 12 months, 8 to 10
pre-designated mice/sex/group were sacrificed and examined. General
examinations for mortality, appearance, behaviour, and signs of
toxicity were performed daily. Body weights were determined weekly for
13 weeks and tri-weekly thereafter. Feed consumption was monitored
weekly. Clinical laboratory examinations (haematology and clinical
chemistries) were performed on 10 mice/sex/group at 12 and 24 months.
Haematological examinations consisted of erythrocyte count, leucocyte
count, thrombocyte count, reticulocyte count, haemoglogin,
haematocrit, differential blood count, mean corpuscular haemoglobin,
mean cell volume, and mean corpuscular haemoglobin concentration.
Clinical chemistries consisted of alkaline phosphatase (ALP),
glutamate-oxaloacetate transaminase (GOT), glutamate-pyruvate
transaminase (GPT), creatinine, urea, blood sugar, cholesterol,
bilirubin, and total protein. No thyroid function tests (e.g. protein-
bound iodine) were performed. Urinalyses were not performed. Body
temperatures were not determined. Gross necropsies were performed on
nearly all mice in the study regardless of time or manner of death.
Absolute organ weights, determined at the 12-month interim sacrifice,
were for thyroid, heart, lung, liver, spleen, kidneys, and testes.
Thyroid weights were not determined, however, from the animals
sacrificed at 24 months. Organ/body-weight ratios were calculated for
individual animals, but means were not presented. Twenty
organs/tissues plus grossly-observed lesions from nearly all mice in
the study were routinely excised, fixed, and microscopically examined.
Based on mean feed consumption and body weights at 12 months,
daily intakes of test material in mg/kg b.w. were calculated to be
0.16 and 0.21 for 1-ppm male and female mice, respectively, 1.56 and
2.06 for 10-ppm mice, and 17.09 and 21.54 for 100-ppm mice. General
examinations did not indicate any notable differences between test and
control animals. Mean feed consumption of 1000-ppm male mice was
increased compared to control male mice (6.94 g/animal/day vs 6.39)
and of 1000-ppm female mice (7.71 g/animal/day vs 6.22). Mean body
weights for 1000-ppm male mice were consistently about 2 grams lower
than those of control male mice from week 16 to termination of the
study. This decreased mean body weight was attributed to the test
material. No other meaningful mean body-weight differences were
observed for any of the groups. Mortality was equivalent in all test
and control groups for male and female mice, respectively. The numbers
of surviving male mice at 24 months were 14/50, 11/50, 15/50, 11/49,
and 16/50 for the control, 1-, 10-, 100-, and 1000-ppm groups,
respectively. The respective numbers for female mice were 21/50,
25/50, 19/50, 20/51, and 18/50. Haematological examinations did not
reveal any meaningful differences between control and test-group male
or female mice. Occasional statistically-significant differences were
observed, but without consistency. ALP-activity levels in 1000-ppm
male and female mice were increased at 12 and 24 months, suggesting
the possibility of liver damage. ALP levels in other dose groups were
generally similar to control levels. GOT and GPT were not increased
above control levels in any consistent pattern. Cholesterol levels
were increased in 1000-ppm male and female mice at 12 and 24 months,
suggesting the possibility of altered lipid metabolism. Bilirubin,
total protein, urea, creatinine, and glucose levels in test male and
female mice were generally similar to control levels.
Gross necropsies on mice sacrificed at 12 months revealed
clearly-enlarged thyroids in 1000-ppm male mice. For mice dying or
moribund-sacrificed during the study, increased incidences of enlarged
or swollen livers, sometimes with nodes, were observed in 10-, 100-,
and 1000-ppm male and female groups. For mice sacrificed at 24 months,
dose-related increased incidences of enlarged or swollen livers and/or
nodular alterations were observed in all treated male and female
groups. These livers also tended to be partly hardened and brittle.
Absolute thyroid weights were significantly increased in 1000-ppm male
mice (p < 0.01), but not in female mice, at 12 months. Thyroid
weights at 24 months were not determined "in order to avoid artifacts
arising during preparation which might hinder histopathological
appraisal". Absolute liver weights of 1000-ppm male mice were
significantly increased at 12 months (p < 0.01) and at 24 months
(p < 0.05), and of female mice at 24 months (p < 0.01). Absolute
liver weights of 100-ppm male and female mice were also significantly
increased at 24 months (p < 0.01). All thyroid and liver effects
described above were considered to be attributable to the test
material. Absolute kidney weights from female mice were significantly
increased at 24 months at 1000 ppm (p < 0.05), at 100 ppm (< 0.01),
and possibly also at 10 ppm (p < 0.05). Absolute heart, lung, spleen,
and testes weights were comparable from test and control male and
female groups, respectively.
Histopathological examination revealed increased incidences of
thyroid hypercellularity in the high-dose male mice at the interim
12-month sacrifce and at the terminal sacrifice. This effect is most
likely related to the test material. In the spleen, an apparent dose-
related increased incidence of lymphoid hyperplasia was observed in
treated female mice. Percentages were 0, 5, 8, 9, and 10 for the
control, 1-, 10-, 100-, and 1000-ppm female groups, respectively.
Frequently-observed non-neoplastic lesions occurring with
similar incidences in control and all treated groups included focal
hepatitis and focal necrosis in the liver, chronic nephropathy and
hydronephrosis in the kidneys, myocardial degeneration in the heart,
interstitial pneumonitis and congestion in the lungs, "reactive"
tissue in the spleen, gastritis in the stomach, atrophy of the
pancreas, subcapsular cell hyperplasia in the adrenals, tubular
degeneration in the testes, cystic fibrosis in the ovaries, cystic
endometrial hyperplasia in the uterus, osteopathy in the bone, and
vascular canalization of compact bone (in females).
With respect to neoplasia, male and female mice in all treated
groups had higher percentages of animals with any kind of neoplasm,
with multiple tumours, and with malignant neoplasms than did
respective control groups. Dose-response relationships, however, were
not evident.
In the liver, clearly-increased incidences of hepatocellular
tumours were observed in treated male and female groups. For male
mice, percentages of animals with adenomas were 0, 11, 10, 7, and 26,
and of animals with carcinomas were 0, 13, 29, 31, and 21 for the
control, 1-, 10-, 100-, and 1000-ppm groups, respectively. For female
mice, comparable percentages for adenomas were 0, 10, 13, 32, and 18,
and for carcinomas they were 2, 2, 5, 26, and 38, respectively. The
increased incidences of hepatocellular adenomas in male mice at
1000 ppm and in female mice at 100 and 1000 ppm, and of hepatocellular
carcinomas in male mice at 10, 100, and 1000 ppm and in female mice at
100 and 1000 ppm, were considered to be related to administration of
the test material.
In the lungs, pulmonary adenomas were frequently observed in all
control and treated male and female groups. Incidences were similar in
all groups. No relationship to treatment with the test material was
evident. In the thyroid, only 2 adenomas (both in the 1-ppm male
group) and 2 adenocarcinomas (1 in the 100-ppm female group and 1 in
the 1000-ppm female group) were observed.
Other tumours frequently observed at similar frequencies in
control and test mice were malignant lympohoma/leukemia complex (males
and females), adenomas in the adrenals (males), theca granulosa cell
tumours in the ovaries (females), and osteomas in the bone (females).
None of these tumour types were attributed to treatment with the test
material (Bomhard & Loser, 1981).
Rat
Propylene thiourea of approximately 99% purity was incorporated
into the feed and offered ad libitum to Wistar TNO/W74 rats for 24
months at dosage levels of 0, 1, 10, 100, or 1000 ppm. The control
group consisted of 100 rats/sex/group and each of the test groups of
50 rats/sex/group. Additional satellite groups of 25 rats/sex/group
were used for clinical laboratory studies. The rats were 5 to 6 weeks
old at initiation of treatment. The mean body weight of the male rats
was 76 g and of the female rats 78 g. All animals were examined at
least daily for mortality, physical appearance, behaviour, and signs
of toxicity. Body weights were recorded weekly for 26 weeks and
biweekly thereafter. Food consumption was recorded weekly. Clinical
laboratory studies (haematology, clinical chemistries, and urinalyses)
were performed on 5 rats/sex/group at 1, 3, 6, and 12 months and on
10 rats/sex/group at termination of the study at 24 months.
Haematological examinations consisted of erythrocyte count, leucocyte
count, thrombocyte count, reticulocyte count, haemoglogin,
haematocrit, differential blood count, mean corpuscular haemoglobin,
mean corpuscular volume, and thromboplastin time (at termination
only). Clinical chemistries consisted of determinations of ALP, GOT,
GPT, glutamate dehydrogenase (GLDH; at termination only), creatinine,
urea, blood sugar, cholesterol, bilirubin, total protein in
plasma, and protein-bound iodine (PBI). Urinalysis consisted of
semiquantitative determinations of glucose, blood, protein, pH, ketone
bodies, bilirubin, urobilinogen, microscopic examination of sediment,
and a quantitative determination of protein in urine. In addition,
rectal body temperatures were recorded of 20 rats/sex/group at 3, 6,
12, and 24 months. Gross necropsies were performed of nearly all rats
in the study, regardless of time or type of death. Organ weights were
recorded only of rats sacrificed at termination of the study. Organs
weighed were thyroid, heart, lung, liver, spleen, kidneys, adrenals,
testes, and ovaries. Organ/body-weight ratios were not calculated.
Approximately 31 organs/tissues plus macroscopically-identified
lesions from nearly all rats in the study were routinely excised,
fixed, and microscopically examined.
The 1000-ppm dosage level was clearly excessive. From the third
week onward, animals in this group gained little or no body weight and
were cachectic. Feed consumption was substantially below that of
control animals. Most rats had a ruffled hair coat and/or heavy loss
of hair. The skin of some rats was covered with a brownish scale.
Mortalities commenced at 3 months. For male rats, 31/50 died by 6
months and 34/50 by 12 months. For female rats, 38/50 died by 6 months
and 40/50 by 12 months. At 64 weeks, the mean body weight of the
surviving male rats was approximately 150 g and of the surviving
female rats was approximately 100 g. At 65 weeks the last survivors in
this group, 12 male and 3 female rats, were sacrificed. Haematological
examinations on male and female rats in this dose group revealed a
marked and widespread decrease in haematopoiesis, which was
characterized by decreased erythrocyte counts, haemoglobin levels,
haematocrits, reticulocyte counts, thrombocyte counts, and leucocyte
counts (in males only). Differential blood counts revealed a relative
increase in mature polymorphonuclear neutrophils and a relative
decrease in lymphocytes. Clinical chemistries indicated highly-
increased ALP levels in male and female rats, which suggested liver
damage, but GOT, GPT, and GLDH levels were not affected. Urea,
creatinine and cholesterol levels were increased in male and female
rats. Urinalyses revealed decreased protein in the urine of male rats,
although haemoglobin was detected more frequently in the urine of male
than female rats. Body temperatures of male and female rats were
clearly lower than those of control rats, but PBI levels were not
affected. Gross necropsies revealed greatly-enlarged thyroids in some
animals. Histopathological examination of organs/tissues revealed the
following non-neoplastic lesions, which were considered to be
related to treatment with the test material: nodular and generalized
hyperplasia of the thyroid (males and females), calculi and
vacuolation of tubular cells in kidneys (males and females), aplasia
and decreased haemato-poiesis in marrow (particularly in males),
vacuolation of hepatocytes in liver (particularly in males), and
atrophy and reduced spermatogenesis in testes. Nine male rats (of 42
examined) had thyroid adenomas. Two female rats (of 25 examined) also
had thyroid adenomas and 1 additional female rat had a thyroid
cystadenoma. The thyroid adenomas/cystadenoma were considered to have
been induced by the test material. It should be recalled, however,
that the dosage level at which these tumours were observed was above
the maximum tolerated dose.
Calculations based on mean feed consumption and mean body weights
at week 53 indicated the following daily intake of test material for
the remaining animals in the study: 1-ppm dose group, 0.06 and
0.07 mg/kg b.w. for male and female rats, respectively; 10-ppm dose
group, 0.56 and 0.74 mg/kg b.w.; 100-ppm dose group, 5.70 and
7.26 mg/kg b.w. Daily observations of these animals indicated no
differences from the control animals. Mean feed consumption was also
similar in test and control groups. Mean body weights of 100-ppm male
rats were consistently 10 to 20 g lower than those of control male
rats from week 20 to termination of the study. This decrease in mean
body weights of the 100-ppm male group is considered to be related to
ingestion of the test material. Mean body weights of all other test
groups were similar to those of the respective control groups. A
suggestion of slightly increased mortality in the 100-ppm male group
was observed at 18 and 24 months. Mortalities were equivalent in all
other test and control groups. The number of male rats surviving to
termination of the study were 85/100, 41/50, 44/50, and 38/50 for the
control, 1-, 10-, and 100-ppm groups, respectively. The respective
numbers for female rats were 83/100, 40/50, 42/50, and 43/50.
Haematological examinations on the 100-ppm male rats strongly
suggested decreased haematopoiesis at irregular times during the
study. Intermittent decreases in erythrocyte count, haemoglobin level,
haematocrit, thrombocyte count, and leucocyte count were observed. In
contrast to the 1000-ppm animals, however, reticulocyte counts tended
to be increased. In the 10-ppm male group, decreased thrombocyte
count, decreased leucocyte count, and increased reticulocyte count
were observed at termination of the study. For 100-ppm female rats,
decreased haematopoiesis was only suggested by marginal and
intermittent decreases in erythrocyte count, haemoglobin level, and
thrombocyte count, and an increase in reticulocyte count. Differential
blood counts in 100-ppm male and female rats revealed a relative
increase in mature polymorphonuclear neutrophils and a relative
decrease in lymphocytes. A similar shift was also observed in 10-ppm
male rats. Clinical chemistries did not reveal increases in enzyme
levels (ALP, GOT, GPT, or GLDH) indicative of liver damage. Bilirubin
and cholesterol levels were increased, however, in 10-ppm and 100-ppm
male rats and possibly bilirubin levels also in 1-ppm male rats. Other
clinical chemistries were negative. Urinalyses were negative. Body
temperatures were not decreased and PBI levels were not affected.
Gross necropsies performed on 100-ppm male and female rats
revealed enlarged thyroids in numerous rats. Mean absolute thyroid
weights from 100-ppm male and female rats were significantly increased
(p < 0.01). From 100-ppm male rats, the mean thyroid weight was 31 mg
compared to 22 mg from the control male group. In 100-ppm female rats,
the mean thyroid weight was 24 mg compared to 19 mg in the control
female group. Mean absolute adrenal weights were significantly
decreased (p < 0.05) in 100-ppm male rats. For these animals, the
mean adrenal weight was 41 mg compared to 48 mg in the control male
group. Other organ-weight differences were unremarkable.
Histopathological examination of thyroids from male and female
rats revealed lesions and/or effects attributable to the test material
at all dosage levels. At 1 ppm, 10 ppm, and 100 ppm, increased
incidences of "many small follicles" were observed. For male rats,
incidences were 7/95 (7.4%), 9/47 (19.1%), 10/45 (22.2%), and 8/47
(17.0%) for the control, 1-, 10-, and 100-ppm groups, respectively.
Respective incidences for female rats were 1/90 (1.1%), 11/45 (24.4%),
23/49 (46.9%), and 1/46 (2.2%). For 100-ppm male and female rats,
increased incidences of "colloid cysts" (up to 6/46), "large
follicles" (up to 6/46), "tall columnar cells lining the follicles"
(up to 2/47, in males only), "vacuolation of epithelial cells" (up to
4/47), and "nodular hyperplasia" (up to 5/47) were also observed.
"Colloid cysts" (2/47) and "nodular hyperplasia" (3/47) were also
reported in 1-ppm male rats, but not in 10-ppm male rats. "No colloid"
was reported in 1-ppm male rats (2/47), "solid areas" in 1-ppm female
rats (2/45) and "vacuolation of epithelial cells" in 10-ppm female
rats (1/49). All of the thyroid lesions described above occurred at a
higher incidence than in the respective male and female control
groups.
Microscopic lesions observed in adrenals from male and female
rats were also attributed to treatment with the test material at
dosage levels of 10 ppm and 100 ppm. For male rats, "vacuolation of
cortical cells" was noted in 9/94 (9.6%), 4/47 (8.5%), 12/47 (25.5%)
and 8/45 (17.8%) for the control, 1-, 10-, and 100-ppm groups,
respectively. Respective incidences for female rats were 26/88
(29.5%), 8/43 (18.6%), 25/43 (58.1%), and 19/48 (39.6%). "Cortical
cysts" in the adrenals were also reported for female rats at
respective incidences of 33/88 (37.5%), 17/43 (39.5%), 26/43 (60.5%),
and 17/48 (35.4%). In addition, "haemorrhage" was increased in 100-ppm
female rats (10/48) compared to control female rats (9/88). Other non-
neoplastic microscopic lesions possibly related to the test material
were "areas of necrosis" in the liver of 100-ppm female rats (4/50 vs.
3/99 in control female rats), "increased haematopoiesis" in the spleen
of 100-ppm female rats (9/50 vs. 6/95 in control female rats),
"pituitary hyperplasia" in 10-ppm (but not 100-ppm) female rats (5/44
vs. 2/92 in control female rats), "pituitary cysts" in 10-ppm (but not
100-ppm) female rats (4/44 vs. 2/92 in control female rats) and
"testicular atrophy" in 100-ppm male rats (3/50 vs. 2/100 in control
male rats).
Additional non-neoplastic lesions observed at higher incidences
in test animals than in control animals, but probably not related to
the test material, were pneumonia in the lungs (males and females),
leucocyte infiltration in the lungs (females), and submucosal
leucocytosis in the trachea (males and females). Other frequently-
observed lesions that occurred with similar incidences in test and
control rats included emphysema, thickened alveolar walls, and
pneumonitis in the lungs (males and females); bile duct hyperplasia
and hepatocyte vacuolation in the liver (particularly in males);
glomerulonephrosis and fibrosis in the kidneys (males and females);
pituitary cysts (particularly in males); ovarian cysts; cystic
endometrial hyperplasia, pyometra, and cysts in the uterus; and
dilated mucosal glands in the stomach (males and females).
Neoplastic lesions, total numbers of tumours (benign and/or
malignant), and total numbers of animals with tumours (benign and/or
malignant) were not increased in test rats compared to control rats,
with the possible exception of male rats with benign tumours;
incidences were 13/100 (13.0%), 11/49 (22.4%), 3/50 (6.0%), and 11/50
(22.0%) for the control, 1-, 10-, and 100-ppm groups, respectively.
Thyroid adenomas were increased in treated male and female rats. For
male rats, the incidences were 1/95 (1.1%), 2/47 (4.3%), 1/45 (2.2%),
and 0/47 (0.0%) for the control, 1-, 10-, and 100-ppm groups,
respectively. For female rats, the respective incidences were 2/90
(2.2%), 2/45 (4.4%), 2/49 (4.1%), and 2/46 (4.3%). In addition, 2/90
(2.2%) control female rats and 2/46 (4.3%) 100-ppm female rats had
thyroid cystadenomas. In view of the clearly-increased incidence of
thyroid tumours in the 1000-ppm male and female rats, and the
substantially-increased incidences of thyroid lesions in the lower-
dose male and female rats, it is likely that the thyroid tumours in
the lower-dose groups, although not dose-related, may nevertheless be
related to treatment with the test material. Pituitary adenomas were
observed in control and test animals at incidences up to 9/44 (20.5%).
For female rats, the incidences were 12/92 (13.0%), 7/43 (16.3%), 8/44
(18.2%), and 9/44 (20.5%) for the control, 1-, 10-, and 100-ppm
groups, respectively. Interstitial cell tumours of the testes were
observed at incidences of 3/100 (3.0%), 2/48 (4.2%), 1/50 (2.0%), and
4/50 (8.0%) for the respective groups. The possible relationship of
pituitary adenomas in female rats and of testicular tumours in 100-ppm
male rats to the test material is problematical. Pheochromocytomas and
medullary tumours of the adrenal were observed in the control and test
animals at equivalent incidences which did not exceed 2/47 (4.3%) in
any group. Other tumour types occurred at low incidences and were not
related to the test material.
A NOEL was not established in this study. Possibly-increased
bilirubin levels in 1-ppm male rats and non-neoplastic lesions in the
thyroid of male and female rats were observed at the lowest dosage
level tested (1 ppm). In addition, it is likely that thyroid tumours
observed in male and female rats at this dosage level and at 10 ppm
and 100 ppm (females only) may have been related to the test material.
Suggestive increased incidences of pituitary adenomas in female rats
and interstitial cell tumours in the testes of 100-ppm rats were
problematical. In male and female rats at 1000 ppm, which was a
clearly-excessive dosage level, thyroid tumours were definitely
related to the test material (Bomhard & Loser, 1980).
Special studies on mutagenicity of propylene thiourea
Propylene thiourea of 99.5% purity was tested in the mutagenicity
studies listed in Table 2.
Table 2. Mutagenicity assays with propylene thiourea
Study type Dosage level and/or Results Reference
conditions
Bacteria tests
Reverse mutation, Dosage levels up to 12.5 Negative Herbold, 1980b
S. typhimurium, mg/plate, without and with
strains TA1535, metabolic activation (from
TA1537, TA100, & rat liver homogenates)
TA98
Reverse mutation, Dosage levels up to 12.5 Inconclusive Herbold, 1981a
S. typhimurium, mg/plate, without and with
strains TA1535, metabolic activation (from
TA1537, TAlO0, & CFW1 male mouse liver
TA98 homogenates)
Pol A1 test, Dosage levels up to 1 mg Inconclusive Herbold, 1981b
E. coli, strains (on filter disc)/plate,
p3478, W3110 with and without metabolic
activation
Special study on effect of propylene thiourea on thyroid function
Rat
Propylene thiourea of about 99% purity was administered in the
feed for up to 24 months to groups of male and female Wistar rats at
dosage levels of 0, 1, 10, 100, or 1000 ppm. Each group contained 40
male and 40 female rats. At 3, 7, and 14 days, and at 1, 3, 6, 12, and
24 months, 5 rats/sex/group were subjected to thyroid function tests.
Twenty-four hours following oral administration of 2 µCi of 125I-NaI
tracer, the rats were sacrificed. Accumulation of iodine by the
thyroid was determined by measuring radioactivity in excised and
weighed thyroid tissue. PBI was also assayed by measuring
radioactivity in plasma protein precipitated by trichloroacetic acid.
Propylene thiourea inhibited thyroid function in a dose-related
manner. Both sexes were affected to about the same degree. Initial
effects were observed at all dose levels at 3 days, as evidenced by
dose-related decreases in iodine uptake by the thyroid and by
decreased PBI levels. By 7 days, compensatory reactions, presumably
due to increased pituitary production of thyrotropic hormone, were
observed to have started in the 1000-ppm and 100-ppm groups.
In the 1000-ppm group, thyroid weights increased approximately
6-fold over control weights, reaching peak levels at 6 months in the
female rats and at 12 months in the male rats. Iodine uptake by the
thyroid, expressed as the amount of radioactive iodine per mg of
tissue, decreased to about 10% of the control levels at these times.
PBI, after an initial decrease to approximately 20% of the control
levels, later rose to control levels by 1-3 months. Mean body weights
in this group were significantly decreased from 7 days to the end of
the study. In the 100-ppm group, thyroid weights increased 2-3-fold
over control weights, reaching peak levels at 6 months. Iodine
concentration in the thyroid, however, remained similar to control
levels throughout the study. PBI levels that were initially decreased
later increased to 2-3 times control levels at 1 month. At 10 ppm,
initially-reduced iodine uptake and PBI levels recovered to control
levels at 7 days and remained similar to control levels for the
remainder of the study. At 1 ppm, results were ambiguous (Weber &
Patzschke, 1979).
Special study on DNA with propylene thiourea
The potential effects of propylene thiourea on DNA metabolism and
binding in the spleen and liver of CF1 male mice were studied. Only
brief summaries of the procedures and results, as reported by the
author, were available to the Meeting, and are presented here.
Fasted male CF1 mice were treated by gavage with PEG 200
(negative control group), 100 mg/kg propylene thiourea dissolved in
PEG 200 (test group), or i.p. with 100 mg/kg cyclophosphamide
(positive control group). Two hours after dosing with PEG 200,
without and with test material, or 24 hours after dosing with
cyclophosphamide, the mice were sacrificed, their spleens removed, and
cell suspensions prepared. Potential primary damage induced by
propylene thiourea to genetic material in the spleen cells was then
studied by the following methodologies. The results presented below
are directly quoted from the author.
Programmed DNA synthesis (semi-conservative DNA synthesis):
Incorporation of 3H-thymidine into DNA of mouse spleen cells during
the synthesis phase of the cell cycle was measured. Results - "Test
substance group: significantly increased 3H-thymidine incorporation
in the DNA of the cells compared with the controls. Reference
substance group: significant suppression of incorporation by
cyclophosphamide compared with the control."
Suppressed programmed DNA synthesis: Incorporation of
3H-thymidine into DNA of mouse spleen cells pre-treated with
hydroxyurea, which suppresses programmed DNA synthesis by about 90%,
was measured. The measurable radioactivity remaining is due, in part,
to continuous DNA repair. Results - "Test substance group: no
significant difference from the control group. Reference substance
group: no significant difference from the control groups."
Unprogrammed DNA synthesis (DNA excision repair): Incorporation
of 3H-thymidine into DNA of mouse spleen cells previously damaged by
gamma or ultraviolet light irradiation was measured. Pre-treatment of
cells with hydroxyurea permitted differentiation between programmed
DNA synthesis and unprogrammed DNA synthesis. Results - "Test
substance group: no significant difference from the control group.
Reference substance group: significant suppression of unprogrammed DNA
synthesis of the spleen cells compared with the control group."
DNA sedimentation in alkaline saccharose gradient (DNA strand
healing): Irradiated spleen cells pre-labeled with 3H-thymidine in
DNA were lysed and the DNA dissociated into individual strands.
Molecular weights of DNA strands were then determined by linear
gradient centrifugation. Breaks in DNA strands that have been repaired
result in restoration of original molecular weights. Results - "Test
substance group: no difference from the control group. Reference
substance group: clear effect on sedimentation of the spleen cell DNA
in the saccharose gradient."
Nucleoid sedimentation in saccharose gradient (supercoiled DNA):
Untreated and irradiated spleen cells were gently lysed in a manner
which preserved the secondary structure of the double helix and also
the tertiary structure of the superhelix as present in the
chromosomes. The supercoiled nucloids thus obtained, which were
largely separated from muclear protein, were then centrifuged in a
saccharose gradient. Undamaged nucleoids form a sediment faster than
damaged nucleoids, whose DNA contains strand breaks or incisions, thus
producing a loss of supercoils. Nucleoid sedimentation rate was
monitored by a photometer. Results - "Test substance group: no
significant difference from the control group. Reference substance
group: significant shift in sedimentation profile of the nucleoids ...
compared with the control group."
In addition, potential binding of propylene thiourea to liver DNA
was studied by the following methodology: Isolated cleaned liver DNA
from CF1 male mice was incubated with 14C-propylene thiourea.
Binding to DNA was determined by measurement of radioactivity in the
DNA. Results - "Test substance group: no binding of the test substance
(PTU) to the DNA. In relation to the quantity of 14C-PTU used binding
is at a level of only two hundred thousanths of the substance to the
DNA."
Cyclophosphamide, the positive control substance, affected nearly
all the parameters of DNA metabolism in the CF1 mouse spleen cells in
this study. The only effect of propylene thiourea was a significantly-
increased programmed DNA synthesis. Possible explanations offered by
the author for this effect include: (i) possible activation by
propylene thiourea of endogenous nucleases, which may stimulate DNA
synthesis; (ii) possible activation by propylene thiourea of
replicons, which may induce thymidine incorporation into DNA; and
(iii) possible reaction by propylene thiourea with hormone receptors,
which may also lead to increased DNA synthesis (Klein, 1981).
Acute toxicity
Technical-grade propineb of 84-87% purity was tested in the
toxicity studies outlined in table 3.
Short-term studies
Rat
Male and female TNO/W74 rats were exposed to propineb aerosols
at analytically-determined concentrations of 0, 5, 8, 29, or 44 mg/m3
five times per week for 3 weeks. Each exposure was for 6 hours. Ten
rats/sex/group were exposed. Animals were examined daily, and weekly
body weights were determined. After the last exposure, standard
haematological examinations, clinical chemistries, and urinalyses were
performed on 5 rats/sex/group. Gross necropsies were conducted and
organ weights determined for thyroid, heart, lung, liver, spleen,
kidneys, adrenals, testes, and ovaries. Histopathological examinations
of 16 to 26 organs/tissues were performed on 5 rats/sex/group.
Table 3. Acute toxicity of propineb
LD50 LC50
Species Sex Route (mg/kg b.w.) (mg/m3) Reference
Mouse M/F Oral > 5000 Thyssen &
Kimmerle, 1978
Mouse M/F s.c. 1500-2000 Thyssen &
Kimmerle, 1978
Mouse M Inhalation > 391 Thyssen &
(1 × 4 h) Kimmerle, 1978
Rat M/F Oral > 5000 Thyssen &
Kimmerle, 1978
Rat F Oral 5900 Flucke &
Kimmerle, 1977
Rat M/F Dermal > 5000 Thyssen &
Kimmerle, 1978
Rat M/F i.p. 102-141 Thyssen &
Kimmerle, 1978
Rat M/F Inhalation > 522 Thyssen &
(1 × 1 h) Kimmerle, 1978
Rat M/F Inhalation > 693 Thyssen &
(1 × 4 h) Kimmerle, 1978
Rat M/F Inhalation > 193 Thyssen &
(5 × 4 h) Kimmerle, 1978
Hamster M Inhalation > 391 Thyssen &
(1 × 4 h) Kimmerle, 1978
Cat M Oral > 500 Thyssen &
Kimmerle, 1978
Sheep M/F Oral 2500 Hoffman, 1983
Rats exposed to 44 mg/m3 exhibited severely-disturbed behaviour
including, in particular, paralysis of the extremities. All the female
rats and 1 male rat at this exposure level died by the 13th exposure.
Animals that died had sharp losses in body weight and were cachectic.
Gross necropsies revealed small spleens and livers, enlarged adrenals,
and inflamed lungs. Histopathology revealed acute vasculature
congestion in the lungs, liver, kidneys, and bronchial lymph nodes,
indicating that the cause of death was cardiovascular failure. One
male rat at 29 mg/m3 also exhibited hindlimb paralysis but survived
to the end of the study. The remaining test animals did not differ
from control animals with respect to appearance, behaviour or body-
weight gains. Haematological examinations, clinical chemistries, and
urinalyses were negative, as were results of gross necropsies, organ-
weight determinations, and histopathological examinations (Thyssen,
1979).
Rabbit
Technical grade propineb of 87.3% purity was dermally-applied to
the shaven backs of male and female New Zealand White rabbits 5 times
per week for 3 weeks at dosage levels of 0, 50, or 250 mg/kg/day. Each
exposure was for 7 hours. Each dosage group contained 6 male and 6
female rabbits, one-half of which had intact and one-half abraded skin
test sites. The test material was emulsified in Cremophor EL and
distilled water prior to application. Animals were observed daily and
treated skin was scored daily by the Draize system. Weekly body
weights were recorded. Prior to dosing and after the final dose,
standard haematological, clinical chemistry, and urinalysis
determinations were made on all rabbits. Gross necropsies included
organ-weight determinations for heart, lung, liver, spleen, kidneys,
thyroid, adrenals, testes, and ovaries. Histopathological examination
of 11 tissues/organs from control and 250-mg/kg/day animals was
performed. Treated and non-treated skin from all rabbits was also
microscopically examined.
Three male rabbits died during the study of severe pneumonitis.
Daily observations, including skin readings, revealed no effects
attributable to the test material. No differences in body weights
between control and test animals were observed. All clinical
laboratory tests and gross necropsies were negative. With the
exception of slightly-increased absolute and relative liver weights in
the 250-mg/kg/day female rabbits, organ weights in control and test
animals were similar. Histopathological examinations of tissues/
organs were negative (Mihail & Kaliner, 1979).
COMMENTS
A mouse oncogenic study with propineb indicated increased
haepatocellular adenomas in male mice and increased pulmonary adenomas
in female mice at 800 ppm in the diet, the highest dosage level
tested. These increases in tumours may have been related to
administration of the test material. Thyroid tumours were not induced
in treated mice in this study. A NOEL for non-neoplastic effects could
not be determined in this study, however, due to insufficient data.
In a long-term study on mice with PTU, an increased incidence of
hepatocellular adenomas was observed in male mice at 1000 ppm in the
diet, the highest dosage level tested. Increased incidences of
hepatocellular carcinomas were also observed in male mice at 10 ppm
and higher. In the same study, increased incidences of hepatocellular
adenomas and carcinomas were observed in female mice at 100 ppm and
higher. Thyroid tumours attributable to PTU were not observed, but
increased thyroid hypercellularity was noted in male mice at 1000 ppm.
In long-term rat studies with propineb, previously reviewed by
the JMPR, an increased incidence of thyroid benign tumours was
observed at 1000 ppm and higher in the diet. Non-neoplastic thyroid
effects were observed in the same study at 100 ppm and higher. In
another study, increased liver and kidney weights were observed at
100 ppm and higher. A NOEL of 10 ppm was determined. In a long-term
study on rats with PTU, thyroid tumours were not related to treatment
with PTU except at 1000 ppm in the diet, which was a clearly-excessive
dosage level. Goitrogenic effects in the thyroid were observed,
however, at dosage levels as low as 1 ppm, the lowest dosage level
tested. A NOEL could not be determined in this study.
Short-term studies on thyroid function in rats with propineb did
not establish an unequivocal NOEL for effects on the thyroid. In a
long-term study on thyroid function in rats with PTU, effects on the
thyroid were observed at 1000 ppm in the diet. Ambiguous effects were
observed at lower dosage levels. Pharmacokinetic studies on rats with
PTU demonstrated preferential uptake of radioactivity from
14C-labeled PTU by the thyroid.
Mutagenic studies on propineb and PTU were negative or
inconclusive. A special study on the effect of PTU on DNA demonstrated
increased DNA synthesis in mouse spleen cells. PTU did not bind to the
DNA of mouse liver cells.
TOXICOLOGICAL EVALUATION
In view of the carcinogenic response in the liver of mice to PTU
and the lack of a NOEL for thyroid effects of propineb in a long-term
study in mice, in short-term studies in rats, and for PTU in a long-
term study in rats, the Meeting recommended that the temporary ADI for
propineb be withdrawn.
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See Also:
Toxicological Abbreviations
Propineb (Pesticide residues in food: 1977 evaluations)
Propineb (Pesticide residues in food: 1984 evaluations)
Propineb (Pesticide residues in food: 1993 evaluations Part II Toxicology)