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Note from FAN:
R48/22 = Harmful: danger of serious damage to health by prolonged
exposure if swallowed
The following was presented
as a word document at
http://ecb.jrc.it/classlab/15503a4_NL_clodinafop-propargyl%20.doc
Classification of clodinafop-propargyl with
R48/22
The Netherlands, May 2005
Rat oral studies
28-day study (Basler, 1988)
Limit dose = 150 mg/kg bw
100% mortality was found in males at 200 mg/kg bw within 7 to
10 days. In these males microscopic
effects were found such as hypocellularity
of the bone marrow, moderate atrophy of splenic white pulp, moderate
atrophy of the thymus. In the females at 200 mg/kg bw and
the males at 40 mg/kg bw effects included haematology, clinical
chemistry and the liver. As shown by the applicant in 155/04 add.3,
the haematological effects were limited and do not warrant classification.
The liver effects are probably secondary to the peroxisome proliferation.
The effects to the male rats at 200 mg/kg would be sufficient
for classification because it is likely that the mortality in
all rats within 7 to 10 days would also be found in some rats
at 150 mg/kg during 28 days.
90-day study (Fankhauser, 1989b)
Limit dose = 50 mg/kg bw
No severe effects were found up to the highest dose tested of
1000 ppm (70/71 mg/kg bw). Reductions in RBC, Hb and Hct were
limited (155/04 ad. 3) and do not warrant classification. Reduction
in monocytes and globulin. Effects on the liver were limited and
probably secondary to the peroxisome proliferation. Effects on
other organs included thymus atrophy and reduced weight (absolute
and relative). The effects seen at or around the limit dose do
not warrant classification.
24-month combined oral toxicity and carcinogenicity (Fankhouser,
1992a)
Limit dose = 6.3 mg/kg bw
Severe effects were found at 300 and 750 ppm (10/11 mg/kg bw and
26/30 mg/kg bw). Effects were seen on haematology (reductions
of RBC, Hb and Hct of ±93% but no secondary effects of
haemolytic anaemia and no change in reticulocytes), liver and
some other organs. Also a reduction in globulin level was found.
The liver effects were severe but probably secondary to
the peroxisome proliferation. The haematological effects were
not severe enough for classification. The other effects were also
not severe enough at or around the limit dose.
Conclusion on rat studies
The effects seen in the 28-day study would warrant classification
but not the effects seen in the 90-day and 24-month study. According
to Annex VI, the longest study should be used. Therefore, the
effects seen in the rat do not warrant classification.
Mice studies
90-day study (Fankhouser, 1989a)
Limit dose = 50 mg/kg bw
Severe effects were found at the highest dose of 400 ppm (53 mg/kg
bw in males and 71 mg/kg bw in females). The
effects were mainly to the liver and probably secondary
to the peroxisome proliferation. As peroxisome
proliferation is not relevant to humans, the secondary
effects in the liver are probably also not relevant.
18-month combined oral toxicity and carcinogenicity (Fankhouser,
1992b)
Limit dose = 8.3 mg/kg bw
Effects to the liver were found at 100 and
250 ppm (11/13 mg/kg bw and 30/33 mg/kg bw). Again, the
liver effects are probably secondary to the peroxisome proliferation.
A dose related increase in thymus atrophy
was found in the males which was also increased at levels without
a reduction in bodyweight gain or reduced food consumption.
Conclusion on mice studies
The effects seen in the longest study with mice do not warrant
classification with R48/22 because the effects were probably secondary
to the peroxisome proliferation. Other effects were not severe
enough for classification.
Dog studies
13-week (Allen et al., 1989)
limit dose = under discussion but at least
50 mg/kg bw
Only limited effects on haematology and clinical chemistry including
reductions in globulin level were found at levels up to 200 ppm
(7.5 mg/kg bw) but were not sufficient for classification. Effects
in the range-finding included immunosuppression. The high
dose in this study consisted of 0.037 mg/kg bw day 1 to 54, 33
mg/kg bw day 55 and 56 and 17 mg/kg bw day 57 to the end. No effects
were seen during the first period. Marked
effects were seen within 2 days at 33 mg/kg bw.
At 17 mg/kg bw also severe effects were found including mortality
in 1⁄4 males with anaemia and several inflammations.
No effect on food consumption was seen in this group according
to the monograph but was seen according to 155/04 ad.3. A temporary
reduction in body weight was seen after 10 or 11 weeks. Other
effects included skin effects, anaemia,
clinical chemistry including changes in globulins and atrophy
of the zygomatic glands and thymus. The reduction in haemoglobin
was limited to 83% and without additional effects of haemolytic
anaemia. The effects seen at 17 mg/kg bw
are severe and would warrant classification.
1 year (Corney et al., 1990)
limit dose = under discussion but at least 12.5 mg/kg bw
No effects were seen up to 3 mg/kg bw. At 16.7 mg/kg bw, a non-significant
reduction in body weight gain was found in both sexes and a non-significant
reduction in food consumption in females. Clinical effects were
seen in both sexes and included skin lesions,
ocular discharge and reddening of sclera, haematological effects
included anaemia which was below 80% at week 13 in females
but above 80% in males and at week 26 and 52 in females. An
increase in reticulocytes indicated an adaptive response of the
bone marrow. Also an increase in
methaemoglobin was found. A combination of methaemoglobin
plus anaemia can result in less than 80% effective haemoglobin.
A whole range of changes in clinical chemistry was seen mainly
in females and included changes in globulin levels. Reductions
in several lipids maybe due to the lipid-reducing activity
comparable to fibrates according to Ind (155/04 add.3). Further,
several changes in organ weights were found including decreases
in several lymph nodes weight. Microscopic increases in
pigment deposition were found in the lymph nodes. Also inflammation
in skin and urinary bladder was found. The effects in two out
of four females were so severe that these animals received food
without clodinafop-propargyl for some periods up to 23% of the
treatment period. Overall, severe effects
requiring a temporary stop of exposure were found especially in
the females with reduction in effective haemoglobin levels sometimes
below 80%, increases in inflammation and fat reduction at 17 mg/kg
bw. This level is just above the minimal limit dose of
12.5 mg/kg bw. Therefore, this study warrants classification with
R48/22.
Conclusion
The studies in dogs show a clear effects at the dose level close
to the minimal limit dose in the longest study including anaemia
with combined reductions in haemoglobin and increased formation
of methaemoglobin sometimes below 80%, increases in inflammations
with indications of immunosuppression confirmed by clearer effects
of immunosuppression at somewhat higher dose levels in the 90
day study and in the range finding and fat reduction. According
to the applicant some of the effects on the thymus in the 90 day
study might be caused by stress due to significant reduction in
food consumption and body weight loss. However, effects on body
weight were only seen during week 10 or 11 of the 13 week study.
Further effects on the thymus were also seen in mice at levels
without an effect on food consumption or growth and in rats. In
dog studies with other substances, no comparable effects (immunosuppression
plus increases in inflammation) were found at levels with reductions
in food consumptions and reduced body weight gain. Only an increase
in thymus atrophy was sometimes but not always found with reductions
in food consumption and decreased body weight gain. Therefore,
the effects seen in the dog studies are considered substance specific
and warrant classification with R48/22 independent whether a dose
limit of 12.5 or 60 mg/kg is used.
Overall conclusion:
Clodinafop-propargyl induces anaemia
in all tested species, peroxisome proliferation in rodents and
increases in inflammation with indications of immunosuppression
and fat reduction in dogs. The dose levels at which severe
effects were seen in rats and mice in the longest studies do not
warrant classification.
However, severe effects were seen
in dogs at a dose level requiring classification with R48/22.
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