Clodinafop-propargyl
CAS No. 105512-06-9
Classification of clodinafop-propargyl with R48/22
The Netherlands, May 2005
 
 

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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

ECBI/155/04 Add. 4

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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