2016 Volume 41 Issue 3 Pages 113-119
Hokko Chemical Industry Co., Ltd. found a novel triazolinone class herbicide regarded as 1-aryl-4-carbamoyl-1,2,4-triazolinone derivatives that shows high level of safety to paddy rice, and high activity and long residual activity against Echinochloa spp. and other weeds. We selected a new paddy rice herbicide ipfencarbazone as the optimum compound. Ipfencarbazone is a pre-emergence and early post-emergence rice herbicide that controls annual grass weeds, annual sedge weeds and some annual broadleaf weeds at a rate of 250 g a.i./ha. It inhibits the biosynthesis of fatty acids in plants (VLCFA). Two formulations containing ipfencarbazone, Winner® and Fighter®, have been registered in Japan since 2013 and various combinations have been launched.
Our target of research was to achieve excellent control on Echinochloa spp., one of the problematic weeds in paddy fields, achieve high level of safety to paddy rice, flexible applicability, and also, easy and labor saving methods by transplanting with tractor mounted machinery applicator during rice transplanting in paddy field. We conducted optimization of the chemical structure, taking into consideration the following points.
We searched and synthesized heterocycles and found new 1-aryl-4-carbamoyl-1,2,4-triazolinone derivatives that showed high activity against Echinochloa spp. and various paddy weeds, we selected a new paddy rice herbicide ipfencarbazone as the optimum compound which belongs to the triazolinone class herbicide. It shows an excellent efficacy on grass weeds, annual sedges and some annual broadleaf weeds. Ipfencarbazone especially demonstrates excellent efficacy on barnyard grass with a wide application window and long residual activity, and is highly safe even at application during transplanting in paddy fields. This paper describes the history of the discovery, synthesis, mode of action, herbicidal performance and safety of ipfencarbazone.
The study on triazolinone class herbicide began in 1990’s, when the market of one-shot herbicides (a combination of sulfonylurea-based herbicide and grass killer) had been expanding in Japan. However, glass killer of one-shot herbicides has various issues such as follows.
In order to solve above issues, our research effort was to focus on developing a new herbicide with its own characteristic structure. Process of the discovery of triazolinone herbicide is shown in Fig. 1.
We took notice of the carbamoyl-sulphonyl-triazole derivatives (2) represented by cafenstrole (1) having excellent herbicidal activity against Echinochloa spp. in early exploratory research of a new herbicide and changed mainly substituent at the sulphonyl group.1) Some compounds exhibited herbicidal activity against Echinochloa spp., but no suitable compound meeting our purpose was found.
Therefore, we researched widely carbamoyl-substituted heterocyclic derivatives (3). Among them, 4-(substituted thio)-isoxazolinone derivatives (4)2) exhibited herbicidal activity against Echinochloa spp., but was not safe enough to paddy rice. Therefore, we researched new isoxazolinone derivatives while focusing on carbamoyl-substituted isoxazolinone structure and found 4-aryl-isoxazolinone derivatives (5) exhibiting high activity against Echinochloa spp. and high level of safety to paddy rice.3) However, the representative compounds did not exhibit sufficient activity against 2.5 leaf stage of Echinochloa spp. under field conditions and no compound having practical herbicidal activity was founded from (5).
Next, we intensively investigated derivatives (6), which changed the isoxazolinone ring as the parent nucleus of 4-aryl-isoxazolinone derivatives (5) to other heterocycles and found new 1-aryl-4-carbamoyl-1,2,4-triazolinone derivatives (7) exhibiting high activity against Echinochloa spp. and various paddy weeds.4,5)
1.2. Optimization of triazolinone derivatives and selection of ipfencarbazoneFor the purpose of improving activity against Echinochloa spp. and safety to paddy rice, we investigated various substituents on the benzene ring (Xn) and the carbamoyl moiety (R1 and R2) of 1-aryl-4-carbamoyl-1,2,4-triazolinone derivatives (7) for the optimaization of its performance. Derivatives (7) were synthesized according to the synthetic schemes of Fig. 2.6,7)
The Structure activity relationship of triazolinone derivatives (7) is shown in Tables 1–4. Their herbicidal activity against Echinochloa spp. at pre-emergence and 1.5 leaf stage, and rice injury after 1 day after transplanting are also described.
 | ||||
|---|---|---|---|---|
| Compound substituents | Efficacy on ECHOR (80 g a.i./ha) | Rice injury (300 g a.i./ha) | ||
| R1 | R2 | Pre-emergence | Early-Post emergence | 1 DAA |
| C2H5 | C2H5 | 1 | 0 | 0 |
| C2H5 | cyc.-Hex | 2 | 2 | 0 |
| n-C3H7 | Ph | 3 | 2 | 0 |
| i-C3H7 | Ph | 4 | 3 | 0 |
| H2C=CH5 | Ph | 3 | 2 | 0 |
| HC≡CCH2 | Ph | 3 | 1 | 0 |
Growth stage on application: pre-emergence and 1.5 leaves stage of ECHOR. DAA: Days after application, ECHOR: Echinochloa oryzicola, Rice: transplnted 2.2leaves stage of rice, Index: Herbicidal activity (% of control), 5: 100–90%, 4: 89–79%, 3: 69–50%, 2: 49–30%, 1: 29–10%, 0: less than 10%.
 | |||
|---|---|---|---|
| Compound substituents | Efficacy on ECHOR (80 g a.i./ha) | Rice injury (300 g a.i./ha) | |
| Ym | Pre-emergence | Early-Post emergence | 1 DAA |
| H | 4 | 3 | 0 |
| 4-Cl | 4 | 3 | 0 |
| 2-F | 3 | 2 | 0 |
| 4-F | 5 | 3 | 0 |
| 2,4-F2 | 5 | 5 | 0 |
| 4-CH3 | 2 | 1 | 0 |
| 4-CF3 | 3 | 1 | 0 |
| 4-CH3O | 0 | 0 | 0 |
| |||
|---|---|---|---|
| Compound substituents | Efficacy on ECHOR (20 g a.i./ha) | Rice injury (300 g a.i./ha) | |
| Xn | Pre-emergence | Early-Post emergence | 1 DAA |
| H | 5 | 4 | 2 |
| 2-Cl | 5 | 5 | 1 |
| 3-Cl | 4 | 3 | 0 |
| 4-Cl | 5 | 4 | 0 |
| 2,4-Cl2 | 5 | 5 | 0 |
| 2-CH3 | 5 | 5 | 1 |
| 2-CF3 | 5 | 4 | 0 |
| 2-CH3O | 4 | 4 | 0 |
| |||
|---|---|---|---|
| Compound substituents | Efficacy on ECHOR (80 g a.i./ha) | Rice injury (300 g a.i./ha) | |
| R | Pre-emergence | Early-Post emergence | 1 DAA |
| H | 5 | 5 | 0 |
| CH3 | 2 | 1 | 0 |
| Cl | 0 | 0 | 0 |
| CF3 | 0 | 0 | 0 |
| CH3O | 0 | 0 | 0 |
Change of substituents at the carbamoyl moiety is shown in Table 1 and Table 2. The compounds introduced with N,N-diethylcarbamoyl and N-cyclohexyl-N-ethylcarbamoyl did not exhibit high activity against Echinochloa spp. The compounds introduced with phenyl group into the carbamoyl moiety exhibited high activity against Echinochloa spp. at pre-emergence, and the compound introduced with N-isopropyl-N-phenylcarbamoyl exhibited highly activity also against Echinochloa spp. at 1.5 leaf stage. Next, we changed the substituents of the benzene ring attached to the isopropylated carbamoyl moiety. Activity against Echinochloa spp. was remarkably increased by introducing fluorine atom, especially two fluorine atoms on the 2- and the 4-positions of the benzene ring. On the other hand, activity against Echinochloa spp. was decreased by introducing methyl group, trifluoromethyl group and methoxy group.
Next, we optimized substituents on the benzene ring at the 1-position of triazolinone ring (Table 3). Introducing chlorine atom increased either activity against Echinochloa spp. or safety to paddy rice. Notably 2,4-dichloro-phenyl derivative exhibited the maximum activity against Echinochloa spp. at pre-emergence and 1.5 leaf stage, and did not exhibit rice injury. In addition, introductions of methyl group, trifluoromethyl group and methoxy group on the 2-position of the benzene ring exhibited high activity against Echinochloa spp. and it is suggested that the substituent on the 2-position of the benzene ring plays an important part.
Moreover, we studied the substituent effect on the 3-position of the triazolinone ring (Table 4). Methyl-substituted compound exhibited weak activity against Echinochloa spp., but with the introduction of chlorine atom, trifluoromethyl group and methoxy group did not exhibit activity against Echinochloa spp.
As a result of detailed investigations of herbicidal characteristics of 1-aryl-4-carbamoyl-1,2,4-triazolinone derivatives (7), we selected ipfencarbazone (8) exhibiting high and long residual activity against 2.5 leaf stage of Echinochloa spp. and high level of safety to paddy rice as the optimum compound.8)
Ipfencarbazone showed excellent efficacy on annual weeds such as Echinochloa oryzicola, Echinochloa crus-gall, Echinochloa spp., Cyperus difformis, Lindernia procumbens, Monochoria vaginalis and some perennial weeds such as Scirpus juncoides, Cyperus serotinus, when applied at pre-emergence or early-post emergence stage of weeds9) (Table 5). It is highly active against Echinochloa spp. from pre-emergence to the 2.5 leaf stage at a rate of 250 g a.i./ha. It especially showed excellent efficacy on Echinochloa spp. at pre-emergence and low concentration (Fig. 4).10)
| Application timings | Dose (g a.i./ha) | Herbicidal activity | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Annual weeds | Perennial weeds | ||||||||
| ECHOR | MOOVA | LIDPY | CYPDI | SCPJO | CYPSE | SAGPY | SAGTR | ||
| Pre-emergence | 250 | 100 | 100 | 98 | 100 | 100 | 100 | 10 | 0 |
| 125 | 100 | 100 | 95 | 98 | 100 | 100 | 0 | 0 | |
| Early-Post emergence | 250 | 100 | 90 | 90 | 90 | 100 | 70 | 0 | 0 |
| 125 | 100 | 80 | 80 | 75 | 85 | 50 | 0 | 0 | |
Rating scale: 0 (no effect )–100 (completely effective).ECHOR: Echinochloa oryzicola, MOOVA: Monochoria vaginalis, LIDPY: Lindernia procumbens, CYPDI: Cyperus difformis, SCPJO: Scirpus juncoides var. ohwianus, CYPSE: Cyperus serotinus, SAGPY: Sagittaria pygmaea, SAGTR: Sagittaria trifolia.* Growth stage on application: pre-emergence and 2.5 leaves stage of ECHOR. Early-Post emergence of other weeds are 2 leaves or 2 pair stage application.
Residual activity of ipfencarbazone against Echinochloa spp. was observed about 70 days after application with a midseason drainage between 33 to 45 days after treatment in the paddy field (Fig. 5).11)
Ipfencarbazone is safe to use with transplanted paddy rice, at a rate of 250 g a.i./ha even under various conditions such as water leaching, shallow planting and different soil types (Fig. 6).9,12–14) In field trials in Japan, Ipfencarbazone was observed to be safe for paddy rice under 0 days after transplanting operation, and it did not cause any practical damage to transplanted rice even when application timing occurred before 0 days prior to transplanting (Fig. 7).11)
Ipfencarbazone applied to the flooded paddy field stayed within the upper 0 to 2 cm of soil surface regardless of the soil type (sandy loam, clay loam, light clay, or heavy clay), due to strong soil adsorption and low water solubility (Tables 6, 7).9,10)
| Soil texture | pH | Organic carbon content (%) | % of distribution of ipfencarbazone in soil | ||
|---|---|---|---|---|---|
| Soil layer from soil surface | |||||
| 0–2 cm | 2–5 cm | 5–10 cm | |||
| Light clay | 6.4 | 3.3 | 91 | 6 | 3 |
Application rate: 250 g a.i./ha.Soil sampling date: 69 days after application.Ipfencarbazone was extracted by acetone.
| Soil texture | pH | organic carbon content (%) | % ECHOR* control | ||
|---|---|---|---|---|---|
| Soil layer from soil surface | |||||
| 0–1 cm | 1–2 cm | 2–3 cm | |||
| Sandy loam | 5.7 | 2.7 | 96 | 7 | 1 |
| Clay loam | 5.7 | 7.2 | 100 | 1 | 0 |
| Light clay | 6.4 | 3.3 | 100 | 5 | 0 |
| Heavy clay | 6.0 | 6.1 | 100 | 1 | 0 |
* ECHOR: Echinochloa oryzicola.Application rate: 250 g a.i./ha.Soil partitioning method, Leaching paddy water from pot: 2 cm/day, for 3 days.Assesment: Measurement of plant length at 20 days after seeding.
Ipfencarbazone showed strong efficacy against Echinochloa spp. by inhibiting cell division and cell growth, and its symptoms on Echinochloa spp. includes reduction of growth inhibition of plant height and number of tillers, greening, twisting and unfurling leaf. These inhibitions result in the kill of the weeds (Fig. 8). As ipfencarbazone is applied to Echinochloa spp. at post-emergence in flooded paddies, it is mainly taken up by roots or basal part of shoot. We investigated the mode of action of ipfencarbazone by using an elongation assay with 14C-labelled stearoyl-CoA and malonyl-CoA. Ipfencarbazone decreased the content of fatty acids with more than 20 carbon atoms in plants (Fig. 9).15,16) However the inhibitory mechanism of ipfencarbazone on the elongation of VLCFAs is still unclear, so we will continue the study of the mode of action.
The acute toxicological studies using rats and mice indicated that ipfencarbazone has very low toxicity. It showed very slight eye irritation and slight skin sensitization. As proven via different testing systems, neither a mutagenic nor teratogenic potential was found. Furthermore, there were no adverse effects in chronic, oncogenic and reproduction studies on ipfencarbazone.
Based on ecological studies, ipfencarbazone exhibited very low toxicities to fish, bird and beneficial insects. A growth inhibition activity was observed for the alga, however, we considered that it is not adverse to the environment when the herbicide is used under normal conditions (Table 8).
| Study | Animal | Results |
|---|---|---|
| Acute oral | Rat | LD50: >2000 mg/kg (M, F) |
| Mouse | LD50: >2000 mg/kg (F) | |
| Rat | LD50: >2000 mg/kga) (F) | |
| Acute dermal | Rat | LD50: >2000 mg/kg (M, F) |
| Rat | LD50: >2000 mg/kga) (M, F) | |
| Acute inhalation | Rat | LC50: >5.9 mg/L (M, F) |
| Eye irritation | Rabbit | Very slightly |
| Rabbit | Very slightlya) | |
| Skin irritation | Rabbit | Non-irritant |
| Rabbit | Non-irritanta) | |
| Skin sensitization | Guinea pig | Slightly |
| Guinea pig | Negativea) | |
| Teratogenicity | Rat, Rabbit | Negative |
| Mutagenicity | in vitro, in vivo | Negative |
a) 2.5% Granule.
14C-Labeled ipfencarbazone was almost metabolized and excreted in rats by 168 hr after oral administration. In rice plants, the translocated radioactivity in the edible parts was very low. Ipfencarbazone was metabolized through cleavage of the carbamoyl moiety, hydroxylation, and conjugated in both animal and plant tissues. In soil and irradiated water, through cleavage of the carbamoyl moiety and further decomposition, it was finally mineralized into carbon dioxide. In the residue studies in rice plants, ipfencarbazon was not detected in grains nor straws. The half-life of ipfencarbazone under paddy field conditions was 8.5–34.4 days.17,18)
A novel triazolinone class herbicide, ipfencarbazone was selected for development as a herbicide for paddy field on the basis of efficacy, selectivity to rice plants, safety, and it demonstrated the applicability as a paddy herbicide. Ipfencarbazone has a high level of safety for paddy field rice at transplanting. Also, it has a wide application window and long residual activity against Echinochloa spp. We offer new weed control options such as application flexibility and excellent crop safety, which enable rice growers to save time and labor in rice cultivation by ipfencarbazone. Currently, some rice herbicide mixtures of ipfencarbazone have been registered, such as Winner®, Kachiboshi®, Kimarite®, Goemon®, Aulic® and Gangsane®.19,20) These products have been used to control paddy weeds in the domestic and Korean countries.
This work is supported by Japan Association for Advancement of Phyto-regulators, National Agriculture and Food Research Organization, multiple prefectural agricultural experiment station, The Institute of Environmental Toxicology, University of Tsukuba, Saitama University and Tokyo Institute of Technology. The authors are thankful for the help of everyone in our company.
