Historical Development of Pesticides in Japan1
Hiroki Ota■ Abstract
This paper aims to provide an overview of the history and development of pesticides in Japan, following a study
by the author on the role of pesticides, their impact on society and the establishment and development of the pesticideindustry in Japan.
Pesticides in Japan can be traced back to 1600. A document from this era, entitled Family Traditions on the
Killing of Insects, records that noxious insects can be exterminated using a mixture of five types of ingredients.
Researchers have also discovered that in 1670, whale oil was poured onto fields as a method of exterminating
leafhoppers. These examples indicate the beginning of pest control in Japan. Up until the mid-19th century, theseprimitive types of pest control were the only methods used in Japan; they were accompanied by mushi-oi – prayers toward off insects.
An industry eventually started to develop in the late 19th century, when various products began to be introduced
from overseas, such as lime sulphur, Bordeaux mixture and other copper agents as well as pyrethrum insect powder,nicotine and other natural products. Arsenic compounds and chlorpicrin became industrialised in the early 20th century;by the 1930s, a good foundation had been laid for the pesticide industry. However, the outbreak of war interrupted theprogress of technology in Japan.
Research and development continued in the West on new synthetic pesticides, even in wartime. While Japan
lagged behind in its technological developments, it was not long after the introduction of DDT, BHC, parathion andother synthetic pesticides that it started producing similar products domestically. By the 1950s, an industry had
developed, with synthetic pesticides not only being produced by dedicated pesticide manufacturers, but also by
specialised chemical companies. Agricultural production improved greatly as a result of the superior performance of
these synthetic pesticides. In the late 19th century, paddy rice typically yielded around 250 kg per 10 ares; by the 1960s,
this figure had increased to more than 400 kg. The current figure is more than 500 kg.
By the 1960s, Japanese companies were already competent enough to develop their own new pesticides. MAS,the first domestically-produced fungicide, hit the markets in 1959, followed by MAF, an improved version, two years
later and then MEP, an insecticide. Other major pesticides also emerged, such as cartap, an insecticide, blasticidin, anantibiotic, IBP, benthiocarb, a herbicide, and giberellin, a plant growth regulator. However, a number of social problems
arose during this time, as parathion and other chemicals were highly toxic to mammals, organomercury compounds
were highly residual and other chemicals such as PCP were highly toxic to fish.
By the 1970s, Japan’s period of rapid economic growth had come to an end and the country was experiencing atime of stable growth. While the pesticide industry also continued to grow during this time, it underwent dramaticchanges. The Agricultural Chemicals Regulation Act was amended in 1971, adding “protecting human health andconservation of living environment” as considerations to ensure “safety of use”. Long-term toxicity testing andenvironmental impact evaluation became required practice for registering pesticides. Testing methods became stricter
with the introduction of good laboratory practice (GLP) for pesticides. These changes meant that thesocially-problematic pesticides of the past were phased out and replaced. Japanese companies continued to develop
new chemicals, resulting in the emergence of insecticides fenvalerate, buprofezin and hexythiazox, fungicides
thiofanate-methyl, isoprothiolane and probenazole, and herbicides pyrazolate, sethoxydim and fluazifop-butyl. Whilethe next two decades saw a major paradigm shift in the pesticide industry, it grew to the point where it was turning overmore than ¥400 billion in a year.
The following is an overview of events from the 1990s to the present day. With the bubble bursting in 1991, theJapanese economy went into a long recession, which continues to this day. This also had a major impact on thepesticide industry, which has had a steady decrease in sales since turning over ¥440 billion in 1996. By 2011, this figure
had dropped by around 20% to ¥350 billion. Major overseas players repeatedly ended up in mergers and acquisitions
due to the rising cost of research and development and the decreasing success rate. Japan lagged a little behind in thisHiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

1trend as well, but by the early 21st century, Japanese companies were consolidating as well. However, even during thistime and since, Japanese companies have continued to work on new chemicals. One of the key points of note of thistime has been the emergence of ultra-high-performance pesticides. One typical example is the insecticide imidacloprid,a ground-breaking chemical modelled on nicotine, a natural product. Japanese companies also invented a number ofcompounds similar to the sulfonylurea herbicide produced by Du Pont, which is effective with an ultra-low dosage ofseveral grams to several tens of grams per hectare.
Japanese companies have thus continued to create new chemicals with a number of advantages. This reportdiscusses the relevant course of events, the reasons why relatively small-scale Japanese companies have achieved such
results, and the future of the industry.
Japanese agriculture will never fail while it is surrounded by high-income consumers who make their purchases
assured of freshness and high quality. Pesticides are a huge part of this. The hope is that Japanese companies willcontinue to produce new, world-class chemicals.
This study focuses on synthetic pesticides rather than biopesticides, which have been the subject of recent
attention.

Profile Hiroki Ota

Contents

Chief Survey Officer, Center of the History of Japanese Industrial
Technology, National Museum of Nature and Science

1. Introduction

3

2. Overview of Pesticides

5

3. The History of Pesticides

19

4. New Pesticides Invented in Japan67

5. Discussion and Future Prospects

98

6. Afterword and Acknowledgements

103

Pesticide Technology Flow Diagram

105

1969 Graduated from The University of Tokyo Faculty ofAgriculture, Department of Agricultural Chemistry (Organic
Chemistry)
1971 Completed Master’s degree at The University of Tokyo
Graduate School of Agriculture (Organic Chemistry)
Joined the product research centre at Mitsubishi Chemical
Industries Co., Ltd.
1980 PhD in agriculture at The University of Tokyo
Research Associate at University of California, Riverside,
Department of Chemistry1982 Mitsubishi Chemical Industries Co., Ltd., Yokohama
Research Center; Agricultural Research Laboratory
1989 Agrochemicals and Animal Health Department
1996 Mitsubishi Chemical Industries Co., Ltd., director of
Agricultural Research Laboratory
1999 Technology Development Office
2001 Director; Science and Technology Office
2003 President, Center for Analytical Chemistry and Science Inc.
2004 Executive Vice-President, Mitsubishi Chemical Group
Science and Technology Research Center2007 Advisor, Mitsubishi Chemical Medience Corporation2009 Retired as Advisor
2012 Chief Survey Officer, Center of the History of JapaneseIndustrial Technology, National Museum of Nature andScience2

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List of Candidates for Registration as
Pesticide Industry Technology

108

1. Introduction
Ever since the dawn of agriculture in Japan during the
Jōmon period, people have had to battle with crop pests.
Agriculture is the act of artificially cultivating large
amounts of a single crop to harvest a large volume of
produce – it is an act that is contrary to nature, so to
speak. In response, nature tries to restore the original
ecosystem by sending in pests that feed on the produce.
In 1732, one million people died of starvation in the
Kyōhō Famine, caused by cold-weather damage and an
outbreak of leafhoppers in western Japan.
This study discusses the history and significance of thedevelopment of agricultural chemicals or pesticides, amajor weapon in the war between agriculture and thepests sent by nature. Many pesticides have now beendeveloped that are far more safe and effective than they
were in the past, with no danger of environmental
pollution. The quality of produce has improved, so thatgeneral consumers no longer have to see worm-eaten
fruits and vegetables. The pesticides used in Japan havebeen the result of the hard work and discovery by ourforefathers before the war, during the turbulent times
after the war and in the age of restoration that followed.
However, a number of social problems arose in the past
because some of the early chemicals developed werehighly toxic to mammals, others were highly residualon crops and soil, while yet others were highly toxic tofish.
In 1947, during the turbulent times following the war,
Professor Sankichi Takei (1896-1982) of the Kyoto
Imperial University Department of Agricultural
Chemistry contributed an article on the future oforganic pesticides to the first number issue of thejournal Pesticides, published by the newly-established
Agricultural Chemicals Association, later the Japan
Plant Protection Association. While the main pesticides
used in Japan at the time were natural products such as
pyrethrum insect powder, derris and nicotine, thisarticle made the following comparison with synthetic
insecticide DDT, which had just been introduced.
“While the best DDT is far better than natural
insecticides pyrethrum insect powder and derris inmany ways, it has the following shortcomings. Natural
products are unstable compounds; after they havewaged war on the insects, they quickly break down
again. They do not residually remain on plants and soil
and so have no long-term side effects; such is thewonder of nature. This vital property is lacking ininorganic compounds such as arsenicals; evenoutstanding synthetic chemicals such as DDT fall far
short of natural products in this regard. At present, wehave to say that ‘nature is far wiser and smarter atchemosynthesis than humans.’ [abridged] It is not just a
dream to say that in the future we could have asynthetic insecticide that is better than pyrethrum or
rotenone in that regard.”
Large quantities of highly-residual pesticides, such as
DDT, BHC and organomercury compounds, were used
to boost food supplies after the war. This opinion
expressed by Takei demonstrated a keen insight into thedarker side of pesticide practices, namely, poisoning,crop contamination and environmental pollution.
Subsequent technological developments were carriedout in light of this consideration. The aim of thisresearch and development was to achieve what Takei
insisted was “not just a dream” – replacing thesepesticides with the gentler, non-residual pesticides wehave today.
What is worthy of note here is that around half of thelatest, high-performance pesticides used in Japan today
were developed by Japanese companies. They are used
as important and key pesticides not only in Japan, but
overseas as well. This study not only traces the historyof the Japanese pesticide industry, but also outlines
Japan’s experience in developing new, world-classchemicals. This study also examines the reasons why
Japan has done so well and achieved so many successstories in pesticide development. Finally, this study
attempts to illustrate the future of the industry.
This report is structured as follows. Chapter 2 provides
an overview of pesticides, including definitions, names,
classifications, production status, improvement toagricultural production, laws and regulations,development processes and contributing technology.
Chapter 3 outlines the history of pesticides from the17th century onwards, referring where possible to thesocial conditions and agricultural environment at thetime.
Chapter 4 lists 20 new pesticides from Japan,
attempting, where possible, to explain their history ofdevelopment and the impact they had. While there are
numerous other Japanese pesticides, the author has had
to select a limited number due to space constraints.
Chapter 5 presents a discussion and considers the future
prospects of the industry, including looking at how
pesticides are perceived in society and the current
awareness of the agricultural environment, as well as
examining the strength and future of the ties between

Hiroki OHTA; Historical Development of Pesticides in Japan
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3the pesticide industry and agriculture.
A technology flow diagram is provided to show an
outline of the pesticide industry, to be referred to where
necessary.
Due to the nature of the technology, the author cannot
avoid using technical terms and chemical structural
formulas in this report. While it is the intention of theauthor to make explanations as plain as possible, thereader is invited to skim-read any parts that are difficult
to understand. Conversely, readers with specialist
knowledge of pesticide science may find the technicalexplanations not detailed enough. These readers areinvited to refer to the reference literature cited where
possible.
With respect to names of companies, the author has
made every effort to use the contemporary name of thecompany at the time the invention was made. However,companies often change due to mergers andacquisitions and the like, so it has not always beenpossible to maintain consistency. The author asks forunderstanding on this point.
The following reference works are cited throughout.
Cited References(1) Uchida, Matazaemon. Jizoku Kanō na Nōgyō to
Nihon no Shōrai [Sustainable Agriculture and the
Future of Japan], The Chemical Daily, 1992.
(2) Hori, Masaakira. Nihon Shin Nōyaku Monogatari

4

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan[The Story of New Japanese Pesticides], Japan Plant
Protection Association, 1973.
(3) Matsunaka, Shōichi. Nihon ni okeru Nōyaku no
Rekishi [The History of Pesticide in Japan], Gakkai
Shuppan Center, 2002.
(4) Kimura, Shigemitsu. Nihon Nōgyō-shi [History ofJapanese Agriculture], Yoshikawa Kobunkan, 2010.
(5) Sasaki, Mitsuru et al. Nihon no Nōyaku Kaihatsu[Japanese Pesticide Development], Pesticide Science
Society of Japan, 2003.
(6) Hamada, Kenji. Nōgyō Shizai Sangyō no Tenkai[The Expansion of the Agricultural Materials Industry]
Vol. 7, pp. 189-218, 2004.
(7) Nōyaku Gaisetsu [Pesticide Overview], Japan Plant
Protection Association, 2011.
(8) Yamamoto, Ryō. Nōyaku-gaku [The Study ofPesticides], Nankodo, 1961.
(9) Umetsu, Noriharu. Nōyaku to Shoku: Anzen to
Anshin [Pesticides and Food: Safety and Security], Soft
Science, 2003.
(10) Nōyaku no Ayumi [The History of Pesticides],Ministry of Agriculture, Forestry and Fisheries Plant
Protection Division (ed.), Executive Committee for the
Plant Protection Project Development 10th Anniversary
Convention, 1960.
(11) Nōyaku Yōran: 2011 [Pesticide Handbook: 2011],
Japan Plant Protection Association, 2011.
(12) Kuwano, Eiichi. Nōyaku no Kagaku: Seibutsu
Seigyo to Shokubutsu Hogo [The Science of Pesticides:
Biological Control and Plant Protection], Asakura,2004.

2. Overview of Pesticides
This chapter discusses the definitions, names,
classifications and role of pesticides, as well as relevantlaws and regulations, development process andcontributing technology. Many general consumers takethe view that while pesticides may be necessary, theyshould be avoided if possible. These consumers areconcerned about the effects of residual pesticide in food.
However, let us objectively examine what the pesticides
used today are like, what role they play and what
processes they go through to become commercial
products.
If we look back through history, the “bright” side ofpesticides in service to humanity is undeniable:
increases in food production, improved quality,
economizing of labor and so on. Conversely, the “dark”
side of pesticides was magnified a decade or so after the
war when, once a stable food supply was secured,concerns arose over ensuring the safety of farmers, foodsafety for general consumers and environmental
problems. In some instances, pesticides actually caused
problems, such as poisoning from parathion; in otherinstances, such as cases of residual mercury in rice,problems were averted before any harm could be done.
Let us examine the current situation. Lessons have beenlearned from the past; modern pesticides are backed by
the latest science and technology. While pesticides are
chemical treatments that have the potential to do both
harm and good, the food that people eat is a chemical
substance in itself. People actually place themselves atconsiderable risk from food poisoning or from toxic
chemicals already found in food (poisonous
mushrooms, blowfish poison and countless others).
Provided pesticides are used appropriately, the risk ofresidual pesticide in food is negligible compared to therisk of food poisoning or the risks from chemical
substances naturally occurring in food. The results oflarge-scale investigations into residual pesticides infood show that this is a negligible issue in terms of boththe frequency of residual pesticide detection and theamounts detected.
Since pesticides are artificially manufactured chemicals,
people seem to have focused on the “dark” images
from the past. Mass media reports also seem to befocused on this “dark” side, with hardly any coveragegiven to the “bright” side.

2.1. Pesticide Definition
Pesticides, or agricultural chemicals, are defined asfollows in Article 1 of the Agricultural Chemicals
Regulation Act, enacted in 1948. While this is a rather
old law, it covers all of the agricultural chemicals
presently used.

(Purpose)
Article 1:
The purpose of this Act is to improve the quality ofagricultural chemicals and to ensure their safe andproper use by introducing an agricultural chemicalregistration system to regulate their sale and use, thus
contributing to the conservation of our living
environment as well as the protection of human healthand stable agricultural production.
(Definition)
Article 1-2:
[1.] For the purpose of this law, the term “Agriculturalchemicals” shall mean fungicides, insecticides, andother substances used to control fungi, nematodes,
mites, insects, and rodents or other plants and animals,
or viruses (hereinafter generically called “diseases andinsect pests”) that may damage crops (including trees
and agricultural and forestry products, and hereinafter
called “Crops, etc.”), and also refers to othersubstances (including those, specified by government
ordinances, that are used as raw materials or materials
to control the diseases and insect pests) and agents
such as growth accelerators and germination
suppressors, etc. used to promote or suppress thephysiological functions of crops, etc.
2. Under this Act, natural enemies used as a means of
the biological pest control referred to in the previous
Paragraph shall also be regarded as “agriculturalchemicals.”
3. For the purpose of this law, “Manufacturers” shallmean those who manufacture or process agriculturalchemicals, “Importers” shall mean those who import
agricultural chemicals, and “Dealers” shall mean
those who sell agricultural chemicals (including
presenting them other than selling them. The same
applies hereinafter).
4. For the purpose of this law, “persistency” shall mean
the characteristics of any agricultural chemical(including the characteristics produced by chemicalchanges of the substance involved) that resides incrops etc. or soil due to the use of the agriculturalchemical.
We can sum up this definition by saying that“agricultural chemicals”, or pesticides, are “fungicides,
insecticides and other substances used to control fungi,
nematodes, mites, insects and rodents or other plants
and animals, or viruses that may damage crops, etc., aswell as other substances and agents such as growth
accelerators and germination suppressors, etc. used topromote or suppress the physiological functions ofcrops, etc.”

Hiroki OHTA; Historical Development of Pesticides in Japan
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5Pesticides also include rodenticides, natural enemies,
insect attractants such as pheromones, repellents,
biopesticides such as effective microorganisms tocombat plant pathogens and spreaders used to boost theeffects of any active ingredients.
“Crops, etc.” is a general term for plants cultivated byhumans and can include rice plants, vegetables, fruit
trees, mushrooms, bamboo shoots and so on. It also
includes golf courses, park lawns and roadside trees.
“Fungi” includes any filamentous fungi harmful tocrops etc., such as molds, as well as any bacterial
pathogenic microbes.
“Diseases and insect pests” include fungi, nematodes,
mites, insects, rodents and viruses, as well as birds,
slugs and crayfish that may damage crops, etc. While
this definition makes no specific mention of “herbicides”
that control weeds that cause major damage to crops,
etc., weeds are included in “other plants and animals”
and herbicides are included in “other substances andagents”.
As shown above, anything that is defined as an“agricultural chemical” in the Agricultural Chemicals
Regulation Act is treated as a pesticide and subject toregulation. However, remedies for insects that are
sanitary hazards (fleas, mosquitos, cockroaches, etc.)
are not covered by the Agricultural Chemicals
Regulation Act even if they contain the same active
ingredients as pesticides; they are subject to thePharmaceutical Affairs Act and other regulations.
Agents used to preserve crops after they have been
harvested (post-harvest agents) are treated as foodadditives and are subject to the Food Sanitation Act.
There are maximum residue limits in place for theseagents. Some fumigants used to preserve grain aretreated as pesticides.

2.2. Names of Pesticides
Pesticides sold on the market must be sold in labelledcontainers. These labels usually include informationsuch as the common name of the product, the chemical
name, the brand name and the category. The example
below is taken from a label for thiophanate-methyl.
This study primarily uses common names that clearly
identify the active ingredient.
This study also uses code number “test names” when
discussing stages of development.
Common name: thiophanate-methyl (name of theactive ingredient determined by the pesticide division of
the International Organisation for Standardization ISO)
Chemical name: dimethyl [1,2-phenylenebis(iminocarbonothioyl)] bis [carbamate] (CAS) or
dimethyl 4,4’-(O-phenylene) bis (3-thioallophanate)(IUPAC)
Brand name: Topsin-M, Top Grass
Category: thiophanate-methyl wettable powder (whenregistering pesticides in Japan, the common name of
the active ingredient is usually given, along with the6

Survey Reports on the Systemization of Technologies; No. 18, March 2013
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type of agent)
Test name: NF-44
There are many types of pesticides and various ways toclassify them. This chapter discusses classification byuse, classification by type of active ingredient,classification by formulation and classification by
toxicity.

2.3. Pesticide Classification
2.3.1. Classification by Use
Table 2.1 shows a classification of pesticides by theiruse.
Table 2.1. Classification of Pesticides by Use
TypeUse
Insecticides
Controlling pest insects that damage
crops
Miticides
Controlling mites that damage crops
Nematicides
Controlling nematodes that damage
crop roots and tissue
Fungicides
Controlling diseases that damage
crops
Insecticide
Controlling pest insects and crop
fungicides
diseases at the same time
Herbicides
Controlling weeds
Rodenticides Controlling rodents that damage crops
Plant growth Promoting/suppressing crop growth
regulators
Attractants
Mainly for attracting pest insects
through scent or other means
Repellents
Using particular scents or tastes
disliked by birds or wild animals
SpreadersAdded to make the agent adhere more
readily to the pest insect or crop
NaturalNatural enemies of pest insects thatenemiesdamage crops
Microbial
Using microbes to control diseases
agentsand pest insects that damage crops
Partially modified from Nōyaku Q & A [Pesticide Q & A], revised
edition, Japan Crop Protection Association (ed.), 2011, p. 36.

2.3.2. Classification by Type of Active Ingredient
The majority of pesticides used today are chemical
pesticides with active ingredients (the chemical content
of the pesticide), while the remainder are biopesticides
or other types. Tables 2.2, 2.3 and 2.4 classify pesticides
according to the chemical composition of their active
ingredients or by their mode of action. It is very
important to know the chemical class of each pesticide,because if pesticides from the same chemical class orwith the same mode of action are used in succession,
this may sometimes reduce the effectiveness of theagent.

Table 2.2. Classification of Pesticides by Active Ingredients (Insecticides, Miticides)
Classification
Acts on the
nervoussystemTypical Pesticides

Organophosphates

alanycarb, oxamyl, carbosulfan, thiodicarb, benfuracarb, methomyl, BPMC,

Carbamates

NAC

Synthetic pyrethroids
Nereistoxins

Chemical Pesticides

Macrolides

Neonicotinoids

etofenprox, cyhalothrin, cyfluthrin, cypermethrin, silafluofen, bifenthrin,
pyrethrin, fenvalerate, fenpropathrin, flucythrinate, fluvalinate, permethrin
cartap, thiocyclam, bensultap
acetamiprid, imidacloprid, clothianidin, dinotefuran, thiacloprid,thiamethoxam, nitenpyram

Avermectins

emamectin benzoate

Milbemycins

milbemectin

Spinosyns

spinosads

Phenylpyrazoles

fipronil, ethiprole

Sodium channel blockers

indoxacarb, metaflumizone

Other

pymetrozine, flonicamid

Intracellular

Electron transport inhibitors I

tebufenpyrad, pyridaben, fenpyroximate, tolfenpyrad

respiration

Electron transport inhibitors II

cyflumetofen

inhibitor

Electron transport inhibitors III

acequinocyl, fluacrypyrim

Uncouplers

chlorfenapyr

InsectgrowthChitin synthesis inhibitors

regulator

Metabolic moulting hormone(IGR)

inhibitors
Juvenile hormone active
substance

chlorfluazuron, diflubenzuron, teflubenzuron, flufenoxuron, lufenuron,
hexythiazox, etoxazole
buprofezin
pyriproxyfen

Other

cyromazine

MetabolicTetronic acidspirodiclofen, spiromesifen

inhibitor

Dihalopropenes

pyridalyl

Diamidesflubendiamide chlorantraniliprole

Acts on thesarcoplasmic reticulum(Other)Insecticides/Miticides

acephate, dimethoate, diazinon, malathion, DDVP, DMTP, MEP, MPP

Blocks spiracles

starch, reduced-starch saccharified product, machine oil, sodium oleate

Biopesticides

Pasteuria penetrans, Bacillus thuringiensis (BT), Monacrosporium
Microbes

phymatopagum, Paecilomyces tenuipes, Beauveria brongniartii, Beauveria
bassiana
Steinernema carpocapsae, Phytoseiulus persimilis, Amblyseius cucumeris,

Natural enemies of

Aphidoletes aphidimyza, Orius sauteri, Orius strigicollis Poppius, Encarsia

insects, mites and nematodes

formosa Gahan, Diglyphus isaea, Aphidius colemani, Dacnusa sibirica,

Neochrysocharis formosa
Nōyaku Q & A [Pesticide Q & A], revised edition, Japan Crop Protection Association (ed.), 2011, p. 37.

Hiroki OHTA; Historical Development of Pesticides in Japan
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7

Table 2.3. Classification of Pesticides by Active Ingredients (Fungicides)
Classification

Typical Pesticides

Multi-site

Inorganic compounds

Bordeaux mixture, lime sulphur (copper, sulphur)contact activity

Dithiocarbamatesthiram, ziram, polycarbamate, manzeb, maneb, propineb

Other

chlorothalonil (TPN), captan, folpet, fluoromide, dithianon, iminoctadine

Phenylamides

metalaxyl

Carboxylic acids, otheroxolinic acid, hydroxy-isoxazole

Benzimidazoles

benomyl, thiofanate-methyl

Other

diethofencarb, pencycuron

Nucleic acidsynthesis
MitosisRespiration

Acid amides (complex II
inhibitors)
QoI (complex III inhibitors)

mepronil, flutolanil, furametpyr, thifluzamide, boscalid
azoxystrobin, kresoxim methyl, metominostrobin, trifloxystrobin,
orysastrobin, pyraclostrobin, famoxadone

QiI (complex III inhibitors)

cyazofamid, amisulbrom

Otherfluazinam, ferimzone

Anilinopyrimidines

mepanipyrim, cyprodinil

Phenylpyrroles

fludioxonil

Dicarboximides

iprodione, procymidone

Organophosphates

EDDP, IBP

Carboxylic acid amides

dimethomorph, benthiavalicarb isopropyl, mandipropamid

Other

isoprothiolane, tolclofos-methyl, propamocarb

Sterol biosynthesis inhibitors

oxpoconazole, pefurazoate, prochloraz, triflumizole, triforine, fenarimol,

Chemical Pesticides

Fungicides

Amino acidsynthesis andproteinsynthesis
Signaltransduction
Lipid and cell
membranesynthesis
Cell membranesterol synthesis

bitertanol, cyproconazole, difenoconazole, fenbuconazole, hexaconazole,
imibenconazole, ipconazole, metconazole, myclobutanil, propiconazole,
simeconazole, tebuconazole, tetraconazole, triadimefon, fenhexamid

Cell membranemelaninsynthesis
Unclear

MBI-R

tricyclazole, pyroquilon, fthalide

MBI-D

carpropamid, diclocymet, fenoxanil

Other

cymoxanil, fosetyl, flusulfamide, diclomezine, cyflufenamid

Plant resistance inducers

probenazole, thiazinyl

Soil fungicides

dazomet, chlorpicrin

Antibacterial agents
Biopesticides

kasugamycin, validamycin, polyoxin
Bacillus subtilis, Agrobacterium radiobacter, non-pathogenic Erwinia
carotovora, Trichoderma atroviride, Talaromyces flavus
Nōyaku Q & A [Pesticide Q & A], revised edition, Japan Crop Protection Association (ed.), 2011, p. 37.

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Table 2.4. Classification of Pesticides by Active Ingredients (Herbicides)
Classification

Typical Pesticides

Inorganic compounds
Synthetic organic pesticides

chlorate, cyanate
Synthetic auxins

2,4-PA, MCPB ethyl, dicamba, triclopyr, quinmerac

ACCase inhibitors

sethoxydim, fluazifop-butyl
imazosulfuron, thifensulfuron methyl, nicosulfuron,pyrazosulfuron-ethyl, bensulfuron methyl, imazapyr,

ALS inhibitors

flumetsulam, penoxsulam, bispyribac-sodium,
pyriminobac-methyl, flucarbazone-sodium
atrazine, simetryn, linuron, DCMU, bromacil,

Photosynthesis inhibitors

phenmedipham, bentazone, ioxynil
oxadiazon, pentoxazone, oxyfluorfen, pyraflufen

PPO inhibitors

ethyl, flumioxazin, fluthiacet-methyl,

Herbicides

carfentrazone-ethyl, pyraclonil
Carotenoid synthesis inhibitors

norflurazon, diflufenican, clomazone

4-HPPD inhibitors

pyrazolate, benzofenap, mesotrione, isoxaflutole

Cell division inhibitors

trifluralin, pendimethalin, dithiopyr
alachlor, butachlor, pretilachlor, propachlor,

Very long chain fatty acid biosynthesis inhibitors

dimethenamid, mefenacet, cafenstrole, indanofan,
anilofos, fentrazamide

Fatty acid synthesis inhibitors

benthiocarb, molinate, EPTC, benfuresate

Cellulose synthesis inhibitors

dichlobenil, flupoxam, isoxaben

EPSP synthase inhibitors

glyphosate

Glutamine synthetase inhibitors

glufosinate, bialaphos

Bipyridiniums

paraquat, diquat

Other
Biopesticides

dymuron, oxaziclomefone, etobenzamid,
cinmethylin, bromobutide, MSMA
Xanthomonas campestris

Nōyaku Q & A [Pesticide Q & A], revised edition, Japan Crop Protection Association (ed.), 2011, p. 39.

2.3.3. Classification by Formulation
The active ingredients in pesticides are not usually usedon their own, but rather processed into products that areeasier to use, safer to store and maximize theireffectiveness. Pesticides are designed and producedwith various adjuvants in them, taking into
consideration the physical and chemical properties of
the active ingredients as well as their application andmanner of use. Let us outline some typicalformulations.
(1) Dust
The pesticide in its primary form (the manufactured
active ingredient) is dispersed into a mineral carriersuch as clay, processed into a dust (45μm or less) andusually applied on fields in this form. To prevent it
scattering, the quantity of particles less than 10μm is
reduced to make it driftless (DL), the currently popular
dusts having particles with an average size of at least
20μm. Flowdust (FD) is an ultra-fine dust with anaverage particle size of 5μm or less. This is alabor-saving product for horticultural use, such as ingreenhouses, and is effective at small doses(300-500g/10a).
(2) Granules
Loose grains of 1.7mm or less are generally called
granules. These are usually dispensed on fields in thisform by hand or with a dispensing machine. There arethree types of granules, categorized by grain size: fine
Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

9

A labor-saving product has been developed for ricecultivation and has reduced the required volume of
product used from 3kg/10a to 1kg/10a. This producthas been increasingly popular in recent years.
(3) Wettable Powders
Technical grade active ingredient is mixed or absorbed
into a mineral carrier such as clay with a grain size ofaround 5μm, together with a dispersant, a wetting agent
and other substances. This product is sprayed on fields
as a dilute suspension in water.
Wettable powders also come in granular dry flowable(DF) and water-dispersible granule (WG, WDG) forms
to prevent scattering of the powder when it is being
diluted.
Liquid formulations are also used, such as watersuspensions (flowable or suspension concentrates (SC)or suspoemulsions (SE)).
(4) Emulsion concentrates
These are clear liquids made by adding organic solventsand emulsifiers to the technical grade active ingredient.
This product is dispensed, having been diluted andemulsified in water. Recently, emulsions of oil in water(EW) and clear/translucent micro emulsions (ME) offine emulsion particles have also been developed.
(5) OtherMicrocapsules for rice seedling boxes have also beendeveloped to provide long-term residual effects.
Water-soluble packs of around 50g provide jumbo
formulation for direct use on paddy fields. There arealso bean-sized granules that can be scattered onto thewater in the rice field; these reduce the amount needing
to be applied to 250-500g/10a, less than the traditional
1kg dosages.
2.3.4. Classification by Toxicity(1) Classification by Acute Toxicity
The Poisonous and Deleterious Substances Control Act
designates pesticides with active ingredients that arehighly toxic to animals (mice, rats) as poisons ordeleterious substances and regulates the handling,
manufacture and sale of them. Other less toxic
pesticides are classified as ordinary substances (ageneral term for anything that is not a hazardous
substance). Highly toxic poisons with a significant riskof injury are designated as “specific poisonous
substances”.
Some formulations may be less toxic even if theiractive ingredient has been designated as a deleterious

10

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan

substance. In many cases, reducing the amount of theactive ingredient reduces the toxicity of the product.
These formulations may be treated as ordinary
substances if they are certified as “exemptions from thedeleterious substance designation”.
Table 2.5 shows the evaluation criteria for toxicity.
Table 2.5. Criteria for Poisonous and Deleterious
Substances
Toxicity Test

Determination

Oral Toxicity (LD５０）

Dermal Toxicity (LD５）

０

Gas (LC50)
Inhalation Toxicity

granules (710μm or less), microgranules (300μm orless) and fine microgranules (210μm or less).

Vapor (LC50)

Dust / Mist（LC50)

Poison50mg/kg or less

Deleterious

Over 50mg/kg but less thansubstance

300mg/kg

Poison200mg/kg or less

Deleterious

Over 200mg/kg but less thansubstance

1,000mg/kg

Poison500ppm (4hr) or less

Deleterious

Over 500ppm (4hr) but lesssubstance

than 2,500ppm (4hr)

Poison2.0mg/l(4hr) or less

Deleterious

Over 2.0mg/l (4hr) but less thansubstance

10mg/l (4hr)

Poison0.5mg/l（4hr) or less

Deleterious

Over 0.5mgl/L (4hr) but lesssubstance
than 1.0mg/l (4hr)
LD50: the dose required to kill 50% of the members of a tested population.
Shown as milligrams of substance per kilogram of test subject body mass.
LC50: the dose required to kill 50% of the members of a tested population
through inhalation. Shown as parts per milligram (ppm) or milligrams of
substance per kilogram of test subject body mass.
Tabulated from the Internal Regulations of the Pharmaceutical Affairs andFood Sanitation Council, Ministry of Health, Labour and Welfare (March
2007).

(2) Classification by Fish Toxicity
Pesticides are classified as follows according to theirdegree of impact on fish and shellfish when used nearwater systems such as rivers. All pesticides except thosein Category A must display a fish and shellfish warninglabel. These evaluations used 50% lethal concentrations
LC50 for carp and daphnia.
Category A:
Category B:
Category Bs:
Category C:

Carp LC50 (48hr)>10ppm
Daphnia LC50 (3hr)>0.5ppm
Carp LC50 (48hr)≤10ppm - >0.5ppm
Daphnia LC50 (3hr) ≤0.5ppm
Any in Category B needing special
attention
Carp LC50 (48hr)≤0.5ppm

2.4. Status of the Pesticide Industry
and Productivity Improvement
2.4.1. Status of the Pesticide Industry
A simple summary of the market situation and businessactivities will provide a better understanding of thepesticide industry. Pesticides hold a dominant positionin the fine chemicals industry, with domestic salesamounting to ¥300 billion per year. This equates toaround 9% of the world market. Japan is the thirdlargest market after the United States and Brazil.
As synthetic pesticides developed in the years after thewar, the scope of business for pesticides expanded
significantly, both in Japan and across the world. A
study by Wood Mackenzie showed rapid growth in theworld pesticide market, from $850 million in 1960 to$11.6 billion in 1980 and then to $26.4 billion in 1990
(1)
. While it plateaued in 1995 due to low produce prices
and increased cultivation of genetically modified crops,
it began to grow again in the 2000s, reaching $38
billion in 2008 (2).
The Japanese market initially showed roughly the same
rapid growth as the world market, peaking in 1994 at¥445 billion. However, a prolonged economic
downturn and a set-aside for rice cultivation and othercrops meant that by 2011 the market had dropped by
20% to ¥355 billion. For changes in the value ofdomestic pesticide shipments, please refer to Section
3.4.4. (1) and an accompanying graph. The rising valueof the yen during this period meant almost no change inthe value of overseas sales when converted into dollars.
Let us examine the main business activities in thepesticide industry. For more details, please refer to the
Shibuya Index = II (3), published in 2009. In summary,the current oligopoly in the worldwide pesticideindustry is the result of repeated, relentless mergers andacquisitions. This is particularly evident overseas.
With the advent of the 1980s, developing new
pesticides meant having to clear tests on their biologicaleffects, their safety in large quantities and their impact
on the environment. This caused a dramatic decline in
the success rate of new products and markedly
increased development costs. This is very similar to thedifficulties arising in recent years in developing new
pharmaceutical products. While medicines are only
given to patients with a prescription from a doctor,
general consumers eat produce treated with pesticide
whether they like it or not (and may be exposed to thepesticide if there are any residual traces). Since
pesticides contend with nature through agriculture, theymust also undergo environmental impact testing.
Despite these differences, pesticides and medicine aresimilar in terms of the difficulties faced in developing
them. Many companies opted for mergers andacquisitions as a way to beat this difficulty and survive.
This trend started overseas. Currently, there are threecompanies in the United States that deal with pesticides
from the research and development stage right throughto manufacture and sale: Dow, DuPont and Monsanto.
In Europe, the three main companies are Swisscompany Syngenta and German companies BASF andBayer. While there are other specialized pesticidecompanies, they are mainly involved in selling generic,
off-patent products. In terms of sales volume, these six
surviving companies are all corporate giants worth wellover ¥200 billion each, with Syngenta taking the lead at¥800 billion. These companies can invest
proportionately large sums into research anddevelopment and are engaged in fierce competition
over invention and development.
Let us examine the situation in Japan. While many
chemicals companies engaged in pesticide research anddevelopment from the 1980s onwards with theintention of breaking into the fine chemicals market,
they had difficulty staying in business amid theeconomic downturn and declining success rate inpesticide development. Since 2000, there has been atrend to sell off pesticide operations in the name of“selection and concentration”. In 2002, Takeda
Pharmaceutical sold its pesticide operations to
Sumitomo Chemical, despite having been along-standing player in the pesticide industry. Also in
2002, Mitsubishi Chemical sold its pesticide operations
to Nihon Nohyaku. In 2004, Dainippon Ink &Chemicals sold its pesticide operations to Nippon Soda.
In 2009, Sankyo sold its pesticide operations to Mitsui
Chemicals.
While Japanese companies have followed the merger
and acquisition trends of the major overseas companies,
they are still nowhere near the same size in terms ofscale. The largest, Sumitomo Chemical, is worth ¥130
billion, followed by Ishihara Sangyo, Kumiai Chemical,
Mitsui Chemicals Agro, Nippon Soda and Nissan
Chemical, each worth around ¥40 billion. Nevertheless,Japanese manufacturers have continued to produce new
pesticide products to rival the major overseas players
and have produced many of the best products currently
available. How is it that they have been able to competewith the major players who have invested far moreheavily into research and development? This isdiscussed in Chapter 6: “Discussion and Future
Prospects”.
Cited References(1) Takayama. Shin Nōyaku no Kaihatsu Tenbō [Prospects
for the Development of New Pesticides], Ikura,
Katsuyata (supervising editor), CMC, 1997, p. 243.
(2) Takayama. Shin Nōyaku Kaihatsu no Saizensen [TheForefront of New Pesticide Development], Yamamoto,
Izuru (supervising editor), CMC, 2003, p. 322.
(3) Shibuya. Shibuya Index – II : 2009, Shibuya,
Shigeyoshi, 2009.
2.4.2. The Role of Pesticides
Synthetic organic pesticides appeared in Japan after thewar. Highly effective at controlling pest insects andweeds, they rapidly improved agricultural productivity
Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

11and acted as a kind of trump card to beat the food crisis.
However, in those days, little consideration was given
to toxicity to mammals, residual toxicity or
environmental impact. Problems arose with lasting
residues of organic mercury on produce and in soil,
DDT, BHC and highly acutely toxic pesticides such asparathion, as well as problems with highly ichthyotoxic
pesticides such as PCP.
This prompted several law changes and the problematic
pesticides all disappeared, replaced by highly effective
yet highly safe pesticides. Currently, farmers and theirproduce are guaranteed to be safe as long as thepesticides are used appropriately (on the right crops in
the right quantity at the right time, etc.) as specified by
the law.
Let us examine the role played by modern pesticides interms of yield size, produce quality and economy oflabor.
(1) Yield Size
The Japan Plant Protection Association has worked
with agricultural experiment stations in various regions
to compare the yield loss and profit loss rates between
areas in which traditional agriculture is practiced andareas in which pesticide-free agriculture is practiced.(1)In principle, no pesticides at all were used in thepesticide-free areas, although, a minimal amount wasused where the experiment was not working. The
results are shown in Fig. 2.6.

Fig. 2.6. Yield Loss and Sales Profit Loss due to Pests
etc. where Pesticides are not used in Cultivation (1)The results show that rice suffered an average yield lossof 27.5%, while the loss in monetary profit was evenhigher at 34%. For rice, anything more than a 10%
yield loss is classed as “very bad” on the Crop Situation
Index, equivalent to a major disaster. While somesavings can be made by not using pesticides, theseresults show that the loss of income from such a yield
loss would cost farmers far more dearly. The results
also show yield losses of almost 100% in apples andpeaches.
Accordingly, this report concludes that, under the12

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan

current circumstances, agricultural production would be
difficult without the use of pesticides.
(2) Produce Quality
Not using pesticides results in a drop in produce quality.
One example is the damage caused to rice by the stinkbug. Rice that has been sucked on by stink bugs
appears speckled, reducing it to a lower grade produce
and significantly lowering its commercial value. From
this perspective, stink bugs are a major pest.
Plants are known to spontaneously produce
phytoalexins when attacked by external enemies (pest
insects, etc.). In some cases, a plant attacked by apathogen produces an antibacterial substance, which
can trigger effects such as food allergies.
When plants are attacked by a mold, the mold can also
produce a mycotoxin. One example of this is
Deoxynivalenol (DON), produced by fusarium scab inwheat. The Ministry of Health, Labour and Welfare
established residue limits for DON in wheat andpromoted the eradication of fusarium scab. Mold canalso produce aflatoxin B1, a mycotoxin, in grains,
peanuts, corn and other crops. Aflatoxin is known to behighly carcinogenic and the Food Sanitation Act
stipulates that no food product may contain any
Aflatoxin.(2)(3) Labor Saving
Studies show an average 41% yield loss in ricecultivation with no weed control.(3) While this was once
prevented by weeding by hand, this practice became athing of the past as herbicides became more popular.
Manual weeding bent over in the hot sun is hard work.
In 1949, it took 50.6 hours per 10 ares; by 2004, thishad been reduced to 1.6 hours (4) (5).
Fruit trees such as apples or mandarin oranges alsoneed to have their blossoms or fruit thinned. In the past,this was done by manual labor. This used to be a hardtask concentrated into a short period of time, but now
the use of chemical fruit thinners has reduced theamount of work by 30-50%. (6).
As discussed above, pesticides are vital agricultural
materials in terms of yield size, produce quality andlabor saving. According to the Statistics of the Ministryof Agriculture, Forestry and Fisheries, pesticide costs
accounted for 6.2% (¥7,409) of the rice production
costs for 2011 (¥119,355/10a). The total number ofworking hours per 10 ares was 26.11 hours, aroundone-eighth of the 200.7 hours spent per 10 ares in 1951.
Of course, rice planting machines, combine harvesters
and other machinery account for a large part of thisreduction in working hours, but pesticides have also
made a significant contribution.

While there has been a recent demand from general
consumers for pesticide-free produce, the price ofpesticide-free produce has risen about 20%. Although
the amount of organic produce (JAS) is increasing year
by year, in 2010 it still only accounted for 0.23% of thetotal agricultural production.
Japanese produce is expected to be consistent in taste,
size and shape, of good quality, with no bruises or otherimperfections. While this may seem excessive at times,
it raises the question of how the use of pesticides can be
reduced while maintaining product quality. This would
require comprehensive technology developments, suchas producing pest-resistant varieties of crops, crop
rotation, rootstock (grafted) cultivation andweather-protected cultivation of crops such as
tomatoes.
Cited References(1) Japan Plant Protection Association (ed.). Nōyaku oShiyō shinaide Saibai shita baai no Byōgaichū no Higaini Kansuru Chōsa Hōkoku [Survey Report on Pest
Damage where Pesticides are not used in Cultivation],
Japan Plant Protection Association, 1993, p. 38.
(2) Ministry of Agriculture, Forestry and Fisheries.
Shokuhin no Kabi Doku ni Kansuru Jōhō [Information
on Mycotoxins in Food Products], accessed 13
December2012.
http://www.maff.go.jp/j/syouan/seisaku/risk_analysis/priority/kabidoku/kabi_iroiro.html(3) Japan Plant Protection Association. Nōyaku Gaisetsu[Pesticide Overview], 2011.
(4) Chisaka. “Zassō Bōjo Gijutsu no Genjō to Kadai ni
Tsuite. [Current Status and Issues with Weed Control
Technology.]” Nōgyō [Agriculture], Dai Nippon
Farmers’ Association, 1995, p. 4.
(5) Takeshita. Journal of Weed Science and Technology,
Vol. 49, No. 3, 2004, p. 220.
(6) Nōyaku Q & A [Pesticide Q & A], 2011, p. 28.

2.5. Pesticide Regulations
Pesticides are regulated by various laws. Whileregulation was more lenient in the pre-war era,legislation was put into place after the war. The goal at
the time was to protect users of pesticides, that is,farmers. However, later issues with residual pesticides
and environmental impact issues triggered a review ofthe laws to consider not only the safety of users(farmers), but also the safety of consumers and theenvironment as well, resulting in the legislation we
have today.
2.5.1. Enacting the Agricultural
Regulation Act (MAFF)

Chemicals

The Agricultural Chemicals Regulation Act, firstannounced in July 1948, and a number of other laws
regulate the production, importation, circulation, saleand use of pesticides. Let us examine the course of
events leading up to the present situation.
Although pesticide production bloomed from the late
1920s onwards, the government had no particularpolicies in place regarding production methods or
product quality and offered only a moderate degree of
guidance in this area. A rapid increase in pesticide
imports at this time saw the government set up an
Association for Regulating Pesticide Imports in 1938
and begin to regulate the import and distribution of four
products: nicotine sulfate, derris, lead and pine resin. In
1940, the government started regulating the distributionof agricultural agents; this practice continued until
1950.
Turbulent times during and after the war saw a shortageof all goods, not least of all an extreme shortage ofpesticides needed to boost food production. This
resulted in overproduction of inferior products andmany ineffective pesticides appeared on the market. To
put an end to this, the government enacted theProvisions of the Ministry of Agriculture and Forestryon the Inspection and Certification of Agricultural
Agents in 1947. Shipments of pesticides were inspectedby the Pesticide Association, established the previous
year, with the aim to facilitate the spread of superior
pesticides.
The following year in August 1948, the more binding
Agricultural Chemicals Regulation Act was enacted.
This law made it mandatory to register and label
pesticides. The government established the new
Ministry of Agriculture and Forestry Pesticide
Inspection Center (now the Food and Agricultural
Materials Inspection Center (FAMIC)). Manufacturers
could not sell any pesticides that had not been inspected
here and registered by the Minister of Agriculture andForestry.
Thus, the focus of the Agricultural Chemicals
Regulation Act was to ensure that high quality
pesticides were manufactured safely and provided tofarmers in order to boost food production. From thattime on, a succession of high-quality, synthetic organic
pesticides began to appear at a rate that has not been
replicated since. These products made a huge
contribution to increasing agricultural productivity andsaving labor.
As Japan entered a time of rapid economic growth, anumber of social problems emerged, such as theeffluence of chemicals into the ecosystem and theresidual impact of this, as well as concerns for general
consumer safety, or, more specifically, concerns about
residual pesticide in produce. The Agricultural
Chemicals Regulation Act was amended several times
and several related regulations were enacted, resulting
Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

13

in the stricter regulatory conditions of the present day.
Sections 3.4.4. (2) and 3.4.5. (1) touch on the mainamendments in more detail.
2.5.2. The Poisonous and Deleterious Substances
Control Act (Ministry of Health, Labour andWelfare)The Poisonous and Deleterious Substances Control Act
was enacted in 1950 to prevent injuries from highly
toxic chemical substances such as pesticides (except forpharmaceutical products or quasi-pharmaceuticalproducts). The classification criteria are given in Table
2.5.
This law stipulates matters relating to the manufacture,import, sale, labelling, storage and disposal of
poisonous and deleterious substances. Any substancethat is not categorized as a poisonous or deleterious
substance is treated as an “ordinary substance” and thislaw does not apply. Highly toxic pesticides have beenphased out and replaced since this law was enacted,
thanks to tighter regulation as well as efforts bydevelopers. In the late 1950s, poisons and specificpoisonous substances accounted for around half of all
pesticides; by 2011, this figure had dropped to 0.8%.
This shall be discussed in detail in Section 3.4.4. (1).
2.5.3. The Food Safety Basic Act (Cabinet Office)
The Food Safety Basic Act was enacted in 2003 toensure food safety for the protection of public health.
This law saw the establishment of the Food Safety
Commission and played a part in establishing thecriteria for evaluating pesticide safety and determining
the acceptable daily intake (ADI) of residual pesticides
in food.
2.5.4. The Food Sanitation Act (Ministry of Health,Labour and Welfare) et al.
The Food Sanitation Act is an old law enacted in 1947.
Let us discuss residue limits in relation to this law.
The Agricultural Chemicals Regulation Act stipulates
criteria for suspending registration for each pesticide.
This means that if a pesticide fails to satisfy certain
criteria, its registration can be suspended. Meanwhile,
the Food Sanitation Act specifies the residue limits.
These are the standard criteria for ensuring food safety.
If the amount of pesticide detected in a foodcommodity exceeds the amount permitted in theresidue limits, the distribution and sale of that foodcommodity is restricted. The total pesticide intake iscalculated from the amount of pesticides residual infood and the amount of food consumed by the average
Japanese person. This intake must not exceed 80% of
the ADI, based on animal experiments and otherresearch.

14

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, JapanThe Positive List System for Agricultural Chemical
Residues in Foods was implemented in 2003 to set
maximum residue limits for all pesticides. This isdiscussed in detail in Section 3.4.5. (2).
Several other laws not mentioned above also relate topesticides. Their names and jurisdictive agencies are
given here.
Ministry of the Environment: Basic Environment Act,
Water Pollution Control Act, Water Supply Act, Waste
Management and Public Cleansing Act
Ministry of Internal Affairs and Communications:Fire Services Act
Ministry of Economy, Trade and Industry: Lawconcerning Pollutant Release and Transfer Register,
Act on the Evaluation of Chemical Substances andRegulation of Their Manufacture, etc.
While some treatments used to control sanitary pests
such as mosquitoes, flies or cockroaches have some ofthe same ingredients as pesticides, their use against
sanitary pests means that they are classed as
pharmaceutical products or quasi-pharmaceuticalproducts and are regulated by the Pharmaceutical
Affairs Act. Treatments targeting nuisance insects suchas termites, wasps, gnats, caterpillars, centipedes andspiders are subject to the Act on the Evaluation ofChemical Substances and Regulation of Their
Manufacture, etc. or the Autonomous Standards of theCouncil for the Extermination of Health Pests.

2.6. Process of Pesticide Development
and Key Technology
This section provides an overview of the development
process and contributing technology that go into thecreation of new pesticides. It takes around ten years todevelop a pesticide and costs more than ¥3 billion to
produce it domestically and up to ¥10 billion to produce
it overseas. The chances of success are also extremely
low; it takes a synthesis of tens of thousands ofcompounds to finally produce a successful agent. The
most difficult part of it is that there is no guarantee thatsuch a huge investment of time and money will actually
succeed. It takes a continuous flow of resources (people,
goods, money) into research and development tosustain a pesticide business and continually produce
new products. This is one of the reasons for the
repeated amalgamation of businesses in the pesticideindustry.
The pesticide development process is shown in Fig. 2.7.
The process from research and development through tosuccessful registration and going on the market requires
a number of contributing technologies, each requiring
its own cutting-edge research and development. The

following is an outline of the development steps.
(1) Exploratory stage (the stage ending with thediscovery of the lead compounds)
This stage is also called Phase Zero, in which theresearch goes from zero to the first stage. Molecular
design is carried out to create a compound that willachieve the development aims. Repeated activity
evaluations (biological screening) are carried out tocome up with a basic structure that is worth taking on to
the next step. There is a diverse range of ways in which
research can progress and there are advantages anddisadvantages to each of them. They can besummarized as follows.
- Random Screening: A means of evaluating theactivity of compounds held by the company orsynthesized by an intermediary or external organizationsuch as a university. Predictably low chance ofdetecting activity.
- Bio-rational approach: A method of molecular
design based on mode of action, metabolism studies, or
knowledge of natural products combined withphysiological/biochemical expertise. The source of theidea is important, and many successful cases have beenachieved this way in the past. Advances in 3-D
structural analysis techniques for protein and other highmolecular compounds as well as advances incomputer-aided technology have enabled spatial
structure analyses of protein at the site of action,
making it easier to design chemical structures that willinteract there.
- Chemical approach: A method of molecular designin which researchers have a good knowledge of specificchemical reactions or companies have their own
intermediates with good knowledge of chemistry. Since
synthetic organic chemistry is a key technology, a goodidea of production costs can be ascertained quite earlyon.
- Approach of altering existing chemicals: A methodof molecular design by taking chemical structures
known to be effective pesticides and altering them sothat they do not infringe existing patents. While this isquite effective at the research level, the product must be
better than the existing products, have competitive
manufacturing costs and not be limited by existing
patents.

Market analysis, goal setting
Prior agents, literature, patents,
knowledge of natural products
Synthetic organic chemistry
Natural product chemistry
Physiology, biochemistry
Molecular biology

Samples (company library, external)
Molecular design

Structure-activity
relationshipEffect/side effect screening(first stage)

Plant physiology
Plant pathology
Weed science
Entomology

Sample preparation

Lead compounds
Patent application
Structure-activity
relationshipEffect/side effect screening(second stage)
Safety screening (initial)

Structure optimization
Physical properties / stability(in light, soil and water)

Candidate compounds

Toxicology
Analytical chemistry
Chemical engineering
Environmental science
Surface chemistry

Small-scale field trials

Physical and chemical properties
Test for metabolic fate (in animals, plants, soil
and water)
Produce residue testing
Impact on aquatic animals and beneficialorganisms

Safety testing (mutagenicity,
Formulation
irritation, teratogenicity,studies
reproduction toxicity, chronic
toxicity, carcinogenicity)

Industrialization research
Official testing
Synthesis process

Registration application

Registration /going on the market

Partially modified from Nōyaku Q & A [Pesticide Q & A], revised edition, Japan Crop Protection Association (ed.), 2011, p. 179.

Fig. 2.7. Pesticide Development Process
Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

15

In reality, research is often done using a combination ofthese methods. There are no royal roads when it comes
to exploratory research. It is largely dependent on
individual skills. The important thing is collaboration
between those responsible for synthesizing compounds
and the researchers who will conduct biological testing.
This stage requires unique creativity. Researchers needto have knowledge of past research, be able to come up
with ideas that are unrestrained by common sense andhave a tenacity of purpose so as not to be discouraged
by low chances of success. This could be likened tomountain climbing. The route up the mountain differs
according to the individual: one person might take adetour to climb safely, while others might climb up an
overhang with no thought for the risk of falling.
Research management is very difficult at this stage.

a problem with the toxicity results, development will be
stopped.
Table 2.8. Test Scores Required for Pesticide
Registration (tabulated from Notice of the
Director of the Ministry of Agriculture, Forestry
and Fisheries Agricultural Production Bureau
No. 12-8147 dated 24 November 2000)
Efficacy

Pest Insects and Diseases to Which Applied
Crop to Which Applied

Side effects

Surrounding Crops
Subsequent Crops
Acute Oral Toxicity
Acute Dermal Toxicity
Acute Inhalation Toxicity(2) Lead Compound Optimization Stage (deciding
on lead compounds to develop)
This stage of development involves maximizing theactivity of the lead compound to make it morecompetitive. It is about optimizing chemical structureand specifying candidate compounds. The research
theme is confirmed at this stage and researchers from anumber of different fields take part in the planning.
Each company has its own development phases andspecifies items to be clarified in each phase.

Dermal Irritation
Ocular Irritation
Dermal Sensitization
Acute Neurotoxicity
Acute Delayed Neurotoxicity
Oral Toxicity Test Repeated for 90 Days
Dermal Toxicity Test Repeated for 21 Days
Inhalation Toxicity Test Repeated for 90 Days
Neurotoxicity Test with Repeated Oral Administration

Synthesis researchers are requested to provide anumber of analogues and also establish a broad-ranging
patent ahead of competitors. They must also prepare
samples of kilogram scale for various tests. Biologicalresearchers have to cover a wide area, from ascertaining
product performance and whether or not there are any
adverse effects on crops, to confirming effectivenessthrough field trials. Researchers also carry out
preliminary studies on formulation, perform initialsafety evaluations (mutagenicity, acute toxicity, fish
toxicity, etc.) and ascertain the physicochemical
properties of the compound (light stability, dynamic
state in soil, analytical methods, etc.).
(3) Final Stage of Development (compliance forpesticide registration)
This stage is where the project goes into full swing andconcerted efforts are put into it. Each company has its
own development phases and specifies items to beclarified in order to move on to the next phase.
Management has to decide whether or not to make alarge-scale investment into the project.
Table 2.8 shows the tests required for pesticide
registration. Most of these tests must be carried out by acertified testing agency in accordance with the Ministryof Agriculture, Forestry and Fisheries Good Laboratory
Practice (GLP) standards for toxicity tests and residue.
To complete the package, it takes more than two years
and costs around ¥1 billion in direct expenses. If there is
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Survey Reports on the Systemization of Technologies; No. 18, March 2013
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Delayed Neurotoxicity with Repeated Administration for 28 Days
Toxicity

Oral Toxicity Repeated for One Year
Carcinogenicity
Reproduction Toxicity
Teratogenicity
Mutagenicity
Impact on Biological Functions
Metabolic Fate in Animals
Plant Metabolism
Soil Metabolism
Water Metabolism
Impact on Aquatic Animals and Plants
Impact on Beneficial Organisms other than Aquatic Organisms
Properties, Stability, Degradation, etc. of Active Ingredient
Water Pollution
Derivation of Predicted Environmental Concentration

Residues

Residues in Crops
Residues in Soil

(4) Pesticide Registration System
An application for pesticide registration is presented to
the Ministry of Agriculture, Forestry and Fisheries withthe above test results included. The Ministry examines
the application with assistance from the Ministry of
Health, Labour and Welfare, the Ministry of theEnvironment, the Cabinet Office Food Safety

Commission and other government agencies. If the
product is deemed suitable, registration is granted andpermission is given to put the product on the market.
There are three sets of criteria to determine thesuitability of a pesticide: the criteria for suspending
registration (if these criteria are not met, registration iscancelled and the product cannot be sold), the residue
criteria (if the amount of pesticide in a crop exceeds thecriteria, sale of the crop is banned and the crop isrecalled) and the pesticide use criteria (standards to beadhered to by users in relation to usage period, usage
times, etc.).
While there are sometimes mass media reports ofpesticides detected in crops in excess of the maximum
residue limits, the opinion is often expressed that “there
are no immediate health effects”. This is due to themanner in which the maximum residue limits are set.
Fig. 2.9 below provides details on the criteria for safety
evaluation and residue on crops.(1)The No Observed Adverse Effect Level (NOAEL) is
determined by the toxicity tests given in Table 2.8. Thislevel is measured in milligrams per kilogram of bodyweight per day. Since the NOAEL is derived fromanimal testing, the Acceptable Daily Intake (ADI) canbe determined by multiplying the NOAEL by a safety
factor (usually 1/100) that takes into account differences
between species and differences between individuals.

The ADI is the amount of a certain substance a person
can habitually consume over a lifetime with no adverse
health effects. This is the maximum permissible amountan individual can ingest based on the average Japanesebody weight of 53.5kg.
The amount of residual pesticide in crops is determinedby residue analyses. For instance, crop samples aretaken 1, 3, 7 and 14 days after a pesticide treatment andthe amount of residue measured. The estimated intakeof residue can be calculated by multiplying the amountof residue (the volume measured plus an additional
placeholder for safety) by the average amount of the
produce consumed by Japanese (e.g. 185g of rice perperson per day). The maximum residue limits are set sothat the estimated intake does not exceed 80% of the
ADI multiplied by the body weight (in parts per
million). If a particular pesticide is used on multiple
crops, the sum of the respective estimated intakes isused. The reason that the maximum residue limits areno higher than 80% of the ADI is because consumers
may also ingest the same pesticide from sources otherthan crops, such as water, air or fish.
While setting the residue criteria is a rather complex
process and somewhat difficult to understand, the main
points are as follows.

Long-term toxicity studies (on animals)

NOAEL mg/kg of body weight/day

Safety factor, usually 100

ADI mg/kg of body weight/day

Result of crop residue
test (ppm)

Intake by crop g/day

Residue criteria by crop (criteria forsuspending registration) ppm

Criteria for use(usage period, usage times)

Acute toxicity
test (on animals)
Irritation test

Test for impact on aquaticplants and animals
Test for impact on beneficialorganisms
Water pollution test

Notes (user safety)

Partially modified from Nōyaku Q & A [Pesticide Q & A], revised edition, Japan Crop Protection Association (ed.), 2011, p. 179.

Fig. 2.9. Pesticide Safety Assessment Flowchart
Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

17Firstly, the criteria are set to ensure that the food that we
eat every day “will have no adverse health effects evenif we eat that food every day for the rest of our lives”.
Conversely, we can also be assured that if we were toeat any food that exceeds the maximum residue limits,“there would be no immediate adverse health effects”.
To put it another way, the maximum residue limit is aregulatory standard rather than a safety standard. The
limits are determined by the results of the numerous
toxicity tests given in Table 2.8 multiplied by further
safety factors. Thus, the maximum residue limits forpesticides are determined based on a whole range oflong-term toxicity studies. Other than pharmaceuticalproducts, nothing else undergoes such extensive safety
testing.
The second point relates to acute toxicity. General
consumers seem to believe that if they were to ingest afood product containing a higher amount of residue
than the maximum residue limit, this would present ahealth hazard or a case of acute toxicity. This
understanding is based on repeated cases of poisoning
as a result of the use of large volumes of highly toxic
synthetic pesticides such as parathion after the war.
However, around 60 years later, only a very small
proportion (0.8%) of pesticides is classed as poisonous
substances and the safety of farmers is now guaranteed.
Meanwhile, the residue criteria are standards relating to
the safety of the food consumed by general consumers.
It is highly unlikely that there would be any cases ofacute adverse effects from this level of exposure topesticides.
Humans have a long history of learning and18

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distinguishing what we can eat and what we cannot eat(toxic substances). However, we have never studied thesafety of the natural chemical substances found in thefood we eat to the same level of detail as we have done
for pesticides. We know about poisonous blowfish andpoisonous mushrooms and we understand that alcohol
is carcinogenic; there have also been past cases of
poisoning in livestock that have eaten large amounts ofbracken (which contains carcinogenic ptaquiloside).
The point is that natural food products are notnecessarily safe. We need to be aware that chemical
substances, whether natural products or compounds,
can be harmful or beneficial, depending on the amountof exposure to them.
Above, we have discussed the process of pesticide
development, the contributing technologies and thefinal stage, the pesticide registration system. The reason
it has become increasingly more difficult to develop
pesticides is that new pesticides have to undergo
detailed checks to ensure their safety, including user
safety checks, safety checks for consumers ingestingproduce on which pesticides have been used andenvironmental impact checks. Chapter 5 discusses how
Japanese companies, despite not being major global
players in the industry, have continually been able toproduce pesticides that rival those of the major Western
corporations and also discusses the future prospects forJapanese companies in the industry.
Cited References(1) Nōyaku Q & A [Pesticide Q & A], revised edition,
Japan Crop Protection Association (ed.), 2011, p. 179.

3. The History of Pesticides
This chapter provides an overview of the history ofpesticides in Japan. The discussion will be divided byera: early (Jōmon period through to the 17th century),
early modern (17th to late 19th century), modern (late19th century to pre-WWII) and present (post-WWII).
The reason for this categorization is that the pesticideindustry began to develop in the present period as
advances were made in science and technology,
especially chemistry. Although there were only ahandful of pesticide varieties of limited effectivenessbefore that time, the roots of the highly effective
pesticides popular today can be traced back to the late
19th century. This chapter also touches on the
agricultural and social environments surrounding theuse of pesticides.

3.1. Prayer and the Beginning ofAgriculture (Jōmon period through tothe 16th century)
Cultivation of crops such as foxtail millet and barnyard
millet to supplement hunting and fishing began in what
is known as the Jōmon period (around 10,000 BC to the
3rd century BC). Paddy rice cultivation was later
introduced to Japan from the Asian continent aroundthe end of the Jōmon period or early Yayoi period. The
remains of paddy fields have been uncovered at several
sites from this era (1).
Around this time, a battle would have commenced
against disease and pest insects that damage crops.
Agriculture is an unnatural task: humans working
against nature to extensively cultivate a single crop inorder to survive and thrive. With a single crop, the fields
are simpler than in their natural state; life also becomes
simpler for the insects (pests) that live there, being
provided with an abundance of suitable food. The crops
are more vulnerable to disease and pest insects thanwild plants are, with yields dropping after an outbreak.
Cold and drought led to starvation; the humanpopulation declined due to countless deaths fromstarvation. The population at the start of the earlymodern period (c. 1600) is estimated to have beenaround 10-12 million, with around 1.6 million hectaresof arable land (2).
Farmers in those days had no means to control pest
insects. To prevent crop damage, they looked to fields
as the object of their faith and developed agriculturalrituals such as prayers. There is an entry on pest insects
in Gleanings from Ancient Stories (2), written 1200 years
ago in 807 by Inbe Hironari of Awa Province(Tokushima). This was an age in which people literally

entreated deities through ceremonies called mushi-oi toward off insects. They would place beef orphallic-shaped ritual equipment in the water inlets in thefield to ward off insect pests, or wave fans with crows
depicted on them to drive off rice pests (pest insects thatdamage rice plants, such as armyworms andleafhoppers). Vestiges of these prayers have continued
as traditions down to the present day, despite thedevelopment of highly effective pesticides.
Cited References(1) Kimura. Nihon Nōgyō-shi [Japanese Agricultural
History], Yoshikawa Kobunkan, 2010, p. 12.
(2) Kimura. Nihon Nōgyō-shi [Japanese Agricultural
History], Yoshikawa Kobunkan, 2010, p. 147.
(3) Nishinomiya. Kogo Shūi [Gleanings from Ancient
Stories], Iwanami Bunko, 2004.

3.2. Mushi-Oi and the Roots ofModern Pesticides (early modern;
17th to late 19th century)
There was a major increase in arable land from the 17th
century onwards. In 1600, Japan had around 1.64
million hectares of arable land; by around 1720, thishad risen to 2.97 million hectares. There was no major
increase in arable land for a long time after that; by thelate 19th century this figure had only risen to 3.05
million hectares (1). The population also continued to
grow. The population of around 12 million in 1600 had
grown to around 31 million by 1721, reaching a peak at
33 million around the time of the Meiji Restoration in1868 (2).
3.2.1. Family Traditions on the Killing of Insects
In 1600, the year of the Battle of Sekigahara, Matsuda
Naiki of Izumo Province (present-day Shimane
prefecture) wrote a document addressed to Namba
Jinemon, entitled Family Traditions on the Killing of
Insects. This document records family remedies forkilling insects using a combination of five types ofingredients and comments on their effectiveness.
Okamoto made the existence of this document known
in 1953 (3) and discussed it in more detail 1992 (4), (5), (6).
A recent survey reaffirmed the existence of thisdocument with the help of the Iinan Town Board of
Education in Iishi District, Shimane. The findings are
outlined here.
There are two extant variants of the document. The
original was written in 1600. One manuscript wastranscribed in 1776; this is held by the Namba family inthe form of a record entitled Kokumin Hōjō-ki [Record
Hiroki OHTA; Historical Development of Pesticides in Japan
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of the Nation’s Fertility] (Fig. 3.1). The othermanuscript is the Family Traditions on the Killing of
Insects, copied in 1845 and passed down by the
Kurahashi family of Akanahachimangū Shrine (Fig
3.2). While the content of the two documents is more orless the same, only the latter has an entry detailing thefollowing prescription.
The document records that a compound of fiveingredients: morning glory seeds, aconitum root, amber(fossilized resin used as a fragrance), camphor andalum can be made into a smoke as is, or boiled and theliquid dispensed where desired to eradicate cutworms,
earthworms, insects on spring grasses and radishes,
leafhoppers, wild boar and deer. There are precise
descriptions of its method of application, the mode oflife of leafhoppers and other details. However, judging
from the ingredients, it would have had rather limited
effectiveness.
Family Traditions on the Killing of Insects is the oldest
extant record of pesticide in Japan and could be hailed
as the root of modern Japanese pesticides.

Fig. 3.3. Prescription from Family Traditions on the
Killing of Insects

3.2.2. Control by Oiling and the Introduction of theAgricultural Book
In 1670, Kuratomi Kichiemon, a village headman from
Chikuzen Province (Fukuoka) discovered a method of
eradicating leafhoppers by pouring whale oil onto
paddy fields (7), (8). The history of Yatsurugi Temple inMizumaki, Onga District, Fukuoka, records that “this isheld to be the beginning of pest insect control inJapanese agriculture” (Fig. 3.4) (9). From a practicalpoint of view, this method discovered by Kuratomi ofusing whale oil to control leafhoppers was indeed the
beginning of effective pest insect eradication in Japan.

Fig. 3.1. Record of the Nation’s Fertility Namba Family

Fig. 3.4. The History of Yatsurugi Temple in Mizumaki,
Onga District, Fukuoka (provided by Mr. Kitake (9))

Fig. 3.2. Family Traditions on the Killing of Insects
Kurahashi family of Akanahachimangū Shrine

In 1697, Miyazaki Yasusada of Chikuzen Province
wrote the ten-volume Compendium of Agriculture (10).
This became very popular as the most systematic
guidebook to agriculture in 18th century Japan. It
records methods for eradicating pest insects, such as
making broth from agarwood or chinaberry powder,sophora root, Japanese andromeda leaves and tobacco
stems, as well as making smoke from sulfur or
wormwood (11).
In 1731, Sugimoto Shōbei of the Tosa domain (Kochi)
compiled Rich Treasury of Records, another guidebook

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for eradicating pest insects (11), (12). This work listed
grassleaf sweetflag, chinaberry, sweet autumn clematis,
sophora, Japanese andromeda, tobacco, St. John’s wort,
Japanese mugwort, rheum, pagoda tree, gingko biloba,
pine needles and cereals as plants that could be used toeradicate pest insects. Animal products that could also
be used included whale oil and fish broth.
All of the plants listed in the Compendium ofAgriculture and Rich Treasury of Records are types of
medicinal plants. Each of these is now known to haveinsecticidal or insect repelling components to it:chinaberry contains azadirachtin; Japanese andromeda
contains grayanotoxin; tobacco contains nicotine.
Presumably, these would have had some degree ofeffectiveness.
In 1788, Nagaki Shichizaemon of Ushu (Akita)
compiled the Methods for Eradicating Rice Pests in
Ushu Akita (13). This document records the use of perillaoil, blowfish oil and shark oil to eradicate pest insects
on fields.
In 1826, Okura Nagatsune of Bungo (Oita) wrote
Eradicating Rice Pests, using diagrams to explain
methods of extermination, mainly the use of whale oil.
In 1844, he wrote Eradicating Rice Pests, Part Two,summarizing other methods of eradication besides
whale oil, such as using mustard oil, canola oil, tung oil
and Japanese andromeda (14). This was Japan’s firstsystematic compilation of pest control methods using
pesticides. It seems to have been widely popularthroughout the entire country, as there is evidence of the
shogunate notifying prefectural governors to use thesemethods in the event of a pest outbreak. This book also
has a number of illustrations showing specifically how
to apply the oil. There are also images of mushi-oi, amethod of pest eradication by incantation, practiced at
the time. It involved marching around the fields burningpine torches, blowing horagai (conch shells) andbeating drums and bells in the hope of burning theinsects. Putting oil on the paddy fields and shaking off
the pest insects into it apparently had the effect ofsuffocating the insects (Fig. 3.5). The late early modern
period saw a famine in 1732 due to a major outbreak ofleafhoppers, the Tenmei Famine in 1783 and the Tenpo
Famine in 1833, caused by cold weather damage. The
damage from the Tenpo Famine in particular was
severe across western Japan, with one million people
dying of starvation. This triggered the widespreadpractice of using oil on fields. In certain regions, themushi-oi or mushi-okuri ceremony is still practiced as a
traditional event in much the same way as it always was.
Fig. 3.6 shows a mushi-okuri ceremony being held in
Muroushimokasama in Uda, Nara (15).

Fig. 3.5. Mushi-Oi Illustration from Eradicating Rice
Pests (14)As discussed above, up until the late 19th century, theonly way farmers could keep pest insects from theirfields was through the use of oils such as whale oil, or
by using medicinal plants – the efficacy and popularityof which are unclear – or by prayer in the form ofmushi-oi. During this era, there were repeated major
famines caused by unseasonable weather, leafhoppers
and other factors, and many people starved to death.
Agricultural production was nowhere near what it istoday. Since the population plateaued at around 30
million from the late 1700s, we can presume that thecountry was only capable of feeding around thisnumber of people.

Fig. 3.6. Mushi-Okuri Ceremony in Murou
shimokasama in Uda, Nara (reprinted from Yamatoji
Photo Album (15))

Cited References(1) Kimura. Nihon Nōgyō-shi [Japanese Agricultural
History], Yoshikawa Kobunkan, 2010, p. 146.
(2) Honkawa. Shakai Jitsujō Dēta Zuroku [Catalogue ofActual Social Data], accessed 31 October 2012.
http://www2.ttcn.ne.jp/honkawa/1150.html(3) Okamoto. Nōyaku Nyūsu 32 [Pesticide News 32],
Nihon Nōyaku, 1953.
(4) Okamoto. Chū-jū Yoke no Gen Fūkei [Traditional
Views of Pest Eradication], Japan Plant Protection
Association, 1992, pp. 120-136.
(5) Akagi-chō-shi [History of Akagi], Akagi Township,
1972, p. 76.

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(6) Nishida. Nōyaku Netto [Pesticide.net], accessed 31
October 2012, as well as personal communication.
http://nouyaku.net/site/tishiki/REKISHI/REKI1.html(7) Konishi. Nihon Nō-sho Zenshū [The Complete Worksof Agriculture in Japan], Vol. 15, annotated Eradicating
Rice Pests, Rural Culture Association, 1977, p. 108.
(8) Kitakyūshū-Shi-Shi: Kinsei [History of Kitakyushu:
Early Modern], City of Kitakyushu, 1990, p. 361.
(9) Kitake. Kitakyūshū no Arekore [Particulars about
Kitakyushu], provided by personal communication on
13 April 2012. http://homepage2.nifty.com/kitaqare/(10) Miyazaki. Nōgyō Zensho [Compendium ofAgriculture] in Nihon Nō-sho Zenshū [The Complete
Works of Agriculture in Japan], Vols. 12 and 13, Rural
Culture Association, 1978.
(11) Sugimoto. Fūki Hōzō-ki [Rich Treasury of Records]
in Nihon Nō-sho Zenshū [The Complete Works ofAgriculture in Japan], Vol. 30, Konishi annotated Fūki
Hōzō-ki [Rich Treasury of Records] (2), Rural Culture
Association, 2003.
(12) Kōchi Ken-Shi [History of Kochi Prefecture], Modern
Edition, Kochi Prefecture, 1974.
(13) Taguchi. Shiryō: Kinsei Akita no Nō-sho [Archives:
Agricultural Books of Early Modern Akita], Mishima
Shobo, 1975.
(14) Okura. Jokōroku [Eradicating Rice Pests] in Nihon
Nō-sho Zenshū [The Complete Works of Agriculture in
Japan], Vol. 15, annotated by Konishi, Rural Culture
Association, 1977.
(15) Nomoto. Yamato-ji Shashin-shū [Yamatoji PhotoAlbum], accessed April 2012, as well as personalcommunication. http://lint.ne.jp/nomoto

3.3. The Emergence of Modern
Pesticides (late 19th century to
pre-WWII): the Appearance of the‘Long-Lived Pesticides’
Japan opened its country to the world in the late 19th
century and began to adopt various goods andtechnologies from overseas in many fields, including
agriculture. While there were negative aspects to this,such as an increasing number of non-native insect pests(such as scale insects) as seeds and seedlings wereintroduced, Western agricultural techniques, such as
selective breeding and using fertilizer, were also
introduced to Japan.
The population rapidly increased from 30 million in thelate 19th century to 80 million before the Second World
War. Meanwhile, the advancement of modern
industrialization saw a steady decline in the number offarmers from 14.6 million around 1880 to 13.74 million
in the 1930s. Conversely, the amount of arable land
grew from 4.7 million hectares in the 1870s to 6.04
million hectares by the 1930s. Advances in agricultural
technology meant that rice production multiplied by 1.8
times, while the yield increased from 200kg to 300kg
per 10 ares (1), (2).
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However, as we shall mention later, there were only alimited number of pesticides at the time. In modern
terms, organic farming was mainstream, which meant
limited productivity. The present-day rice yield isaround 500kg per 10 ares.
This chapter discusses early pesticides including oil,inorganic compounds (such as lime sulfur, Bordeauxmixture, copper agents and arsenicals) and natural
products (such as pyrethrum insect powder, nicotine
and derris), as well as early synthetic organic pesticides
and their development, such as organomercury
compounds and chloropicrin. It is worth mentioning
here that industrial pesticide production began during
this time and four pesticides emerged: machine oil, lime
sulfur, Bordeaux mixture and chloropicrin. These four
pesticides are still listed on the pesticide register andhold a very important place as key pesticides. Althoughmany highly effective pesticides have been developedsince the 1930s, this time period is historicallysignificant, as it was when industrial production beganon these four major long-lived pesticides.
3.3.1. Oil
Using whale oil on fields to eradicate pest insects dates
back to the 17th century. This practice became popularin the late 19th century and it continued into the 1930s,
although there was a transition taking place fromanimal oil to mineral oil. Synthetic insecticides such as
BHC introduced to Japan after the war replaced whale
oil as a leafhopper eradicator.
Machine oil works as an insecticide by physicallycovering insects with a hydrocarbon coating andsuffocating them to death. This means that the insects
can never become resistant to the treatment. Oil
emulsion concentrates were produced and sold from thelate 1920s onwards as a means of controlling spider
mites in particular. It is still in popular use today, with5,000 tons of it being sold to eradicate scale insects andleaf mites on fruit trees and vines, such as mandarins,
pears and grapes.
3.3.2. Inorganic Compounds(1) Lime Sulfur
Lime sulfur was first produced in 1851 by a Frenchman
named Grison (3). It was introduced to Japan in the late
19th century and became widely used after anexperimental field test was conducted on scale insects
on fruit trees in 1907 (4). It was later used to control
wheat leaf rust. Lime sulfur production started in Japan
in 1910 by Nippon Seimi Seizo (now Nissan Chemical
Industries) under the name of “liquid sodium sulfate”
and in 1912 by Kanto Sanso (now also Nissan
Chemical Industries) under the name of “Sanso liquid”.
This marked the beginning of industrial production of

pesticides in Japan (5). As the product was tested on awide range of applications, it rapidly expanded as apesticide for wheat and an insecticide-fungicide for fruit
trees. By 1939, the market had grown to 22,500 tons (6).
It inevitably declined in use due to its strong alkalinity
and sulfurous odor, as well as the emergence of otherhighly effective pesticides after the war. Despite thisdecline, however, 5,000 tons of it were produced in
2008.
The main ingredient in lime sulfur is calcium
polysulfide (CaSx x=4-5) made by boiling lime andsulfur together in water. It works as an insecticide or
fungicide by producing free sulfur from oxygen andcarbon dioxide in the air. The sulfur released has a SH
inhibiting effect on the electron transport chain in themetabolic energy system (7). The 2012 Mode of Action
Classification of the Fungicide Resistance Action
Committee (FRAC), a sub-branch of CropLife
International, classified the mode of action of sulfur andother inorganic substances such as copper as “Multi-site
contact activity” M1-M9, with the comment that they
are “generally considered as a low risk group without
any signs of resistance developing to the fungicide” (8).
This is one of the main reasons it has continued to be
used for the past 100 years.
(2) Bordeaux Mixture and Other Copper
Formulations
In 1885, Pierre-Marie-Alexis Millardet, a professor at
the University of Bordeaux in France, discovered bychance that a mixture of copper sulfate, lime and water(what became known as “Bordeaux mixture”) was
effective against diseases in grapes. The mixture was
first used in Japan in 1897 at a vineyard in Ibaraki (9). It
was later used to control disease damage in fruit trees,such as pears, apples and mandarins, fruits andvegetables, such as melons, tomatoes and cabbages,
and other crops such as cereals and konjac.
The chemical composition of Bordeaux mixture iscalcium copper sulfate (CuSO4, zCu(OH)2, yCa(OH)2,
2H20), and several different varieties can be made using
the ingredients in different proportions. For instance,
Bordeaux mixture type 4-4 is a mixture of 400g copper
sulfate, 400g caustic lime and 100L water. The mixture
achieves its effect by means of the well-known
bactericidal properties of copper ions, which have a SH
inhibiting effect on the electron transport chain in the
respiratory system. Bordeaux mixture became popular
because it could be prepared by farmers as the needarose (so-called mixing in the garden), although it has
some drawbacks in that it is tedious to prepare andcannot be stored. A number of other copper
formulations were produced as improved versions of
this product, such as dusts, wettable powders andchelating agents. After the war, organocopper
formulations were also developed. Fig. 3.7 shows thesecopper fungicides.

Fig. 3.7. Copper Fungicides

Production of copper fungicides started in the 1910s
with companies such as Furukawa, Nissan Chemicals
and Sankyo (10). The pre-war production volume of
1,000 tons per year increased after the war; by 1957,
this figure had grown to 5,000 tons. Despite a later
downward trend, there were still 4,000 tons of orders
placed in 2010.
Recently, opinions changed regarding organic
agriculture and products appeared on the market
claiming to be organic produce. However, production
methods were vague and there was concern that thiswould cause confusion in the market. Accordingly, theJapan Agricultural Standards (JAS) for Organic
Produce were defined in 2000. These standards
stipulated the basic criteria for production methods, inprinciple prohibiting the use of chemically synthesized
fertilizers, pesticides and recombinant DNA technology
and giving details on materials that can be used in
exceptional cases (11). Permissible pesticides include
machine oil, lime sulfur and the copper formulations
mentioned above. For further details, see Section 3.4.5.
(1).
(3) Arsenicals
Inorganic arsenicals have long been known for theirinsecticidal effect. Paris Green (copper (II)acetoarsenite) and London Purple (a mixture of lime
arsenate and calcium arsenate) were pigments known tohave an insecticidal effect (12). In 1892, lead hydrogenarsenate (PbHAsO4) was found to be effective against
gypsy moth larvae; this was first imported to Japan in1908 by Yokohama Ueki (later Toa Agricultural
Chemical). In 1921, an experimental station in
Hokkaido used calcium arsenate (Ca3(AsO4)2) tocontrol rice leaf beetles. In 1922, Furukawa (later
Nihon Nohyaku) and Yokohama Ueki started industrial
production of lead hydrogen arsenate. In 1932, Nihon
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Nohyaku started manufacturing calcium arsenate; in
1935, Nihon Jinzo Hiryo (later Nissan Chemical)
started manufacturing ferric arsenate (FeAsO4).
Japanese companies also started exporting pesticidesaround this time and production drastically increased.
In 1941, Japanese companies produced 4,500 tons oflead hydrogen arsenate, calcium arsenate and ferricarsenate (13). At the time, lead hydrogen arsenate waslabeled as a “toxic agent”. Fig. 3.8 shows posters fromthe time encouraging its use.
Arsenicals release arsenic into the digestive system of
the insect and are toxic; they are also highly toxic toanimals. They are designated as poisons, having anacute oral toxicity of 80mg/kg in rats. Many cases ofacute poisoning have been from inorganic arsenic
compounds. Inorganic arsenic compounds are generally
highly toxic, while organic arsenic compounds are lesstoxic. Trivalent arsenic is more toxic than pentavalentarsenic. Arsenic works as a poison by bonding with andinhibiting enzymes such as SH-group myocardiallactate dehydrogenase. The Ministry of theEnvironment has made detailed reports on the healthimpacts of arsenic and its compounds (14).
Lead hydrogen arsenate and other arsenicals became
popular from the 1910s onwards as key pesticides.
Lead hydrogen arsenate was the first pesticide to beregistered when the post-war pesticide registration
system began.
By around 1959, 3,000 tons of lead hydrogen arsenate
was being produced every year. Fig. 3.9 shows aregistration form and a product label from that time.
However, production later gradually decreased. It was
designated as a residual pesticide on crops in 1971 andits registration was revoked in 1978, bringing its
half-century of service to an end.

1925, poster on the right from 1930) (provided by theJapan Plant Protection Association Plant Protection
Museum)Left: Registration Form for Lead Hydrogen
Arsenate (the first pesticide registered)
Right: Product Package for Sale
Fig. 3.9. Lead Hydrogen Arsenate Registration Formand Product Package (provided by Nihon Nohyaku,Inc.)

3.3.3. Organomercury Compounds
Mercuric chloride (HgCl2), an inorganic mercury, wasused to disinfect seeds and sterilize soil since the late
19th century. While formalin and copper formulations
such as Bordeaux mixture were used as sprays and seedtreatments for rice and wheat, they were not very
popular as they were not sufficiently effective and there
were concerns about harmful side effects.
Organomercury compounds were introduced and theirefficacy against rice blast and other crop diseases madethem very popular.
In 1914, German company Bayer, part of IG Farben,
the world’s largest chemical group at the time, invented
Uspulun(methoxyethylmercury
chloride
CH3OCH2CH2HgCl) and confirmed its efficacy against
wheat smut by seed treatment. The product went tomarket the following year and was introduced to Japan
in 1921 (15), (16). By 1935, it was evident that using
Uspulun to disinfect seeds was very effective against awide range of diseases, such as rice blast and wheat
smut, and the product became widely popular (Fig.
3.10).
Japanese manufacturer Sankyo started marketing
Mercuron (phenylmercury acetate C6H5HgOCOCH3)
in 1937.

Left: Using Toxic Agent to Eradicate Pests from Sweet
Potatoes (Iwate)
Right: Controlling Pests on Potatoes (Hokkaido)

Fig. 3.8. Posters Encouraging the Use of Toxic Agent(Lead Hydrogen Arsenate) (poster on the left from24

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan

Sanei Shoten (later Nihon Tokushu Noyaku Seizo)
introduced Bayer Ceresan (phenylmercury acetate
C6H5HgOCOCH3) to Japan in 1938. This productgained a lot of attention in Manchuria, where it proved
to be effective against seedling blight in cotton (17).
However, wartime conditions soon made it extremely
difficult to import anything from Germany. Sanei

Shoten had imported and marketed Uspulun andCeresan and managed to secure a technology licensing
contract for both products from IG Farben. The
decision for an importer/distributor to take on thetechnology licensing for the world’s largest chemicalcompany shows something of the resourcefulness of
those company managers. Sanei Shoten took thisopportunity to establish Nihon Tokushu Noyaku Seizo,Inc. in 1941 and rushed to complete its Hachioji factory
the following year, with the intention of producing 100
tons of Uspulun and 200 tons of Ceresan per year. Even
during wartime, this factory continued manufacturing atfull capacity until it was destroyed in an air raid in
August 1945.
Organomercury compounds thus became popularagainst a wide range of diseases in rice, wheat and othercrops. This trend continued until the 1950s and 1960s,
when problems started arising from mercury pollution
in industrial wastewater, such as Minamata disease andNiigata Minamata disease, and organic mercury rice
blast treatments were found to be leaving residual traces
on rice. In 1966, the decision was made to replace theseproducts with non-mercurial pesticides, under the
instruction of the Ministry of Agriculture and Forestry.
By 1973, registration had lapsed for all organomercury
pesticides. This is discussed in the next section.

Pyrethrum Flowers (Innoshima, Hiroshima)

Fig. 3.11. Pyrethrum Flowers, from 100 Years at Kincho(18)

Natural pyrethrins and their derivatives are called
pyrethroids. As advances were made in organic
synthesis technology, many synthetic pyrethroids also
developed from the late 1960s onwards. These newdevelopments were used not only for home gardening
and disease control, but also for agricultural pesticides.
The production of natural pyrethrum gradually declined
as the number of synthetic products increased.
(1) Origins and Production of Pyrethrum
In the early 19th century, an Armenian named Jumtikoff
discovered that powdered Caucasian chrysanthemums
had insecticidal properties (19). By the mid-19th century,use of the Dalmatian chrysanthemum from theDalmatian region (later Croatia) as an insecticide had
spread throughout Europe. While the three following
types of chrysanthemums are pyrethrums, theDalmatian chrysanthemum has the highest pyrethrin
content and is the most commonly used for insecticides(20), (21).
Dalmatianchrysanthemum(Chrysanthemum
cineraliaefolium)
Persian chrysanthemum (Chrysanthemum roseum)
Armenian chrysanthemum (Chrysanthemum Marshalli
Ascherson)

Uspulun Mercury Seed Treatment Product Package
Fig. 3.10. Uspulun Product Package (2)3.3.4. Pyrethrum (Pyrethrins)
The (dried) flowers (ovaries) of Chrysanthemum
cinerariifolium, a type of pyrethrum (Fig. 3.11) (18),contain 1.2-1.5% pyrethrins, which have insecticidal
properties. This section discusses the rapid
development of pyrethrins in Japan from the late 19th
century to the pre-war era, as well as the history ofpyrethrum cultivation and its industrial use.

While there is a record of pyrethrum (powder) being
first introduced to Japan around 1860 (22), this is notdefinitive, as another record states it was first
introduced by Keirindo in 1881 as a flea powder, while
yet another record states pyrethrum was introduced toJapan in 1884 by Austrian Georg Hütterot (23), (24). In any
case, it seems safe to say that pyrethrum was introduced
to Japan in the late 19th century.
Another record states that Kizo Tamari introduced an
American variety of pyrethrum to Japan in 1885 andgrew them on a field at Tokyo Agricultural and Forestry

Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

25

School, while still another record states that Nagayoshi
Nagai (1845-1929), the so-called father ofpharmacology (and discoverer of ephedrine), planted
and cultivated a German variety in the Medical Herb
Garden in Meguro, Tokyo (23), (25).
Pyrethrum cultivation was popularized by Eiichiro
Ueyama, the owner of a mandarin plantation in
Wakayama. Ueyama established Ueyama Shoten (nowKincho) in 1885 at the same time as he obtained
pyrethrum seeds from H.E. Amoore, the manager of aplant company in San Francisco. The following year,
Ueyama began full-scale pyrethrum cultivation in
Wakayama. He then set about promoting pyrethrum
cultivation across the entire country. To popularize
pyrethrum cultivation, Ueyama wrote and published
Guide to Pyrethrum Cultivation in 1890 and worked
hard in Hokkaido and Inland Sea coastal regions such
as Okayama to promote the effectiveness of pyrethrum
as a pesticide as well as ways to cultivate and dry it (26),(27). Hokkaido became the center of pyrethrum
production from the 1910s; by the mid-1930s, thecultivation area had increased to 20,000 hectares in
Hokkaido alone (and 29,000 hectares nationwide).
Dried flower yields rose to 13,000 tons, 70% of theworld’s production. Two-thirds of this was exported,making Japan the top pyrethrum producer in the world.
These exports decreased in the early 1940s because of
the war; production also decreased as food production
became a more pressing need. After the war, domestic
cultivation of pyrethrum dropped off due to theemergence of synthetic organic pesticides such as DDT
and BHC, as well as synthetic pyrethroids allethrin.
Currently, pyrethrum is not produced at all in Japan. It
is still grown in Kenya, Tanzania, Rwanda, Tasmania
and China, with around 10,000 tons of dried flowers
produced in 2010.
(2) Pyrethrin Chemistry
Dried pyrethrum flowers contain 1-1.5% pyrethrin; thepyrethrin content starts to increase from when theflower buds, reaching its maximum level at full bloom(28), (29)
. When extracted with petroleum-based solvents,
the products can contain around 20% pyrethrin. Fig.
3.12 shows six mixtures of homologues. There are two
carboxylate moieties: chrysanthemic acid and pyrethricacid and three alcohol moieties: pyrethrolone,cinerolone and jasmorolone. Combinations of these arecalled Pyrethrin I and II, Cinerin I and II and Jasmolin I
and II. Fujitani et al. (30) isolated the pyrethrins;
Yamamoto et al. (31) estimated the chemical structurefrom the structure of the degradation product,
Staudinger et al. performed further research on theplanar structures (32), while La Forge et al. (33) made thefinal clarifications in this respect. The carboxylate
moieties have a cyclopropane skeleton structure, while
the alcohol moieties have a cyclopentenolone skeleton
structure.
26

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan

Crombie determined in 1954 that the carboxylate
moieties have a three-dimensional structure of (+) 1R,
3R-trans (34), while Katsuda et al. determined in 1958
that the alcohol moieties have a three-dimensional
structure of (+) S cis (35).

R1
Pyrethrin I
Pyrethrin II
Cinerin I
Cinerin II
Jasmolin I
Jasmolin II‐CH3‐CO2CH3‐CH3‐CO2CH3‐CH3‐CO2CH3

R2‐CH=CH2‐CH=CH2‐CH3‐CH3‐CH2CH3‐CH2CH3

Fig. 3.12 Natural Pyrethrin Chemical Structures
With the planar and steric structures having beenclarified, major developments were made in synthetic
pyrethroid research from the late 1950s onwards. Many
pyrethroids were invented and further developed foruse in the home or against sanitary pests, as well as for
agriculture. Japanese researchers played a major role inthese developments.
(3) The Insecticidal Effects of Pyrethrins and their
Uses
Pyrethrins have an immediate (knock-down) effect on
many pest insects at low doses. They are far less toxic
and far more selective than other pesticides when it
comes to their effect on mammals. While they have ahighly effective median lethal dose LD50 for insects at
0.2mg/kg, the lethal dose is 4,500 times more selective
for mammals (rats) at 900mg. They are quite highly
toxic to fish (36).
Pyrethrins are effective against agricultural pests suchas caterpillars, cabbageworms, aphids, brassica leaf
beetles and leafhoppers, as well as sanitary pests suchas flies, mosquitoes, lice and cockroaches. While they
have a knock-down effect in agricultural use, they havea drawback in that they are less stable than nicotine orderris when exposed to ultraviolet rays, oxidation orheat. Accordingly, their effects are less consistent andless durable (residual). As a result, extracts, pyrethrum
soaps and other solutions are used to control
leafhoppers, aphids and caterpillars. While these wereused as a substitute for derris during the war when it
became difficult to import, they did not become very
popular, due to the appearance of arsenicals. However,pyrethrins became popular insecticides for household
use or on livestock due to their knock-down effect.
1935 saw more than 10,000 tons produced, including
exports. The industry had grown to meet the demands

of the world.
(4) Invention of Mosquito-Repelling Incense
While pyrethrum was initially popular as a flea powder,
Ueyama found that it worked to repel mosquitoes whenmixed with sawdust and smoked in an incense burner.
Ueyama developed this further and invented
mosquito-repelling incense in 1890 (18). This was madeby mixing pyrethrum powder with a flour paste or otherbinder and forming it into sticks, using the conventional
Japanese production method for making incense sticks
for Buddhist altars. Thus, the world’s firstmosquito-repelling incense sticks came into being (Fig.
3.13).
However, these thin sticks would only last for about 40
minutes and it would take two or three of them burningat once to kill any mosquitoes. In 1895, Ueyama’s wife,
Yuki, suggested the idea of improving these sticks bymaking them into coils. A wooden prototype from thistime has survived to this day (Fig. 3.14). Ueyama
finally achieved a method of manufacturing by coilinga thick incense stick. The product went to market in1902 (37). Products, wooden extruders andcommercially-made extruders from this time still exist
today (Figs. 3.15, 3.16, 3.17). The manufacturingmethod improved from the late 1920s onwards,
progressing from hand-wound to punched-out. Modern
coils can burn for around seven and a half hours. The
method of burning pyrethrum as mosquito-repellent
incense was a ground-breaking invention, using smoke
and vaporization to achieve a wide range of effects. The
mosquito coil is well-known and used not only in Japanbut overseas as well. Fig. 3.18 shows posters used
overseas at the time.

Wooden Mosquito Coil Prototype from 1895

Fig. 3.14. Wooden Prototype of the World’s First
Mosquito Coil (provided by Kincho)

Hand-Wound Mosquito Coil c. 1919

Fig. 3.15. Early (1919) Hand-Wound Mosquito Coil(provided by Kincho)

Wooden Mosquito Coil Extruder (Incense Stick Pipe)

Fig. 3.16. Wooden Mosquito Coil Extruder(provided by Sanda Mosquito Fumigation Archives)

The World’s First Mosquito-Repelling Incense Sticks

Fig. 3.13. The World’s First Mosquito-Repelling
Incense Sticks (provided by Kincho)
Early 20th-Century Mosquito Coil Extruder

Fig. 3.17. Mosquito Coil Extruder (provided byKincho)Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

27

Fig. 3.18. Pre-War Overseas Mosquito Coil Posters (provided by Kincho)
As discussed above, Japanese pyrethrum technology
led the world from the time pyrethrum was introduced
to Japan in the late 19th century through to post-war
chemical research. Specifically, Japanese researchers
were instrumental in isolating its active ingredients,
determining its molecular structure, cultivating it andalso developing new uses for it. Based on thisgroundwork, many synthetic pyrethroid pesticides havebeen developed for agriculture since the 1960s. Whiledetails will be given in a later section, for now we cansay that Japanese technological development is leading
the world in this area.
3.3.5. Nicotine: Origins of the Modern Synthetic
Organic Pesticides
Nicotine and pyrethrum, discussed in Section 3.3.4, arematchless as far as the origins of modern syntheticorganic pesticides go. This section traces the history of
nicotine from its introduction to Japan in the late 19th
century through to the pre-war and post-war eras andattempts to highlight the important role that it has
played.
Nicotine is an alkaloid found in plants of the Nicotiana
genus of the Solanaceae family. It exists in the form of
citric or malic acid salts (Fig. 3.19). In practical use, it isgenerally found in tobacco powder or nicotine sulfate.
28

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan

Fig. 3.19. Nicotine
Tobacco was introduced to the French elite as a
medicinal plant by Frenchman Jean Nicot in 1560. In
1828, Germans Reimann and Posselt isolated achemical substance from a tobacco leaf by steam
distillation and named it nicotine, after Jean Nicot (38).
Nicotine was first synthesized by Craig in 1902,
followed by Speath (1928) and Craig (1933). In
practice, there are two varieties of Nicotiana: tobacco(Nicotiana tabacum), with 2-5% nicotine content, andmapacho (Nicotiana rustica), with 5-14% nicotine
content (39).
The oldest record of the insecticidal properties oftobacco is in a document from 1690 stating that it wasused to exterminate lace bugs. In 1746, Collinson
discovered that it was effective against the plumweevil(40). In 1910, Gillette used nicotine sulfate tocontrol codling moths in pears and peaches (41).

In Japan, tobacco extract was produced by the
Monopoly Bureau in 1908, while Yokohama Ueki
started importing nicotine sulfate from the United Statesin 1910 (42), (43). It was found to be effective against allkinds of pest insects, such as aphids, thrips, rice borers
and moths in rice, vegetables and fruit trees, andbecame widely popular during the 1910s and 1920s.
Before the war, Japan was using 100 tons of nicotine
sulfate and 2,000 tons of tobacco powder; in the late
1950s, even after synthetic pesticides such as DDT and
BHC appeared, Japan was still using 300 tons of
nicotine pesticides. However, the role of nicotine
pesticides all but died out once other high-performancepesticides appeared. The biggest drawback with
nicotine is that it is highly toxic to mammals and has
been designated as a poison. The median lethal dosage
LD50 for nicotine sulfate in rats is 75-83mg/kg (44).
The mode of action of nicotine produces an insecticidal
effect by bonding to the nicotinic acetylcholine
receptors (nAChR) in the synaptic membrane andcausing antagonistic stimulation (45).
Although nicotine thus poses a problem of acutetoxicity to mammals, it was used as a highly effective
pesticide from the late 19th century through to thepost-war era of increased food production. Many
researchers worked hard to develop new nicotine
analogues, but they went for a long time without any
success. However, in the 1990s, nearly 50 years after
the war, a number of so-called neonicotinoids began toappear, as shall be mentioned later in Section 4.20:
Imidacloprid. These pesticides were modeled on thecomposition of natural pesticides and are highly
effective without being toxic to mammals. Who at thetime could have predicted such an amazing
development?
3.3.6. Derris (Rotenone): South Asian Leguminous
Plant Root
Derris (rotenone) (Fig. 3.20) is a pesticide compoundfound in the root of the derris plant (Derris elliptica)
from South Asia.

and use them as poison for arrows or for putting inwaterways to catch fish (46). The first documented
references to it are Rumphius in 1747 as a fish poison(47)
and Oxley in 1848 as a pesticide (48). In terms ofchemistry, Nagai isolated its chemical composition in1902 and called it rotenone (49). In 1932, Takei et al.,Butenandt et al. and La Forge et al. each independently
determined and published its chemical structure.
Miyano of the University of Tokyo accomplished its
total synthesis in 1958 (50), (51). Chemical research on
rotenone has thus been spearheaded by Japanese
researchers.
Derris was one of the top three natural pesticides in
pre-war Japan, along with pyrethrum and nicotine. First
imported to Japan from Singapore in 1912, it was soon
found to be very effective. Factory production began in
1923, with a number of different formulations, such as
derris powder, derris emulsion concentrate and derrissoap. While it was not as fast-acting as pyrethrum, it
was reliably lethal against pest insects such as aphids,
lace bugs and various leaf beetles. While it had thedisadvantage of being highly toxic to fish it had theadvantages of being relatively harmless to mammals
and not residual on crops, as it would break down anddissipate quite early on after application.
Later studies have shown that the mode of action ofrotenone achieves an inhibitory effect on the electrontransport chain in the respiratory system that governs
energy metabolism. It is known to work as an
insecticide by inhibiting electron transfer in
NADH-ubiquinone oxidoreductase Complex I in the
mitochondrial respiratory chain (52), (53), (54).
Production of rotenone increased greatly from the late
1920s onwards, mainly by Nihon Nohyaku, which hadtaken over Derris Seizai, the main manufacturer ofderris products. It became one of the leading pesticides
in Japan, along with pyrethrum and nicotine, with 250
tons used in 1942. However, imports from South Asia
were suspended during the war and there was adramatic decline in the amount of derris used. While it
made a brief comeback after the war, it was designatedas a water pollutant due to its high fish toxicity. It
declined in use from the late 1950s onwards and its
registration finally lapsed in 2006.
3.3.7. Chloropicrin: the First Synthetic Organic
Pesticide

Fig. 3.20. Derris (Rotenone)
Derris has long been known to have insecticidal andfish toxic properties. People would grind up the roots

Chloropicrin (Fig. 3.21) has a long history. Scottish
chemist John Stenhouse discovered it by chlorinating
picric acid in 1848 (55). It is a volatile liquid with a very
high vapor pressure of 2.7kPa/20ºC at its boiling pointof 112ºC. Being highly lachrymal, it was used as teargas in the First World War.

Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

29

W. Moore discovered the effectiveness of chloropicrin
against maize weevils in 1917 and this discovery was
published by Bertrand. Ryo Yamamoto of RIKEN
accordingly synthesized the first chloropicrin
compound in Japan in 1918 and validated the effect thefollowing year. At the time, carbon disulfide (CS2) orhydrocyanic acid gas was used for fumigating
warehouses; the former was potentially explosive andcould lower the quality of stored grain, while the latter
was highly toxic to humans. Chloropicrin grew inpopularity because of these drawbacks with the existingproducts. However, chloropicrin has its own drawbackin that it is highly lachrymatory, although this is atransient symptom. This disadvantage led to theappearance of methyl bromide (CH3Br) in 1950, which
kept up a steady 1,000-ton shipment volume until
around 1985.

1934: Nippon Soda (Nihongi factory), Nippon Kayaku(Ogura factory)
1946: Mitsubishi Kasei
After the war, chloropicrin became a key chemical
agent, with its use in soil fumigation becoming anestablished countermeasure against Granville wilt in
tobacco and root-knot nematodes. The chloropicrin use
steadily increased as it became more widely adopted asa countermeasure against damage from continuous
cropping – not only for tobacco, but also for fruit andvegetable plants such as potatoes, sweet potatoes,
cabbage, Chinese cabbage, daikon radish and eggplants.
Chloropicrin shipments reached 5,000 tons in the late1970s; by 2009, this figure had grown to 9,000 tons andwas worth ¥9 billion.
As mentioned above, chloropicrin was firstmanufactured 90 years ago and remains a major
long-lived pesticide with a wide range of uses.
However, chloropicrin is an acutely toxic deleterious
and highly irritant substance. Farmers have to take extra
care, as it is very awkward to handle. Nevertheless, it isstill being sold in high volumes for the following
reasons.

Left: Chloropicrin
Right: Chloropicrin Product from the Late 1940sFig. 3.21. Chloropicrin and a Chloropicrin Productfrom the Late 1940s (provided by Mitsui
Chemicals)
Around the same time it was being used for warehouse
fumigation, chloropicrin also became known for its
effectiveness as a soil sterilizer and insecticide whenused to fumigate soil. Its efficacy against soil diseases
and nematodes, such as the various insect pests on
lettuce, mulberries, ginger, burdock, potatoes and sweet
potatoes, was confirmed during the 1910s and 1920s.
However, it did not become widely popular until after
the war, as it was difficult to handle because of its
strong irritativeness and highly priced for the time (56).
Chloropicrin was the first synthetic organic pesticide inJapan, produced by the following companies as shown
below. Fig. 3.22 shows a chloropicrin product from thelate 1940s.
1921: Sankyo (Mukojima factory)
1928: Hodogaya Soda
1930: Mitsui Chemicals

30

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan(1) Effective insecticide-fungicide(2) No observed residue on crops(3) Localized production of fruit and vegetables;
facilitated large-scale agriculture of fewer varieties(4) TheJapan
Chloropicrin
Manufacturers’
Association has developed and promoted
application methods and dedicated applicationequipment to ensure safety for users and avoid
harm to workers or surroundings(5) Methyl bromide, which has the same effects as
chloropicrin,wasdesignatedasan“ozone-depleting substance” in 1992 and has been
restricted in use except where absolutely necessary(57)

In the future, the hope is that we will not simply rely on
treatments such as chloropicrin to control soil diseases,
but instead develop various other pest control
technologies from a holistic approach that incorporates
other methods, such as using water or steam to sterilize
soil, crop rotation or developing new cultivation
methods.
3.3.8. Summary of the late 19th Century to the
Pre-War Era
Above, we have given an overview of pesticides inJapan from the late 19th century through to the pre-war
era. This period saw the development of new
agricultural technology and the emergence of new
pesticides that could not have previously been imagined.
This was a time of vastly improved agricultural

productivity. However, the war dealt a serious blow tothis productivity; Japan’s defeat was catastrophic to thegrowing pesticide industry. Agricultural production
dropped dramatically due to wartime shortages. Fig.
3.22 shows posters promoting food security in wartime.

neonicotinoids that have appeared since the 1980s.
Table 3.23 shows the volumes and values of the main
pesticides produced before and during the war (1).
There are several distinguishing characteristics about
this table. Firstly, there is a major increase in overallpesticide production from the late 1920s onwards.
Usage increased by nearly four times from just under¥6 million around 1935 to a peak figure of ¥21 million
in 1941. This figure plummeted due to disruptions andshortages until the end of the war.
The main insecticides were inorganic arsenicals, thenatural products pyrethrum, nicotine and derris, andchloropicrin, used for fumigation. While machine oil
was used from the 1910s to the 1930s, it dropped out ofuse due to the war. The only fungicides used during thistime were copper agents and lime sulfur. Mercury
compounds were recommended as a countermeasure toboost food production during the war and began toincrease in use from around 1939. They started to
become popular from around the late 1940s due to theireffectiveness at disinfecting seeds.

Wartime Posters for Increased Food Production (Hokkaido, Ibaraki)

Fig. 3.22. Wartime Posters for Increased Food
Production (provided by the Japan Plant Protection
Association Plant Protection Museum)

While many synthetic organic pesticides appeared
during and after the post-war rebuilding of Japan, given
the level of science and technology at the time, there is
no way anyone could have foreseen the current state ofJapan’s pesticide industry.

Some of the pesticides that appeared during this time –machine oil, lime sulfur, copper agents and chloropicrin– are truly long-lived pesticides, as they are still used
today. Pyrethrum and nicotine are also important, as
they were the sources for the synthetic pyrethroids andTable 3.23. Volumes and Values of Pesticides Produced Before and During the War (58)
1934
vol.
821
8
131
214

val.
481
4
340
366

1939
vol.
2,043
817
231
656

Nicotine sulfate
Tobacco powder
Machine oil emulsion
Soda compound
Pine resin compound

88
726
1,405
415

571
79
84
48

Pine resin
Caustic soda
Chloropicrin
Formalin
Sodium cyanide

303
20
99
233
21

Copper sulfate
Quicklime
Mercury
Copper agents
Lime sulfur

Volume unit: tons
1942
vol.
val.
911
911
2,403
985
145
72
252
958
2,100
5,775

Value unit: ¥1,000
1945
vol.
val.
250
240
1,200
640
42
25
24
912
640
1,613

val.
2,025
378
817
1,889

1941
vol.
1,168
3,213
170
105
2,400

val.
1,168
1,317
87
399
6,600

112
1,990
2,070
-

1,059
197
805
184

80
2,000
1,170
-

665
220
269
-

37
2,131
637
-

307
234
147
-

10
1,000
50
-

24
110
12
-

74
52
268
169
50

40
524
227
1,400
300

18
157
710
910
810

550
1,200
300

1,529
804
372

500
1,130
200

1,390
757
248

45
500
100

158
335
124

1,526
4,380
58
9,367

1,049
207
29
774

4,500
15,00020
22,500

2,250
370
250
3,000

5,427
15,000
18
9,000

2,876
345
162
810

4,300
10,000
51
8,500

2,279
230
459
765

2,700
4,000
35
750
6,000

1,782
92
415
960
540

Other (spreading agents, etc.)

819

963

11

1,834

2,977

3,871

3,100

3,416

970

1,367

Total

-

5,608

-

17,663-

21,494-

18,933

-

9,349

Item
Lead arsenate
Calcium arsenate
Ferric arsenate
DerrisPyrethrum

Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

31

Cited References(1) Kimura. Nihon Nōgyō-shi [History of Japanese Agriculture],
Yoshikawa Kobunkan, 2010, p. 266.

(27) Ueyama. Jochūgiku Saibai-sho [Guide to Pyrethrum Cultivation],
Ueyama, Eiichirō (ed.), Ueyama Eiichirō Nōen, 1890.

(2) Ministry of Agriculture, Forestry and Fisheries, Agricultural andHorticultural Bureau, Agriculture Division. Nihon no Inasaku [RiceCultivation in Japan], Chikyusha, 1984.

(28) Katsuda et al., “Studies on the degradation of pyrethrins” Botyu
Kagaku 20. p15-21 (1955)(3) Sato. Nōyaku to Jogai [Pesticides and Damage Control], Hōbun Shoin,
1947, p. 128.

(29) Katsuda et al., “Studies on the degradation of pyrethrins” Botyu
Kagaku 21. p139-144 (1956)(4) Ministry of Agriculture, Forestry and Fisheries, Development andPromotion Bureau, Plant Protection Division. Nōyaku no Ayumi [Historyof Pesticides], Executive Committee for the Plant Protection Project
Development 10th Anniversary Convention, 1960, p. 1.

(30) Fujitani: “Chemistry and Pharmacology of Insect Powder” Arch. Exp.
Path. Pharmak. 61. p47-75 (1909)(5) Hyaku Nijū-nen-shi [A 120-Year History], Nissan Chemical Industries,
2007, p. 43.
(6) Ministry of Agriculture, Forestry and Fisheries, Development andPromotion Bureau, Plant Protection Division. Nōyaku no Ayumi [Historyof Pesticides], Executive Committee for the Plant Protection Project
Development 10th Anniversary Convention, 1960, p. 146.

(31) Yamamoto: “The Insecticidal Principle in Crysanthemum
cinerariaefolium. Part II and III. On the constitution of pyrethronic acid” J.
Chem. Soc. Japan 44. p311-330 (1923)(32) Staudinger et al.: “Insektnotende stoffe I-VI and VIII-X. Helv. Chi.
Acta. 7. p177-458 (1924)(33) Laforge et al.: “Constituents of pyrethrum flowers XVIII. The structure
and isomerism of pyrethrolone and cinerolone” J. Org. Chem. 10
p114-120 (1945)(7) Sato et al. Nōyaku-gaku [The Study of Pesticides], Asakura Shoten,
2003, p. 63.

(34) Crombie et al.: “The chrysanthemum carboxylic acids. VI. The
configuration of the crysanthemic acids. J. Chem. Soc. p470 (1954)(8) Fungicide Resistance Action Committee (FRAC):
http://www.frac.info/frac/publication/anhang/FRAC-Code-List2011-final.
pdf, 3 May 2012, accessed 1 November 2012.

(35) Katsuda et al. “The absolute configuration of naturally derived
pyrethrolone and cinerolone. Bull. Agric. Chem. Chem. Soc. Japan 22
p427-428 (1958)(9) Matsunaka. Nōyaku no o-Hanashi [Talk of Pesticides], Japan Standards
Association, 2000, p. 121.

(36) Eliott: “Synthetic pyrethroids, in Synthetic Pyrethroids, ed by Elliott”
Amer. Chem. Soc, Washington DC. p1-28 (1977)(10) Ministry of Agriculture, Forestry and Fisheries, Development andPromotion Bureau, Plant Protection Division. Nōyaku no Ayumi [Historyof Pesticides], Executive Committee for the Plant Protection Project
Development 10th Anniversary Convention, 1960, p. 136.

(38) Ueno. Tabako no Rekishi [The History of Tobacco], Taishukan, 1988.

(11) Notice of the Ministry of Agriculture, Forestry and Fisheries No. 59,
dated 27 October 2000.
(12) Sato et al. Nōyaku-gaku [The Study of Pesticides], Asakura Shoten,
2003, p. 5.
(13) Ministry of Agriculture, Forestry and Fisheries, Development andPromotion Bureau, Plant Protection Division. Nōyaku no Ayumi [Historyof Pesticides], Executive Committee for the Plant Protection Project
Development 10th Anniversary Convention, 1960, p. 146.
(14) Ministry of the Environment. Hiso Oyobi sono Kagōbutsu ni
kakawaru Kenkō Risuku Eikyō Hyōka ni tsuite (An) [Impact Assessmenton the Health Risks Related to Arsenic and its Compounds (Draft)],
http://www.env.go.jp/council/07air/y073-10/mat05_2.pdf (accessed 6
May 2012).
(15) Tanaka. Nōyaku Seigi [Detailed Exposition on Pesticides], Yokendo,
1956, p. 79.
(16) Toku Nō 1, Nihon Tokushu Noyaku Seizo, 1966, p. 19.
(17) Horio. Nōyaku Koto-Hajime [Pesticide Guide], Nihon Tokushu
Noyaku Seizo, 1966, p. 57.
(18) Kincho no Hyakunen [Kincho Centennary], Kincho, 1988.
(19) Tanaka. Nōyaku Seigi [Detailed Exposition on Pesticides], Yokendo,
1956, p. 198.
(20) Katsuda,Y. “Progress and Future of Pyrethroids” Topics in Current
Chemistry 314 p1-30 (2012) Springer Verlag Berlin Heidelberg(21) Katsuda, Y. “Development of and Future Prospect for Pyrethroid
chemistry”, Pestic Sci., Vol. 55, 1999, pp. 775-782.
(22) Sato. Nōyaku to Jogai [Pesticides and Damage Control], Hōbun
Shoin, 1947, p. 222.
(23) Matsubara. Nihon Nōyaku-gaku Shinenpyō [Chronology of Pesticide
Studies in Japan], Center for Academic Societies, 1984, p. 24.
(24) Kuwayama. “Jochūgiku [Pyrethrum]”, Nōyaku Koto-Hajime[Pesticide Guide], Nihon Tokushu Noyaku Seizo, 1966, p. 20.
(25) Katsuda. “Piresuroido Kagaku no Hatten to Tenbō [Progress andFuture of Pyrethroids]”, Nihon Satchū-zai Kōgyō-kai 30-nen no Ayumi[30-Year History of the Household Insecticide Industry Association ofJapan], Household Insecticide Industry Association of Japan (ed.), 2001,
p. 110.
(26) “Piresuroido Kagaku no Hatten to Tenbō [Progress and Future of
Pyrethroids]”, Nihon Satchū-zai Kōgyō-kai 30-nen no Ayumi [30-Year

32

History of the Household Insecticide Industry Association of Japan],Household Insecticide Industry Association of Japan (ed.), 2001, p. 136.

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan(37) Kincho no Hyakunen [Kincho Centennary], Kincho, 1988.
(39) Yamamoto. Nōyaku-gaku [The Study of Pesticides], Nankodo, 1959, p.
83.
(40) Tanaka. Nōyaku Seigi [Detailed Exposition on Pesticides], Yokendo,
1956, p. 218.
(41) Sato. Nōyaku to Jogai [Pesticides and Damage Control], Hōbun
Shoin, 1947, p. 318.
(42) Matsubara. Nihon Nōyaku-gaku Shinenpyō [Chronology of Pesticide
Studies in Japan], Center for Academic Societies, 1984, p. 27.
(43) Nōyaku no Ayumi [History of Pesticides], Executive Committee for the
Plant Protection Project Development 10th Anniversary Convention, 1960,
p. 135.
(44) Nicotine Sulfate Research Committee. “Ryūsan Nikochin no Dokusei
Shiken no Gaiyō [Overview of Nicotine Sulfate Toxicity Tests]”,
Pesticide Newsletter Special Edition, 1993, p. 4.
(45) M. Tomizawa, and I. Yamamoto: J. Pestic. Sci., 18, (1) p91 (1993)(46) Takei et al. Derisu [Derris], Asakura Shoten, 1944, p. 1.
(47) G.E. Rumphius: Herbarium amboinense, Amsterdam. Pt. 5, 492P.,
illus.Amsterdam, (1747)(48) T. Oxley: Some account of the nutmeg and its cultivation. J. IndianArchiperago and East Asia, 2(10),641-660, (1848)(49) Nagai. Journal of the Chemical Society of Tokyo, Vol. 23, 1902, p. 744.
(50) M. Miyano et al., Chem. Ber., 91, Nr.10 (1958)(51) M.Miyano et al., Chem. Ber.,93, Nr.5,Nr.8 (1960)(52) Fukami. Chemistry and Biology, Vol. 10, No. 8, 1972, p. 506.
(53) Yoshida. Chemistry and Biology, Vol. 26, No. 8, 1988, p. 506.
(54) Miyoshi. Chemistry and Biology, Vol. 33, No. 3, 1995, p. 151.
(55) Tanaka. Nōyaku Seigi [Detailed Exposition on Pesticides], Yokendo,
1956, p. 326.
(56) Kotake. “Kunjō-zai Kurorupikurin 70-nen no Ayumi [70-Year Historyof Chloropicrin Fumigation]”, Plant Protection, Vol. 45, No. 1, 1991, p.
23.
(57) Otaka. “Dojō Kunjō-zai o meguru Aratana Kadai [New Challenges
surrounding Soil Fumigation]” Symposium Abstracts, New Agenda on
Pesticide and Pest Control, Japan Plant Protection Association, p. 63.
(58) Excerpt from Nōyaku no Ayumi [History of Pesticides], Executive
Committee for the Plant Protection Project Development 10th Anniversary
Convention, 1960, p. 146.

3.4. Advancement of Modern
Synthetic Pesticides since the War
3.4.1. Overview
This section discusses the dramatic development ofsynthetic pesticides from the turbulent times during andafter the war to the present day, presenting this 70-year
period in four stages.
To begin, Section 3.4.2 discusses the rebuilding period(1945-1960), in which integrated chemical
manufacturers and other companies used overseas
technology licensing to start full-scale manufacture ofsynthetic organic pesticides. Next, Section 3.4.3
outlines the emergence of new domestically-invented
pesticides (1960-1970), when rising Japanesemanufacturers started developing their own products.
Section 3.4.4 discusses the tightening of regulations forproblematic pesticides and the emergence of substituteproducts (1970-1990), as well as the problems
occurring with toxicity and residues and how they weredealt with. Section 3.4.5 traces the time from when theindustry reached its full growth to when it had todownsize (1990-present) and discusses how challenges
were
faced
and
the
emergenceofultra-high-performance pesticides.
Compared with the crawling pace of technologicaldevelopments during Japan’s period of national
seclusion and the slow progress that was made on
inorganic compounds and natural pesticides in the late
19th and early 20th century, the 70-year period since thewar has been a time of accelerated technologicaldevelopment. Agricultural productivity has increased
and the food situation has improved significantly. While
the rise in productivity can of course be partly attributed

to selective breeding, better cultivation techniques andthe widespread use of agricultural machinery, anothermajor contributing factor is the development of new,highly effective pesticides. Let us consider ricecultivation, for example. Disease control over rice blastand other diseases, pest control over insects such as riceborers and leafhoppers and the herbicides that weredeveloped after the war doubled the previously unstable
crop yield to a steady 500kg/10a. The advent of
mechanization and the on-going development ofeffective herbicides reduced the labor hours per unit
area to almost one-sixth of what it was previously andmade the back-breaking task of weeding under theblazing sun a thing of the past. Table 3.24 shows a timetrend of rice yield and labor hours per 10a of paddy
rice.
While the above is the “lighter” side of pesticides, there
is also a “darker” side. This has been an age ofproblems: safety issues resulting from pesticides thatare highly toxic to mammals, issues with residual
pesticides in produce, soil and waterways, as well as theissue of environmental impact on beneficial organisms
and fish. The post-war rebuild period saw the import of
DDT, BHC and Drins, as well as mass industrial
production of organophosphates and PCP. These were
all released into crop fields. These early pesticides wereground-breaking inventions for the science andtechnology of the time and their superior pest control
properties ensured their widespread popularity.
However, the science and technology of the day was
unable to keep track of the risks involved with theseproducts. Many farmers suffered acute poisoning fromfailing to take appropriate care when handling thesepesticides in the field.

Cultivated area (ha)Yield per 10a (kg)Labor hours per 10a (h)Fig. 3.24 Trends in Rice Yield and Labor Hours over Time (1), (2)Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

33

Table 3.25 compares the instances of pesticide
poisoning between this period and the present day. The
table shows that 40-45 deaths and 700 cases of
non-fatal poisoning occurred due to the widespread useof highly acutely toxic pesticides such as parathion
from the late 1950s to the early 1970s.

aspects: problematic pesticides were restricted and theregulations were tightened. Businesses shifted the aimof their research to developing pesticides that were safer
and less environmentally impacting. This was achieved
from the 1970s onwards with a succession of highly
effective, less toxic, less residual pesticides to replace
the existing products.

As mentioned in the notes, this table does not include
applications other than the intended use (such as
suicide/homicide). Although parathion was designatedas a specific toxic substance in 1955 and major
restrictions were put on its usage, it actually grew inusage because it was a wonder drug for rice and fruit
trees and it was quite inexpensive. Eventually, a law
change in 1971 banned its use for the sake of safety andit was replaced by less toxic pesticides. As a result, thenumber of accidents gradually decreased; from the
1990s, the number of deaths and poisonings fromspraying pesticides dropped by more than 90%.

From the 1990s onwards, a number of new, highly
effective pesticides were developed to fulfill thesecriteria. Many of these became world-famous Japanese
products. Typical examples are the neonicotinoids,
using nicotine as a lead compound, and new, effective
miticides with novel modes of action.
This era has seen a shift towards developing safer, moreenvironmentally-conscious agricultural technology
based on the idea of “sustainable agriculture.”
Pesticides released into the environment must now havea lower environmental impact than ever before. Whileagriculture in itself is an act contrary to nature in that it
involves cultivating a large amount of a single crop, thisis an age in which sustainable agriculture must preserve
the environment as much as possible. We need toincrease our food production, but we can no longer
expect an increase in arable land. The role of pesticides
has now become all the more crucial. To a certain
extent, there has to be a trade-off between this and the
difficult task of environmental protection and harmony.
In the future, we will need to integrate all areas ofscience and technology such as cultivation methods andbreeding; we cannot rely on pesticides alone.

There were also problems of residual pesticides oncrops and soils from using large amounts of pesticides
with long-lasting effects, as well as issues with waterpollution and negative impacts on fish and otherbeneficial organisms. We cannot deny that society at thetime could not have expected these consequences andthat the appropriate legislation came a little too late. The
level of science and technology at the time was also
unable to keep up with the widespread popularity ofthese new pesticides.
Successive steps were made to rectify these negative
Table 3.25. Instances of Pesticide Poisoning (3)(individual persons)Year (average)

Deaths (no. while spraying)

1957-1960
1961-1965
1966-1970
1971-1975
1976-1980
1981-1985
1986-1990
1991-1995
1996-2000
2001-2005
2006-201045
38(20)
39(15)
21(4)
17(6)
12(2)
6(2)
3(1)
2(0)
4(1)
3(0)

Poisoning(no. while spraying)681
322(296)276(252)
233(216)
158(147)
68(59)
54(45)
20(13)
52(41)
64(54)
50(28)

Total (no. while spraying)726
360(316)315(267)
254(220)
175(153)80(61)
60(47)
24(14)
54(41)
68(55)
53(28)

Cited References: Partially modified from Nōyaku Gaisetsu [Pesticide Overview], Japan Plant Protection Association, 2011.
Notes:
Figures for 1957-1975 are taken from a survey by the Ministry of Health and Welfare Pharmaceutical Affairs Bureau
Figures for 1976-2000 are taken from a survey by the Ministry of Agriculture, Forestry and Fisheries Development and Promotion Bureau
Plant Protection Division
Later figures are taken from a survey carried out on all the administrative divisions of Japan through collaboration between the Ministry ofAgriculture, Forestry and Fisheries and the Ministry of Health, Labour and Welfare
http://www.maff.go.jp/j/nouyaku/n_topics/h20higai_zyokyo.html (accessed 29 July 2012)
These statistics do not include suicides/homicides
Accidents that do not occur while spraying are the result of misuse or accidental ingestion

34

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan

Cited References(1) Table created from the Ministry of Agriculture,
Forestry and Fisheries crop statistics
http://www.maff.go.jp/j/tokei/kouhyou/sakumotu/sakkyo
u_kome/index.html#r (accessed 5 November 2012).
(2) Table created from 50-Nen-shi [50-Year History],
Hokko Chemical Industry, 2001, p. 283.
(3) Nōyaku Gaisetsu [Pesticide Overview], Japan Plant
Protection Association, 2011.
3.4.2. The Rebuilding
Technology Licensing

Period(1945-1960):

Rebuilding Japan after the war was a major challenge.
The agricultural environment was a serious issue.
Agricultural productivity had dropped significantly –65% of that of the 1930s – due to a shortage of laborand fertilizer. Overseas food imports had beensuspended and supply to the government by farmers
had dropped off, while the consumer population had
increased as five million overseas Japanese were
repatriated. Japan entered an unprecedented food crisis.
A rationing system was established and food assistance
was provided by the United States. The land reform in1946 set tenant farmers free. The government took
measures such as enacting the Agricultural
Cooperatives Act in 1947 (1). The outbreak of the
Korean War in 1950 brought about a special
procurements boom which hastened the rebuilding ofJapan. The rebuild was so quick that Japan was “nolonger in the post-war period” by 1956.
The pesticide industry was also seriously damaged.
Worth ¥21.5 million in 1941, this figure had dropped to¥9.3 million by 1945. The revival of the pesticideindustry started with the surviving pre-war pesticidecompanies and major chemical companies such asalkali industries beginning to manufacture pesticides
using overseas technology licenses. The government
was also active in passing legislation and taking othermeasures to prevent the mass production of inferior
goods.
(1) Enacting of the Agricultural Chemicals Control
Act
Although pesticide production bloomed from the late
1920s onwards, the government had no particularpolicies in place regarding production methods or
product quality and offered only a moderate degree of
guidance in this area. A rapid increase in pesticide
imports at this time saw the government set up an
Association for Regulating Pesticide Imports in 1938
and begin to regulate the import and distribution of four
products: nicotine, derris, lead and pine resin. In 1940,
the government started regulating the distribution ofagricultural agents; this practice continued until 1950.
Turbulent times during and after the war saw a shortageof all goods, not least of all an extreme shortage ofpesticides. This resulted in overproduction of inferior
products and many ineffective pesticides appeared on
the market. While there was a movement towards
tighter control over pesticides from the late 1920s, thelegislation was delayed because of the war. The
government finally enacted the Provisions of the
Ministry of Agriculture and Forestry on the Inspection
and Certification of Agricultural Agents in 1947.
Shipments of pesticides were inspected by the Pesticide
Association, established the previous year, with the aim
to facilitate the spread of high quality pesticides that had
been granted certificates of inspection.
The following year, in August 1948, the more binding
Agricultural Chemicals Control Act was enacted. Thislaw made it mandatory to register and label pesticides.
The government established the new Ministry ofAgriculture and Forestry Pesticide Inspection Center(now the Food and Agricultural Materials Inspection
Center (FAMIC)). Manufacturers could not sell any
pesticides that had not been inspected here andregistered by the Minister of Agriculture and Forestry.
There were 449 pesticide registrations in 1948.
Thus, the focus of the Agricultural Chemicals Control
Act was to ensure that the manufacture of high quality
pesticides was stable and that they were provided tofarmers in order to boost food production, the urgent
issue of the day. From that time on, high-quality,
synthetic organic pesticides began to appear at a ratethat has not been replicated since. These products madea huge contribution to increasing agricultural
productivity and saving labor.
The Poisonous and Deleterious Substances Control Act
was enacted in 1950 to prevent injuries from highly
toxic chemical substances such as pesticides (except forpharmaceutical products or quasi-pharmaceuticalproducts). For more details on the classification of
poisons and deleterious substances, see Section 2.3.4.
This law stipulates matters relating to the manufacture,import, sale, labeling, storage and disposal of poisonousand deleterious substances. Any substance that is not
categorized as a poisonous or deleterious substance istreated as an “ordinary substance” and this law does not
apply. In 1955, a high proportion of pesticides produced
were toxic, with 27.7% designated as specific toxic
substances, 20.2% as poisons and 9.4% as deleterious
substances. Given the state of society and the level ofscience and technology at the time, there was little
choice but to use pesticides that were effective yethighly toxic.
(2) The Emergence of Organochlorine Pesticides(DDT, BHC, Drins, D-D)
The ground-breakingly effective organochlorine
pesticide
DDT(abbreviationofdichloro-diphenyl-trichloroethane) was introduced to
Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

35

Japan during this period (Fig. 3.26). Austrian chemist
Othmar Zeidler first synthesized DDT fromchlorobenzene and chloral in 1874. DDT became thefocus of much attention once Paul Müller (1899-1965)
from Swiss company J.R. Geigy discovered its
insecticidal properties in 1938 (3), (4), (5). Müller wasawarded a Nobel Prize in Physiology or Medicine in1948 for his findings.

Fig. 3.26. DDT

However, the use of large quantity of DDT brought thebuildup of DDT resistance in insects, so its efficacy
became less consistent. In agriculture, DDT was notadequate from the start against aphids, scale insects andleafhoppers and was gradually replaced by BHC(benzene hexachloride) (Fig. 3.28).

Fig. 3.28. γ-BHC

DDT was introduced to Japan by the GHQ right after
the war. It was put out in large quantities to control
communicable diseases by eradicating fleas, lice andflies. Further investigations were carried out on its use
as an agricultural pesticide and it was soon shown to beeffective against rice borers and other vegetable pests,
such as cutworms and caterpillars. Later studies showed
the mode of action for DDT as affecting insect nerveaxons, like pyrethrins, causing abnormal stimulation by
preventing sodium ion channels from closing (6). It has
relatively low toxicity to mammals.
As Nichizui Trading had a patent license from J.R.
Geigy, Nippon Soda and other alkali companies
sublicensed the patent and started industrial productionof DDT in 1947. In 1951, production reached 1,600
tons.

BHC was first synthesized by English scientist Michael
Faraday (1791-18967). Slade et al., of British company
ICI, and Frenchman Dupire discovered in 1941-1942
that its gamma isomer (called Lindane) had highly
insecticidal properties (7).
BHC was introduced to Japan a little later than DDT. It
became widely used in agriculture as it was effective
against a wide range of pest insects, especiallyleafhoppers, a major pest in rice cultivation. The
existing pest control method of using whale oil ormachine oil on rice fields fell out of use as BHC
appeared on the scene.
As luck would have it, BHC had no patent restrictions.
In 1947, Asahi Glass and Kanegafuchi Chemical
started manufacturing the technical product, while
Nippon Soda, Toyo Soda, Mitsubishi Kasei and otheralkali companies also started manufacturing thechemical. By 1950, there were 15 companies producing
it; by 1954, there were 17. By 1958, these companies
were producing more than 2,000 tons a month (8).
Production of the gamma isomer Lindane started in
1952.
The effects of BHC differ from those of DDT. BHC
suppresses the effects of gamma-aminobutyric acid
(GABA), which controls the release of acetylcholine
from the cholinergic presynaptic membrane in thecentral nervous system, thereby releasing acetylcholine
and causing abnormal stimulation (9).

J. R. Geigy DDT PatentFig. 3.27. J. R. Geigy DDT Patent (Japan Patent No.
169665)36

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan

Drins are organic chlorine compounds with cyclic diene
structures. Three of them, Aldrin, Endrin and Dieldrin,
were introduced to Japan in 1955 by Shell USA. In
1957, Velsicol introduced Heptachlor, and they started
growing in popularity across Japan. They received a lotof attention as they were generally more effective than
DDT and BHC; in 1959, Japan had imported more than
1000 tons of active ingredients. However, usage ofthese products was later restricted as they were highlyacutely toxic and highly toxic to fish; this restriction
dropped their usage dramatically.

Fig. 3.29. Drins
Shell also developed soil fumigant D-D to eradicate
root-knot nematodes, a soil pest harmful to fruit andvegetable plants. This product was used in Japan from1950 onwards. The main ingredient in D-D is
1,3-dichloropropene. Its mode of action is achieved byreactive chlorine reacting to and inhibiting SH enzymes.
This product is still in production, with about 9,000 tons
being produced per year, worth around ¥5 billion.
(3) Introduction of Organophosphate insecticides(Parathion, Malathion, Diazinon, Dipterex, EPN,etc.): Ground-Breakingly Effective, yet Highly
Toxic…
Gerhard Schrader (1903-1990), of Bayer under IG
Farben, researched organophosphate compounds withthe aim of developing new insecticides. In 1944, hediscovered parathion (10), (11). While Schrader was also
famous for inventing Sarin and other nerve gases, theaim of most of his research was agricultural
applications. There are two types of parathion: ethyl
ester (parathion) and methyl ester (methyl parathion)(Fig. 3.30). With patent rights going to the Allies at theend of the war, American Cyanamid (ACC) obtained
the patent in the United States and gained the Japanese
patent as well (12).

Parathion

Methyl Parathion

Fig. 3.30. Parathion and Methyl Parathion (Folidol)
Parathion was introduced to Japan in 1951 by Bayer
under the name “Folidol E605.” It became theimmediate focus of attention, as it was more effective
than BHC and DDT against the rice borers that would
eat their way into the pith of the plant. Registered on thepesticide register in 1952 and subsidized by the
Ministry of Agriculture and Forestry’s Increased Food
Production Plan, it became wildly popular. To meet thedemand, Nihon Tokushu Noyaku started importing itfrom Bayer, while Sumitomo Chemical started
importing it from ACC. The volume of imports
skyrocketed from 8,200 tons in 1953 to 240,000 tons
the following year (13).
Parathion works as an insecticide by blocking
neurotransmission with an inhibitory effect onacetylcholinesterase (AChE), a catabolic enzyme foracetylcholine,whichisresponsibleforneurotransmission. Since mammals also have thisneurotransmission mechanism, it is highly acutely toxic
to humans and animals to varying degrees. The acutetoxicity of parathion and methyl parathion in rats is
10mg/kg and 30mg/kg respectively, equal to that ofpotassium cyanide. As parathion is also permeable
through skin, care must be taken by those who spray it
and anyone entering fields on which it has been sprayed.
Consequently, it was designated as a “specific toxic
substance” in 1953. People had been aware of thissafety issue from the outset, but they knew it was a very
effective pesticide, so it remained highly popular after
1953. Fig. 3.31 shows posters of products at the time
(10).

Posters for Folidol from Germany

Fig. 3.31. Parathion Emulsion (Folidol) (10)Domestic production of parathion was a naturalconsequence of the following circumstances. While
Sumitomo Chemical, Nippon Soda, Ihara Agricultural
Chemicals, Nissan Chemical, Mitsui Chemicals andother companies bid for the technology import license,
it was Sumitomo Chemical that won solemanufacturing rights from ACC in October 1954. The
following year, Sumitomo also gained a technology
import license from Bayer for methyl parathion andstarted producing 100 tons per month.
Thus, parathion made a major contribution to boosting
Japan’s food production, hailed as a wonder chemical
for its ground-breaking efficacy against the rice borer.
Before then, farmers had no means of avoiding the riceborer other than delaying their planting and growing;
however, this sometimes resulted in a lower yield due
to typhoon damage. Parathion solved this problem,
enabling earlier rice planting. A field trial at theagricultural experiment station in Shikoku showed 99%
control of rice borers in the parathion test area
compared to the control, with a 45-55% yield increase
and a better quality product (14).
Given the popularity of parathion, Sumitomo Chemical
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37

promptly set about researching and developing neworganophosphate compounds and had soon
successfully developed MEP (Fenitrothion, Sumithion),a less toxic substitute for parathion. This is discussed in
Section 4.3.

was eradicated with this formulation, meaning thatheavy fertilizing now resulted in higher crop yields.
Although Ceresan was a Bayer product, Ceresan lime
was a Japanese invention and thus worthy of special
mention here.

A number of other organophosphate insecticides
besides parathion have been developed in the West andintroduced to Japan (Fig. 3.32). The relatively low-toxic
ones are still used today. The numbers in parentheses
indicate the year registered (or when the registration
lapsed).

Organomercury pollution became a social and politicalissue with the outbreak of Minamata disease in the late
1950s caused by wastewater containing methylmercury
and Niigata Minamata disease in the Agano Riverregion in the late 1960s. It was then discovered thatusing mercuric pesticides containing phenylmercuric
acetate, such as Ceresan (although it had a different
chemicalstructurefromtheproblematic
methylmercury), resulted in microscopic mercury
residues on rice and that Japanese people’s haircontained three times more mercury than non-Japanese.
In light of these findings, the Ministry of Agriculture
and Forestry finally issued a notice “on the promotionof non-mercuric pesticides” in 1966. In 1968,
organomercury compounds stopped being used on rice
blast; in 1970, registration was cancelled for all
mercurial pesticides used on fruit and vegetable plants;
in 1973, registration was finally cancelled for seeddisinfecting as well, and organomercury pesticides
disappeared off the market.

Fig. 3.32. Organophosphate Insecticides(4) The Emergence of Rice Blast Mercury Dust
(Ceresan Lime)
As discussed in Section 3.3.3, organomercury
formulations such as Uspulun and Ceresan wereintroduced to Japan in the late 1930s and were mainly
used for seed treatment. They became widely popularfor controlling various diseases such as rice blast andwheat smut. Until then, the only available treatments
were Bordeaux mixture and lime sulfur, so theappearance of mercurial seed disinfectants was
ground-breaking in terms of side effects and ease ofuse.
There was a major outbreak of rice blast in Kochi andHiroshima in 1949. While applying Ceresan directly tofields did have some side effects on crops, researchers
discovered a method of mixing it with five parts
quicklime and dispensing it on fields in powder form,
thus producing the uniquely-Japanese Ceresan lime (15).
The results were outstanding and the formulation was
registered on the pesticide register in 1952. It was themain fungicide product used in Japan until 1965. Given
the success of Ceresan lime, developers worked on anumber of other organomercury formulations. In 1965,
130 dusts, 31 wettable powders and 29 emulsifiable
concentrates from 17 active ingredients were registered.
By 1966, usage had increased to 11.6 tons of dusts,
2,600 tons of wettable powder and 779 kl ofemulsifiable concentrates (16). While rice blast was
known to be often caused by heavy manuring culture, it
38

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan

Organomercury formulations played a major part ineradicating rice blast and other diseases and, although
they were highly residual, it took a long time for people
to finally stop using them, as there were very few
alternative pesticides. It is fortunate that no specificharm was caused as a result of this residual mercury.
(5) The Popularity of Herbicides such as
2,4-PA(2,4-D), 2,4,5-T, MCPA and PCP
2,4-PA(2,4-D), 2,4,5-T and MCPA are herbicides withplant-hormone-like auxin activity. They wereintroduced to Japan soon after the war (Fig. 3.33).

Fig. 3.33. Indoleacetic Acid and Phenoxyacetic Acid
Herbicides
The history of indoleacetic acid can be traced back to
the 19th century, when Charles Darwin (1809-1882)
discovered phototropism in gramineous coleoptiles (17).
Later, Kögl et al. showed that phototropism is the resultof a growth promotion activated by plant hormones. In
1934, they discovered that this growth promotion is
activated by indoleacetic acid (IAA) (18), (19). Kögl et al.

also discovered that using high concentrations of IAA
acts as a growth suppressant (20). This group of plant
hormones later came to be called auxins.
A number of researchers discovered substituted
phenoxyacetic acids with auxin activity in the early
1940s. For details on these discoveries, see J. Troyer (18)and Orvin C. Burnside (21). We shall provide a simple
history of this invention here.
William Templeman of ICI in the United Kingdom
discovered that substituted phenoxyacetic acidderivatives were effective against weeds among grain
crops and applied for a patent in 1941 (22). Separately,
FD Jones of ACP in the United States discovered thepesticidal properties of 2,4-PA and applied for a US
patent (23).
Another group from Rothamsted Experimental Stationin the United Kingdom and a group at Chicago
University in the United States also confirmed the sameherbicidal properties around the same time. Due towartime restrictions on the disclosure of patents andliterature, nobody knew until after the war that four
completely independent research institutions had madealmost identical inventions at almost the same time.
These chemicals were introduced to Japan right after
the war. The Japanese confirmed their effectiveness,with 2,4-PA (2,4-D, sodium salt) being registered inJapan in 1950. In 1951, Nissan Chemical and Ishihara
Sangyo obtained a patent license for 2,4-PA from ACP(later Amchem), followed by Mitsui Chemicals in 1955
with a patent license from ICI for 2,4-D, 2,4,5-T and
MCP. Companies started manufacturing their own
sodium salts, amine salts and esters. During this time,
there were disputes between ICI and ACP over thescope of the patents, but they eventually reached asettlement and each company started manufacturing
their own product.
The various salts and esters in 2,4-PA and MCPA
quickly became popular for their effectiveness on
broad-leaf weeds in rice and other crops. They played amajor role in economizing labor. While they initiallycould not be used without draining the rice fields, it wassoon discovered that 2,4-D and MCPA ethyl ester
granules could work directly on submerged fields.
These products became widely popular from around
1954.
PCP (Pentachlorophenol) (Fig. 3.34) was originallyused as a preservative for timber. PCP sodium salt was
first developed for agricultural use as a fungicide forfruit trees and registered as such in 1955.

Fig. 3.34. PCP
PCP is very effective against echinochloa species of
weeds that are not easily controlled with 2,4-PA andMCPA. It quickly became popular after it was
registered as a herbicide in 1956. It was later developed
into a granule formulation and was widely used against
barnyard grass, a major rice weed. By late 1955, it was
being used on around one third of Japan’s ricecultivation areas.
PCP’s mode of action works by inhibiting ATP
production through the uncoupling of oxidative
phosphorylation in the energy metabolism system (24).
PCP barium salt has received much attention as a
substitute for mercurials, as it is also effective against
rice blast. It was registered as a fungicide in 1963.
However, it was always known that PCP is highly toxic
to fish. The Ministry of Agriculture and Forestry issued
some administrative guidance at the end of 1960 as acounter-measure to prevent any harm, but fish wereaffected nonetheless. Major social and political issues
arose in the Ariake Sea and Lake Biwa regions in 1962
when the fishing industry was badly affected by PCP
effluence from a severe rainfall after PCP had beenused. The damage to the fishing industry caused by
PCP that year was as high as ¥2.6 billion in thecurrency of the day (25). The Agricultural Chemicals
Control Act was amended the following year as a result,to legally regulate the use of pesticides harmful toaquatic plants and animals. In 1971, PCP wasdesignated as a water polluting pesticide, with major
restrictions placed on its use. Other herbicides emerged
and its registration was finally revoked in 1990.
(6) Summary and Introduction to Other Pesticides
As mentioned above, the fifteen-year period after the
war was a time of rebuilding. It was a time in which a
number of highly effective, synthetic organic pesticides
were introduced to Japan from the West. It was a timein which Japanese pesticide companies usedtechnology licensing to build up their own development
capabilities and lay a foundation for later pesticide
development. Pesticide shipments were worth a mere
¥15 million in 1946, just after the war (or ¥21.5 million
in terms of the value of the yen in 1958); by 1959, thisfigure had grown to over ¥90 billion. Licensed
technology and imported goods accounted for around
50% of this market (26). This truly shows how
dependent Japan was on other countries during thistime.
However, this was also a time of magnified issues
Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

39stemming from the overuse of pesticides such asparathion that were highly toxic to mammals andhighly residual pesticides such as DDT, BHC andmercurials. A fixed negative image of pesticides as
being poisonous took hold among ordinary consumers.
It took a lot of time and the successive appearance ofimproved pesticides to rectify this.
The other pesticides introduced to Japan during thistime are given below (Fig. 3.35) without any additional
details.
Tokyo Organic Chemical brought in dithiocarbamate
fungicides Zineb (Dithane) and Ambam (Dithane
Stainless) from Rohm and Haas. Nippon Soda
introduced miticide CPCBS (Sappiran) from Dow,
while Nippon Kayaku brought in Chlorobenzilate(Akar) from J.R. Geigy. Nippon Soda also brought infungicide Triazine from Pittsburgh Coke & Chemical.

Fig. 3.35. Pesticides Introduced in the Post-War
PeriodCited References(1) Kimura. Nihon Nōgyō-shi [Japanese Agricultural
History], Yoshikawa Kobunkan, 2010, p. 338.
(2) Nōyaku no Ayumi [History of Pesticides], Executive
Committee for the Plant Protection Project Development
10th Anniversary Convention, 1960, p. 146.
(3) O. Zeidler: “Verbindungen von Chloral mit Brom- und
Chlorbenzol” Berichte der deutschen chemischen
Gesellschaft Vol 7. Issue2. 1180-1181 (1874)(4) P. Müller USP 2329074 (A) 1943-09-07(5) Japanese patent S20-169665.
(6) Yamashita et al. Nōyaku no Kagaku [The Chemistry ofPesticides], Buneido Publishing, 1996, p. 151.
(7) Fukunaga et al. Nōyaku Kagaku [Pesticide Chemistry],
Nikkan Kogyo Shimbun, 1960, p. 78.
(8) Nōyaku no Ayumi [History of Pesticides], Executive
Committee for the Plant Protection Project Development
10th Anniversary Convention, 1960, p. 186.
(9) Sato et al. Nōyaku-gaku [The Study of Pesticides],Asakura Shoten, 2003, p. 126.
(10) Toku Nō 1, Nihon Tokushu Noyaku Seizo, 1966, p.
347.
(11) Fukunaga et al. Nōyaku Kagaku [Pesticide
Chemistry], Nikkan Kogyo Shimbun, 1960, p. 33.
(12) Nōyaku no Ayumi [History of Pesticides], Executive
Committee for the Plant Protection Project Development
10th Anniversary Convention, 1960, p. 64.
40

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan(13) Nōyaku no Ayumi [History of Pesticides], Executive
Committee for the Plant Protection Project Development
10th Anniversary Convention, 1960, p. 188.
(14) Tsuchiyama et al. Ōyō Dōbutsu Gakkai Nihon Ōyō
Konchū Gakkai Gōdō Taikai Kōen Yōshi [Abstracts
from the Joint Conference of the Society of Applied
Zoology and the Japan Society of Applied Entomology]
1956, Vol. 16, 10 April 1956.
(15) Okamoto. “Seresan Sekkai no Kyōdō Kenkyū [Joint
Research on Ceresan Lime],” Nōyaku Koto-Hajime[Pesticide Guide], Nihon Tokushu Noyaku Seizo, 1966.
(16) Hori. Nihon Shin Nōyaku Monogatari [The Story of
New Japanese Pesticides], Japan Plant Protection
Association, 1973, p. 1.
(17) Darwin, C. R. 1880. “The Power of Movement in
Plants.” London: John Murray 592p
(18) James R. Troyer “In the beginning: The multiple
Discovery of the first hormone herbicides” Weed
Science, 49: 290-297. 2001(19) Kögl, F., A. J. Haagen-smit, and H. Erxleben. 1934“Über eine neues Auxin (‘Hetero-Auxin’) aus Harn.”Zeit. Physiol.Chem. 228: 90-103.
(20) Kögl, F., A. J. Haagen-smit, and H. Erxleben. 1934“Über den Einfluss der Auxine auf das Wulzelwachstum
und die chemische Natur des Auxins der
Grascoleoptilen.” Zeit. Physiol.Chem. 228: 104-12, 121.
(21) Orvin C. Burnside “The History of 2,4-D and Its
Impact on Development of the Discipline of Weed
Science in the United States” Phenoxy Herbicides
Chapter 2., www.24d. org/abstracts/chapter2.pdf.
Accessed 17 July 2012.
(22) W. G. Templeman et al. British Patent Application
April 7,1941:issued Dec 13, 1945. Corresponding
Japanese patent (Patent Publication No. Sho. 26-2250).
(23) F. D. Jones, “Methods and composition for killing
weeds.” US Patent 2,390,941 (1945). Application in
Canada June 2,1944, in United States May 4, 1945,
issued December 11, 1945. Corresponding Japanese
patent (Patent Publication No. Sho. 26-2499).
(24) Sato et al. Nōyaku-gaku [The Study of Pesticides],Asakura Shoten, 2003, p. 165.
(25) Kawabe et al. “PCP no Ryōba e no Higai [PCP
Damage to Fishing Grounds],” Nippon Suisan
Gakkaishi, Vol. 31, No. 9, 1965, p. 732.
(26) Nōyaku no Ayumi [History of Pesticides], Executive
Committee for the Plant Protection Project Development
10th Anniversary Convention, 1960, pp. 9 & 146.

3.4.3.
The
EmergenceofNew,
Domestically-Invented Pesticides (1960-1970)
Following the special procurements boom for the
Korean War in 1950, Japan experienced an economic
boom from 1954, followed in turn by another boom in1958 and the Izanagi boom of 1965-1970. Dramaticchanges in the agricultural environment went hand inhand with this period of rapid economic growth. The
farming population dropped significantly in the 1960s
as people transitioned into non-agricultural occupations.
This move was undergirded by the mechanization ofagriculture and an economizing of labor due topesticides. Agricultural productivity also improved; it
was an age of excess rice, with the total area of paddy
rice fields reaching a peak of 3.17 million hectares in
1969. This later decreased as consumers shifted awayfrom rice consumption, dropping to just over 1.5
million hectares by 2011.
The economic recovery was also linked to the pesticideindustry, with synthetic organic pesticides introduced
after the war playing a huge part in the rapid growth.
Pesticide shipments were worth ¥28 billion in 1960; ten
years later, they had almost tripled to ¥83 billion.
Ninety per cent of the pesticides during this period weresynthetic, while the remaining 10% were natural andinorganic products. From 1955 onwards, mass synthetic
pesticide manufacturers were divided into two
categories: active ingredient manufacturers (theso-called integrated manufacturers) and formulation
manufacturers (the traditional type of specialized
pesticide manufacturers).
Japanese companies built up some expertise during thistime. Proficient at synthesis technology thanks to theirexperience with licensing, they embarked on their own
research and development with the aim of producing
new pesticides for themselves. This was a period oftime fraught with problems: mammalian toxicity
problems, such as with parathion; fish toxicity problems,such as with PCP; residue problems, such as with DDT,
BHC and mercurials. There were high hopes for a safer
substitute to be developed.
(1) Publication of Silent Spring
American scientist Rachel Carson (1907-1964)
published Silent Spring in 1962. It was translated into
Japanese and released by Shinchosha as Sei to Shi no
Myōyaku [Elixir of Life and Death] in 1964. This book
had a major impact on society, sounding the alarm
against DDT, BHC and organochlorine pesticides suchas the drins as causing environmental pollution and thedestruction of ecosystems. This book made people
aware of the seriousness of the impact of pesticides on
the environment. Pesticide manufacturers were required
to perform environment and ecosystem impact
assessments when developing pesticides. In this regard,
this book was hugely significant. However, the bookdraws attention to the proper use of pesticides and does
not say that pesticide use should be abolished altogether.
It was later pointed out that many human lives were lost
because of a ban on DDT, which was used to control
malaria-carrying mosquitoes. For instance, the numberof malaria cases in Sri Lanka in the 1960s dropped
from 2.5 million per year to almost zero due to the useof DDT; when DDT was later banned, this figure
reverted to what it had been before. According to theWorld Health Organization (WHO), DDT has saved 5
million lives and prevented 100 million cases of disease(1). This raises the difficult question of whether

environmental destruction takes precedence overhuman lives. We must also give level-headed
consideration to the good that has been achieved by
DDT.
(2) Insecticides
Low-toxic organophosphate MEP (Sumithion) was
developed and registered on the Japanese pesticide
register in 1961. It was a radical improvement onparathion and other highly acutely mammalian toxic
pesticides and became a world-renowned product. Thisis discussed in more detail in Section 4.3. Many otherhighly safe organophosphates were developed. Typicalcompounds still used today include PAP (Elsan,
registered in 1963), developed by Bayer, and CYAP(Cyanox, registered in 1966), developed by Sumitomo.
Many carbamate insecticides that appeared during thisperiod were a new chemical structure. These originatedfrom physostigmine (eserine), a toxic alkaloid found incalabar seeds (Physostigma venenosum) from West
Africa (Fig. 3.36). It has a strong cholinesterase
inhibiting effect and is used in medicine as a pupil
contractant, but has no insecticidal effects. Metcalf et al.
from the University of California carried out researchmodeled on this compound and later discovered
insecticides with carbamate groups (2), (3), (4), (5). Fig. 3.37
shows some typical carbamate insecticides and theiryear of registration/cancellation on the Japanesepesticide register.

Fig. 3.36. Physostigmine
NAC (Denapon) was discovered by Union Carbide
Corporation (UCC) in the United States. It was firstregistered in Japan in 1959, followed by a number ofother carbamates. Each of these was very effective
against leafhoppers on rice plants. While theorganophosphate Malathion was often used at the time,
a problem arose around 1962, when green riceleafhoppers started becoming resistant to Malathion.
Since carbamates were also effective against these
Malathion-resistant green rice leafhoppers, they became
widely popular and are now viewed as one of therepresentative rice insecticides of that time. However,they were not so effective against the rice borer.
During this time, Japanese companies had beenworking on pesticides to rival NAC, PHC and APC.
Many products that had dropped due to resistanceproblems had their registration lapse when thesecompeting products appeared, but NAC, MIPC and
BPMC are still worth several hundred million yen in
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41

sales.

Fig. 3.37. Carbamate Insecticides
Like organophosphates, the mode of action for
carbamates works by inhibiting acetylcholinestrase(AChE) in the neurotransmission system. They blockneurotransmission by the carbamoylation of the AChEhydroxyl group. While some carbamate compounds arehighly toxic to mammals, the ones registered in Japanare relatively safe (deleterious substances).
Some time later, DuPont discovered oxime carbamates,
which have no benzene ring in their chemical structure.
Methomyl (Lannate) was registered in Japan in 1970; alittle later, Oxamyl (Vydate) was registered in 1981 (Fig.
3.38). While these work as AChE inhibitors as with thecompounds above, they have the drawback of being
quite highly toxic to mammals. However, they have theadvantage of being very effective against chewing
insects on fruit and vegetable plants and are still used
today.

42

cultivation. Later, further research was devoted tomaking them less toxic to mammals, which was theirmain drawback. This research resulted in the so-called
second generation carbamates that appeared from thelate 1980s to the early 1990s. These results are
discussed in Section 4.16.
In 1967, Takeda Pharmaceutical invented and marketed
Cartap (Padan), an insecticide with a unique chemical
structure. Modeled on nereistoxin found in marine
animals, this compound became widely popular as it
was effective against a wide variety of pest insects. The
outstanding academic research was also a goodachievement for Japan. This is outlined in Section 4.6.

Fig. 3.38. Oxime Carbamate Insecticides(3) Fungicides
A succession of long-awaited domestically invented
fungicides began to appear during this time. Ihara
Agrochemical developed and marketed MAS (Asozin),a fungicide for rice sheath blight and Japan’s first
domestically-produced pesticide, in 1959, followed by
MAF (Neoasozin). Post-war Japan had depended on
licensed technology imports for its synthetic pesticides,
but now production of its own pesticides had begun.
This is discussed in detail in Section 4.1.

Carbamate insecticides appeared in the middle of thisperiod and became so popular they were second only toorganophosphates as the main insecticides for rice

Blasticidin S is the world’s first agricultural antibiotic,
discovered by the University of Tokyo in 1961 andjointly developed by Kaken Chemical, Toa Agricultural

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan

Chemical and Nihon Nohyaku. It became widely used,having come at a time when there was a demand fornon-mercurial fungicides, as problems had developedwith the organomercury fungicides that were used inlarge quantities after the war. In 1965, Hokko Chemicaldeveloped Kasugamycin, an antibiotic for rice blast.
These two products held much academic value. This is
explained in further detail in Section 4.2.
In 1965, Ihara Agrochemical (now Kumiai Chemical)
brought out EBP (Kitazin), followed by IBP (Kitazin P).
Together with Blasticidin, these organophosphate rice
blast treatments became wildly popular as a
non-mercurial secret weapon in the war against crop
diseases. They could penetrate into the plant, whichmeant they could be of practical use in the rice field.
Section 4.7 discusses these products in more detail.
Polyoxin is an agricultural antibiotic that is very
effective against diseases such as rice sheath blight,
powdery mildew on fruit and vegetable plants,
Alternaria alternata in pears and Alternaria mali inapples. It was discovered in 1967 by RIKEN
researchers and developed by Kaken Chemical (6), (7).
Other agricultural antibiotics include Validamycin(Validacin), effective against rice sheath blight,
developed by Takeda Pharmaceutical registered as apesticide in 1972 (8), (9). Takeda Pharmaceutical also
marketed Mildiomycin (Milanecin), very effective
against powdery mildew, in 1983 (10). Thus, this period
saw a succession of agricultural antibiotic fungicides
developed by Japanese companies. A major advantage
of antibiotic fungicides is that they are effective at low
concentrations and therefore safe to mammals andnon-residual on crops. Japan leads the world intechnology development in this field. Fig. 3.39 shows
the structures of Polyoxin, Validamycin and
Mildiomycin.

Fig. 3.39. Agricultural Antibiotic Fungicides
In 1969, Sankyo developed and marketed
Hydoroxyisoxazole (Tachigaren), shown to be effective
against soilborne diseases such as seedling wilt, brownspot disease and sheath blight (Fig. 3.40). With achemical structure similar to isoxazole, this fungicide ismade up only of carbon, oxygen and hydrogen. It has
also become widely used in seed raising, as it iseffective for promoting rooting and growth as well as
growing healthy seedlings. It is also used as a fungicide
on rice, vegetables, sugar beets and other produce inJapan and at least another 30 countries around theworld (11), (12), (13).

Hydroxy isoxazole (Tachigaren)

Fig. 3.40. Hydroxy isoxazole (Tachigaren)(4) Herbicides and Plant Growth Regulators
While the herbicide PCP mentioned above wasregistered in 1956, it rapidly grew in popularity for ricecultivation after it was developed into granules in 1960.
However, the early conception that it was toxic to fish
proved to be true. When the Agricultural Chemicals
Control Act was amended in 1963, PCP usage wasregulated and the use of substitute formulations was
encouraged.
Two major Japanese herbicides appeared during thistime. One was CNP (MO), developed by Mitsui
Chemicals and registered in 1965 (See Section 5.5 fordetails); the other was Benthiocarb (Saturn), developedby Kumiai Chemical and registered in 1969.
Benthiocarb is effective on perennial weeds and has
become one of the top herbicide products for ricecultivation, recognized as a superior herbicide
formulation.
A number of other herbicides were registered during
this time as well. Photosynthesis-inhibiting traizine
herbicides on the market included CAT (Simazine),
Prometryn (Gesagard), Atrazine (Gesaprim) and
Simetryn (Gibon). Urea pesticides included DCMU
(Carmex), Linuron (Lorox) and Siduron (Tupersan),while DCPA (Stam) was a typical amide pesticide.
Dinitroaniline herbicide Trifluralin (Trefanocide) wasused on a variety of crops including rice, wheat andvegetables and was particularly effective against rice
weeds. Trifluralin is still widely used today and has amarket worth ¥2 billion.
Let us now mention plant growth regulators. Giberellin,developed by Kyowa Hakko, was officially registeredon the pesticide register as a plant growth regulator in
1964. While it is mainly used on seedless grapes, it has
a number of other applications as well. Giberellin isdefinitely worth a special mention, as the entire processfrom its discovery in the early 20th century to thedetermination of its structure and its development as a
Hiroki OHTA; Historical Development of Pesticides in Japan
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43pesticide has been spearheaded by Japanese technology.
This is discussed in Section 4.4. Other products weredeveloped and marketed during this time, including
rooting promoter 1-Naphthyl-acetamide (Rootone),
fruit accelerator 4-CPA (Tomato-tone) and growth
retardant Daminozide (B-nine). These are still in use
today.
Cited References(1) Fukuda. Nōyaku ni taisuru Gokai to Henken[Misunderstanding and Prejudice against Pesticides],The Chemical Daily, 2000, p. 228.
(2) R. L. Metcalf et al., J. Agr. Food Chem. 13, p220
(1965)(3) Nishizawa. Shin Nōyaku Sōsei-hō [New Pesticide
Creation Methods], Yamamoto et al. (eds.), Nankodo,
1965, p. 36.
(4) R. L. Metcalf et al., J. Econ. Entomol. 43, p670 (1950)(5) Shigematsu. Journal of Synthetic Organic ChemistryVol. 29, No. 3, 1971, p. 254.
(6) S. Suzuki et al., J. Antibiotic., 29, p848 (1965)(7) Hori. Nihon Shin Nōyaku Monogatari [The Story of
New Japanese Pesticides], Japan Plant Protection
Association, 1973, p. 479.
(8) T. Iwasa et al., J. Antibiotic., 24, p107 (1971)(9) Hori. Nihon Shin Nōyaku Monogatari [The Story of
New Japanese Pesticides], Japan Plant Protection
Association, 1973, p. 577.
(10) S. Harada et al., J. Antibiotic., 31, p519 (1978)(11) K. Tomita et al., Ann. Rep. Sankyo Res. Lab. 25, p1(1973)(12) Sato et al. Nihon no Nōyaku Kaihatsu [JapanesePesticide Development], Pesticide Science Society ofJapan (ed.), Soft Science, 2003, p. 209.
(13) Gijutsu Shiryō: Tachigaren-zai [Technology
Resources: Tachigaren], Sankyo Corporation (ed.),1998.
3.4.4. Tighter Regulation of Problematic Pesticides
and the Emergence of Substitute Pesticides(1970-1990)(1) Overview
The 1970s saw the end of Japan’s period of rapid
economic growth and a transition to a period of slow
growth. Although Japan had already become theworld’s second largest economic superpower in the late1960s, the dollar shock took place in 1971 and aJapanese archipelago remodeling plan was issued thefollowing year. This was followed by the oil shock in
1973 as well as rampant inflation, known to theJapanese as kyōran bukka, or price frenzy.
Japan’s Four Big Pollution Diseases (Minamata
Disease, Niigata Minamata Disease, Yokkaichi Asthma,
Itai-itai Disease) occurred as side effects of the rapid
economic growth. This became a social issue during
this period, with the Environment Agency (later the
Ministry of the Environment) created in 1971 and aflurry of activity in the area of environmental
improvement during this time as well.
44

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Manufacturing and shipping in the pesticide industry
continued as it had during the rapid economic growth
period, despite reductions in rice field land due to a
set-aside policy enacted in 1971. Pesticide shipments
multiplied 3.7 times in ten years, from ¥83 billion in1970 to ¥320 billion in 1980. A number of highly
effective new pesticides appeared during this time,
meaning a stable, high yield of good quality produce,
despite a drop in the working population engaged inagriculture. Once the increase in food production had
been achieved, views changed about pesticides. Thischange in viewpoint started being reflected in thegovernment during this time. The “negative aspects” ofpesticides came to be viewed as problematic – namely,
toxicity to mammals and marine life, lasting residues oncrops and soil and the risk of long-term toxicity fromexposure to or ingestion of these residues, as well as theimpact on the environment and on beneficial organisms
such as natural enemies. In other words, the existing
regulations to ensure “user safety” and protect against
acute toxicity were tightened to ensure “end consumer
safety” as well as to minimize the impact of pesticides
on the environment, such as water and soil. During thisperiod, stricter pesticide regulations were placed on
new and existing products alike.
Let us now move forward to the 1980s. The economy
continued to slump due to the second oil shock in 1979,
while a high-yen recession followed the Plaza Accord
in 1985. While later ultra-low interest policies sparked
the bubble economy boom, this did not last long andthe economy dropped once more when the bubble burst
in 1991.
Agricultural mechanization, such as the introduction ofrice planters and combine harvesters, compensated forthe decline in the agricultural work force; combinedwith the growing use of pesticides, this made for afavorable agricultural environment with increased
productivity. Most of the government’s agricultural
measures were to do with rice prices, and most farming
continued as side-line businesses with no majorchanges such as large-scale restructuring.
The pesticide industry transitioned from a period of
rapid growth to a period of moderate growth due to therecession and the reduction in acreage; this was also atime of excessive competition in the industry. The
growth in shipments of the past decade peaked at ¥400
billion, 1.3 times what it had reached in the 1970s. Afterpeaking in 1986, shipments have continued to gradually
decline to the present day. Fig. 3.41(a) shows the trends
in pesticide shipments.

Ordinary substances

Poisons
Deleterious substances

regulations and the appearance of new, safer pesticides.
By 1970s, the proportion of specific toxic substances
had dropped to 0.4% and poisons to 0.8%. Thesefigures have continued to drop; by 2010, specific toxic
substances accounted for 0.0%, poisons 0.8% anddeleterious substances 14.9%. The remaining 84.3%
are classed as ordinary substances, indicating asignificant increase in pesticide safety.

Specific toxic substances
Annual Trends in Pesticide Shipments (units: ¥107) tabulated from Pesticide
ManualFig. 3.41(a) Annual Trends in Pesticide Shipments(tabulated from Pesticide Manual)Fig. 3.41(b) shows the amount of pesticides produced (t,kl) per application. While the trends shown do not differ
from those shown in Fig. 3.41(a), based on the value of
shipments, we see that pesticide usage peaked in the
1970s and then dropped significantly. This is because
there was less demand for pesticides due to reductions
in planted areas, as well as a reduction in the amountneeded per unit area. This was made possible by thedevelopment of improved pesticide formulations withhighly effective active ingredients. To use an analogy, it
was like being able to achieve with a spoonful ofhousehold detergent what used to require a cupful.

Trends in Amounts of Pesticides Produced (unit:ktons) (byApplication) tabulated from Pesticide ManualFig. 3.41(b) Trends in Amounts of Pesticides
Produced (by Application) (tabulated from Pesticide
Manual)Fig. 3.42 shows how pesticide safety improved after thewar. The initial post-war period, when synthetic organic
pesticides came to the fore, has the highest proportionof highly toxic chemicals such as parathion. More than
50% of all pesticides were designated as poisons or
specific toxic substances during this period. While there
were a number of social problems during this time,such as a rising number of accidents among farmers,
the conditions significantly improved with tighter

Trends in Pesticide Production by Toxicity (value ratio) tabulated from
Pesticide ManualFig. 3.42 Trends in Pesticide Production by Toxicity(value ratio) tabulated from Pesticide Manual
As mentioned above, pesticide regulations tightened
during this period. All pesticides, whether new orexisting, had to undergo various tests, especially safety
tests, based on the new standards and a number ofexisting pesticides were weeded out. The increased
number of test criteria and the increased cost ofdevelopment presented a high hurdle for new pesticides.
As a result, the success rate for new inventions dropped.
However, despite this, Japanese companies continued
to place huge amounts of effort and investment intodeveloping their own pesticides and came up with anumber of world-renowned products.
(2) Stricter Regulations and Amendments to theAgricultural Chemicals Control Act
The sale of organomercury compounds (sprays) wasbanned in 1970 (1). The following year, the sale of DDT,
BHC, Aldrin and Dieldrin was banned and theAgricultural Chemicals Control Act was amended
significantly (2). As discussed in Section 3.4.2 (1), theAgricultural Chemicals Control Act enacted in 1948
focused on ensuring that high quality pesticides were
manufactured safely and provided to farmers in order toboost food production, the urgent issue of the day. The
aim was to ensure the safety of farmers, the users ofpesticides. The amendment incorporated a strong focus
on making farmers safer through appropriate use ofpesticides, ensuring public health and protecting living
environments.
The directive (3) from the Ministry in light of thisamendment specifically stipulated that: (1) acutetoxicity tests, chronic toxicity tests and residue tests on
crops and soil had to be carried out; (2) the criteria for
Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

45suspending registration included crop-residual
pesticides (lead arsenate, Endrin), soil-residual
pesticides (Dieldrin, Aldrin) and water-polluting
pesticides (Telodrin, Endrin, Benzoepin and PCP); (3)even registered pesticides could have their registrationsuspended (or revoked) if they were considered to beseriously hazardous.
The Good Laboratory Practice Standards for Pesticide
Toxicity Tests (METI GLP) were enacted in 1984. GLP
is a system originally used in the field of medicine.
GLP for medicine was put in place in the United Statesin the 1970s after it was found that fraudulent data wasbeing used in drug applications. The requirements forpesticide registration include 32 toxicity tests, 4
metabolism tests, 15 physiochemical properties tests, 10
environmental impact on aquatic animals tests and acrop residue test. Each of these tests has strictly
regulated GLP compliance criteria for the testing
institution, including its organizational structure, a clear
indication of its responsibility system, its adherence touniform Standard Operation Procedure (SOP), itstesting carried out in accordance with protocol andoperating procedures, its recording of experiments, itsstoring of related materials and independent quality
assurance system. All new pesticides must meet thesecriteria, as does all toxicity data required for
re-registering existing pesticides every three years.
(3) Insecticides
While the main insecticides during this period wereorganophosphates, a number of new ones appeared thatwere comparatively low-toxic. However, many of thesedisappeared off the market with the appearance ofhigh-performance pesticides. The following are typicalexamples of these pesticides still in use today. Dow
registered Chlorpyrifos (Dursban) in 1971. Sankyo
developed and registered Isoxathion (Karphos) in 1972.
Even today, this product is widely used because of its
effectiveness against a wide range of pest insects on
fruit and vegetable plants. Chevron developed Acephate(Orthene) and put it on the market in 1973. This
product is highly systemic and can be used in theplanting hole as well as sprayed; it still has a ¥7 billion
market. Bayer Japan developed Prothiofos (Tokuthion)in 1975. This pesticide is still widely used on fruit andvegetable plants because of its delayed but durable
effects and its effectiveness against a wide range ofinsect pests, including soil pests. ICI marketed
Pirimiphos-methyl (Actellic) in 1976. Thus, a numberof organophosphate insecticides were developed andalthough they are still used today, the competition todevelop new ones all but came to an end during thisperiod. Fig. 3.43 shows the structures of thesechemicals.
The next insecticides to appear on the scene were thesecond generation carbamates in the 1980s; these were46

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan

far less toxic to mammals. The first on the market was
Carbosulfan (Advantage) in 1983. This was followedby Benfuracarb, registered by Otsuka Chemical in 1986.
The next to appear was Alanycarb (Orion), developedby Otsuka Chemical in 1991. For details on these, refer
to Section 4.16.

Fig. 3. 43. Organophosphate Insecticides Developedin the 1970s
With the advent of the 1980s, a number of new major
insecticides appeared with completely different
chemical structures from the existing products. In 1983,
Sumitomo Chemical put Fenvalerate (Sumicidin) on
the market – the world’s first pyrethroid for agriculturaluse. With this, a number of other synthetic pyrethroids
were developed for agriculture. For details on thisproduct, refer to Sections 4.14 and 4.18. Fierce
competition ensued with each company furiously
developing their own version of these new-generation
synthetic pyrethroids; by 1995, a great number of new
pesticides had emerged. However, it is very interesting
to note that no more of these have been produced sincethen.
In 1983, Nihon Nohyaku put out Buprofezin (Applaud).
This was the first insect growth regulator (IGR)
produced in Japan. For details, refer to Section 4.13.
Nippon Soda registered Hexythiazox (Nissorun) in
1985, the forerunner of the high-performance miticides.
Between 7 and 80 times more active than existing
miticides, it was wildly popular and was also used
overseas. For details, refer to Section 4.15.
As mentioned above, these two decades were a time of
weeding out the old pesticides with safety issues andother problems and replacing them with a number of
products that were far safer to mammals. Many of thesenew products were from Japan: Japanese companies
were starting to see the fruits of their concentrated
research and development efforts during the post-war
rebuilding period.
(4) Fungicides
Several world-renowned Japanese fungicides weredeveloped in the 1960s. Nippon Soda first brought out
Thiophanate (Topsin) in 1969, followed by the more
effective Thiophanate-methyl (Topsin M) in 1971.

These new fungicides had unprecedented chemical
structures; they had systemic activity and were highly
effective against a number of diseases in fruit andvegetable plants and other crops. This pesticide became
popular in Japan and a renowned product throughout
the world. Refer to Section 4.9 for details.
Fthalide (Rabcide) was invented by Kureha andregistered in 1970 as a fungicide for rice blast (Fig.
3.44) (4). Fthalide strongly inhibits hyphal penetration
after appressorium formation in Pyricularia oryzae. Its
mode of action is known to work by inhibiting Melanin
Biosynthesis Inhibitors Reductase (MBI-R) in
Pyricularia oryzae (5). Soon after Fthalide appeared,
overseas manufacturers developed two rice blast
fungicides with the same effect. One was Tricyclazole(Beam), marketed by Dow in 1981; the other was
Pyroquilone (Coratop), marketed by Ciba-Geigy in1985. Fig. 3.44 shows their chemical structure .

Fig. 3.44. Rice Blast Fungicides (MBI-R Inhibitors)
Two more major rice blast fungicides appeared during
this period, both invented by Japanese manufacturers.
One is Isoprothiolane (Fuji-one), invented by Nihon
Noyaku and registered in 1974; the other is
Probenazole (Oryzemate), invented by Meiji Seika andalso registered in 1974. These became major pesticides
and very popular due to the fact that rice blast was offrequent occurrence, the fact that both products had
systemic activity and the fact that they were highly
effective both for submerged applications and seedlingbox treatment. For details, refer to Sections 4.10 and
4.11.
As discussed above, in the fifty years following the war,
fungicides transitioned from being mainly inorganic
compounds such as copper, mercury and arsenic tosyntheticorganic
compounds.
Remarkable
improvements were also made in terms of theirperformance. Competition to develop new products
continued and a succession of new pesticides are being
developed with new modes of action. Many of the newfungicides work by inhibiting particular enzymes
pinpointed in the metabolic pathway. However,continued use of such fungicides will result in amutation in the part that is being inhibited, meaning thatthe fungicidal effect can easily be weakened if there is abuild-up of resistance to it. There is a need to prevent
resistance building up by avoiding continuous use of
the same product.
(5) Herbicides

A number of major herbicides were developed during
this period and since. We shall first discuss herbicides
for paddy rice agriculture – the main Japanese market –followed by herbicides for upland field agriculture.
CNP (MO), a herbicide for controlling barnyard grassin paddy rice fields, was developed and marketed by
Mitsui Chemicals in 1965, as discussed in Section 3.4.3(4). For more details, refer to Section 4.5.
Benthiocarb (Saturn) was developed and marketed by
Kumiai in 1969. This is discussed in Section 4.8.
Stauffer brought out Molinate (Ordram) in 1971. The
following year, Rhône-Poulenc registered and marketed
Oxadiazon (Ronstar), while Monsanto did the samewith Butachlor (Machete). The emergence of thesebarnyard grass killers enabled a so-called “sequential
application” involving multiple applications of
products: a combination of pretreatments during theearly rice growth phase and foliar-soil treatments during
the medium growth phase. By 1974, this system wasbeing used on 6.2 million hectares of land, 2.3 times thetotal area of paddy rice fields (6), (7), (8).
Other barnyard grass killers were developed.
Ciba-Geigy developed Pretilachlor (Solnet) in 1984,
followed by Bayer Japan with Mefenacet (Hinochloa)
in 1986. Mitsubishi Yuka started selling Dimepiperate(Yukamate) in the same year. Stauffer went to market
with Esprocarb (Fujigrass) in 1988, while Tosoh started
marketing Pyributicarb (Eigen) the following year.
Thus, a large number of superior-performing herbicides(able to eradicate barnyard grass through to the matureleaf stage) appeared during this period, with fierce
competition between companies to develop and market
new products.
Fig. 3.45 shows the chemical structures of the above
barnyard grass killer.
Next, we shall discuss Cyperaceae herbicides andbroadleaf (including perennials) herbicides used inconjunction with barnyard grass treatments. While
hormone herbicides such as 2,4-PA (2,4-D) and MCPB
and triazine herbicides such as Prometryn and Simetryn
were used for this purpose, a number of more effective
herbicides were developed.
In 1979, Mitsui Chemicals developed and marketed
Naproanilide (Uribest), highly effective against
perennial weed Sagittaria pygmae Miq. (Urikawa) andannual broadleaf weeds (9), (10). Its mode of action works
by the same hormonal effect as 2,4-PA. This
formulation won the company the 33rd Okochi
Memorial Grand Production Prize in 1986 for“development of the paddy rice herbicide
Naproanilide.”
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47

Fig. 3.45. Barnyard Grass Herbicides from the 1980s
In 1974, Showa Denko (now SDS Biotech) registered
Dymron (Shoron), highly effective against Cyperaceae
weeds, particularly Scirpus juncoides. This product isstill widely used today in combination formulations.
Sumitomo Chemical started selling Bromobutide(Sumiherb) in 1986. This is a N-benzyl-butanamide
with intentionally bulky substituents in the amide
structure and is effective at low doses against perennial
weeds such as Scirpus juncoides, needle spikerush(Eleocharis acicularis) and flatsedge (Cyperus
serotinus) (11). Sales of this product grew rapidly in the
mid-2000s due to its effectiveness against weeds
resistant to Sulfonylurea herbicides, which havebecome a problem in recent years.
Mitsubishi Yuka developed the similarly-effective
Clomeprop (Yukahope) and started marketing it in1988 (12). Fig. 3.46 shows the chemical structure ofthese herbicides.
Let us now discuss Pyrazolate (Sanbird), a herbicidewith a completely new chemical structure developed by
Sankyo and registered in 1979 (13), (14), (15). Pyrazolate
immediately gained popularity due to its superior
efficacy against annual broadleaf weeds and perennial
weeds such as Sagittaria pygmae Miq.(Urikawa) –considered difficult to eradicate in those days,
waterplantains (Alisma canaliculatum) and flatsedge(Cyperus serotinus). This herbicide enabled a transition
48

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan

from the existing sequential application to a so-called“one-shot application,” which reduced the number ofapplications, thereby saving labor. Later, a number of
new one-shot herbicides came on the scene and began
to become very popular from around 1983, replacing
the existing sequential herbicides. Pyrazolate wasarguably one of the first one-shot herbicide
formulations.
Pyrazolate kills weeds by inhibiting biosynthesis ofcarotenoids, which are pigments found in thechloroplasts of plants. After a variety of investigations,its mode of action has been found to inhibit
4-hydroxyphenylpyruvate dioxygenase (4-HPPD) thathelps to produce plastoquinone, which governs theelectron transport chain in photosynthesis. Several
4-HPPD inhibitors have been discovered, as a numberof companies started working on research anddevelopment in this area once Pyrazolate appeared on
the scene. Typical herbicides include Pyrazoxyfen,
marketed by Ishihara Sangyo in 1985, and Benzofenap,
developed by Mitsubishi Yuka in 1987. Other
herbicides with the same mode of action but completely
different chemical structures include isoxazole andtriketone compounds, which have been actively
developed since 1995. For more details, refer to Hirai etal. (16). Thus, Pyrazolate sparked the development of a
new division of paddy rice herbicides. As a result, it
won the company the 32nd Okochi Memorial Grand
Production Prize in 1985. Fig. 3.47 shows the chemical

structure of the 4-HPPD inhibitors.
A super-herbicide for paddy-field broadleaf weeds
appeared in 1987: Bensulfuron methyl, developed by
DuPont. This super-herbicide brought the amount ofactive ingredient per hectare down into the double
digits: 50-75g, far less than the existing products. The
sulfonylurea (SU) chemical structure was completely
unprecedented; it came to be called SU (ALS inhibitor)
as its mode of action worked in a new way by
inhibiting acetolactate synthase (ALS). SU first
appeared in 1982 in the United States in the form ofChlorsulfuron for broadleaf weeds in wheat;
Bensulfuron methyl was a modified version of thisdeveloped for use on paddy-rice fields. As this type ofherbicide became known, many companies set out on
research and development in the footsteps of DuPont.
This resulted in the development and marketing of
Pyrazosulfuron by Nissan Chemical in 1989,
Imazosulfuron by Takeda Pharmaceutical in 1990 and
Halosulfuron by Nissan Chemical in 1993. The ensuingcompetition to develop SU herbicides has continued tothis day. For details, see Section 4.19.
As mentioned above, this period saw the successive
development of paddy rice herbicides with markedly
improved effectiveness against barnyard grass,
Cyperaceae and broadleaf weeds. As a number ofdifferent combinations of these paddy rice herbicides
were developed, they gradually replaced the existing
formulations, thereby causing a transition from theexisting method of sequential application to that of
one-shot application. The subsequent advances in
one-shot herbicides shall be mentioned later.
Finally, let us discuss herbicides in a non-rice context(fruit trees, vegetables, non-agricultural land, etc.).

Glyphosate (Roundup), developed by Monsanto, wasregistered in Japan in 1980. It is a non-selective
foliage-applied herbicide with a delayed effect thatworks by moving down to the roots and killing theplant. Its mode of action is known to work by inhibiting
the enzyme 5-enolpyruvylshikimate-3-phosphatesynthase (EPSP) in the biosynthesis of aromatic aminoacids (phenylalanine, tyrosine and tryptophan) (17). As it
quickly loses its effectiveness in soil, it has no effect on
succeeding crop, so it is widely popular forundergrowth in orchards, furrows between vegetable
plants and on non-crop land. It soon became aworld-renowned product, with shipments in Japan
worth over ¥20 billion – the highest-selling pesticide inJapan. In the United States, the introduction of
Glysophate-resistant crops such as soy and corn has
meant that this originally non-selective herbicide can beused without affecting the quality of the produce.
Businesses have sprung up selling seeds and herbicides
as a pair. This product is still widely used today.
Meiji Seika developed and registered the non-selective
herbicide Bialaphos (Herbiace) in 1984 (18), (19). This
product is a metabolite produced by Streptomyces
hygroscopicus bacteria and was the first herbicide in theworld produced by fermentation. It has a tripetidechemical structure with a unique carbon- phosphorus
bond. Its mode of action is known to build up toxic
levels of ammonia by inhibiting the biosynthesis ofglutamine, one of the amino acids (20). Bialaphos won
the company the 35th Okochi Memorial Grand
Production Prize in 1988 for agrochemical production
and also for the high academic value of the research. In
the same year, Hoechst registered Glufosinate (Basta),
which has a similar chemical structure and the samemode of action as Bialaphos. Fig. 3.48 shows thesechemical structures.

Fig. 3.46. Naproanilide, Dymron, Bromobutide, Clomeprop

Fig. 3.47. 4-HPPD Inhibiting Herbicides

Hiroki OHTA; Historical Development of Pesticides in Japan
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49

Fig. 3.48. Non-Selective Herbicides
Nippon Soda developed and registered grass-weed
herbicide Alloxydim (Kusagard) in 1980, followed by
Sethoxydim (Nabu) in 1985. With a completely
unprecedented cyclohexanedione chemical structure,these were major world-renowned products developed
for the sugar-beet, rapeseed, cotton and soybean
markets. Significant modifications were later added tothis chemical skeleton to develop several related
herbicides. Details are given in Section 4.12.
Ishihara Sangyo developed and registered
Fluazifop-butyl (Onecide) in 1986. This product had
the same effect as Sethoxydim, mentioned above; thatis, it is selective against grass weeds. In 1989, Nissan
Chemical developed and marketed Quizalofop-ethyl(Targa), which has a similar chemical structure. Since
the main market for these two formulations is overseas,
they were promoted with overseas development inmind from the beginning. For details, see Section 4.17.
Cited References(1) MAF Ordinance No. 68, 30 November 1971.
(2) Amended Enforcement Order for the Agricultural
Chemicals Control Act, Government Ordinance No. 368,
10 December 1971.
(3) MAF Directive Agriculture Policy No. 2538, 14 June
1972.
(4) Chida. Journal of Pesticide Science, Vol. 14, No. 3,
1989, p. 363.
(5) Miura. Shin Nōyaku Kaihatsu no Saizensen [TheForefront of New Pesticide Development], CMC Books,
2003, p. 61.
(6) Takeshita. Journal of Weed Science and Technology,
Vol. 49, No. 3, 2004, p. 220.
(7) Takeshita. Shokutyō, Vol. 44, No. 12, 2011, p. 535.
(8) Takeshita. Shokutyō, Vol. 45, No. 1, 2011, p. 29.
(9) T. Yoshimoto, K. Igarashi, Y. Takasawa, M. Umemoto
and T. Takematsu: CHEMTECH, 19, p431 (1989)(10) Mitsui Toatsu Chemicals., Inc.: Research andDevelopment in Japan Awarded the Okochi Memorial
Prize 1987, The 33RD Technology Prize, p94 (1987)
50

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan(11) Kirino. Journal of Pesticide Science, Vol. 9, No. 3,
1984, p. 571.
(12) Sunohara. Journal of Weed Science and Technology,
Vol. 45, No. 2, 2000, p. 124.
(13) Nakagawa et al. Journal of Pesticide Science, Vol. 13,
No. 2, 1988, p. 363.
(14) Kadotani et al. Nihon no Nōyaku Kaihatsu [JapanesePesticide Development], Pesticide Science Society ofJapan (ed.), Soft Science, 2003, p. 291.
(15) M. Ishida, K. Matsui, T. Yanai, K. Kawakubo, T.
Honma, K. Tanizawa, M. Nakagawa and H. Okudaira:Ann. Rep. Sankyo Res. Lab., 36, p44 (1984)(16) Hirai et al. Shin Nōyaku Kaihatsu no Saizensen [TheForefront of New Pesticide Development], CMC Books,
2003, p. 166.
(17) Yamashita et al. Nōyaku no Kagaku [The Chemistryof Pesticides], Buneido Publishing, 1996, p. 280.
(18) Tachibana et al. Nihon no Nōyaku Kaihatsu[Japanese Pesticide Development], Pesticide Science
Society of Japan (ed.), Soft Science, 2003, p. 355.
(19) Ogawa et al. Scientific Reports of Meiji Seika Kaisha,Vol. 13, 1973, p. 42.
(20) K. Tachibana, T. Watanabe, Y. Sekizawa and T.
Takematsu: J. Pestic. Sci., 11, p27 (1986)

3.4.5. Full Growth to Downsizing: Successive
Emergence of Ultra-Performing Pesticides asRegulations Tighten (1990-present)
Japan’s bubble economy burst in 1991, although it waslater followed by a period of economic expansion.
However, the poor economic recovery was made worseby the so-called “Lehman Shock” in September 2008;
the unfavorable conditions have continued to thepresent day. This recession has continued for so longthat it became known as the lost ten years, then as thelost twenty years.
The agricultural environment has also slumped during
this time. Japanese agricultural production has steadily
slowed since import liberalization of beef, oranges andother products in 1991. Japan’s food self-sufficiency

has fallen year by year: in 1965, Japan’s foodself-sufficiency rate was 73% on a calorie basis and
86% on a production volume basis. By 2011, thesefigures had dropped to 39% and 66% respectively.
Viewing this product by product provides a better
perspective on food productivity. Japan’s degree of foodself-sufficiency (2011) on a quantity basis by product isshown below. The figures for meat, eggs and dairy
products shown below do not account for
self-sufficiency in animal feed. Otherwise, Japan’s
self-sufficiency ratio is over 50% in most areas except
for wheat and beans.
Rice
Wheat
TubersBeans
Vegetables
Fruit
Meat
Beef
Pork
ChickenEggs
Dairy products
Fish

95 %
11
76
9
71
38
54
43
52
66
95
65
52

Japan’s absolute food consumption volume has also
dropped. In particular, rice consumption has steadily
dropped since peaking at 118.3kg/person/year in 1962,
falling to 57.8kg/person/year by 2011 (1). The farming
population peaked in 1960 at 14.54 million; by 2012,
this had dropped to 2.51 million, with the average age
also rising to 65.9 years (2).
The pesticide industry has also entered a time ofstagnation and decline in keeping with the agricultural
climate. As shown in Fig. 3.41(a) above, the value of
shipments reached a peak of ¥445.5 billion in 1996 andcontinued to drop thereafter, falling 20% to ¥355.2
billion by 2011. Meanwhile, increasing concern overconsumer food safety led to the enactment of the Food
Safety Basic Act in 2003; the Food Sanitation Act wasalso amended accordingly.
Amidst these circumstances, the hurdles became
increasingly higher for developing new pesticides andthe success rate dropped each year. Major
amalgamations took place overseas in an attempt to
avoid the risks of the industry, and Japan eventuallybecame caught up in the aftereffects as well, withseveral Japanese companies disposing of their pesticide
operations. However, even in the midst of these harshconditions, Japanese companies have carried on puttingout new pesticides. This is testament to the level oftechnology infrastructure for pesticide development thatJapanese companies have managed to build up over along period of time.
(1) Regulatory Trends
In 1990, the Ministry for the Environment formulated
the Provisional Guidelines on the Prevention of Water
Pollution from Pesticides used on Golf Courses withthe aim of preventing water pollution from pesticides
used on golf courses. While pesticides were necessary
for maintaining golf courses, this became a social issue
that attracted media attention as the government had
fallen behind in its regulation of these pesticides. These
regulations were intended to ensure proper use ofpesticides. Each year since, the Ministry for theEnvironment has continued to measure theconcentration of pesticides in water draining from golfcourses. A survey in 1990 examined 46,000 samples
from 1,455 golf courses and found 10 cases (0.02%) of
readings over the indicated limit. Later studies tested
over 100,000 samples each year, with the number ofsamples over the limit remaining steady (around0.002% of all samples); since 2001, there have been no
samples over the limit (3), (4). While this can be attributed
to the enforced proper use of pesticides, we also see that
this problem was not always there.
In 2000, the Ministry of Agriculture, Forestry and
Fisheries set out the Japan Agricultural Standards(JAS) for Organic Produce (4) due to confusion in themarket from vague definitions of organic cultivation, as
society tried to produce crops while protecting theecosystem by reviving and using traditional naturalorganic fertilizers and pesticides rather than chemicalfertilizers and synthetic pesticides. These standards
strictly stipulated that only produce that had had nochemically synthesized fertilizers or pesticides used on
it and no genetic modification done to it could be soldas “organic produce.” The standards also regulated thepermissible fertilizers and soil ameliorating products
and stipulated that where pesticide use could not be
avoided, then only pyrethrum, machine oil, lime sulfur,
copper formulations, antibiotics such as Milbemectin,
natural enemies and sex pheromone agents could be
used. However, the organic produce yield in Japan has
remained low, accounting for 0.23% of the total amountof produce produced in 2010 (5).
In 2003, other standards were formulated to allow thesale of produce labeled as “specially cultivatedagricultural products,” or produce cultivated where thenitrogen content of the chemical fertilizer used and theamount of synthetic pesticides used is 50% or less than
the normal level (6).
Let us now mention “Specified Pesticides.” Productsthat are not registered as pesticides, but clearly work as
such without any damage to people, animals or marine
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51

life, are designated as “Specified Pesticides” (or“Specified Pest Control Agents”) and may be used as
pesticides (7), (8). Currently, sodium bicarbonate, vinegar
and local natural enemies (such as ladybirds,
Coccinella septempunctata) have been designated as
such.
Finally, let us discuss the “positive list system”
introduced in 2006 by the Ministry of Health, Labourand Welfare (9), (10). This system sets maximum residue
limits (including uniform standard values) for all
pesticides, feed additives and veterinary drugs(collectively referred to as pesticides, etc.) and residualin food products (all food products, including produce,
processed food, meat, eggs, dairy products and fish) as
well as prohibits the sale and distribution of any productwith any pesticide residues over the maximum limits.
The existing system became known as the “negative list
system,” as it simply listed the regulated pesticides andregulated those pesticides only, with no regulatory
principles in place. As a result, there were cases of theJapanese authorities being unable to regulate certain
imported pesticides used overseas as there were noresidue standards in place for those particular pesticides.
The positive list system has meant that all pesticides canbe regulated; any pesticides with no defined maximum
residue limit must conform to the uniform standard
value of 0.01ppm (1/100,000,000) - the designated“amount at which there is no fear of harm to humanhealth.”When used properly in accordance with usage
standards, pesticides will not leave any residue in foodproducts over the maximum residue limits. If residues
are within the standard limits, they are harmless tohuman health. Even if food products containing
amounts over the maximum residue limit were to beingested from time to time, it would not cause any
immediate health damage. This is because thesemaximum limits are based on the maximum residue
amount able to be continually ingested throughout alifetime with no health damage. The maximum residue
limits, particularly the uniform standard values, are aregulatory yardstick (to indicate whether or notpesticides are being used properly) rather than a safety
standard.
How much residual pesticide do we actually ingest in
the food we eat? The Ministry of Agriculture, Forestry
and Fisheries, the Ministry of Health and Welfare andother government departments have conductednationwide studies to address this question. Here weshall outline the official totals taken from tests carriedout by the Ministry of Health and Welfare at local
public bodies and quarantine stations (11). The results
show an extremely low detection rate for pesticide
residues and an extremely low rate of instances ofresidues exceeding the maximum residue limits. This
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Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japanshows that the guidance on the proper use of pesticides
has been effective.

No. Tested
Pesticides
detected
Domestic
products
Imported
products
Residue inexcess oflimit
Domestic
products
Imported
products

Produce

Processed
Foods

3,455,719

463,330

9,804(0.28%)

954(0.21%)

2,314(0.36%)

29(0.27%)

7,490(0.27%)

925(0.20%)

417(0.012%)84(0.03%)

21(0.003%)0(0.00%)

396(0.014%)84(0.03%)

Thus, pesticide legislation has been developed with themain aims of preventing environmental pollution andensuring the safety of the food eaten by end consumers.
An extensive follow-up survey has raised no points ofissue on this point; thus, it is safe to say that theguidance on proper pesticide usage has produced
positive results.
(2) Insecticides
A number of highly effective insecticides have beendeveloped since 1990, leading a transition from the ageof organophosphates and carbamates to an era of new
insecticides with new modes of action. Of the 61 newly
registered active ingredientsfor insecticides(excluding pesticides with lapsed registrations andbiopesticides such as natural enemies) registered by
2011, 34 (55.7%) were invented by Japanesecompanies. This is a good example of the strong
research and development capabilities of Japanesecompanies. Let us now outline some of the main
Japan-made insecticides.
There are three organophosphate formulas developedfor use against soil pests. Ishihara Sangyo registered
Fosthiazate (Nematorin) in 1992 (12). FMC brought out
Cadusafos (Rugby) in 2001, while Agro-Kanesho
registered Imicyafos (Nemakick) in 2010 (13), (14). While
the active ingredient in Cadusafos is a poison andhighly toxic to mammals, it has been downgraded to adeleterious substance by preparing it in microcapsules(Note 1). Both of the other two formulations are
low-toxic to mammals, but selectively effective against
root-lesion nematodes, root-knot nematodes and othergreen vegetable pests. Safety issues such as frequentirritation while fumigating against soil pests and theissue of methyl bromide depleting the ozone layermean that there is scope for other means of chemical
control to be developed in place of these formulations.
Fosthiazate has become widely popular since going on
the market and is currently worth ¥3 billion in
shipments. Fig. 3.49 shows the chemical structures ofthese formulations.

metamorphosis. Since this is species-specific, it has theadvantage of being highly safe to mammals and also
safe to beneficial insects such as bees. However, IGRs
also has the disadvantages of being slow-acting, as they
are effective as a stomach poison, as well as having asignificant impact on crustaceans.

Fig. 3.49. Fosthiazate, Cadusafos, Imicyafos

Duphar brought out the benzoylphenylurea (BPU)
compound Diflubenzuron (Dimilin) in 1981. Thiscaught the attention of other companies, who thenworked on BPUs, resulting in another seven productsby the present day. These products, shown in Fig. 3.50,
inhibit the biosynthesis of chitin, a component in insect
exoskeletons, thereby hindering ecdysis. The numbers
indicate the year of registration (or lapse thereof).

Section 3.4.4 (3) mentions synthetic pyrethroid
insecticides, typified by Fenvalerate (Sumicidin), whichappeared in 1983. Five such pyrethroids had beendeveloped by 1995 and continued to be popular as key
insecticides. For details, see Sections 4.14 and 4.18.
Shinzo Kagabu, of Nihon Tokushu Noyaku (nowBayer Japan), invented Imidacloprid (Admire) andregistered it in 1992. Called a neonicotinoid, as its modeof action is similar to the natural insecticide nicotine, it
became the best-selling insecticide in the world,
reaching ¥100 billion in sales. It truly is asuper-pesticide. This insecticide sparked intensive
research and development by various companies overthe next decade, resulting in another sevenneonicotinoids by 2002, each with different
characteristics. These are discussed in Section 4.20.
There was a flurry of research on insect growth
regulators (IGRs) - named for their insecticidal effectcaused by a new mode of action - during this time, witha significant number of IGRs produced. Buprofezin(Applaud), with a thiadiazine structure, was the first
IGR to be produced in Japan, brought out by Nihon
Nohyaku in 1983. For details, see Section 4.13.

During this period, companies also developed IGRs
modeled on the insect hormone ecdysone (a steroidal
prohormone that governs ecdysis and metamorphosis,
also called molting hormone or prothoracic glandhormone). These have a dibenzoyl hydrazine structure
and are very effective against Lepidoptera larvae on
fruit and vegetable plants. They have the advantage ofbeing highly selective and so have little effect on natural
enemies and pollinators. The first of these was
Tebufenozide (Romudan), registered and marketed by
Rohm and Hass in 1994. This was followed by
Chromafenozide (Matric) in 1999, jointly developed by
Nippon Kayaku and Sankyo. In 2001, Rohm and Hassdeveloped and marketed Methoxyfenozide (Falcon) (15).
These products work as insecticides by disrupting
feeding behavior and promoting ecdysis within a few
hours of being eaten by insects. Their chemical
structures are shown in Fig. 3.51.

IGRs work as insecticides by disrupting particularbiological functions in insects, namely ecdysis andFig. 3.50. Benzoylphenylurea Insecticides

Hiroki OHTA; Historical Development of Pesticides in Japan
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53

Fig. 3.51. Dibenzoyl Hydrazine Insecticides
Sumitomo Chemical developed and marketed
Pyriproxyfen (Lano) in 1995. This IGR works as an
insecticide by promoting larva growth and preventing
metamorphosis in the same manner as a juvenile
hormone (JH). Similarly-acting insecticides include
Methoprene, used for disease control against flies andmosquitoes, and Fenoxycarb (Insegar), registered by
Maag in 1990 as an insecticide for Lepidopterae(registration lapsed in 2004). Pyriproxyfen is quite
stable in light and is very effective against hard-to-killinsects such as whiteflies, thrips and scale insects. It has
a number of different effects on insects at the juvenilestages, such as inhibiting metamorphosis in larvae,
inhibiting adult eclosion and preventing eggs fromhatching, but it has no effect on adult insects (16). Fig.
3.52 shows the chemical structures of these IGRs.

Fig. 3.52. JH-Emulating IGRs
Let us now discuss the miticides that emerged during
this period, which were unprecedented both in terms ofchemical structure and mode of action. Fifteen of thesemiticides have now been registered since theappearance of Hexythiazox (Nissorun) in 1985,
mentioned previously. Five of these are inventions byoverseas manufacturers, while the remaining ten were
all invented and developed by Japanese manufacturers.
Miticides have a relatively small global market as well

54

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japanas quite a short product lifespan. Accordingly, it is quitedifficult to recoup any research and development costs
and, as a result, major overseas corporations havetended to put less effort into developing miticides thanJapanese companies have.
Milbemectin (Milbenock, Koromite) is a miticidal
antibiotic produced by actinomycetes found in the soil
in Hokkaido and isolated by Sankyo. This wasdeveloped into a mixture of Milbemycin A3 and A4 andput on the market in 1990. Highly effective against a
broad range of mites, it is widely used on fruit andvegetable plants as there has been no observed
cross-resistance as seen in existing miticides. Its modeof action is achieved by functioning as an agonist (Note2) in the Cl-channel for gamma-aminobutyric acid
(GABA) in the nervous system, fatally activating thechannel. It is worth noting that of the numerous
miticides, this is the only formulation to which noresistance has developed. One probable reason for thisis that Milbemycin quickly dissipates after application(17). This distinguishing characteristic has meant that thisproduct is still widely used today. For further details,
refer to Ide et al. (18).
While Lepimectin (Aniki) is not a miticide, we shallmention it here as it has a similar chemical composition
to Milbemectin. Registered as a pesticide in 2010 by
Sankyo (now Mitsui Chemicals Agro), it was
discovered by altering the structure of Milbemectin(ester structure added at the 13-position) to give it an
insecticidal effect. It works rapidly on insects such as
Lepidopterae, Hemipterae and thrips and is particularly
effective against butterflies (19). Fig. 3.53. shows the
structure of these two formulations.
Our discussion now turns to the miticides from thisperiod in the mitochondrial electron transport inhibitor(METI) category. Nissan Chemical developed andmarketed Pyridaben (Sanmite) in 1991, while Nihon
Nohyaku did the same for Fenpyroximate (Danitron)
the same year (21). This was followed by thedevelopment and sale of Tebufenpyrad (Pyranica) by
Mitsubishi Chemical in 1993 (22) and Pyrimidifen(Miteclean) by Ube Industries/Sankyo in 1995 (23).
These high-performance miticides started to dominate
the industry from the late 1980s onwards, when the
afore-mentioned Hexythiazox was in its heyday. These
formulations rapidly gained popularity in the early
1990s, accounting for half of the miticide market. They
were all effective at low doses, fast-acting and worked
at all stages in the spider-mite life cycle. They are all
known to inhibit Complex I in the mitochondrial
electron transport chain in the respiratory system. Whilevarious different companies worked on their own
versions of these miticides, they all had the same modeof action. Sale of these formulations gradually
decreased as some cross-resistance was observed a few
years after these products first went on sale.
Another compound with the same mode of action is
Tolfenpyrad (Hachihachi), developed as an insecticide.
This product was jointly developed by Mitsubishi
Chemical and Otsuka Chemical and registered in 2002.
It is widely popular due to its superior effectivenessagainst a wide range of insects, including Lepidopterae,
Hemipterae and thrips. It is also effective against
powdery mildew on eggplants, watermelons and otherplants. Fig. 3.54 shows the chemical structures of theseformulations.

Milbemectin (Milbenock)

Lepimectin (Aniki)

Fig. 3.53. Milbemectin and Lepimectin

Fig. 3.54. METI Inhibitors
Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

55

Etoxazole (Baroque) is a new miticide invented by
Yashima Chemical and registered in 1998. Yashima
Chemical came up with Etoxazole through research on
oxazoline chemistry. While it is not very effective on
mature spider-mites, it is incredibly effective against
insect eggs and nymphs. In terms of its ppb level, it is
100 times more powerful than other miticides such as
Hexythiazox. Its mode of action is not yet clearly
known, although it is presumed to work like
Hexythiazox by inhibiting ecdysis (24).
Otsuka Chemical invented Cyflumetofen (Danisaraba),a miticide with a completely new benzoylacetonitrile
structure and put it on the market in 2007. It is
fast-acting and is specific to spider-mites while having
no effect on beneficial insects. Its mode of action isconjectured to work by inhibiting Complex II in the
mitochondrial electron transport chain (25).
Nissan Chemical invented acrylonitrile miticide
Cyenopyrafen (Starmite) and registered it in 2008.
Cyenopyrafen has strong ovicidal activity for all kindsof spider-mites and has none of the cross-resistanceissues seen in existing miticides. Like Cyflumetofen,
mentioned above, it works by inhibiting Complex II in
the mitochondrial electron transport chain (26), (27), (28).
Nihon Nohyaku presented a report on the powerful
miticide Pyflubumide (NNI-0711) at a conference in2012 (Fig. 5.52). It also works by inhibiting Complex II
in the mitochondrial electron transport chain, although
it is still in development and has not yet been put on themarket (29), (30).
Fig. 3.55 shows the chemical structures of the miticides
mentioned above that have been recently developed orare still in development.

Fig. 3.55. Japanese Miticides Developed since 1998
Thus, previously unimaginably highly effective
miticides were successively developed. The Japanese

56

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan

miticide market is worth over ¥12 billion, shared
between these highly effective formulations. While
overseas manufacturers developed other miticides
during this time, these have all been
domestically-developed products pioneered by
Japanese manufacturers (such as Acequinocyl,
Bifenazate and Fluacrypyrim). The overwhelming
majority of miticides are developed by Japanesemanufacturers. Resistance to a product is an on-goingbattle and new miticides are in constant demand. Our
future hope lies in the development of formulations
with new modes of action, or softer formulations thatare safer for natural enemies and other environmental
factors.
Finally, let us return to insecticides. There have been agreat number of insecticides developed recently with
unprecedented chemical structures and unprecedented
modes of action. Several of these were invented anddeveloped by Japanese companies; we shall examine
these here.
Sumitomo Chemical invented Pyridalyl (Pleo) and put
it to market in 2004. Highly effective against
Lepidopterae and thrips, it is also effective against pest
insects that have become resistant to existing pesticides,
such as organophosphates, synthetic pyrethroids andIGRs. While its mode of action is not yet clearly known,
it is thought to work through a completely
unprecedented mechanism (31), (32), (33).
Ishihara Sangyo developed a fluorine-containing
pyridine insecticide, Flonicamid (Ulala), and registered
it in 2006. While it has no effect on Lepidopterae, it isselectively effective against aphids and thrips on fruitand vegetable plants and has systemic activity. Its modeof action is unknown, but it does not fit into any of theexisting categories (34).
In 2007, Nihon Nohyaku developed and marketed
Flubendiamide (Phoenix), with an unprecedented
phthalic acid diamide structure and a completely new
effect (35). This formulation drew attention for its
specific effectiveness against Lepidopterae, such asleafrollers on fruit trees and armyworms, diamondback
moths, etc. on vegetable plants. It works as a stomach
poison with residual effectiveness. While its effects areslightly delayed, it causes the body of the insect tofatally crumple up on itself (36). Its mode of action isachieved by acting on the ryanodine receptors (RyRs)
that govern the contractions of the insect’s muscles.
Flubendiamide activates the RyRs, releasing calcium
ions into the muscles of the insect and causing theinsect to fatally crumple up. Hatano provides moredetails on this mode of action (37). The appearance ofFlubendiamide piqued the attention of pesticide
manufacturers worldwide and a developmentcompetition ensued. DuPont won out with thedevelopment of Chlorantraniliprole (Acelepryn), which
has similar effects, registering it in 2009. A number ofmanufacturers are currently focusing on this area of
pesticides and future developments are promising.
Nihon Nohyaku developed Metaflumizone (Accel), an
insecticide with a semicarbazone structure, andregistered it in 2009. It is very effective against
Lepidopterae on vegetable and tea plants. Reports showthat its mode of action works in the sodium channel in
the nervous system (38). While synthetic pyrethroids are
known to work in the sodium channel, Metaflumizone
is thought to have a different mode of action, as it also
works on insects that have built up a resistance tosynthetic pyrethroids. Indoxacarb (Tornado), registeredby DuPont in 2001, also has a similar mode of action(39). Metaflumizone also can be regarded as having thering-opened structure of Indoxacarb.
Nihon Nohyaku registered quinazolinone-structured
Pyrifluquinazon (Colt) in 2010. This formulation ishighly effective against aphids, stink bugs, thrips andscale insects on fruit and vegetable plants. It iscategorized as an insect behavior regulator (IBR), as it
prevents insects from feeding and sucking and causes
them to immediately drop off plants (40), (41), (42). While its
mode of action is not clearly known, it is similar to
Pymetrozine (Novartis), which went on the market in

1998. There is also a partial chemical resemblance
between them.. The research team at Nihon Nohyaku
started investigating methoxyacrylate fungicides in thelate 1980s. They discovered that the aminoquinazoline
derivative they had synthesized as an intermediate had
insecticidal properties, so they researched it further.
They introduced the perfluoroalkylated aniline structure,
the intermediate in Flubendiamide, resulting in
Pyrifluquinazon.
Fig. 3.56 shows the chemical structures of thesecompounds.
As mentioned above, a number of pesticides that haveemerged during this period are highly effective, safe tomammals and have little impact on the environment. A
succession of new products is being developed with
unprecedented chemical structures, new pesticidal
characteristics and new modes of action. Although there
are high hurdles to surmount in development, it is worth
noting that many of the new products have been
discovered by Japanese companies and many of thesehave become world-renowned products. As insects
have begun to build up resistance to existing
insecticides, there is a continuous need for new
insecticides with new modes of action and further
development is expected.

Fig. 3.56. New-Effect Insecticides developed since the 2000s
Cited References(1) MAFF Basic Information on the Food Self-Sufficiency
Rate www.maff.go.jp/j/zyukyu/zikyu_ritu/012.html, accessed
23 November 2012.
(2) MAFF Basic Data on Agriculture, Forestry and Fisheries
http://www.maff.go.jp/j/tokei/sihyo/index.html, accessed 23
November 2012.
(3) Japan Crop Protection Association. Nōyaku Q & A [Pesticide
Q & A], 2011, p. 211.

(4) MAFF Bulletin No. 59, 20 January 2000;
http://www.maff.go.jp/j/jas/jas_kikaku/yuuki.html(5) Rated Performance of Organic Produce, Etc. 2010
http://www.maff.go.jp/j/jas/jas_kikaku/pdf/jiseki_h22_241016r.
pdf(6) Notice of the Ministry of Agriculture, Forestry and Fisheries,
Food Marketing No. 3889, 1 October 1992
http://www.maff.go.jp/j/jas/jas_kikaku/tokusai_a.html(7) MAFF / MOE Bulletin No. 1, 2003

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57

(8) Japan Plant Protection Association. Nōyaku Gaisetsu[Pesticide Overview], 2011, p. 300.
(9) Ministry of Health, Labour and Welfare. Act for Partial
Revision of the Food Sanitation Act, etc., Act No. 55, 2003;
promulgated 30 May 2003.
(10) Hattori. Symposium Address Overview “Pojitibu Risuto
Seido no 5-nenkan [Five Years of the Positive List System],”Japan Plant Protection Association, 17 January 2011.
(11) Ministry of Health, Labour and Welfare. Publication of test
results for pesticide residues in food (2005-2006), announced 29
October 2012.
http://www.mhlw.go.jp/topics/bukyoku/iyaku/syoku-anzen/zanr
yu2/121029-1.html(12) Koyanagi et al. Journal of Pesticide Science, Vol. 23, No. 2,
1998, p. 174.
(13) Osaki et al. Plant Protection, Vol. 64, No. 5, 2010, p. 333.
(14) Agro-Kanesho. Pesticide Compendium: Imicyafos, FAMIC,
10 December 2007.
(15) Yanagi et al. Journal of Pesticide Science, Vol. 31, No. 2,
2006, p. 182.
(16) Hatakoshi et al. Journal of the Agricultural Chemical Societyof Japan, Vol. 77, No. 8, 2003, p. 730.
(17) Aoki et al. Journal of Pesticide Science, Vol. 19, No. 3, 1994,
S125-131.
(18) Ide et al. Annual Report of Sankyo Research Laboratories,
Vol. 45, 1993, p. 1.
(19) Ichinose. Plant Protection, Vol. 64, No. 9, 2010, p. 626.
(20) Hirata et al. Journal of Pesticide Science, Vol. 20, No. 2, 1995,
p. 213.
(21) Hamaguchi et al. Journal of Pesticide Science, Vol. 20, No. 2,
1995, p. 203.
(22) Okada et al. Journal of Pesticide Science, Vol. 25, No. 3,
2000, p. 310.
(23) Plant Protection, Vol. 50, No. 10, 1996, p. 41.
(24) Suzuki et al. Journal of Pesticide Science, Vol. 26, No. 2,
2001, p. 215.
(25) Takii. Nōyaku kara Agurobaioregyurētā e no Tenkai[Development from Pesticides to Agro-bioregulators], CMC,
2009, p. 101.
(26) Takii et al. Abstracts from the 31st Annual Convention of thePesticide Science Society of Japan, 2006, pp. 113-114.
(27) IUPAC International Congress of Pesticide Chemistry Kobe,
Japan, Poster Ⅰ-1-i-21C (2006)(28) Haruyama. Agriculture of the Month, Vol. 8, 2008, p. 46.
(29) Furuya et al. Lecture No. A304, 37th Annual Convention of thePesticide Science Society of Japan, 2006.
(30) Nakano et al. Lecture No. A305, 37th Annual Convention of
the Pesticide Science Society of Japan, 2006.
(31) Tsuchiya. Journal of Pesticide Science, Vol. 30, No. 3, 2005,
p. 278.
(32) Sakamoto et al. Journal of Pesticide Science, Vol. 37, No. 3,
2012, p. 283.
(33) S. Saito, S. Isayama, S. Sakamoto, K. Umeda and K.
Kasamatsu: Brighton Crop Prot. Conf. –Pests and Diseases, 1,
p33 (2002)(34) M. Morita, T. Ueda, T. Yoneda, T. Koyanagi, S. Murai and N.
Matsuo: Brighton Crop Prot. Conf. –Pests and Diseases, 1, p59(2000)(35) T. Nishimatsu et al., The BCPC Congress 2005 Congress
Proceedings, 1, p57 (2005)(36) M. Tohnishi et. Al., J. Pestic. Sci., 30, (4), p354 (2005)(37) Hatano. Nōyaku kara Agurobaioregyurētā e no Tenkai[Development from Pesticides to Agro-bioregulators], CMC,
2009, p. 75.
(38) V. L. Salgado et al., Veterinary Parasitology, 150, p182 (2007)(39) Tsurubuchi et al. Japanese Journal of Applied Entomology
and Zoology, Vol. 47, No. 1, 2003, p. 29.
(40) M. Uehara, T. Shimizu, S. Fujioka, M. Kimura, K. Tsubata

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National Museum of Nature and Science, Japanand A. Seo: Pestic. Sci., 55, p343 (1999)(41) Suwa et al. Abstracts from the 53rd Annual Convention of theJapanese Society of Applied Entomology and Zoology, 2009, p.
132.
(42) Suwa et al. Plant Protection, Vol. 65, No. 3, 2011, p. 192.
Note 1: Microcapsule formulations are made from a slurry coatedin a polymeric membrane for the purpose of controlled release.
This has the effects of reducing unwanted toxicity, durability ofeffect (residual activity) and reducing any harmful side effects on
crops.
Note 2: An agonist is a substance that acts on (stimulates) thereceptor (point of action) in the same way as a naturally occurring
substance (in this case, GABA).

(3) Fungicides
Let us now discuss the main fungicides developed
during the 1990s and since, with particular focus on
those developed in Japan. A number of rice blast
fungicides with various different characteristics weredeveloped after the war, such as mercurials,
organochlorides, organophosphates and antibiotics.
During this period, some fungicides emerged with
unprecedented effects and modes of action.
First, let us mention the rice blast fungicides that workby inhibiting biosynthesis of melanin. Kureha
developed and marketed Fthalide (Rabcide) in 1970. As
discussed in Section 3.4.4 (4), this is classified as a
MBI-R, a second-generation MBI. Other MBI
formulations with new chemical structures different
from Fthalide were developed in the late 1990s. As
shall be mentioned later, these formulations arethird-generation MBIs, called MBI-Ds, because they
act at a different step in the rice blast melaninbiosynthesis process from Fthalide, inhibiting thescytalone dehydrogenase (1).
Bayer Japan developed and marketed Carpropamid(Win) in 1997. Inventor Shinzo Kagabu had been
focusing on substituted cyclopropane-carboxylic acidderivatives and examining related compounds after
reading a published paper on momilactone as an
inducer (resistance inducer) of rice phytoalexin(Note 1).
Meanwhile, while investigating herbicides, Kagabu
discovered that amides derived from substituted
phenethylamine and bulky carboxylic acid derivatives
worked as a fungicide against rice blast. Combining
these two areas of research resulted in Carpropamid(Fig. 3.57). The initial aim for this research was todevelop fungicides that were active in inducing
resistance and although it was indeed proven to induce
resistance, it became known more for its effect of
inhibiting melanin biosynthesis (2), (3). This success was
the result of the attention paid to a number of research
papers, the idea of developing that work into a leadcompound and the tenacity to overcome a string of
failures. Kagabu also invented world-renowned
Imidacloprid, and thiacloprid (see Section 4.20) aroundthe same time. While Kagabu attributes theseinventions as a gift from God (3), the true reason for his
success was not a gift. It was the result of the wealth ofknowledge and experience at his disposal, the way inwhich he brought out those ideas and, most importantly,
his tireless hard work and his good fortune (serendipity,
the power to bring about success).

Lead Compound 1

Lead Compound 2

Carpropamid (Win)Fig. 3.57. Carpropamid and its Lead Compounds
Following the appearance of Carpropamid, Sumitomo
Chemical developed and marketed Diclocymet(Delaus) in 2000 (4), while ACC and Nihon Nohyaku
did the same for Fenoxanil (Achieve) the same year.
Takeda Pharmaceutical developed and marketed
Ferimzone (Take-blass) in 1991. Reports indicate that,
unlike the MBIs, this fungicide acts on the cellular
membrane to prevent hyphal growth (5). Fig. 3.58 shows
the chemical structures of these products.

Diclocymet (Delaus)

Fenoxanil (Achieve)

Ferimzone (Takeblass)Fig. 3.58. Rice Blast Pesticides developed since the1990s (other than Melanin Synthesis Inhibitors)
Next, we shall discuss ergosterol biosynthesis inhibitors(EBIs), which are fungicides that work by inhibiting thebiosynthesis of ergosterol (a lipid component thatmakes up the cellular membrane in molds andbiosynthesized from squalene, equivalent to cholesterolin animal cells). Since the appearance of this type offungicide in the 1970s, companies have been working
on developing them. They are widely popular as they
have systemicity, working as prevention and a cure, andare also very effective on a wide range of diseases on
wheat, soybeans, vegetables and fruit plants. From the
1990s onwards, these have been the most significant
fungicides for agriculture. Resistance to EBIs is slow todevelop and there is little risk of the effect weakening,although there is a growing resistance to many of thesepesticides because of long-term use. Little research has
been done on these pesticides since 2000.
The first EBI developed in Japan was Triforine (Saprol),invented by Celamerck and registered in 1977. In 1983,
Bayer marketed Triadimefon (Bayleton). This triggered
other companies to start their own development and anumber of other EBIs emerged. The EBI development
rush lasted 20 years from the late 1980s. There are

more than 20 EBIs currently registered in Japan. Sevenof these are Japanese inventions, each with their own
distinguishing characteristics. Fig. 3.59 shows thechemical structures of these formulations and lists their
manufacturers. All of them have nitrogen-containing
hetero-cyclic ring structures, such as imidazole andtriazole.
Just as the development competition over EBIs ebbed alittle into the 1990s, a new fungicide emerged with a
new mode of action: strobilurin fungicides, modeled onnatural strobilurin, a fungicidal substance found in
Strobilurus tenacellus, a type of basidiomycete (6). This
has a distinctive methoxyacrylate structure. The first
strobilurin fungicide registered in Japan was
Kresoxim-Methyl (Stroby), developed by BASF andregistered in 1997. This was followed by Azoxystrobin(Amistar), developed by Zeneca and registered in 1998.
Later, more than 20 companies competed to develop
the next strobilurins, ushering in the age of thestrobilurin fungicide. Currently, there are 10 suchproducts on the pesticide register. Two of these weredeveloped by Japanese companies and are shown in Fig.
3.60.
Shionogi invented Metominostrobin (Oribright) and put
it to market in 1998. This product proved to be effective
against rice blast and a wide range of other rice diseases
such as sheath blight and leaf blight. While the researchteam at Shionogi was developing isoxazole derivatives
as herbicides, they also noted that these had some minor
fungicidal effects. They developed this into a ring
opened heterocyclic structure, resulting in
Metominostrobin (7).
Kumiai Chemical registered Pyribencarb (Fantasista)very recently, in 2012. This formulation is distinctive
for its suitability for a wide range of diseases on fruitand vegetable plants as well as its effectiveness against
fungi that have grown resistant to strobilurin (8), (9). It has
only just been registered, but it is expected to grow in
popularity in future.
The mode of action of the strobilurins mentioned aboveis known to work by inhibiting respiration in fungi byinhibiting Complex III (Qo) in the mitochondrial
electron transport chain (Note 2).
This effect is achieved by strobilurins, mentioned above
as being produced by molds; however, this does notmean that strobilurins inhibit respiration in molds.
Reports indicate that these fungi have various defense
mechanisms in place, such as low susceptibility at the
point of action. The growing resistance to these types offungicides in powdery mildew in wheat and downy
mildew in cucumbers could have something to do withthese defense mechanisms.

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Fig. 3.59. Ergosterol Biosynthesis Inhibitors (EBIs)

Fig. 3.60. Typical Strobilurin Fungicides

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Japanese companies have invented a number of otherfungicides besides EBIs and strobilurins since 2000.
Each of these has a different mode of action from thetwo mentioned above and is effective against fungi thatare resistant to existing formulations.
Ishihara Sangyo registered Cyazofamid (Ranman) in
2001 and put it on the market. It is effective against lateblight in potatoes and downy mildew in grapes (bothoomycetes). Initially sold in Japan, it later spreadthroughout 16 countries. It was discovered as a result offurther developments on cyanoimidazole andbenzimidazole structures, known through patents tohave fungicidal properties. While its mode of action isachieved by inhibiting respiration, like the strobilurins,
it is known to act in a different position (electrontransport chain Complex III (Qi)) (10).
NipponSoda
developed
andregisteredoxime-ether-structured Cyflufenamid (Pancho) in 2002.
This fungicide is distinctive for its broad ranging effects
on powdery mildew on wheat, vegetables and fruit
plants, as well as its effectiveness against diseases
showing signs of resistance to existing fungicides.
Nippon Soda already had experience with oxime-ether
compounds from having developed the herbicide
Alloxydim and presumably applied this knowledge toexisting fungicides to produce Cyflufenamid. While its
mode of action is completely different from any
existing formulations, the details of it are not yet clearly
known (11).
Kumiai Chemical developed and marketed
Benthiavalicarb isopropyl (Mamolot) in 2007. Thisfungicide has an amino acid valine amide carbamate
structure and works as both prevention against and curefor blight and downy mildew. Kumiai worked on
developing structures based on the fungicidal propertiesof valine derivatives patented by Bayer, resulting in thisbenzothiazole skeletal structure. Reports indicate that its
mode of action is achieved by inhibiting biosynthesis ofcell walls (12), (13).
NissanChemicaldeveloped
sulfamoyltriazole-structured Amisulbrom (Leimay) andput it to market in 2008. This product is highly effective
against blight and downy mildew, penetrating quickly
into plants to produce a high preventive effect (14), (15).
While its mode of action is presumed to work by
inhibiting respiration like the aforementioned
Cyazofamid, no detailed reports have been made. The
two are similar in chemical structure, both having asulfamoyl-based azole skeleton.
Mitsui Chemicals developed and marketed carboxylic
acid-amide-structured Penthiopyrad (Affet) in 2008.

This product shows superior effectiveness against awide range of diseases, such as grey mold, powdery
mildew, leaf mold, scab and monilia blossom blight. It
is also highly effective against fungi that havedeveloped resistance to existing fungicides. Its mode ofaction works by inhibiting succinate dehydrogenase in
the respiratory electron transport chain Complex II (16),(17). While other carboxylic acid-amide fungicides havebeen developed with this mode of action, such as
Mepronil (Basitac; registered by Kumiai Chemical in1981), Flutolanil (Moncut; registered by Nippon Soda
in 1985) and Furametpyr (Limber; registered by
Sumitomo Chemical in 1996), Penthiopyrad is highly
effective against diseases that these other fungicides
have failed to beat. It is also effective against newly
problematic diseases that have developed resistance to
EBIs and strobilurins.
Ishihara Sangyo started marketing Pyriofenone(Property) in the United Kingdom. This fungicide has abenzoylpyridine structure and is very effective against
powdery mildew in wheat, cucumbers and other crops(18), (19). The fungicidal action of this fungicide isachieved by inhibiting the formation of haustoria andconidia in the parasitic fungus and interfering with themorphology of secondary appressoria and hyphae. The
chemical structure of this product was developed byreplacing the benzene ring in Metrafenone, developedby BASF, with a pyridine ring – the result of Ishihara’s
wealth of experience with pyridine. This product has
not yet been registered in Japan. Fig. 3.61 shows the
new fungicides developed by Japanese companies in
the 2000s discussed above.
As discussed above, there have been major
developments in fungicides since the 1990s. This era
has seen the successive appearance of MBI-D, a new
type of melanin biosynthesis inhibitor, ergosterol
biosynthesis inhibitors (EBIs), effective against a broad
range of fungi, and strobilurin fungicides. A number ofother fungicides have also emerged, with new modes ofaction and new chemical structures. It is worth notingthat many of these were developed by Japanesecompanies. Given the intrinsic problem of fungi
developing resistance to products, there are limitations
to fungicides, in that the continuous use of productswith the same mode of action should be avoided or thedoses should be reduced, etc. in order to delay thebuild-up of resistance to some extent. From thedevelopers’ perspective, there is an on-going demand todevelop new pesticides with new modes of action, but
the hurdles to clear are getting increasingly higher, suchas having to create highly effective pesticides while
ensuring their safety and assessing their impact on theenvironment.

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Fig. 3.61. New Fungicides developed since 2000
Cited References(1) Miura. Shin Nōyaku Kaihatsu no Saizensen [The Forefront of
New Pesticide Development], CMC, 2003, p. 49.
(2) Kurahashi et al. Journal of Pesticide Science, Vol. 24, No. 2,
1999, p. 204.
(3) Kagabu. Journal of Synthetic Organic Chemistry Vol. 58, No.
6, 2000, p. 6060.
(4) A. Manabe, K. Maeda, M. Enomoto, H. Takano, T. Katoh, Y.
Yamada and Y. Oguri: J. Pestic. Sci., 27, (3) p257 (2002)(5) Matsuura et al. Journal of Pesticide Science, Vol. 19, No. 4,
1994, p. S197.
(6) T. Anke et al., J. Antibiot. 30, p806 (1977)(7) Mashiko et al. Journal of Pesticide Science, Vol. 26, No. 2,
2001, p. 203.
(8) S. Kataoka, M. Takagaki, T. Nakano, K. Kaku, S. Fukumoto,
S.
Watanabe, K. Nozaki and T. Shimizu: 11th IUPAC International
Congress of Pesticide chemistry, Book of Abstracts (2), 138(2006) (9) S. Kataoka, M. Takagaki, K. Kaku and T. Shimizu: J.
Pestic. Sci. 35, (2) p99 (2010)(10) Oshima et al. Journal of Pesticide Science, Vol. 29, No. 2,
2004, p. 147.
(11) Sano et al. Journal of Pesticide Science, Vol. 32, No. 2, 2007,
p. 151.
(12) Y. Miyake, J. Sakai, M. Shibata and K. Nagayama: British
Crop Prot. Conf., 1, p105, (2005)(13) Sakai et al. Journal of Pesticide Science, Vol. 35, No. 4, 2010,
p. 501.
(14) Takahashi et al. Abstracts from the 32nd Annual Convention of
the Pesticide Science Society of Japan, 2007, SI3.
(15) Manabe et al. Nōyaku kara Agurobaioregyurētā e no Tenkai[Development from Pesticides to Agro-bioregulators], CMC,
2009, p. 36.
(16) Sakurai et al. Journal of Pesticide Science, Vol. 36, No. 4,
2011, p. 520.
(17) Katsuta. Abstracts from the 32nd Annual Convention of thePesticide Science Society of Japan, 2007, SI9, p. 33.
(18) Patent No. 2004-168757 (Ishihara Sangyo)(19) Fine Chemicals, Vol. 39, No. 10, 2010, p. 43.

62

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan(Note 1) Phytoalexins are antimicrobial secondary metabolites
produced in plants under stress when infected by a fungus orsimilar. “Phyto” means “plant;” “alexin” means “defensive
substance.”(Note 2) Mitochondria are organelles within a cell; these havecomplexes (enzymes) in their membranes that govern the electrontransport chain that produces energy during respiration.

(4) Herbicides
Let us examine the developments in herbicides fromthe 1990s onwards. Besides the paddy rice barnyard
grass killers discussed in Section 3.4.4 (5), a number ofother effective herbicides appeared during this time.
Researchers in the late 1990s worked on modes ofaction and clarified that chloroacetamide herbicides(such as Butachlor and Pretilachlor), which had
previously been thought to work by inhibiting protein
synthesis,
actually
workedbyinhibiting
Very-Long-Chain Fatty Acid Elongase (VLCFAE) infatty acid synthesis (1), (2). This prompted thedevelopment of a number of herbicides having thismode of action.
Tokuyama Soda (now Tokuyama) started pesticide
research and development in 1980, working jointlywith Utsunomiya University. A study involving adding
various heterocycles to chloroacetamide herbicides
resulted in Thenylchlor (Alherb) with a thiophene
heterocycle, registered in 1993. Multiple times more
active than existing chloroacetamide herbicides, it wasvery effective not only against barnyard grass, but also
against Cyperaceae and Monochoria vaginalis (3), (4).

Hodogaya Chemical developed and marketed
Etobenzanide (Kickby) in 1995. Selectively effective
against barnyard grass, this was used in combination
formulations (5).

Uniroyal was the first to identify the herbicidal
properties of the tetrazolinone structure, the herbicidal
effect on barnyard grass significantly increased withimprovements to the structure (10).

ChugaiPharmaceuticalinvented
Cafenstrole(Himeadow) and put it on the market in 1996. Effective
against barnyard grass until the 2.5 leaf stage andlong-lasting, it is very popular as a base substance for
combination formulations. By 1998, it was a major
herbicide, being used on more than 450,000 hectares. It
is also suitable for use on turf. Its carbamoyl triazole
structure is unprecedented among herbicides (6), (7).

Kumiai Chemical developed Fenoxasulfone, very
effective against barnyard grass and also annual weeds,
and applied for registration in 2012. It is expected to
become a popular formulation. With asulfonyl-substituted isoxazoline structure, it should bevery effective at low doses of 100-250g. Kumiai
Chemical also developed the similarly-structured
Pyroxasulfone, which is very safe on major crops suchas wheat, maize and soybeans, very effective against
broadleaf weeds such as Chenopodium album(Common lambsquarters) and Abutilon theophrasti(velvetleaf) and also effective on glyphosate-resistantweeds, which have become a problem in recent times.
Pyroxasulfone was registered in 2011 in Australia andin 2012 in the United States (11), (12), (13).

Indanofan (Trebiace) is a new herbicide combining an
oxirane ring with an indandione structure. Inspired by
the oxirane-structured maize herbicide Tridiphane (nolonger in use), Mitsubishi Chemical worked on
developing its own compound, resulting in Indanofan,with a new chemical structure previously unseen in a
herbicide, and registered it in 1999. This product is very
effective against barnyard grass at the 2.5 leaf stage andbroad-leaf weeds at a low dosage of 120-150g per
hectare (8), (9).
Fentrazamide (Innova) is a paddy rice herbicide
invented by Bayer Japan. Registered in 2000, thisproduct became very popular, marketed as the main
ingredient in a combination formulation, making a
name for itself as a key barnyard grass killer. While

All of the herbicides discussed here work by inhibiting
VLCFAE, mentioned above. While these represent awide range of different chemical structures, there is still
potential for a completely new compound to bediscovered that works in the same way, and there ismuch promise for future development. This is a good
example showing the importance of researching thetarget mode of action when inventing new pesticides.
Fig. 3.62 shows these VLCFAE inhibitors.

Fig. 3.62. VLCFAE Inhibitors developed since 1990

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Next, we shall discuss carotenoid synthesis (4-HPPD)
inhibitors, which have been actively researched since
the late 1990s. Section 3.4.4 (5) touched on 4-HPPD;
the forerunner of these formulations was Pyrazolate(Sanbird), developed by Sankyo in 1979. Once
Japanesecompanies
starteddeveloping
pyrazole-structured herbicides in the late 1980s, nofurther development was done on pyrazole derivatives.
SDS Biotech later discovered the triketone derivative
Benzobicyclon (Show Ace) and registered it in 2001.
While it had been known since the 1980s thattriketone-structured compounds had herbicidal effects,
SDS started developing it for use on paddy rice fields.
After a number of modifications to the structure,
Benzobicyclon became the first such herbicide highly

suited for use in paddy rice cultivation. It proved to bevery effective against annual broadleaf weeds andperennial weeds at doses of 200-300g per hectare (14), (15),(16). It rapidly became popular due to its effectiveness on
weeds such as Scirpus juncoides and Monochoria
vaginalis that had become resistant to SU herbicides; by2009, it was being used on 500,000 hectares. Other
herbicides in this category include Tefuryltrione(Mighty One), developed and marketed by Bayer Japan
in 2010, and Mesotrione (Callisto), developed andmarketed by Syngenta.
Much research has gone into the area of 4-HPPD
inhibitors since the appearance of the triketone structureand future developments are expected.

Fig. 3.63. Triketone 4-HPPD Inhibitors developed since 2000
Finally, let us discuss the significant development thathas taken place during this period on herbicides thatwork by inhibiting chlorophyll biosynthesis.
Compounds with this effect have a long history datingback to diphenyl ether herbicides. While we shalldiscuss this in more detail in Section 4.5, let us mention
here that NIP (registered in 1963), CNP (registered in1965) and Chlomethoxynil (X-52) require light in order
to work as herbicides and were thus initially called lightdependent or photobleaching herbicides. Later,

Rhône-Poulenc developed Oxadiazon (Ronstar), with acompletely different chemical structure. This
formulation is still used as a paddy rice herbicide.
Mitsubishi Chemical developed and marketed
cyclic-imide-structured Chlorphthalim in 1981. This
formulation is still used today as a herbicide for turf.
While these products have completely different
chemical structures, they are light-dependent herbicides,
like the diphenyl ether products (Fig. 3.64).

Fig. 3.64. Early Light-Dependent Herbicides (PPO Inhibitors)
In the late 1980s, research showed that theseformulations killed plants by means of reactive oxygen
produced during photosynthesis as a result of inhibiting
protoporphyrinogen-IX oxidase (PPO), a synthase for
protoporphyrin IX in the chlorophyll biosynthesis
process (17), (18), (19). Development competition ensued
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Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japanand a number of these PPO inhibitors were producedby various different companies.
Sumitomo Chemical developed Flumiclorac pentyl(Resource) in 1994 as a herbicide for use on soybeans(20)
and also registered Flumioxazin (Sumisoya) inJapan in 2000. It then registered this product in the
United States in 2001 for use on soybeans and peanuts(21).
Kaken Pharmaceutical developed Pentoxazone (Vexor)
for use on barnyard grass and broadleaf weeds and put
it to market in 1997. Effective against annual weeds ingeneral, this product is also very effective on common
false pimpernel and Monochoria korsakowii (mizuaoi)that have become resistant to sulfonylurea pesticides (22).
Currently, more than 40 combination formulations
include this product and it is very popular as a paddy
rice herbicide.
Nihon Nohyaku developed and marketed Pyraflufen
ethyl (Ecopart) in 1999. This formulation is highly
effective on broadleaf weeds (such as Galium spurium)in wheat at low doses comparable with sulfonylurea
pesticides (6-12g/hectare). It has also been registeredoverseas in Europe. Unlike the existing PPO inhibitors,
this formulation has a unique chemical structure, with abenzene ring bonded to hetero ring carbon atoms (C-Cbond) (23), (24).
Kumiai Chemical developed and marketed Fluthiacet
methyl (Velvecut) in 2002. This product is very
effective on Abutilon theophrasti (velvetleaf), a noxious
weed on maize crops, at doses of 3-10g/hectare (25). It
was registered in the United States in 1991 for use on
soybeans and maize.
While we have discussed the PPO inhibitors developed
by Japanese companies, there has been intensecompetition among overseas companies in this field aswell. Herbicides produced by overseas companies andregistered in Japan for use on the Japanese rice market
include Carfentrazone ethyl (Hardy), registered by
FMC in 1999, Oxadiargyl (Fenax), registered by
Rhône-Poulenc (now Bayer) in 2001, and Pyraclonil(Pyraclon), registered by Schelling (now Bayer) in2007. Fig. 3.65 shows the chemical structures of these
PPO inhibitors.

Fig. 3.65. PPO Herbicides
As discussed above, a number of high-performance
herbicides have emerged since 1990. In terms of modeof action, there has been much research anddevelopment on ALS inhibitors, VLCFAE inhibitors,
4-HPPD inhibitors and PPO inhibitors. However, there
also have been two significant issues. One is the issueof reduced effectiveness due to a build-up of resistance,
as seen with the ALS inhibitors. The other issue is thatof Roundup tolerance in upland crops such as soybeans.
Herbicides are no longer thought to have far lessproblems with resistance than insecticides or fungicides
and no longer have a long lifespan. While continuous
development of new herbicides with new effects is themost-cited way to solve this, there needs to be a betterway of preventing the build-up of resistance, regardlessof whether a new or existing product is used. While theemergence of genetically-modified crops such as
Roundup-tolerant soybeans has made it possible toefficiently produce a stable yield, we are now seeing abacklash against the use of a single herbicide to solve
all problems. Further research on herbicides is needed
to solve this issue.
Cited References(1) P. Böger: J. Pestic. Sci., 28, (3), p324 (2003)(2) Tanetani et al. Journal of Pesticide Science, Vol. 36, No. 4,
2011, p. 527.
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65

(3) Ogasawara et al. Journal of Weed Science and Technology, Vol.
34, No. 2, 1989, p. 131.
(4) Kato et al. Journal of Synthetic Organic Chemistry Vol. 56, No.
3, 1998, p. 56.
(5) Anzai et al. Journal of Weed Science and Technology, Vol. 40,
1995, p. 28.
(6) M. Kanzaki et al., Brighton Crop Protection
Conference-Weeds, 3 (7C-1), p923 (1991)(7) Kanzaki et al. Journal of Weed Science and Technology, Vol.
45, No. 2, 2000, p. 118.
(8) A. Hosokawa, T. Shike, M. Katsurada, O. Ikeda, N. Minami
and T. Jikihara: J. Pestic. Sci., 26, (1), (2001)(9) Jikihara et al. Journal of Synthetic Organic Chemistry Vol. 59,
No. 9, 2001, p. 845.
(10) Yanagi et al. Journal of Pesticide Science, Vol. 27, No. 2,
2002, p. 199.
(11) Takahashi et al. Abstracts from the 35th Annual Convention of
the Pesticide Science Society of Japan, 2010, p. 52.
(12) Tanetani et al. Journal of Pesticide Science, Vol. 37, No. 3,
2012, p. 269.
(13) S. Knezevic, A. Datta, J. Scott and P. Porpiglia: Weed
Technol., 23, p34 (2009)66

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan(14) Sekino. Journal of Pesticide Science, Vol. 27, No. 4, 2002, p.
388.
(15) K, Sekino, H. Koyamagi, E. Ikuta and Y. Yamada: J. Pestic.
Sci., 33, (4), p364 (2008)(16) Komatsubara et al. Journal of Pesticide Science, Vol. 34, No.
2, 2009, p. 136.
(17) M. Matringe et al., Biochem. J., 240. P231 (1989)(18) P. Böger and K. Wakabayashi: “Peroxidizing Herbicides”
Springer Verlag, (1999)(19) B. Nicolaus, G. Sandmann and P. Böger: Z. Naturforsch. 48c,
p326 (1993)(20) Hashimoto et al. Sumitomo Chemical 1995-1, 1995, p. 4.
(21) Nagano et al. Sumitomo Chemical 2001-1, 2001, p. 14.
(22) Hirai et al. Journal of Pesticide Science, Vol. 26, No. 2, 2001,
p. 194.
(23) T. Mabuchi, Y. Miura and T. Ohtsuka, J. Pestic. Sci., 27, (1),p39 (2002)(24) Miura et al. Journal of Synthetic Organic Chemistry Vol. 61,
No. 1, 2003, p. 2.
(25) T. Miyazawa, K. Kawano, S. Shigematsu, M. Yamaguchi and
K. Matsunari: Brighton Crop Protection Conference-Weeds,p23 (1993)

4. New Pesticides Invented in Japan
This section discusses new Japanese pesticides thathave become world-renowned products. We shall begin
by outlining the current status of the Japanese pesticide
register (as of June 2012). The figures below indicate
the number of registered so-called organic compounds.
Inorganic compounds, ordinary low-molecular-weightcompounds, adjuvants, rodenticides, natural enemies
and other biopesticides are excluded, as are the numberof such pesticides developed by Japanese companies (1),(2).
Insecticides: 122 registered; 54 of Japanese origin(44.3%)
Fungicides: 98 registered; 43 of Japanese origin(43.9%)
Herbicides: 138 registered formulations; 51 of Japaneseorigin (44.0%)
Plant growth regulators: 25 registered formulations; 11of Japanese origin (41.5%)
Total: 383 registered formulations; 159 of Japaneseorigin (41.5%)
Thus we see that over 40% of pesticides were madeand developed in Japan. Mergers among major
companies in the West have meant that overseas
companies far outweigh Japanese companies in termsof scale; overseas research and development
investments are also far greater. Nevertheless, thecomparatively small-scale Japanese companies havedemonstrated an ability to create pesticides more
efficiently and have discovered a number of pesticides
that have either become world-class products or proved
to be of immense scientific value.
This section discusses the development history andsignificance of the more impacting of these pesticides
and also examines why so many successful Japanesepesticides have emerged. It must be noted that there aremany other Japanese pesticides that could not bementioned here due to space constraints.
Cited References(1) Shibuya. “Shibuya Index” 15th Edition, Shibuya Index
Research Group, 2010.
(2) Food and Agricultural Materials Inspection Center (FAMIC)
website(accessedJune2012).
http://www.acis.famic.go.jp/toroku/index.htm

4.1. The Invention of Fungicides MAS(Asozin) and Neoasozin (MAF), theFirst Pesticides Discovered in JapanMAS (Asozin) and MAF (Neoasozin) are organic

arsenic fungicides invented by Ihara Noyaku (later
Kumiai Chemical Industry Co., Ltd.) for use on rice
sheath blight and Glomerella cingulata (ripe rot) ingrapes (Fig. 4.1).

MAS Asozin

MAF Neoasozin

Fig. 4.1. MAS Asozin and MAF Neoasozin
Methyl arsine sulfide (MAS; Asozin) was firstregistered in 1959, while ferric methanearsonate (MAF;
Neoasozin), which had less side effects on crops, wasregistered in 1961. These were very effective and MAF
in particular was used in the development of a numberof combination formulations. These were the first
synthetic pesticides originally developed in Japan.
While early trans-planting, dense planting and heavy
fertilizing were popular methods used in rice cultivation
at the time, this resulted in repeated occurrences ofsheath blight, one of the two worst rice diseases alongwith rice blast (1). In 1968, this disease is said to haveaffected 2 million hectares of land. Accordingly, MAF
became very popular due to its efficacy against rice
sheath blight. Ihara Noyaku allowed other companies tosell this product and it reached an 80% market share in
1968, with 300 tons of active ingredients and 40,000
tons of formulated product sold (2).
Later, these figures dropped as other subsequentfungicides appeared, such as the polyoxins andValidamycin. Registration for MAF finally lapsed in1998 and its role in the industry came to a close. Let us
now outline the history of its development.
Ihara Noyaku was a pesticide manufacturer establishedin 1949 out of what had been a citrus growers’
association in Shizuoka that had started making
machine oil and lime sulfur in the late 1920s. Having
had experience making parathion and malathion
formulations and working on research and development,
the company was keen to develop its own products andbreak into the industry as an active ingredient
manufacturer (Note 1). In 1953, it sent two researchers
to the Tokyo Institute of Technology and started
investigating synthetic pesticides in earnest. Focusing
on arsenic, in the same group, 5, as same as phosphorus,

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these researchers discovered its fungicidal properties
and successfully developed MAS. In 1959, thecompany put a synthesis plant into operation and started
its journey as a fully-fledged active ingredient
manufacturer.
Originally a formulation manufacturer, Ihara Noyaku
began focusing on research and development soon after
the war, when organic pesticides were brought in fromoverseas. In 1959, it went one step further, establishingan integrated research and development institutedealing with chemistry, entomology, formulations, plant
pathology and toxicology, with all systems in place as afully-fledged agrochemical company (Fig. 4.2). Its
serious research and development focus – an executive
decision by management – was exceptional for thetimes, but this laid the foundation for its later
development of a number of major proprietary
pesticides such as IBP and Benthiocarb.

Synthetic Organic Chemistry Vol. 22, No. 3, 1964, p. 170.
(Note 1) Active ingredient manufacturers are companies that
exclusively make and sell technical products (active ingredients as
industrial chemical products). By contrast, formulation
manufacturers are companies that process technical products into
formulations (pesticide products) such as wettable powders or
emulsifiable concentrates. Some technical product manufacturers
also make and sell their own formulations.

4.2. The Discovery of Blasticidin S(Bla-S), the World’s First Agricultural
Antibiotic and the SubsequentAppearanceofKasugamycin(Kasmin)Blasticidin S is an antibiotic produced by Streptomyces
glyseochromogenes that is effective against filamentous
fungi such as rice blast. Discovered and developed inJapan, it is the world’s first agricultural antibiotic.
Lauryl sulfate was registered on the pesticide register in
1961, while benzylamino benzenesulfonate, with fewerside effects on crops, was registered the following year,
both for use on rice blast (Fig. 4.3).

Blasticidin S (Bla-S)
Fig. 4.3 Blasticidin S (Bla-S)
Fig. 4.2. Ihara Integrated
Research andDevelopment Institute, completed in 1959 (3)The invention of Asozin won the company the 7th
Okochi Memorial Grand Technology Prize (1960) (4)and the 3rd Synthetic Organic Chemistry Award(Technology) (1963) (5). It was the first time that either
prize had been awarded to anyone in the pesticideindustry, showing the significance of this invention that
became the forerunner of Japanese pesticides.
Cited References(1) Kosaka. Kongetsu no Nōyaku [Pesticide of the Month], Vol.
20, No. 4, 1976, p. 230.
(2) Ihara nōyaku-shi [The History of Ihara Noyaku], Kumiai
Chemical Industry Co., Ltd., 1969, p. 108.
(3) Provided by Kumiai Chemical Industry Co., Ltd.
(4) Nagasawa et al. “Nōyaku toshite no Yūkihiso-zai no Kaihatsu
Kenkyū to sono Kigyō-ka [Development Research andCommercialization of Organic Arsenicals as Pesticides],”
Okochi Memorial Award Financial Digest, Vol. 2, Okochi
Memorial Foundation, 1962, p. 113.
(5) Nagasawa. “Yūki Hiso Keinōyaku no Gōsei to sono Kaihatsu
oyobi Kigyō-ka [Synthesis of Organic Arsenical Pesticides andtheir Development and Commercialization],” Journal of68

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan

While organomercury fungicides had been used to treat
rice blast, these were largely replaced by Blasticidin S.
Although its registration eventually lapsed in 2004
(Note 1) due to the emergence of some resistant fungi
and the development of higher performance pesticides,
this fungicide played a significant role in the Japanesepesticide industry (1).
As discussed in Section 3.4.2 (4), rice blast mercury
dust was developed in 1953 and became very popular
due to its superior efficacy. However, as social issues
began to emerge, such as Minamata disease, Niigata
Minamata disease and mercury pollution in industrial
wastewater in the late 1950s and early 1960s, and as it
also became evident that rice blast mercury dust left
trace residues on rice, there was an increasing demandfor highly effective, non-mercurial pesticides.
A group from the University of Tokyo led by Sumiki,
Yonehara et al. joined with Fukunaga, Misato et al.
from the Ministry of Agriculture and Forestry
Agricultural Technology Research Institute started
investigating
the
rice
blast
effectsofantibiotic-producing actinomycetes collected from soil
from around Japan. This study began in 1950 andscreened 10,000 samples. This resulted in the discovery
of Blasticidin S (meaning “blast killer”) in soil from
Saikazaki in Wakayama. This was jointly developed by
Toa Agricultural Chemical (now Kumiai Chemical),Nihon Nohyaku and Kaken Chemical (now Kaken
Pharmaceutical) (2), (3).
The mode of action is to inhibit protein biosynthesis. It
works as a prevention and a cure due to its systemic
properties (4).
However, as this formulation became more popular,
there were issues with eye irritation while spraying dust
formulation. Various additives were investigated toalleviate this problem with the eyes; researchers
eventually discovered that adding calcium acetate
reduced this problem dramatically. From 1974 onwards,
this was no longer an issue.
Thus, Blasticidin S became an establishednon-mercurial rice blast fungicide, reaching anequivalent of 70 tons of technical product in shipments
in 1964. It later dropped in usage as new rice blast
fungicides were developed, but it is still worth special
mention as the world’s first agricultural antibiotic. It
won the company the 11th Okochi Memorial Grand
Production Prize in 1964 (5).
In 1965, four years after Blasticidin S went on themarket, Hokko Chemical developed a new rice blast
antibiotic, Kasugamycin (product name Kasmin) (6), (7).
Kasugamycin is an amino-sugar antibiotic produced by
Streptomyces kasugaensis found in soil from Kasuga
Shrine in Nara as a result of joint research by Hokko
Chemical and Hamao Umezawa from the Institute ofMicrobial Chemistry (Fig. 4.4).

Fig. 4.4. Kasugamycin (Kasmin)
While Kasugamycin showed no direct effect on rice
blast fungus in a petri dish experiment, it demonstrated
powerful antimicrobial properties in acidic
environments inside rice plants, with a distinctive
curative effect. Like Blasticidin S, its mode of action
works by inhibiting protein synthesis, inhibiting theformation of mRNA and tRNA ribosomes that trigger

this synthesis. Kasugamycin is very safe to use, as it isvery low-toxic to mammals and aquatic organisms.
However, its effectiveness may decrease with
continuous use, as resistance can build up. In 1971, theeffectiveness of this fungicide was confirmed to havedecreased in the Shonai region of Yamagata due tocontinuous use. Meanwhile, it has also been confirmedthat its effectiveness returns after several years of notusing it (8). Accordingly, Kasugamycin is still being
produced to the scale of 150 tons of active ingredients(2011), as it is highly effective against rice blast andvery safe to use. There are more than 35 different
formulations of it, as a standalone product or in
combination formulations, and it holds an important
place in the industry as one of the main rice blast
treatments.
As mentioned above, organomercury compounds were
replaced by Blasticidin S, followed by Kasugamycin. A
succession of other effective rice blast formulations
appeared, starting with PCP sodium salt (Chlon),developed in 1955, followed by PCP barium salt
(Gobe), PCBA (Blastin), PCMN (Oryzon) and CBA(Minocol) between 1963 and 1968. However, these
fungicides were not widely used and soon disappeared
off the market for various reasons, includinginconsistent effects, residues on paddy straw affecting
later crops and toxicity to fish. Later, Japanesemanufacturers developed better rice blast treatments,
such as IBP (Kitazin), Isoprothiolane (Fuji One) andProbenazole (Oryzemate), as we shall discuss later.
Cited References(1) Hori. Nihon Shin Nōyaku Monogatari [The Story of
New Japanese Pesticides], Japan Plant Protection
Association, 1973, p. 37.
(2) Gojūnenshi [A Fifty-Year History], Nihon Nohyaku
Co., Ltd., 1981, p. 239.
(3) Nijūgonenshi [A Twenty-Five-Year History], Toa
Agricultural Chemical Co., Ltd., 1967, p. 168.
(4) Yamashita et al. Nōyaku no Kagaku [The Chemistry ofPesticides], Buneido Publishing, 1996, p. 64.
(5) Takagi. “Nōyaku Burasutosaijin S 24-nen no Tenkai[The 24-Year Development of Blasticidin S],”Ōkouchi-shō 30-nen no Ayumi [The 30-Year History of
the Okochi Memorial Award], Okochi Memorial Award
30th Anniversary Commemorative Publication Editorial
Committee, 1987, p. 210.
(6) Gojūnenshi [A Fifty-Year History], Hokko Chemical
Industry Co., Ltd., 2001, p. 40.
(7) Hori. Nihon Shin Nōyaku Monogatari [The Story of
New Japanese Pesticides], Japan Plant Protection
Association, 1973, p. 124.
(8) Yamaguchi. “Nōgyō-yō Kōseibusshitsu Seizai no Ōyō[Application of Agricultural Antibiotic Formulations],”
Agricultural Antibiotic Handbook, p. 99.
(Note 1) Lapsing of registration means the cancellation of
the registration of a pesticide if the triennial re-registration

Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

69

application has not been made due to product adjustment
or economic reasons. Registration may also lapse if it has
been revoked due to safety concerns or other issues. In
such cases, measures are taken such as recalling the
product or banning it from being used or sold.

4.3. The Emergence of Low-Toxic
Organophosphate Insecticides (MEP,
Fenitrothion) Sumithion
As mentioned in Section 3.4.2 (3), the appearance oforganophosphate pesticides soon after the war, such asparathion and methyl parathion, was revolutionarily
beneficial and made a huge contribution to increasing
food production, a pressing need in post-war Japan.
This section discusses the post-parathion era: theinvention, development and spread of MEP(Sumithion), discovered by Sumitomo Chemical. MEP
is the forerunner of the major international pesticides
produced in Japan; 50 years after it was developed, it isstill a dominant Japanese pesticide used throughout theworld (Fig. 4.5).

Nishizawa et al. of Sumitomo Chemical held concerns
about this toxicity to mammals from the outset and in1956 set about exploring low-toxic organophosphatepesticides to replace parathion. This started out as aseries of trial-and-error experiments by three or four
researchers. Their method of evaluating insecticidal
activity and mammalian toxicity at the initial
exploration stage was unprecedented in the West (1).
These efforts paid off, meeting the initial target with
MEP in 1959, the fourth year of research, and they
immediately applied for a patent. As luck would have it,they later found out (1) that they had secured this patent
only weeks before Bayer applied for the same patent (2),(3).
Two years later, with a good supply of valid data
accumulated through practical development tests, MEP
was registered as Pesticide No. 4962 on the Japanesepesticide register on 26 December 1961 and put on themarket the following year (Fig. 4.6). While early sales
were slow due to the popularity of parathion, it
eventually became a popular insecticide due to its
capacity to be used on fruit and vegetable plants as wellas rice and also for its efficacy against sanitary pests
such as mosquitoes and flies.

Fig. 4.5. Organophosphate Insecticides
G. Shrader of the German company Bayer invented
parathion and methyl parathion in 1944. These wereintroduced to Japan in 1951 and became wildly popular
due to their superior effectiveness, with imports starting
the following year. Sumitomo Chemical initially
imported these products from the American CyanamidCompany (ACC) and marketed them in Japan, but later
decided to produce them domestically due to theiroutstanding performance. In 1953, Sumitomo obtained
a technology license from Japanese patent-holders
ACC and Bayer and began production.
While parathion is quite highly acutely toxic tomammals, with a median lethal dose in rats of
2-22mg/kg, it is highly effective against rice stem
borers. Conversely, while other organophosphate
compounds with lower toxicity to mammals (such as
DEP and malathion) were later introduced to Japan,
they were less effective against rice stem borers;
consequently, parathion and methyl parathion held themonopoly.

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Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, JapanMEP Emulsion Concentrate Registration Certificate (Sumithion Emulsion,
Sumitomo Chemical)

Fig. 4.6. Registration Certificate for MEP Emulsion
Concentrate (Sumithion Emulsion, Sumitomo
Chemical)Domestic production continued to increase, with morethan 10,000 tons of technical product manufactured in
1999 and 6,000 tons of this being exported. As of 2010,
more than 15 different standalone formulations on thepesticide register contained MEP, with a shipment valueof ¥2.97 billion. Another 49 combination formulations
also contain MEP; if we calculate the MEP proportionof these shipments, the total comes to ¥5.4 billion. It has
a wide range of applications, including rice, wheat,beans, deciduous fruit trees, citrus, vegetables, tea,ornamental flower, household disease control, forestry
and termites.
Sumitomo pushed into the overseas market from the
beginning; in the early 1960s, it started exporting to
Kenya, Korea, Taiwan and other countries. Long-term
efforts to promote the product have paid off, with MEP
now being used in 60 countries around the world on
crops such as rice, wheat and maize, as well as fruit
trees, vegetables, coffee, cacao, rapeseed, cotton, grain
storage pest control and forestry. It is also used against
malaria-bearing mosquitoes, locust outbreaks in desert
regions and termites. In recognition of the contribution
this product has made in Japan and overseas, thecompany was awarded the 9th Okochi Memorial Grand
Technology Prize in 1962 (4).
As shall be discussed below, the insecticidal activity of
MEP is equal to or greater than that of parathion. It isalso far less toxic to mammals and therefore around 90
times safer than parathion. In terms of toxicity
classification, it is treated as an ordinary substance (5), (6).

MEP
Parathion
Methylparathion

LD50 in rice stem
borers (μg/larva) (5)
0.092
0.223

LD50 in mice
(mg/kg) (6)
870
9.8
26.0

LD50 in rats
(mg/kg) (1)
800
2-22
20-62

Thus, MEP has very selective toxicity. The reason forthis has been debated to be one of the following: (1) the
differences in acetylcholinesterase (AChE) between
mammals and insects at the point of action; (2) the
differences in absorption and translocation to the pointof action; (3) the substrate specificity of thecounteracting enzymes. However, it is still not clearly
known why there is such a difference in toxicity when
the only difference is whether or not there is a methylgroup at meta position in the benzene ring; this hascome to be known as magic methyl (7), (8).
Let us now discuss the manufacture of MEP. While it
can be manufactured by condensing the intermediates
0,0-dimethyl-chlorthiophosphate(DMCT)
and4-nitrometacresol (NMC), Sumitomo developed aefficient chemical process for these key intermediatesand established a consistent production system (1). The
company now uses this system to produce 10,000 tons
per year, making pricing competitive enough todominate the world market (Fig. 4.7).

Cited References(1) Nishizawa. “Satchū-zai Sumichion no Hatsumei to30-nen no Rekishi [The Invention of the Insecticide
Sumithion and its 30-Year History],” Chemistry &Chemical Industry, Vol. 45, No. 11, 1992, pp.
2074-2078.
(2) Japanese Patent No. 37-7964(3) Japanese Patent No. 37-15147(4) Ueda. “Sumichion no 25-nen [25 Years of Sumithion],”Ōkouchi-shō 30-nen no Ayumi [The 30-Year History of
the Okochi Memorial Award], Okochi Memorial Award
30th Anniversary Commemorative Publication Editorial
Committee, 1987, p. 151.
(5) Ishikura. “Sumichion no Oitachi [The Early Days of
Sumithion],” Toki o Koete [Beyond Time], Sumitomo
Chemical Co., Ltd., p. 7.
(6) Y. Nishizawa et al: “Studies on the Organophosphorus
Insecticides Part VII. Chemical and Biological Properties
of New Low Toxic Organophosphorus Insecticide. O,
O-Dimethyl-O-(3-methyl-4-nitrophenyl)
phosphorothioate” Agr. Biol. Chem., Vol. 25. No. 8
p605-610 (1961)(7) Sasaki. “Fenitorochion [Fenitrothion],” Nihon no
Nōyaku Kaihatsu [Japanese Pesticide Development],
Pesticide Science Society of Japan, 2003, p. 69.
(8) Nishizawa, Eto. “Gōsei Satchū-zai no Kenkyū, Yūki
Rinsan Esuteru [Synthetic Pesticide Research:
Organophosphates],” Shin Nōyaku Sōsei-hō [NewPesticide Creation Methods], 1965, p. 25.

4.4. Gibberellins:
Hormones

MiraclePlant

We shall now discuss the history of the technology
development behind the seedless grapes such as
Delaware that are commonly eaten these days. Let us
disclose the secret to seedless grapes. It has been morethan 50 years since seedless grapes appeared on theworld market in 1960 and it has now becomecommonplace to have grapes without seeds. The coreof this technology is a plant hormone called gibberellin(Fig. 4.8). This was discovered in Japan, where aJapanese scientist isolated and identified its structure,
which was then put to practical use by Kyowa Hakko.
This is a prime example of Japan’s world-class scienceand technology. For details on gibberellin research, see
the cited work (1).

Fig. 4.8. Gibberellin A3
Fig. 4.7. Method of Manufacturing MEP

4.4.1. From Discovery to Structure Determinationand Synthesis
Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

71

The discovery of gibberellin can be traced back to 1898.
Shotaro Hori from the Agricultural Experiment Stationof the Ministry of Agriculture discovered that bakanae– a disease that makes rice seedlings etiolated and thestem elongated – was caused by a filamentous fungus
and published his exposition on the existence of
bakanae (Fig. 4.9) (2). This was the first paper written on
bakanae.

Fig. 4.9. (2) Paper from 1898
Bakanae was also rampant in Taiwan at the time. Eiichi
Kurosawa, actively researching this disease at theAgricultural
Experiment
StationoftheGovernment-General of Taiwan, noted that affected
seedlings would grow remarkably long and discoveredin 1926 that a kind of “toxin” produced by the bakanae
fungus significantly promoted growth in the riceseedlings (3). This was an age in which there was noconcept of “microbes producing biologically active
substances,” so demonstrating this for the first time wasa major achievement in itself. A number of researchers
were inspired by Kurosawa’s work and started studying
the growth promoting substance produced by the
bakanae fungus.

work was interrupted for a long period of time as Japan
went to war. This research was attracting attention
overseas as well. While research had drawn to a halt inJapan, it was carried on in the United Kingdom and theUnited States and gained a lot of ground, particularly
with mass culture techniques for Gibberella fujikuroi.
Research in Japan eventually revitalized after the war
and a study by Takahashi in 1955 showed that theactive substance Gibberellin A was a mixture of threesubstances and named them GA1, GA2 and GA3,
respectively (6). British researcher Cross was the first to
identify the chemical structure of Gibberellin A3 in
1959. While total synthesis of the compound was very
difficult due to the complex chemical structure, Moriachieved total synthesis of GA2, GA4, GA9 and GA10 in1968 (using bridging) (7). Corey achieved total synthesisof GA3, the main component of gibberellin (8), (9).
Around 136 varieties of gibberellins have been found inplants, molds and bacteria; these have all been
numbered in order of their discovery (10). The typecurrently used as a pesticide is the most popular: GA3.
Industrial production of gibberellin started overseas; by1950, US company Merck and UK company ICA had
already established the technology for mass culture.
Kyowa Hakko started researching the production andpractical application of gibberellin in 1956; after
validating its results, it licensed the production
technology from Merck and started marketing it as“agricultural material.” Fig. 4.11 shows an early sample
production tank.

In 1935, Teijiro Yabuta of Tokyo Imperial University(Fig. 4.10) isolated the active ingredient from abakanae fungus culture medium and named it
gibberellin after the scientific name of the fungus,
Gibberella fujikuroi. This was the first use of the namegibberellin (at the time, it was pronounced according to
the German reading of the word) (4).

Fig. 4.11. Deep Stirrer Culture Tank (11)Fig. 4.10. Prof. Teijiro Yabuta of Tokyo Imperial
University (1)Three years later, Yabuta and Sumiki successfully
crystallized Gibberellin A and B (5). However, their72

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan

It was officially registered as a “plant growth regulator”
in 1964 to comply with the 1963 amendment of theAgricultural Chemicals Control Act. Its registration isstill current.
Thus, gibberellin has the longest history of all plant
growth regulators. While almost 60 years have passedsince it was registered as a plant growth regulator, its
registration number 6001 is the oldest one still on theregister and it still has the highest number of shipmentsof all plant growth regulators. There are six different
formulations of gibberellin on the market according to
the application, as a solution in water, liquid
formulations, pastes, etc.) sold by Kyowa Hakko Bio,
Meiji Seika and Sumitomo Chemical. While ordervolumes peaked at ¥2.4 billion in 1994, this dropped
due to a decline in grape production, its primary use.
Recent figures have held steady at just over ¥1.1 billion(11).

dropping and help sudachi and other fruit to stay green.
It is also used on persimmons to prevent fruit droppingand on pears to promote ripening.
(3) Vegetables: Promoting Germination and
Growth, Increasing Produce Yield
Gibberellin can promote germination and growth invegetables and enlarge the yielded produce. For
instance, it can increase the fruit yield and promoteripening and runner growth in strawberries. Fig. 4.13
shows an example of promoted growth in a cabbage
plant.

4.4.2. The Effects of Gibberellin and its Use as a
PesticideThe physiological actions of gibberellin are
wide-ranging, as shown below. A number of studies
have been carried out in this area, as the effects differ
significantly according to the amount used, the crop andvariety targeted and the stage of growth. Some
examples are given below.
(1) Seedless Grapes: Promoting Parthenocarpy(Note 1) and Later Fruit Enlarging Effect (Fig. 4.12)
Grapes are treated (poured on each bunch with a cup)with a 100ppm dilution of gibberellin 14 days before
full bloom to promote parthenocarpy, followed byanother treatment with a 100ppm dilution 10 days after
full bloom to enlarge the fruit. This enables the grapes
to grow without seeds and also allows them to be
harvested early. The amount used and time of
application varies according to the variety of grape.

American researchers are amazed at the growth of a cabbage
plant treated with gibberellin.
(1)Fig. 4.13. Cabbage Growth Promotion(4) Flowering Plants: Promoting Budding, Growthand Blooming
Gibberellin promotes budding and growth in flowering
plants such as cyclamen and chrysanthemum, as well as
breaking dormancy.
(5) Cedar, Cypress
Promoting floral differentiation for timber trees andimproves seedling productivity.

Untreated fruit on the 10th day after full bloom; the treated fruit is already enlarged (treated on 26 May) (1)Fig. 4.12. Seedless Grapes (untreated at left, treatedat right) (1)(2) Citrus Trees: Suppressing Budding, Preventing
Fruit Abscission, etc.
Spraying citrus trees with a 0.5-50ppm dilution ofgibberellin can suppress budding, prevent fruit fromAs mentioned above, research on gibberellin began in
the 19th century and Japanese technologicaldevelopments have led the world in discovering it,
determining its structure, chemically synthesizing it andapplying it as a pesticide. Seedless grapes, which are
now commonplace, are the visible result of thetechnological developments achieved by the
researchers of years long past.
Researchers have recently made progress on its modeof action, while recent X-ray analyses have identified
the three-dimensional structure of the receptor protein

Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

73complexes that bind to gibberellin. Future progress on
this technology will hopefully enable the molecular
design of new compounds with gibberellin-like activity
and also in future enable the production of new plants
by controlling the responses of this plant hormone (12).
Cited References(1) Kiseki no Shokubutsu Horumon: Minna de Sodateta
Jibererin [Miracle Plant Hormone: the Gibberellin We
All Grew], Kyowa Hakko Industry Co., Ltd. (ed.),Kenseisha, 1980.
(2) Hori. Results from the Ministry of Agriculture andCommerce Agricultural Experiment Station, Vol. 12, No.
1, 1898.
(3) Kurosawa. Transactions of the Natural History Societyof Formosa, No. 87, 1926.
(4) Yabuta. Agriculture and Horticulture, Vol. 10, No. 1,
1935, p. 17.
(5) Yabuta et al. Journal of the Agricultural Chemical
Society of Japan, Vol. 14, 1938, p. 1526.
(6) N. Takahashi, H. Kitamura, A. Kawarada, Y. Seta, M.
Takai, S. Tamura, and Y. Sumiki: Bull. Agr. Chem. Soc.,
Japan, 19, (4) p267 (1955)(7) K. Mori, M. Shiozaki, N. Itaya, M. Matsui, and Y.
Sumiki: Tetrahedron, Lett., 1968, p2183 (1968);
Tetrahedron, 25, p1293 (1969)(8) E. J. Corey, R. L. Danheiser, S. Chandrasekaran, P.
Siret, G. E. Keck and J.-L. Gras: J. Amer. Chem. Soc.,
100, p8031 (1978)(9) E. J. Corey, R. L. Danheiser, S. Chandrasekaran, G. E.
Keck, B. Gopalan, S. D. Larsen, P. Siret and J.-L. Gras: J.
Amer. Chem. Soc., 100, p8034 (1978)(10)
http://www.plant-hormones.info/gibberellins.htm(accessed 7 May 2012)(11) Kiseki no Shokubutsu Horumon: Minna de Sodateta
Jibererin [Miracle Plant Hormone: the Gibberellin We
All Grew], Kyowa Hakko Industry Co., Ltd. (ed.),Kenseisha, 1980, p. 12.
(12) Saka et al. Nihon no Nōyaku Kaihatsu [JapanesePesticide Development], 2003, p. 365.
(13) K. Murase, Y. Hirano, T. Sun, and T. Hakoshima,
Nature 456, (7221) p520 (2008)(Note 1) Parthenocarpy is the production of fruit without
seeds by developing the ovaries of flowering plants
without pollination or fertilization. It is also called
parthenogenesis and occurs naturally in some plants suchas bananas and pineapples.

4.5. Post-PCP Paddy rice Herbicide
CNP
(MO),
FollowedbyChlomethoxynil
CNP (Chlornitrofen, MO) is a diphenyl ether paddy
rice barnyard grass herbicide invented by Mitsui
Chemicals and was registered in 1965. As mentioned in
Section 3.4.2 (5), the emergence of the PCP granulearound 1960 meant a means of soil treatment against
barnyard grass before and after transplanting rice. PCP

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was a ground-breaking formulation that provided relief
from the hard task of hand weeding that had longplagued farmers. However, a lower-toxic formulation
was in great demand, as PCP was highly toxic to fish.
Although Mitsui Chemicals was the leading
manufacturer of PCP, it promptly set about exploringother less ichthyotoxic herbicides, focusing on diphenyl
ether compounds, and came up with CNP, a
low-ichthyotoxic replacement for PCP (Fig. 4.14) (1).
Rohm and Haas had developed and registered a similar
compound, NIP (Nitrofen) (Fig. 4.15), slightly earlier in
1963, so CNP had to settle for second place. However,
CNP proved to be a safe, long-lasting barnyard grass
killer with little side effects on rice, even in young
seedlings for transplanting and it soon outstripped its
predecessor NIP in popularity. While rice field acreage
peaked in 1969 at 3.17 million hectares, CNP was usedon 1 million hectares the following year. By 1974, it
had become a large-scale commodity, being used on
more than 2 million hectares (2), (3). In 1968, Mitsui
Chemicals won the 15th Okochi Memorial Grand
Technology Prize for the “development andcommercialization of rice herbicide MO-338.”
Another barnyard grass herbicide in the same category
is Chlomethoxynil (X-52) (Fig. 4.16), registered in
1973. Chlomethoxynil was invented by Nihon
Nohyaku and jointly developed with Ishihara Sangyo.
Despite its late start, it had more consistent efficacy andby 1978 had become a major product to rival CNP,
used on 600,000 hectares (4).

Fig.4.14 CNP(MO) Fig.4.15 NIP
Chlomethoxynil(X-52)

Fig.4.16

These diphenyl ether compounds came to be called
light-dependent herbicides, as they required light inorder to be effective. However, later research showedthat this chemical structure works by inhibiting
protoporphyrinogen IX oxidase in the chlorophyll
biosynthesis process, achieving a herbicide effect as thebuilt-up protoporphyrinogen IX photosynthesizes,
releasing reactive oxygen, which destroys cellular
membranes (5), (6), (7).
Usage of diphenyl ether herbicides decreased from thelate 1970s onwards with the appearance of
higher-performing rival herbicides such as Benthiocarb
and their role eventually came to an end. Registration
for NIP lapsed in 1982, followed by CNP in 1996 andChlomethoxynil in 1997. In the case of CNP, thecancellation of registration was triggered by trace
amounts of dioxins in it. There was also some question

as to whether an outbreak of gall bladder cancer in
Niigata was caused by trace residues of CNP in tap
water. While there was no clear causal relationshipepidemiologically, it was difficult to prove its “safety”
to counteract these “misgivings,” so its registration had
to be withdrawn. In any case, CNP demonstrated
unprecedented superiority as an initial soil treatment
agent for rice cultivation and made a significant
contribution to rice production.
Cited References(1) Hori. Nihon Shin Nōyaku Monogatari [The Story of
New Japanese Pesticides], Japan Plant Protection
Association, 1973, p. 145.
(2) Matsunaka. Nōyaku no o-Hanashi [Talk of Pesticides],Japan Standards Association, 2000, p. 138.
(3) Mitsui Tōatsu Kagaku sha Shi [History of Mitsui
Toatsu Chemicals], Mitsui Toatsu Chemical Co., Ltd.
Company History Compilation Committee, 1994, pp.
431, 567.
(4) Gojūnenshi [A Fifty-Year History], Nihon Nohyaku
Co., Ltd., 1981, pp. 394, 430.
(5) M. Matringe et al., Biochem. J., 240. p.231 (1989)(6) P. Böger and K. Wakabayashi: “Peroxidizing
Herbicides” Springer Verlag, (1999)(7) B. Nicolaus, G. Sandmann and P. Böger: Z.
Naturforsch. 48c, p326 (1993)

4.6. Cartap (Padan), the Only
Insecticide Derived from Bioactive
Substances Produced by Animals
Cartap (Padan) (Fig. 4.17) is a uniquely-structure
insecticide invented by Takeda Pharmaceutical(pesticide division now taken over by Sumitomo
Chemical) and registered in 1967. Highly effective
against a wide range of pest insects, including
Lepidopterae such as rice stem borers, Hemipterae suchas aphids, and thrips, it is widely used in Japan andacross the world.
The invention of this compound was modeled on
nereistoxin (Fig. 4.18), a natural toxin with asulfur-containing dithiolane structure, found in eunicids,
which are used as fishing bait. The method of
discovering new pesticides by modeling naturally
bioactive substances is currently widely used, with anumber of examples including antibiotics produced byactinomycetes and synthetic pyrethroids, modeled on
pyrethrins found in plants (pyrethrum). However, thisnereistoxin-related compound is the only pesticide to be
derived from bioactive ingredients produced by animals.
Another very interesting point is that the entire researchand development process, from the discovery of
nereistoxin to its synthesis and the invention of Cartap,
has been the result of Japanese work.

Fig. 4.17. Cartap (Padan)Fig. 4.18. Nereistoxin

The discovery of nereistoxin dates back to the 1920s,
when it was observed that flies coming into contact
with dead eunicids (a family of polychaetes in theannelid phylum) used for fishing bait would become
paralyzed and die. Having examined cases ofheadaches, vomiting and breathing difficulties amongpeople dealing with eucinids, in 1922 Dr. Masahiro
Nitta, a medical doctor, started researching if this wascaused by a toxin. In 1930, he named this toxic
ingredient nereistoxin. In 1934, he isolated it,
hypothesized on its chemical structure and confirmed
its toxicity to mammals (1). Completely independent
from Nitta’s work, another researcher named Inagawa
isolated nereistoxin and published its molecular formulaas C5H11NS2 (2). There was no further progress on thisarea of research until Hashimoto and Okaichi of the
University of Tokyo confirmed its molecular structure
to be 4-N,N-dimethylamino-1,2-dithiolane in 1962 (3).
Sakai from Takeda Pharmaceutical embarked on a joint
research project with Hashimoto of the University ofTokyo in 1960, focusing on the unique chemical
structure and biological activity of nereistoxin. This
study confirmed the efficacy of neriestoxin against ricestem borers, a major pest (4). They also achieved total
synthesis of it, which enabled them to define its
chemical structure as well as to produce large quantities
of it for research samples, which sped up the research (5),(6), (7). Uneme provides a detailed review of thestructure-activity relationship of related compounds (8).
Of
theserelatedcompounds,
1,3-Bis(carbamoylthio)-2-(N,N-dimethylamino)
propane hydrochloride (product name Cartap) was
selected for production and went on the market in 1967.
Cartap had an unprecedented chemical structure for an
insecticide; its distinguishing characteristics are outlined
below.
(1) It has the same mode of action as nereistoxin.
Studies have shown that when it is absorbed into thebody of the insect, it kills the insect by blocking thecholinergic synaptic acetylcholine receptors, whichgovern stimulus transmission in the central nervous
system (9), (10). Since this effect differs from existing
compounds that work on the nervous system, such asorganophosphates, carbamates and pyrethroids, there islittle chance of cross-resistance. Further, since the actual
effect activates once the nereistoxin is inside the bodyof the insect, Cartap is considered to work as a so-called
pro-drug (Note 1).
Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

75

(2) It is highly effective against a wide range of pest
insects, such as rice stem borers and other Lepidopterae,
leafhoppers, aphids and other Hemipterae, and ricewater weevil and other beetles. It is suitable for fruit andvegetable plants as well as rice.
(3) It is systemic and therefore effective throughout theentire plant as it is absorbed through the roots or leaves.
This allows it to be used in rice nursery boxes.
As mentioned above, the invention of Cartap was theresult of a long process involving the isolation andstructure determination of eunicid toxins, which started
in the 1920s. It has been the result of Japanese
academic research and the sharp minds of company
researchers, as well as the later high-level research anddevelopment capabilities in examining its biologicaleffect and achieving total synthesis of it. While it has
been 45 years since Cartap first went on the market, it isstill a major product worth almost ¥2 billion indomestic shipments due to its superior efficacy. It has
also been actively marketed overseas, with 3,800 of the
4,500 tons produced in 1999 being exported to 40
countries around the world, to be used on a wide rangeof plants, including rice, vegetables and grain crops (8).
This won the company the Okochi Memorial Grand
Technology Prize in 1971 for the “invention andcommercialization of rice stem borer formulation.”Once Cartap went on the market, other companies
started developing nereistoxin analogue pesticides. Oneof these is Thiocyclam (Evisect), developed by Sandoz(now Syngenta) (Fig. 4.19) and registered in 1981 by
Sankyo and Nippon Kayaku. Another is
low-mammalian-toxic Bensultap (Ruban), developed
by Takeda Pharmaceutical in 1986 (Fig. 4.20).

Agriculture and Forestry, No. 5. 1935, p. 49.
(3) Okaichi et al. Agr. Biol. Chem., 26, (4) p224 (1962)(4) Sakai. Japanese Journal of Applied Entomology andZoology, Vol. 8, No. 4, 1964, p. 324.
(5) Hagiwara et al. Chem. Pharm. Bull., 13, (3) p253
(1965)(6) Numata et al. Chem. Pharm. Bull., 16, (2) p311 (1968)(7) K. Konishi,: Agr. Biol.Chem., 32 (10) p1199 (1968)(8) Uneme. Nihon no Nōyaku Kaihatsu [JapanesePesticide Development], Pesticide Science Society ofJapan, 2003, p. 17.
(9) Sakai. Journal of Pesticide Science, Vol. 6, No. 3, 1981,
p. 358.
(10) M. Sakai: Rev. Plant Protec. Res., 2, p17 (1969)(Note 1) Pro-drugs are pharmaceutical products that havein-vivo drug metabolism mechanisms; while thecompounds themselves are not pharmaceutically active,
they activate once they metabolize. This is a medical term
also used for pesticides. They are also called
pro-pesticides.

4.7. The Emergence of Non-Mercurial
Organic Rice Blast Fungicides (EBP,
Kitazin and IBP, Kitazin P)
EBP (Kitazin) (Fig. 4.21) and IBP (Kitazin P) (Fig.
4.22) are organophosphate rice blast fungicides
invented by Ihara Chemical (now Kumiai Chemical).
While EBP went on the market first in 1965, it wassuperseded by the more consistent, less odorous IBP(Iprobenfos, Kitazin P), which hit the market two years
later in 1967.

Fig. 4.21. EBP (Kitazin)

Fig. 4.19. Thiocyclam (Evisect)Fig. 4.22. IBP (Kitazin P)

Fig. 4.20. Bensultap (Ruban)
Cited References(1) Nitta. Journal of the Pharmaceutical Society of Japan,
Vol. 54, 1934, p. 648.
(2) Inagawa. Bulletin of the Mie Imperial College of76

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While Blasticidn S appeared in 1962 and Kasugamycin
in 1965 in response to the demand for non-mercurial
rice blast treatments discussed in Section 5.2, EBP and
IBP were the world’s first organophosphate fungicides.
The focus of research at Ihara Chemical had been to
explore new pesticide possibilities; as part of this, thecompany had also been researching organophosphate
compounds. While the initial aim was to discover aninsecticide, the fungicide research group found thatorganophosphates were effective against rice blast,resulting in EBP and IBP. Another cause for success
was the use of the bio-assay method of examining riceinoculated with rice blast.
IBP is highly systemic and is absorbed by the roots orleaves and is translocated throughout the entire rice
plant. Its effects are long-lasting and highly curative.
Developers produced a granule formulation to takeadvantage of these strengths, which in turn has
popularized a new method of application by applying
the granules to the surface of the water in the rice field.
While existing formulations were commonly sprayeddirectly onto the plants in dust or liquid form, themethod of sprinkling granules onto the water has theadvantage of only needing to be applied once.

(i-C3H7O)2POH + S  (i-C3H7O)2POSNa(i-C3H7O)2POSNa + ClCH2Ph  IBP
Other organophosphate rice blast fungicides like IBP
have been developed by a number of other companies.
While EDDP (Hinozan), developed by Bayer, is still inuse, ESBP (Inezin) and BEBP (Conen) had theirregistrations lapse due to issues such as residual odor inrice (Fig. 4.23), (Fig. 4.24), (Fig. 4.25).

Fig. 4.23. EDDP (Hinozan)

The mode of action of IBP is known to have afungicidal effect by inhibiting the lipogenesis ofphospholipids such as the phosphatidylcholines thatmake up the biomembrane of the fungus (1).
IBP has also been confirmed to be effective against
stem rot and sheath blight as well as rice blast and toturn lower internodes into dwarf plants. It reduces
lodging, which then produces the secondary effect ofhigher yields (2), (3).
Thus, IBP appeared at a time when non-mercurials
were in demand and played a major role as a key
fungicide against rice blast. Shipments in 1977 totaled
27,000 tons of standalone formulations and 23,000 tonsof combination formulations, while production oftechnical product exceeded 4,000 tons (4). While thesefigures later dropped due to the emergence of more
effective fungicides, it is still selling to the tune ofhundreds of millions. These results won the company
the Okochi Memorial Grand Technology Prize in 1967
and the Synthetic Organic Chemistry Award in 1970,
definite proof of the superiority of this invention.
Let us now discuss the industrial manufacture of IBP.
For practical application, IBP requires a concentrationof around 500ppm, quite a substantial amountcompared to the 30ppm required for the existingorganomercury compounds and the 10-20ppm for
Blasticidin S. To make the product more competitive,
production of the technical product had to cost as little
as possible. Following a manufacturing feasibility study,
the company decided to take the efficient route ofsynthesizing IBP by first making diisopropyl phosphitefrom phosphorus trichloride and isopropyl alcohol, thenturning this into diisopropyl phosphorothiolate throughsulfurization in an alkali environment, then reacting thiswith benzyl chloride (4).
PCl3 + i-C3H7OH  (i-C3H7O)2POH

Fig. 4.24. ESBP (Inezin)Fig. 4.25. BEBP (Conen)
Cited References(1) Sato et al. Nōyaku-gaku [The Study of Pesticides],Asakura Shoten, 2003, p. 58.
(2) “Kitajin P-ryu-zai no Anzen-sei to Tamokuteki riyō[The Safety and Multiple Applicability of Kitazin P
Granular Formulation],” Manual of Technology
Popularization (Technical Document), Kumiai Chemical
Industry Co., Ltd., 1976.
(3) Kumiaikagakukōgyō 50-nen-shi [50-Year History of
Kumiai Chemical Industry], Kumiai Chemical Industry
Co., Ltd., 1999, p. 83.
(4) Manual of Pesticide Active Ingredients Vol. 1, 1981, p.
181.

4.8. The Emergence of Benthiocarb(Saturn), the Super-Herbicide for
Rice
Benthiocarb (Saturn) (Fig. 4.26) is a pre-, and early-post
application rice herbicide invented by Kumiai
Chemical and registered in 1969. While the appearanceof CNP as discussed in Section 4.5 enabled near-total
control over major rice weed barnyard grass as well as

Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

77broadleaf weeds, there was a demand for an even better
pesticide that would target needle spikerush and otherperennial weeds on which CNP had insufficient effect.
Since Benthiocarb was equally effective against annual
weeds and perennial weeds alike, it came to dominate
the market as a super-herbicide. The product nameSaturn comes from the name of the Roman god of
agriculture.

Fig. 4.26. Benthiocarb (Saturn)Kumiai Chemical started exploratory research on newrice herbicides in three directions: an easy-to-use
treatment with a broad time window for application;
efficacy against not only annual weeds such as
barnyard grass, but also perennial weeds withoutcausing any side effects in rice; and low toxicity for
mammals and aquatic organisms (1). As Kumiai
Chemical had developed the rice blast fungicide IBP,
the company could overlap this research with particularfocus on S-benzyl-thiolcarbamic acid ester-related
compounds, to which it could apply the same
technology. The result was Benthiocarb. This is a good
example of extremely well-executed collaboration
between biological researchers, who madeimprovements to the biological assay, and synthesis
researchers, who performed the structural development.
Benthiocarb is thought to act mainly as a leaf sheath
growth inhibitor at the germination stage by inhibiting
protein and lipid biosynthesis, but the details are notclearly known (2), (3), (4).
Benthiocarb is intergenerically selective between riceand barnyard grass. While it is safe on transplanted rice
at realistic concentrations, it is effective against
barnyard grass until the 2-leaf stage. It is also highly
effective against Cyperaceae, Monocholia vaginalis
and needle spikerush. It has been marketed as astandalone product and also developed into several
combination formulations to give it a wider window ofapplication as well as better efficacy against a wider
range of weeds. Several of these formulations are given
below. Using this product in combination compound
formulations has given it a wider range of uses, not only
as an initial soil treatment agent around planting time,
but also as a foliar and soil treatment agent at the laterleaf stage.
Saturn S granules (Benthiocard + Simetryn)
Saturn M granules (Benthiocard + CNP)
Kumi-Lead SM granules (Benthiocarb + Simetryn +
MCPB)
78

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Kumi-Shot SM1K granules (Benthiocarb + Mefenacet+ Bensulfuron methyl + MCPB)
Wolf Ace 1K51 granules (Benthiocarb + Mefenacet +Bensulfuron methyl)
As discussed above, Benthiocarb is a key sequential
treatment herbicide in the paddy rice production. Its
popularity spread wildly from 1970 onwards; by 1974,
it had become a super-herbicide used on 1.7 million
hectares, or 65% of Japan’s rice lands (5). These figureslater dropped with the emergence of a number of othernew, high-performance herbicides (such as Butachlor,
Pretilachlor and Mefenacet). Later, another onset ofnew, high-performance pesticides appeared from 1993
onwards (such as Pyributicarb, Cafenstrole,
Thenylchlor and Oxaziclomefone) and the ensuingcompetition spelled the end of Benthiocarb’s role inJapan.
However, it was actively promoted overseas for riceand other crops and most of its present use takes place
overseas, mainly in the United States, Russia, Korea,
Cuba, Egypt, Taiwan and Thailand. It continued to
grow as a major world product, with over 90,000 tons
being exported across 55 countries until 1997. While
the amount of exports has dropped since peaking at
9,000 tons in 1978, it is a long-lived product, with morethan 2,000 tons still being exported in 2008 (6).
Consequently, this product has won the company anumber of awards, including the 19th Okochi Memorial
Grand Technology Prize in 1972 for “development andcommercialization of the new herbicide Saturn,” the21st Chemical Society of Japan Award for TechnicalDevelopment in 1972 for “development of theherbicide Saturn and establishing a manufacturingsystem for it” and the 15th Synthetic Organic ChemistryAward in 1973 for “development of the new herbicide
Saturn.” This shows how outstanding this invention is.
Cited References(1) Sugiyama et al. “Josō-zai ‘Benthiocarb’ no Kaihatsu toJitsuyō-ka Kenkyū [Development of the New Herbicide‘Benthiocarb’ and Studies on its Application],” Chemical
Education, Vol. 24, No. 5, 1976, p. 360.
(2) Kimura et al. “Josō-zai Benchiokābu no Sayō Kikō [Mode of
Action of the Herbicide Benthiocarb],” Journal of Weed Scienceand Technology, Vol. 12, 1971, p. 54.
(3) Kimura. Nihon no Nōyaku Kaihatsu [Japanese Pesticide
Development], 2003, p. 263.
(4) Matsunaka. Satān Dokuhon [Saturn Guidebook], Kumiai
Chemical Industry Co., Ltd., 1978, p. 60.
(5) Satān Dokuhon [Saturn Guidebook], Kumiai Chemical
Industry Co., Ltd., 1978, p. 41.
(6) Noda. Satān Dokuhon [Saturn Guidebook], Kumiai Chemical
Industry Co., Ltd., 1978, p. 202.

4.9. Thiophanate (Topsin)
Thiophanate-Methyl (Topsin

and
M),

World-Class,
Fungicides

Broad-Range

Thiophanate(Topsin)
(Fig.
4.27)
and
Thiophanate-methyl (Topsin M) (Fig. 4.28) arethioallophanate structured fungicides invented by
Nippon Soda and effective against a broad range of
diseases. Ethyl ester Thiophanate (Topsin) was the firstof the two to be registered, in 1969, while the more
effective methyl ester Thiophanate-methyl (Topsin M)
was registered two years later in 1971.

Fig. 4.27. Thiophanate (Topsin)

Fig. 4.28. Thiophanate-Methyl (Topsin M)
Nippon Soda started working on a new fungicide
around 1965 and came up with Thiophanate andThiophanate-methyl,
both
with
completely
unprecedented chemical structures, after researching thestructure of thioallophanic acid, an organic sulfur
compound. Thiophanate was gradually replaced by
Thiophanate-methyl; only the latter is in use today.
Thiophanate-methyl is fast-acting and long-lasting
against a broad range of diseases at low concentrations.
When applied to leaves, it is systemic throughout theentire plant, passing through the cuticle andtranslocating within the plant, acting as a prevention
and cure and stopping the spread of any infection. It issafe to use and has no side effects on crops.
This fungicide is a powerful inhibitor at all stages in thelife cycle of pathogenic fungi except spore germination(1), (2). This means it can be used against diseases on abroad range of plants, including fruit trees and vines,
such as citrus, apples, pears and grapes, vegetables, root
crops, wheat and other grains, beans, tea, specialty
crops such as tobacco, and ornamental plants (3), (4).
Around 1000 tons were sold in 1975. While this figure
later dropped, it has stood the test of time, still being
widely used as a key pesticide in 2008, registered foruse on 86 types of crops and 186 diseases. An overseas
market for this product also developed very early on foruse on grains, fruit and vegetables; it has become aworld-class product registered in 80 countries aroundthe world (5).
The mode of action of Thiophanate-methyl is mainly
achieved by inhibiting karyokinesis in cells (1). As
Nippon Soda was developing Thiophanate-methyl,
DuPont was independently working on Benomyl(Benlate), a benzimidazole compound, which it
marketed in Japan in 1971, and Carbendazol (Sanmate),
which followed two years later. Later research showedthat Thiophanate-methyl metabolizes into Carbendazol,
a Benomyl metabolite, in vivo (1), (5) (Fig. 4.29). This is agood example of a pro-drug. It is very interesting thatdifferent formulations developed by different
organizations at the same time happen to metabolize
into the same compound. For this reason,
Thiophanate-methyl is also classified as abenzimidazole compound. However, there is a point ofissue in that these fungicides have the same mode ofaction, which could lead to a build-up of resistance with
continued use. In fact, resistance has already been
observed in grey mold, black spot and powdery
mildew.
As discussed above, Thiophanate-methyl was
ground-breaking at the time, as it worked as aprevention and a cure. This turned it into a world-classproduct, used on a wide range of diseases on vegetables,
fruit and other plants. While the later emergence ofother high-performance pesticides has meant a decline
in its usage, it is still a major world-class pesticide. This
achievement won the company the International Plant
Protection Award from the International Plant
Protection Convention in 1970, the Okochi Memorial
Prize in 1975 for “research and development of thefungicide Thiophanate (Topsin)” and the Prime
Minister’s Invention Award, one of the National
Commendations for Invention, in 1976.

Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

79

Fig. 4.29. Active Substance of Thiophanate-Methyl and Benomyl

Cited References(1) Hashimoto. Nihon no Nōyaku Kaihatsu [JapanesePesticide Development], Pesticide Science Society ofJapan, 2003, p. 181.
(2) Yasuda et al. Japanese Journal of Phytopathology, Vol.
39, 1973, p. 246.
(3) Kataoka. Nōyaku Jidai [Pesticide Times], Vol. 158,
1988, p. 41.
(4) Kataoka. Nōyaku Jidai [Pesticide Times], Vol. 177,
1998, p. 31.
(5) Sato. Nōyaku Jidai [Pesticide Times], Vol. 190, 2008, p.
1.
(6) Mizuno. Nōyaku Jidai [Pesticide Times], Vol. 177,
1998, p. 15.

4.10. The Invention of Isoprothiolane(Fuji One), a Rice Blast Fungicidewith a New Organosulfur Structure
and Diverse Secondary Effects
Isoprothiolane (Fuji One) (Fig. 4.30) is a rice blast
fungicide with a new chemical structure invented anddeveloped by Nihon Nohyaku. Registered in 1974, thisfungicide is widely popular due to its consistent
efficacy.

Fig. 4.30. Isoprothiolane (Fuji One)
Treatments for rice blast, a major rice disease, were in
80

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan

great demand in the late 1960s and early 1970s. Since
there was such a large market for it, every pesticide
manufacturer devoted its attention to researching anddeveloping its own fungicides. Nihon Nohyaku
developed the organochlorine rice blast treatment
PCMN (Oryzon) and put it on the market in 1966.
However, it was later found that residues of thisformulation formed a degradation product in rice straw,
which caused unwanted side effects in any secondary
fruit and vegetable crops on which this straw was used.
It had to be withdrawn from sale, creating a demand fora new rice blast fungicide. Nihon Nohyaku had started
exploratory research on new rice blast formulations in
the early 1960s, focusing on organosulfur compounds
rather than organophosphates or organochlorine. While
there were already organosulfur compounds on themarket in the form of dithiocarbamate ester compounds
sold as fruit and vegetable fungicides, they had little
effect on rice diseases. The company developed thisfurther, resulting in Isoprothiolane, with a ketene
dithioacetal structure previously unseen in a fungicide,in 1968 (1). For details on the optimization of thechemical structure during this process, see Taninaka etal. (2), (3), (4).
Various ingenious methods of testing had to be
employed to test its biological effects (5). In others
words, methods had to be developed that would not
only test its preventive effect (preventing disease byadministering treatment to inoculate seedlings against
rice blast fungi) – a common test at the time – and its
curative effect (stopping the spread of disease byadministering the treatment to seedlings already underattack), but also test its systemic effect (secondary
effects on developing leaves that have not been treated).
Researchers also investigated its submerged application
effect to examine its efficacy in being absorbed throughthe roots when irrigated onto rice seedling pots (2). A
large-scale field experiment commenced in 1968,
confirming its expected systemicity when applied inwater; these effects were also long-lasting. It also
proved to be excellent in nursery box application withno side effects in the rice seedlings, thus becoming
widely popular.

including Korea, Taiwan and China, bringing the total
to 13,900 tons in shipments and a value of ¥10.4 billion.
This outcome won the company the 22nd Okochi
Memorial Grand Technology Prize in 1975 for“development of systemic crop protectant
Isoprothiolane(FujiOne),”
provinghowground-breaking this invention was.

Researchers investigated which part of the rice blast
fungus life cycle this formulation was effective in. Fig.
4.31 shows the propagation cycle of rice blast fungus
once a flying spore attaches to the leaf of a rice plant,
namely: spore germination  appressorium formation
 infection peg formation  mycelial growth 
lesion formation  spore formulation. Isoprothiolane
has hardly any effect at the spore germination stage, but
strongly inhibits the development of infection pegs
following appressorium formation (6). Researchers also
investigated the mode of action and confirmed that it
inhibits the lipogenesis of phospholipids such as thephosphatidylcholines that make up the biomembrane of
the fungus, similar to IBP. While some IBP-resistantfungi selected in the laboratory showed somecross-resistance to Isoprothiolane, Isoprothiolane iseffective against the moderate field-level resistance to
IBP. Accordingly, there are subtle differences between
the two (6), (7).

Cited References(1) Taninaka et al. Patent No. 681205 (Publication No.
47-34126)(2) K. Taninaka, H. Kurono , T. Hara, and K. Murata: J.
Pestic. Sci., 1, 115-122 (1976)(3) Taninaka. “Ketenjichioasetāru Yūdōtai no Nōyaku e noŌyō ni kansuru Kenkyū [A Study on the Pesticidal
Application for Ketene Dithioacetal Derivatives],”
Journal of Pesticide Science, Vol. 3, 1978, pp. 203-209.
(4) Taninaka. Nōyaku no Seiyūki Kagaku to Bunshi Sekkei[Pure Organic Chemistry and Molecular Design ofPesticides], Eto, Morifusa (ed.), Soft Science, 1985, p.
463.
(5) Taninaka. Nihon no Nōyaku Kaihatsu [JapanesePesticide Development], Pesticide Science Society ofJapan, 2003, p. 219.
(6) Fuji Wan Dokuhon: 20-nen no Ayumi [Fuji One
Guidebook: A 20-Year History], Nihon Nohyaku Co.,
Ltd., 1993, p. 33.
(7) Uesugi. “Ine Imochi Byōkin no Yakuzai Taisei[Resistance to Rice Blast Treatments],” Journal of
Pesticide Science, Vol. 6, 1981, pp. 239-246.

4.11. The Invention of Probenazole(Oryzemate), a World-Class Induced
Resistance Fungicide
Fig. 4.31. The Isoprothiolane-Sites of Action in the
Rice Blast Fungus Life Cycle (6)Let us now mention the diverse secondary effects ofIsoprothiolane. Besides achieving its main target of
preventing rice blast, Isoprothiolane is also confirmed
to work against stem rot, control leafhoppers, prevent
seedling blight, nurture good seedlings, improveripening in rice, prevent white root rot in pears andother fruit trees, and stimulate growth in carnations,strawberries and fruit tree saplings (6). Isoprothiolane isworth special mention as it is rare to have so many
biological effects, not only as a fungicide, but as an
insect repellent and a plant growth regulator.
As mentioned above, Isoprothiolane went on themarket in 1974 and became widely popular due to its
superior efficacy. By 1984, it had become a large-scalepesticide selling 9,400 tons in granular form and incombination formulations to the value of ¥5.6 billion.
The market had also expanded into Northeast Asia,

Probenazole (Fig. 4.32) is the world’s first induced
resistance fungicide (also called a plant defense
activator) invented by Meiji Seika (now Meiji Seika
Pharma). Registered in 1974, this formulation soon
became very popular due to its superior, long-lasting
efficacy against rice blast. While a lot of higher eating
quality rice is grown, such as Koshihikari, it issusceptible to lodging and rice blast. Probenazole has
played a major role in helping to solve these issues.

Fig. 4.32. Probenazole (Oryzemate)
Meiji Seika had been exploring fungicides for ricediseases since around 1960 and in the process
discovered Probenazole, a saccharin derivative. The
key to the success of this research was using in vivo
testing to check the inoculation of rice seedlings against
rice blast fungus rather than petri dish tests. While
Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

81Probenazole showed hardly any antibacterial properties
in itself, when applied to an infected plant, it prevented
disease by inducing and activating the plant’s resistanceto the disease. This was the first such ground-breaking
fungicide in the world. Probenazole’s product name
Oryzemate means “friend (mate) of rice (Oryzae sativaL.).” (1)Since Probenazole was readily absorbed through theroots, it was first developed into a granule form forsubmerged application. Less labor-intensive and longer
lasting formulations were later developed, such as
controlled release formulations for nursery boxes,
throwing formulations, inter-row formulations andcombination formulation with insecticides. The total
combined shipments for these formulations since 1974
is worth ¥292.3 billion (to 2011) (Fig. 4.33).

Sales: ¥100,000,000

In 1993 there was a major onslaught of abnormal
weather (low temperatures, heavy rain, typhoons),
resulting in repeated outbreaks of rice blast, with 45%
of Japan’s 2.13 million hectares of paddy rice fields
affected by leaf blast and 43% by panicle blast.
Consequently, the national Crop Situation Index

dropped to “Very Bad” – 74% of the average year – and3 million tons of emergency rice imports were made.
Given these circumstances, Oryzemate granules grewincreasingly popular as they produced good results (2).

Oryzemate standalone formulations

Oryzemate combination formulation

Oryzemate long‐term nursery box
treatments

Inter‐row Oryzemate formulations

Oryzemate short‐term nursery box treatments

Fig. 4.33. Cumulative Trends in Oryzemate Formulation Shipments (formulated by Meiji Seika from thePesticide Handbook)

Probenazole shows outstanding efficacy against rice
blast, rice leaf blight and grain rot, as well as otherbacterial diseases such as bacterial spot in cucumbers
and soft rot in cabbages. However, it works only as apreventive measure rather than a cure.
Despite Probenazole having no direct antibacterial
properties in itself, as mentioned above, it prevents ricepenetration, mycelial growth, lesion expansion, spore
formation and spore germination in rice blast fungus (3),(4), (5). While its mode of action has no clearly-defined
point of action, current genetic-level research indicatesthat Probenazole induces resistivity, that is, it activatesthe signal transduction pathway for systemic acquired
resistance (SAR) (1), (2), (6). Specifically, it kills host cellswith reactive oxygen such as superoxide, then produces
antibacterial substances such as oxidized fatty acids,

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Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japanphytoalexins and PR proteins, and then activates thephenylpropanoid system that governs lignin synthesisin the cell walls to contain the rice blast fungus. At thispoint, infection-specific PR genes are expressed andsalicylic acid is stored as a transmitter. Since it does not
act directly on the fungus, but on theresistance-inducing signal pathway, there is little risk ofresistance developing to this fungicide.
As well as being a scientifically-outstanding invention,
Probenazole also played a large part in disease control
in crops, especially rice. This won the company the
Okochi Memorial Grand Technology Prize in 1978 for“development and commercialization of Probenazole.”
As mentioned above, Probenazole appeared in 1974 as
the world’s first induced resistance fungicide. It was along time before any other similarly effective
fungicides appeared. Finally, after more than 20 years,
several other fungicides appeared with similar modes ofaction, listed below. Novartis (now Syngenta) released
Acibenzolar-S-methyl (Fig. 4.34) in 1998; registration
for this lapsed in 2006. This was followed by Tiadinil(Fig. 4.35), put out by Nihon Nohyaku in 2003, andIsotianil (Fig. 4.36), jointly developed by Bayer andSumitomo Chemical and put to market in 2010. Since
each of these is mainly used on rice blast, it isconceivable that they were modeled on the mode ofaction of Probenazole.

Fig. 4.34. Acibenzolar-S-methyl (Bion)

Cavara) in Its Life Cycle J. Pestic. Sci. 2, p395 (1977)(5) T. Watanabe et al., : “Effects of Probenazole(Oryzemate®) on Rice Plants with Reference toControlling Rice Blast J. Pestic. Sci. 4, p53 (1979)(6) Iwata. “Plant Activator,” Jisedai no Nōyaku Kaihatsu[Next-Generation Pesticide Development], Pesticide
Science Society of Japan (ed.), Soft Science, 2003, p.
169.

4.12.
Dedicated
Graminicides
Alloxydim
andSethoxydim:
Trailblazing World-Class Products
Alloxydim (Kusagard) (Fig. 4.37) and Sethoxydim(Nabu) (Fig. 4.38) are grass killers invented by Nippon
Soda with a new cyclohexanedione structure.
Registered in Japan in 1980 and 1985 respectively, theyfirst expanded into the overseas market, with
Alloxydim marketed in Europe in 1978 for use on
sugar beet and rapeseed. Sethoxydim was registered in1983 in the United States and was marketed there foruse on soybeans, cotton and onions. While bothformulations have the same effect, Sethoxydim has
higher activity, a broader herbicidal spectrum and issafer on crops than Alloxydim, and eventually became
more popular (1), (2), (3), (4).

Fig. 4.35. Tiadinil (V-GET)

Fig. 4.37. Alloxydim (Kusagard)

Fig. 4.36. Isotianil (Routine)
Cited References(1) Iwata. “Purobenazōru [Probenazole],” Nihon no
Nōyaku Kaihatsu [Japanese Pesticide Development],
Pesticide Science Society of Japan, 2003, p. 195.
(2) “Orizemēto no Ayumi [The History of Oryzemate],”Orizemēto Kinen 30 Shūnenkinen-shi [Oryzemate
30-Year Anniversary Publication], Meiji Seika Co., Ltd.,
2003, p. 128.
(3) Tashiro. “Imochi-byō Bōjo-zai no Tokuchō to
Kōkatekina Tsukaikata [Distinguishing Characteristics
and Effective Ways to Use Rice Blast Treatments],”
Abstracts from the “Countermeasures against Stink
Bugs and Panicle Blast” Symposium, Japan Plant
Protection Association, 2004, p. 39.
(4) T. Watanabe: “Effects of Probenazole (Oryzemate®) on
Each Stage of Rice Blast Fungus (Pyricularia oryzae

Fig. 4.38. Sethoxydim (Nabu)
Nippon Soda successfully developed the miticide
Benzoximate (Citrazon) after researching varioushydroxamic acid derivatives in the late 1960s and early
1970s. In the process of modifying the structure further,
Nippon Soda discovered a series of chemical classes
with selective herbicidal properties against grassy
weeds. Further investigation resulted in Alloxydim,
followed by the more effective and less phytotoxic
Sethoxydim. This was a long-awaited major invention

Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

83for Nippon Soda in the herbicide field. Development
continued on Alloxydim in Europe and on Sethoxydim
in the United States (5), (6).
Both herbicides have the same unprecedented effect,
being highly selective against annual and perennial
grassy weeds at doses of 200g/hectare, while having noeffect on broadleaf crops (such as soybeans, sugar beets,
cotton, sunflowers, rapeseed and vegetables). Moreover,while most existing herbicides worked by soil
application either pre- or early post-germination
treatment, these were unprecedented highly systemic
foliar treatments that were quickly absorbed into theplant. Conversely, they had little effect in soil
applications, as they would quickly break down in soil.
Their mode of action is known to work by competitive
inhibition of acetyl-CoA carboxylase (ACCase) in lipid
biosynthesis. This is the first case of this mode of action
in a herbicide.
As mentioned above, Alloxydim and Sethoxydim are

effective foliar treatments for the main grassy weeds,
which made them popular overseas. By 1991, they
were registered in 65 countries. Since grassy weeds
take up a large portion of the herbicide market, theseherbicides drew the attention of overseas manufacturers,
resulting in the development of the related compounds
shown below (Fig. 4.39).
Clethodim (Select; Valent 1998)
Tralkoxydim (Grasp; ICI 1986 (France))
Cycloxydim (Focus; BASF 1989 (France))
Butroxydim (Falcon; Zeneca 1996 (EU))
Profoxydim (Aura; BASF 1998 (Spain))
Tepraloxydim (Honest; BASF 2000)
It is worth noting that this cyclohexanedione structure
discovered by a Japanese manufacturer went on to
occupy a large portion of the global herbicide market.
This achievement won Nippon Soda the 31st Okochi
Memorial Grand Prize in 1984 for “research anddevelopment of cyclohexanedione pesticides.”Fig. 4.39. Cyclohexanedione Herbicides
Cited References(1) Ishikawa et al. Journal of Pesticide Science, Vol. 10,
No. 2, 1985, p. 301.
(2) H. Ishikawa, S. Yamada, H. Hosaka, T. Kawana, S.
Okunuki, and K. Kohara, J. Pestic. Sci., 10, p187 (1985)(3) Hosaka. Nihon no Nōyaku Kaihatsu [JapanesePesticide Development], Pesticide Science Society of84

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan

Japan, 2003, p. 305.
(4) Sawaki. Journal of Synthetic Organic Chemistry Vol.
39, No. 5, 1981, p. 408.
(5) Nihon Sōda 70-nen-shi [70-Year History of Nippon
Soda], Nippon Soda Co., Ltd., 1992, p. 346.
(6) Okunuki. Nōyaku Jidai [Pesticide Times], Vol. 153,
1985, p. 40.

4.13. Buprofezin (Applaud): An Insect
Growth Regulator (IGR) with a New
Chemical Structure
Buprofezin (Applaud) is an insecticide with a newchemical structure, invented by Nihon Nohyaku andregistered in 1983. It is highly effective against
Hemipterae such as leafhoppers, whitefly and scale
insects. It has a completely new thiadiazine chemical
structure. Although it has no effect on adult insects, it
acts specifically at particular stages of the insect life
cycle, namely ecdysis, egg-laying and hatching. It isthus more of an insect growth regulator (IGR) than an
insecticide. It is the first pesticide produced in Japan tohave this effect.
Nihon Nohyaku put the fungicide Isoprothiolane on themarket in 1974, as mentioned in Section 4.13. Thisfungicide was found to have a density inhibitory effecton leafhoppers in addition to its fungicidal activity. The
company started working on exploratory research on
synthesizing related compounds with the idea that there
would be good future prospects for pesticides that not
only killed insects but also acted at particular stages in
the insect life cycle, such as ecdysis, egg-laying andhatching. This was around the same time that Dutch
company Philips-Duphar invented Diflubenzuron(Dimilin), a benzoylurea chitin biosynthesis inhibitor(ecdysis inhibitor) (registered in Japan in 1981) andmuch attention was being drawn to the fact that this was
highly effective against insects resistant toorganophosphates and other chemicals. This
exploratory research took the form of screening forchemicals that acted as quickly as existingorganophosphates as well as longer-term observations
to check the delayed ecdysis-inhibiting effect (1).
Tireless synthesis experiments resulted in Buprofezin,with a perhydro-1,3,5-thiadiazine skeleton formed byreacting N-chloromethyl carbamoyl chloride with
substituted thiourea (2), (3). This is a completely new
chemical structure, although it looks similar in parts tohaving used a diflubenzuron cyclic structure, which has
the same ecdysis-inhibiting effect (Fig. 4.40).

Buprofezin (Applaud)

Diflubenzuron (Dimilin)

Fig. 4.40. Buprofezin (Applaud) and Diflubenzuron(Dimilin)

Buprofezin is a relatively narrow-spectrum insecticidewith the specific effect of inhibiting ecdysis in thelarvae of Hemipterae such as leafhoppers, whitefly andscale insects. This selectiveness is an advantage, as itmeans it has little impact on beneficial insects such as
natural enemies and bees.
It has a very powerful effect on insect larvae, with alethal median dose of 1 ppm or less, far more powerfulthan organophosphate and carbamate insecticides.
While it does not kill adult insects, its confirmed
secondary effects of shortening their life span as well as
inhibiting egg-laying and hatching are of great interest.
Like Dimilin, its mode of action is achieved byinhibiting biosynthesis of chitin, a component in the
cuticle layer of the epidermis of the insect. The
inhibition of egg-laying and hatching in adult insects is
confirmed to be due to the inhibition of prostaglandin
E2, an oviposition stimulant (4), (5).
As mentioned above, Buprofezin became widely used
due to the new IGR effect and its efficacy. It became ahit formulation, with ¥22.8 billion in shipments withinfour years. With resistance to existing insecticides
becoming problematic, this was a highly valuable
formulation, since it had no issue with cross-resistance(Note 1). The market for it expanded overseas for use
on various grains, fruit trees and vegetables; by 2007, it
had been registered and widely used in 88 countries (6).
This outcome won the company the Okochi Memorial
Grand Technology Prize for “research and developmentof the insect growth regulator Buprofezin” in 1988 and
the Japan Science and Technology Agency Presidential
Award in 1990.
Cited References(1) Ikeda. Seibutsu ni Manabu Nōyaku no Sōsei [TheCreation of Biologically-Inspired Pesticides], Soft
Science, 1986, p. 193.
(2) Yasui et al. “Bupurofejin [Buprofezin],” Nihon no
Nōyaku Kaihatsu [Japanese Pesticide Development],
Pesticide Science Society of Japan, 2003, p. 102.
(3) Ikeda et al. “Satchū-zai Bupurofejin no Kaihatsu[Development of the Insecticide Buprofezin],” Journalof Pesticide Science, Vol. 11, 1986, pp. 287-295.
(4) Y. Izawa, M. Uchida and M. Yasui: Agr. Biol. Chem.,
50, 1369 (1986)(5) Uchida. “Bupurofejin no Konchū Seiiku Seigyo Kikō
[The Insect Growth Control Mechanism of Buprofezin],”
Journal of the Agricultural Chemical Society of Japan,
Vol. 61, No. 12, 1987, p. 1609.
(6) “Bupurofejin Nōyaku Shōroku: Nōrin Suisan Shōhi
Anzen Gijutsu Sentā [Buprofezin Pesticide Abstract:
Food and Agricultural Materials Inspection Center],”
Nihon Nohyaku Co., Ltd.
http://www.acis.famic.go.jp/syouroku/buprofezin/buprof
ezin_01.pdf (accessed 29 August 2012).

Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

85

(Note 1) Cross-resistance here means resistance to one
pesticide (lowering its efficacy) resulting in resistancedeveloping to other pesticides. Also called cross-tolerance.

4.14. New-Generation Agricultural
Synthetic Pyrethroid Fenvalerate(Sumicidin)
Fenvalerate (Sumicidin) is a synthetic pyrethroid
insecticide for agriculture, invented by Sumitomo
Chemical and developed into a world-renowned
product. Registered in Japan in 1983, this global
product had already been on the market in the UnitedStates as an insecticide for cotton since 1979. While its
chemical structure is a modified version of natural
pyrethrins, if the two were compared side by side, theydiffer to the point of questioning whether or not one isan analogue of the other (Fig. 4.41). It took a lot of
research to come up with this product.
As mentioned in Section 3.3.4, pyrethroids have a long
history. It has been nearly 130 years since pyrethrum
was introduced to Japan in 1885. The first 50 years
were spent researching the chemical structure of theinsecticidal component of pyrethrum, with the chemical
structure finally being elucidated in the 1950s. With
developments in synthetic organic chemistry,
researchers then worked on clarifying thestructure-activity relationship, which resulted in theinvention of a number of highly effective synthetic
pyrethroids.

Fenvalerate (Sumicidin) Pyrethrin

Fig. 4.41. Fenvalerate and Pyrethrin
Sumitomo Chemical continued actively researching
synthetic pyrethroids, resulting in the development of anumber of insecticides, mainly for household use andfor disease prevention. This paper cannot discuss thesehousehold and disease-prevention formulations in detaildue to space constraints.
While pyrethrins, a component of pyrethrum, had beenused in agriculture before the war and synthetic
pyrethroids allethrins (1) had been on the market since
1967, these did not become very popular, as they werehighly priced and were not very effective as insecticides
on outdoor fields. This was because they had poor
photostability and poor durability (residual activity) as
they were susceptible to heat and oxidization and easily
broke down in the environment. When the morecompetitively priced and more effective DDT, BHC
and organophosphates appeared after the war,
pyrethrins and allrethrins were hardly used for
agriculture any longer.
This problem was solved by Permethrin, Cypermethrin
and Deltamethrin (2), invented by British researcher
Michael Elliott, as well as Fenpropathrin (3), discoveredby Sumitomo Chemical (Fig. 4.42). These inventions
all appeared around the same time, from the late 1960s
to the early 1970s.

Fig. 4.42. Agricultural Pyrethroids (3-membered rings)

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Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan

Sumitomo Chemical discovered the alcohol componentof pyrethrins to comprise a stable 3-Phenoxybenzyl
alcohol
and
its
cyano
substitute,α-cyano-3-phenoxy-benzyl alcohol (4). Meanwhile,
Elliott identified its acid component as dihalovinyl
chrysanthemic acid to protect a light-sensitive doublebond. Permethrin, Cypermethrin and Deltamethrin are
combinations of these. Sumitomo Chemical also
invented Fenpropathrin on discovering that tetramethyl
cyclopropane carboxylic acid (5) is very stable. These
inventions enabled a long-awaited expansion into
agriculture.
Around the same time, Sumitomo Chemical discoveredthat α-substituted phenylacetic acids without thecyclopropanecarboxylic acid 3-membered ring
structure – previously thought necessary in pyrethroid
compounds – had highly effective insecticidal
properties. This resulted in Fenvalerate, with the resultspresented at a conference in 1974 (6).
Fenvalerate was around ten times more active thanexisting organophosphate insecticides. Effective against
a wide range of pest insects, including Lepidopteraesuch as the common cutworm and diamondback moth,
Dipterae such as houseflies, Dictyopterae such as
cockroaches and Hemipterae such as aphids, it becamea major global product used on a broad range ofapplications, including cotton, grains, fruit trees andvegetables.
Sumitomo
Chemicalcompletedmanufacturing equipment capable of producing 1200
tons per year and used this technology to start
producing 1500 tons per year in the United States from1982 onwards. These achievements won the company
the 27th Okochi Memorial Prize in 1982 for“development of Fenvalerate.” (7)Following the appearance of Fenvalerate, another two
pyrethroids appeared with a non-3-membered ring
structure. One was Flucythrinate, invented by ACC andregistered in 1986. The other was Fluvalinate, invented
by Katsuda and registered in 1987. Their chemical
structures are shown in Fig. 4.43.

Flucythrinate (Payoff)

Fig. 4.43. Agricultural
3-membered rings)

Fluvalinate (Mavrik)

Pyrethroids(without

Given the aforementioned long history of pyrethroids,
the invention and development of Fenvalerate had amajor impact on the world by paving the way to
expansion into agricultural applications. Accordingly,

overseas manufacturers followed suit in the 1970s, withcompetition ensuing over research and development.
This resulted in the development and sale of a total of
19 different synthetic pyrethroids in Japan by 1995.
There were also more than nine new insecticides forhousehold use or disease prevention. It is worth noting
here that of the 19 formulations, eight were Japanese
inventions, while eight of the nine new household or
disease prevention formulations were Japanese
inventions. We can truly say that Japan has beaten the
major overseas players in this field.
Although synthetic pyrethroids have the advantage ofbeing very safe for mammals, there are several
problems with them. Firstly, they are unable to be usedon rice fields in Japan, as they are highly toxic to fish
and other aquatic organisms. Secondly, there areconcerns that flies and mosquitoes may develop
resistance to them. Thirdly, they affect phytoseiidae, thenatural enemies of spider mites, which could result in aresurgence of spider mites in greater numbers than
before pyrethroid use. As shall be discussed later, later
insecticides such as Etofenprox are less ichthyotoxic
and there is hope that they will be able to be used onrice fields.
Finally, Yoshio Katsuda has written some excellent
reviews and articles on the development and prospectsof pyrethroid chemistry, cited below (8), (9), (10).
Cited References(1) M. S. Schechter, N. Green, and F. B. LaForge, J. Am.
Chem. Soc., 71, p3165 (1949)(2) M. Elliott, A. W. Farnham, N. F. Janes, P. H. Needham,and D. A. Pulman, Nature 248 p710 (1974)(3) Matsuo et al. Patent No. 48-10225.
(4) Itaya et al. Journal of the Agricultural Chemical
Society of Japan, Vol. 57, No. 11, 1983, p. 1147.
(5) M. Matsui, and T. Kitahara, Agr. Biol. Chem., 31, (10),p1143 (1967)(6) N. Ohno, K. Fujimoto, Y. Okuno, T. Mizutani, M.
Hirano, N. Itaya, T. Honda and H. Yoshioka, Agr. Biol.
Chem., 38, (4), p881 (1974), Lecture No. 346, Ses 7A,
Third International Congress of Pesticide Chemistry at
Helsinki (1974)(7) Yoshioka et al. Ōkouchi-shō 30-nen no Ayumi [The30-Year History of the Okochi Memorial Award], 1987.
(8) Katsuta. Nihon Satchū-zai Kōgyō-kai 30-nen no Ayumi[The 30-Year History of the Japan Insecticides Industrial
Association], Japan Household Insecticide Industry
Association, 2001, p. 110.
(9) Y. Katsuda: “Development of and future prospects forpyrethroid chemistry” Pesticide Science., 55. p.775(1999)(10) Y. Katsuda: “Progress and Future of Pyrethroids”
Topics in Current Chemistry 314 p1 Springer-Verlag
Berlin Heiderberg 2011

Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

87mode of action is not yet known in detail.

4.15. High-Performance
Hexythiazox (Nissorun)

Miticide

Hexythiazox (Nissorun) is a major agricultural miticide
invented by Nippon Soda and registered and marketedin 1985 (Fig. 4.44). It has an unprecedented chemical
structure and distinctive effects. It is selectively
effective against parasitic spider mites on fruit trees,
vegetables, tea, cotton and other crops. While othermiticides were developed in Japan after this invention,
Hexythiazox was the forerunner of the Japanese
miticides.

Fig. 4.44. Hexythiazox (Nissorun)
Spider mites belong to the spider family rather than theinsect family. They are a type of plant parasite and are amajor parasitic pest on leaves and fruit. They multiply
quickly and once an outbreak occurs, the damage canbe devastating. Miticides are in great demand, as
regular insecticides have no effect on these pests. As
highly effective insecticides such as DDT became
popular after the war, there was a decline in natural
spider mite enemies such as phytoseiidae, resulting in
more apparent damage from spider mites. Since spider
mites reproduce quickly, they quickly acquire resistance,
meaning that any existing miticides soon lose theirefficacy. Consequently, new miticides are in great
demand.
Nippon Soda developed and marketed CPCBS(Sappiran, licensed from Dow) in 1954, followed by
CPAS/DDDS (Mikazin, Milbex) in 1962 and MNFA
(Nissol) in 1965. It then developed Benzomate(Citrazon) in 1971, occupying a large share of themarket as “Miticidal Nippon Soda.” However,registration for each of these formulations has lapsed
due to resistance problems.
Nippon Soda continued to work on developing new
formulations and discovered a thiazolotriazine
compound with miticidal properties while investigating
fungicides. The researchers altered this compound andthis resulted in Hexythiazox (1), (2), (3), (4).
The effects of Hexythiazox are 7-80 times more
powerful than existing miticides, such as those fortwo-spotted spider mites, Kanzawa spider mites, citrus
red mites and European red mites. While it has no effecton adult mites, it is highly effective at all other stages ofgrowth and sufficiently residual. It does not affectphytoseiidae, the natural enemy of spider mites. Its
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Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, JapanThus, Hexythiazox emerged as a far more effective
miticide than existing formulations and became wildly
popular. Within three years of going on the market in1986, it had become a major product, gaining a nearly
40% share of the domestic market, thanks to the timingof its appearance, at a time when there was a shortageof effective miticides due to resistance problems.
However, as previously mentioned, when miticides areused in such large quantities, resistance to them willquickly build up. Hexythiadox also developed its own
resistance problems across the country and usage of it
declined. Global discussions began around this time on
countermeasures to resistance and an international
agreement was made to avoid the build-up of resistanceas much as possible by using miticides with different
modes of action in rotation where possible.
Since the appearance of Hexythiazox, Japanesecompanies have led the development of miticides.
There is always a demand for new miticides with new
chemistry and new effects to avoid cross resistance. The
development capabilities of Japanese companies haveprovided the main means to meet this challenge (5). For
details on these new miticides, see Section 3.4.5 (2).
Cited References(1) Nippon Sōda 70-nen-shi [70-Year History of Nippon
Soda], Nippon Soda Co., Ltd., 1992, p. 350.
(2) Miyake. Nihon no Nōyaku Kaihatsu [JapanesePesticide Development], Pesticide Science Society ofJapan, 2003, p. 165.
(3) Yamada et al. Journal of Pesticide Science, Vol. 12, No.
2, 1987, p. 327.
(4) Ishimitsu et al. Journal of Synthetic Organic ChemistryVol. 52, No. 2, 1994, p. 103.
(5) Asada. Chemistry and Biology, Vol. 33, No. 2, 1995, p.
104.

4.16. Low-Toxic, Second-Generation
Carbamate Insecticides Benfuracarb(Oncol) and Alanycarb (Orion)
Benfuracarb (Oncol) is a carbamate insecticide for use
on rice and vegetable plants, discovered by Otsuka
Chemical and registered in 1986. Alanycarb (Orion) is
an insecticide for use on fruit and vegetable plants,
developed by Otsuka Chemical and registered in 1991
(Fig. 4.45).

Benfuracarb (Oncol)

Alanycarb (Orion)

Fig. 4.45. Benfuracarb and Alanycarb

Both of these insecticides have been designed to be
selectively toxic: for insects and not for mammals, inorder to reduce the acute mammalian toxicity of theiractive ingredients (1), (2), (3). The active ingredient in
Benfuracarb is Carbofuran (Furadan), developed by
FMC (Fig. 4.46), while the active ingredient in
Alanycarb is oxime carbamate Methomyl (Labin),developed by DuPont (Fig. 4.47). These two active
ingredients were developed between the late 1960s andearly 1970s and both have an acetylcholinestrase(AChE) inhibitory effect as their mode of action.
However, since mammals also have this enzyme, bothhave the drawback of being highly acutely toxic tomammals as well. Consequently, Carbofuran was neverregistered in Japan, while certain preparations of
Methomyl were exempted and registered on thepesticide register as deleterious substances.

Fig. 4.46. Carbofuran

Fig. 4.47. Methomyl

Dr. Roy Fukuto of the University of California pointed
out that the mammalian toxicity of carbamate
insecticides could be reduced while preserving theirinsecticidal properties by substituting the nitrogen atomof the carbamyl group. During the 1980s, a number ofcompanies used this method of reducing toxicity (4).
Otsuka Chemical came up with these insecticides aspart of this process. These formulations take advantageof the differences in metabolic capacity between insects
and mammals, transforming into active carbamates in
insects, but breaking down and metabolizing into
phenolic compounds with no effect on AChE in
mammals, thereby reducing their mammalian toxicity.
In pharmaceutical terms, they work as pro-drugs. Their
toxicity to insects (houseflies) and mammals (mice) isshown below, indicating no loss of insecticidal
properties but over 90% reduction in mammalian
toxicity (1), (2), (3), (5), (6), (7).

Carbofuran
Benfuracarb
Methomyl
Alanycarb

LD50 on topicalapplication to insects(μg/g)
6.7(houseflies)
9(houseflies)
0.45(common cutworm)
3.9(common cutworm)

LD50 oral toxicity
in mice (mg/kg)
5.6
106
16
412

Benfuracarb became widely popular in nursery box
applications due to its efficacy against problematic ricewater weevils and its residual effects. It was also
popular due to its superior efficacy in soil applications
for vegetables against a wide range of pests, including
Lepidopterae, Hemipterae and thrips.
Benfuracarb was also marketed in Europe in 1983 andis used in 50 countries around the world to control
major pest insects such as hairworms and aphids onmaize, sugar beets, potatoes and other crops.
Alanycarb is effective against larger Lepidopterae, leaf
rollers and worms on fruit trees and aphids and otherpests on vegetable plants.
As mentioned above, Benfuracarb and Alanycarb are
widely popular as second-generation carbamates; that is,
carbamate insecticides with reduced toxicity tomammals. This invention is very significant, not only interms of safety, but also in terms of improved biologicalefficacy in the field. Interestingly, while the compound
has around twice the weight, the effectiveness isequivalent to the parent compound. The use of apro-drug to solve the issues with existing highly active
substances is a good example of superior science andtechnology.
Cited References(1) Umetsu. Journal of Pesticide Science, Vol. 9, No. 1,
1984, p. 169.
(2) Umetsu. Journal of Pesticide Science, Vol. 11, No. 3,
1986, p. 493.
(3) Umetsu. Nihon no Nōyaku Kaihatsu [JapanesePesticide Development], Pesticide Science Society ofJapan, 2003, p. 131.
(4) T. R. Fukuto; J. Pesticide Sci., 2, p541 (1977)(5) Otsuka Chemical. Pesticide Times, Special Volume 533,
2001, p. 1.
(6) Otsuka Chemical. Journal of Pesticide Science, Vol. 14,
1989, p. 517.
(7) Food Safety Commission website (accessed 25
October 2011)
http://www.fsc.go.jp/fsciis/foodSafetyMaterial/show/syu02930230149

4.17. Fluazifop-butyl (Onecide) andQuizalofop-ethyl(Targa):theGraminicides that Followed after
Sethoxydim
Fluazifop-butyl(Onecide)isanaryloxy
phenoxypropionic acid grass killer invented by Ishihara
Sangyo and registered in Japan in 1986. It was widely
popular overseas, beginning with its registration in
Argentina in 1982.
Quizalofop-ethyl (Targa) is a herbicide in the samechemical group, invented by Nissan Chemical andregistered in 1989. Since it is mainly used overseas, it
Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

89was developed first for the overseas market, registeredin the United Kingdom in 1983, France in 1984 and theUnited States in 1988. It is a major product worth over
¥5 billion and registered in more than 60 countries
worldwide. Both of these formulations have the samemode of action as Sethoxydim, discussed in Section
4.12, and so have similar effects and applications.
In the early 1970s, Hoechst discovered
Diclofop-methyl, another product in the same chemicalcompound group (1), (2).
Ishihara Sangyo had carried out exploratory research on
new herbicides such as Chlomethoxynil by altering thediphenyl ether structure,. and later came up with
Fluazifop, with a substituted pyridyloxyphenoxy
chemical skeleton (3), (4), (5).
Nissan Chemical started researching this chemicalskeleton in the late 1970s, noting that the aryloxy
phenoxypropionic acid structure was selective against
grassy weeds. Developers then expanded the phenoxy
structure to a nitrogen-containing aromatic ring,
resulting in Quizalofop-ethyl with a fused-ring
quinoxaline skeleton (6), (7), (8), (9). This was Nissan
Chemical’s first world-class product.

While compounds in this series have aryloxypropionicacid structures, it is interesting to note that they
demonstrate no auxin-like activity, but are selective
against grassy weeds. This effect is similar to thecyclohexanedione-structured
Sethoxydim;
later
research has shown that its mode of action works byinhibiting lipogenesis through non-competitive
inhibition of ACCase (10), (11), (12). Thus, they interestingly
have completely different chemical structures, but aretreated the same way by plants. Only the R isomer ofthis phenoxypropionic acid shows activity; the S isomershows no substantial activity. Both herbicides currently
on the market have been switched to theoptically-active (R isomer) form.
These have become widely known as a group that is
highly active against grassy weeds. They have caught
the attention of many manufacturers, with the following
herbicides later developed and emerging on theJapanese market. Cyhalofop butyl is highly selective
and good for rice cultivation; accordingly, a number ofstandalone and combination formulations of it havebeen developed to control barnyard grass in its laterstage of growth. A number of other related compounds
have been developed for the overseas market as well (13),(14), but have been omitted here.

Fig. 4.48. Diclofop-methyl, Fluazifop-butyl and Quizalofop-ethyl

Fig. 4.49. Aryloxy Phenoxypropionic Acid Herbicides
90

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Cited References(1) H. J. Nestler: 4th International Congress of Pesticide
Chemistry, Zurich, Abstr., No.II-15, Pergamon Press(1978)(2) W. Becker et al., Ger. Offen. 2 223894 (1973)(3) Nishiyama et al. Patent No. 58-40947.
(4) Haga et al. Nihon no Nōyaku Kaihatsu [JapanesePesticide Development], 2003, p. 336.
(5) Haga et al. Journal of Pesticide Science, Vol. 12, No. 2,
1987, p. 311.
(6) Ura et al. Patent No. 55-113764.
(7) G. Sakata, K. Makino, Y. Kwamura, and T. Ikai, J.
Pestic. Sci., 10, (1) p61 (1985)(8) Ura et al. Journal of Synthetic Organic Chemistry Vol.
48, No. 10, 1990, p. 921.
(9) Suzuki et al. Journal of Pesticide Science, Vol. 16, No.
2, 1991, p. 315.
(10) J. D.Burton et al., Biochem, Biophys. Res. Commun.,
148, p1039(1987)(11) Nakahira et al. Journal of Pesticide Science, Vol. 15,
No. 2, 1990, p. 245.
(12) Nakahira. Journal of Pesticide Science, Vol. 23, No. 3,
1998, p. 357.
(13) Yamaguchi et al. Nōyaku kara Agurobaioregyurētā eno Tenkai [Development from Pesticides toAgro-bioregulators], CMC, 2009, p. 116.
(14) Hirai et al. Shin Nōyaku Kaihatsu no Saizensen [TheForefront of New Pesticide Development], CMC, 2003,
p. 135.
(15) Takahashi et al. Shin Nōyaku no Kaihatsu Tenbō[Prospects for the Development of New Pesticides],
CMC, 1997, p. 141.

4.18.
Etofenprox(Torebon):Achieving Low-Ichthyotoxicity with
Synthetic Pyrethroids
Etofenprox (Torebon) is a synthetic pyrethroid
insecticide invented and developed by Mitsui
Chemicals. It is characterized by being the firstpyrethroid in the world to be low-ichthyotoxic, aproblem in existing pyrethroids, meaning it could be
used not only on fruit and vegetable plants, but also on
rice, Japan’s most important crop. It was registered inJapan in 1987 (Fig. 4.50).

battle among a number of companies in the late 1970s
to develop new synthetic pyrethroids. Mitsui Chemicals
started working on developing a new product thatwould rival Fenvalerate and Permethrin – with known
chemical structures – as an insecticide with low-toxic
for fish.
During the course of this research, researchers at Mitsui
Chemicals tried modifying the ester portion – the only
thing that had not been tried. They swapped the ester
bond for an ether bond and this resulted in Etofenprox.
The ester portion had been viewed as an essential
moiety for any activity to show, but it turned out that theradical idea of replacing this moiety was the key to theinvention of Etofenprox. This compound remains
highly insecticidal, but is stable in both acid and alkali
environments, due to the ether bond. It was also foundto be significantly less toxic to fish and therefore able tobe used on rice fields (1), (2), (3), (4).
Another noteworthy characteristic is that its chemical
structure comprises only carbon, oxygen and hydrogen,with no nitrogen or halogen atoms. This radical
structural change was the most significant achievement
in pyrethroid history since Fenvalerate. The structure
has evolved so much that it is difficult to imagine that it
is a structural analogue of natural pyrethrins and has thesame effect.
Highly effective against a broad spectrum of insect
pests, including Lepidopterae, Hemipterae, Coleopterae,
Dipterae and Orthopterae, it is also effective against
insects that have developed resistance toorganophosphates and carbamates, such as leafhoppers.
Based on the above, Etofenprox took over from
Fenvalerate as the number one synthetic pyrethroid. As
at 2006, it was included in 157 standalone andcombination formulations on the pesticide register andused on 58 types of crops, including rice. Since it also
has little impact on the environment, it is widely used inaerial spraying. It is truly a super-product, with total
shipments reaching ¥170 billion in the 20 years since itwent on the market. It is also popular for its efficacy inhousehold use and in disease prevention (flies,
mosquitoes and termites).

Fig. 4.50. Etofenprox (Torebon)

Etofenprox has become a world-renowned product,continuing to be used to this day in more than 50
countries around the world, including the United States,
to control malaria-carrying mosquitoes and other insect
pests.

With the appearance of Fenvalerate (Sumicidin),discussed in Section 4.14, synthetic pyrethroids reachedthe level of usability in agriculture and expanded into awide range of applications, including fruit andvegetable plants, cotton and grains. This sparked a

These achievements won the company the Nikkei
Superior Products Award in 1988, the Pesticide Science
Society of Japan Achievement Award in 1990, theSynthetic Organic Chemistry Award in 1991 and the
Okochi Memorial Grand Technology Prize in 1992.
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91

Other related compounds were developed after
Etofenprox went on the market, including the miticide
Halfenprox (5), developed and registered by Mitsui
Toatsu Chemicals in 1994, the registration for which
lapsed in 2006. Yoshio Katsuda of Kincho also
developed the silicon-containing Silafluofen (6),registered in 1995. Silafluofen is an ether-bonded,carbon-chain compound that is safer for fish thanEtofenprox.

Halfenprox (Annivers)

Silafluofen (Mr Joker)

Fig. 4.51. Non-Three-Ringed Pyrethroids
Cited References(1) K. Nakatani, T. Inoue, S. Numata, K. Oda, T. Udagawa,and M. Gohbara: “MTI-500; A novel Insecticide.” 5thInternat. Cong. Pestic. Chem., Kyoto, Japan, 29th (1982)(Abstract I a-9)(2) Udagawa et al. Nihon no Nōyaku Kaihatsu [JapanesePesticide Development], Pesticide Science Society ofJapan, 2003, p. 149.
(3) Numata et al. Journal of Synthetic Organic ChemistryVol. 50, No. 2, 1992, p. 160.
(4) Yoshimoto et al. Ōkouchi-shō Jushō Gyōseki
Hōkoku-sho [Okochi Award Winners Performance
Report] (No. 39, 1992), p. 57.
(5) K. Tomoda, S. Numata, and, S. Shiraishi: Abstr.; 12th
Int. Plant Prot. Congr., Rio de Janeiro, Brazil, p12 (1984)(6) Katsuda et al. Patent No. 61-87687.

Chlorsulfuron DuPont

Fig. 4.52. Chlorsulfuron
While DuPont started out with Chlorsulfuron, otherpesticide manufacturers started developing their own
SU herbicides, resulting in the development of morethan 50 herbicides, each with its own distinguishing
characteristics. Refer to the Cited References for details
on the course of these developments (4), (5), (6).
The mode of action of SU formulations is known to beachieved by inhibiting acetolactate synthase (ALS) at
the early stage of biosynthesis of branched-chain aminoacids such as leucine, valine and isoleucine, essential
amino acids in plants.
Following the development of these SU herbicides,
several other series have been developed with different
chemical classes but the same mode of action. These
include the imidazolinones developed by ACC, thetriazolinones developed primarily by Bayer, thetriazolopyrimidines developed by Dow and thepyrimidinyl carboxy herbicides developed primarily by
Kumiai Chemical. Japanese manufacturers developed anumber of ALS inhibitors to rival the companies in theWest. Below, we shall outline the main herbicides
developed by Japanese manufacturers.
(1) Pyrazosulfuron-ethyl (Sirius) andHalosulfuron-methyl (Inpool) (Fig. 4.53)

4.19. Acetolactate Synthase (ALS)
Inhibitors: the Rise of Sulfonylurea(SU) Herbicides and Various Later
Developments
In 1977, G. Levitt et al. of DuPont applied for a patent
for a ground-breaking sulfonylurea (SU) herbicide witha new chemical structure (1). The compound theypresented on at a conference in 1981 made a striking
entrance with herbicidal properties at low doses ofseveral grams to several tens of grams per hectare, anamount more than two digits less than for of existingherbicides (2). The first such product to be developed
was Chlorsulfuron (Glean), marketed in the UnitedStates in 1982 for use on broadleaf weeds in wheat andbarley (Fig. 4.52). It became a super-product, withusage in the United States reaching 72,000 lb. (32.7t) ofactive ingredient per year on 5.5 million acres (around
2.2 million hectares) from 1988 to 1999, mainly for
winter wheat cropping (3).

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Fig. 4.53. Pyrazosulfuron-ethyl,
Halosulfuron-methyl and Metazosulfuron
Pyrazosulfuron-ethyl (Sirius) is an SU formulation
invented and developed by Nissan Chemical; the aryl
portion of the structure is converted to a pyrazole ring.
It is effective at controlling stubborn rice weeds such as
Eleocharis kuroguwai and Sagittaria trifolia at very
low doses of 21g/ha and is also very safe on rice. It wasregistered in Japan in 1989. Its distinguishing
characteristics have made it just as popular a pre- andearly-post one-shot herbicide as Bensulfuron methyl. It
has become a major herbicide, currently sold in 20 of
the main rice-growing countries around the world (7), (8).
Nissan Chemical then developed Halosulfuron-methyl(Inpool) (9). This formulation is distinctive for its
efficacy against Cyperaceae, its safety and its
selectivity on maize, turf and rice. It was first marketedin the United States in 1994 for use on maize, and thenregistered in Japan in 1995 for use on rice and turf. It isa major product, currently used in 38 countries aroundthe world.
Nissan Chemical also discovered Metazosulfuron, its
third SU with a pyrazole structure (6), (10). It is said to besafe to use on rice. It was first marketed in Korea in
2010, with an application in progress for registration in
Japan. This formulation is highly effective against
annual weeds, including barnyard grass, and stubborn
perennial weeds such as Eleocharis kuroguwai, Scirpus
planicumis and Scirpus nipponicus.
Nissan Chemical started exploring SU formulationsquite early on. Its development of a method of de novo
synthesis for pyrazole derivatives led to thedevelopment of these three SUs. This achievement won
the company the 34th Synthetic Organic Chemistry
Award
in
1992
for
“development
andcommercialization
of
the
new
herbicidepyrazosulfuron-ethyl.”(2) Flazasulfuron (Shibagen) and Nicosulfuron(Onehope) (Fig. 4.54)

use on maize, registered and sold in Japan as well as
another 38 countries (12), (13).
These two formulations have their aryl structure
replaced by substituted pyridines. Researchers at
Ishihara Sangyo had been working on substituted
pyridines and tested many derivatives, finally resulting
in the invention of these. Following up all options in
exploratory research on new pesticides by adding afluorine atom to a pyridine ring is a classic case of a
successful method of molecular design led by syntheticorganic chemistry. There are now a total of sevenindependently-developed
substituted
pyridine
derivatives on the market, beginning with
Fluazifop-butyl, discussed in Section 4.17. While thedetails are omitted, the following shows these pesticides
by year of development.
Herbicide Fluazifop-butyl (Onecide 1986)
Insecticide Chlorfluazuron (Atabron 1989)
Herbicide Flazasulfuron (Shibagen 1989)
Fungicide Fluazinam (Frowncide 1990)
Herbicide Nicosulfuron (Onehope 1994)
Insecticide Flonicamid (Ulala 2006)
Fungicide Pyriofenone (Property 2012)(3) Imazosulfuron and Sulfosulfuron (Fig. 4.55)

Imazosulfuron (Takeoff)

Sulfosulfuron (Monitor)

Fig. 4.55. Imazosulfuron and Sulfosulfuron(4) Propyrisulfuron (Zeta-One) (Fig. 4.56)

Flazasulfuron (Shibagen)Nicosulfuron (Onehope)Fig. 4.54. Flazasulfuron and Nicosulfuron
Ishihara Sangyo developed Flazasulfuron (Shibagen), a
SU herbicide that is selective on turf, and registered it in1989. Unlike existing grass herbicides, it is effective
against annual weeds, perennial weeds and broadleaf
weeds at low doses of 50g/ha in a foliar application andis characteristically safe on turf (11). This was followedby the development of the structurally-analogous
Nicosulfuron (Onehope), developed for use on maize.
This was registered in 1994 and had the distinguishing
characteristic of being effective at low doses of40-60g/ha in foliar applications against stubborn maize
weeds such as couch grass and Johnson grass. Its safety
to maize has been verified as being due to the rapid
degradation in maize, rather than differences insensitivity at enzyme level. It has become popular for

Fig. 4.56. Propyrisulfuron
Propyrisulfuron (Zeta-One) is a SU herbicide for ricedeveloped by Sumitomo Chemical and registered inJapan in 2010. Its chemical structure is a condensed
imidazopyridazine ring similar to Imazosulfuron,mentioned above. Its two main distinguishing
characteristics are its capacity to control barnyard grass
up to the 3-leaf stage at doses of 90g/ha and its efficacy
against SU-tolerant common falsepimpernel and
Scirpus juncoides (19), (20).

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93

The main rice herbicides in use today are one-shot
herbicides used in the pre-to early post treatment to savelabor. Combination formulations of three to fivedifferent herbicides including SU formulations havebeen developed to control multiple weeds in one
application. However, Propyrisulfuron achieves thesame effect as a standalone formulation, as it targets a
broad spectrum of weeds. This has the major advantageof reducing the number of active ingredients used onfields; it is expected to become widely popular in
future.
(5) Pyrimidinyl carboxy (PC) Herbicides
Pyrimidinyl carboxy (PC) herbicides are a group ofcompounds developed by Kumiai Chemical. To date,herbicides in this group include cotton herbicide
Pyrithiobac-sodium salt (Staple) and rice herbicides
Pyriminobac-methyl (Hieclean), Bispyribac-sodium
salt (Nominee) and Pyrimisulfan (Best Partner) (Fig.
4.57). Since each of these acts as a herbicide by
inhibiting ALS like the aforementioned SU herbicides,
they are classified as a group in the ALS inhibitor.

PC compounds to achieve selectivity for rice. This aim
was achieved by introducing oxime ether at sixth
position in the pyrimidinyl salicylic acid structure. It ischaracterized by being specifically effective against
early water grass, a major rice weed, at low doses of
30g/ha until the 3-leaf stage. Registered in 1996, it is
now mainly used as a mixture base for barnyard grass
formulations (25), (26), (27).
Bispyribac-sodium salt (Nominee) is the third PC
herbicide developed by Kumiai Chemical to beregistered on the pesticide register. Used as a foliar
treatment during transplanting or directly planting inrice fields, it is highly effective against a broad range of
weeds, including mature barnyard grass, at low doses of
20-45g/ha. It is also used to suppress weeds on ridges
between rice fields. Registered in Japan in 1997, it isvery safe to use on rice, with clear selectivity between
rice and barnyard grass. It has also been registered in 34
countries around the world, including the United States,
mainly for direct planting use on rice fields. In 2002, its
estimated area of use was 1.6 million hectares (28), (29), (30),(31).
Pyrimisulfan (Best Partner) is a new formulation
registered in 2010. It is a rice herbicide structurally
modified from PC herbicides.
Kumiai Chemical aimed to produce a herbicide thatwould control as many weeds as possible and also be
effective against the once-problematic SU-tolerant
Monocholia vaginalis and Scirpus hotarui. Developers
replaced the ether bridge structure between benzene
and pyrimidyl ring with a carbon bridge and then madethe radical structural change of replacing the carboxylic
acid moiety with a sulfonamide structure, thus creating
the company’s fourth ALS inhibitor (32), (33), (34), (35).

Fig. 4.57. PC Herbicides
Pyrithiobac-sodium salt is characterized by havingcarboxylic acid substituted at ortho position in thebenzene ring, with the sulfonylurea portion of a SU
compound replaced with thioether. This structure was
the result of experience with SU herbicides anddiphenyl ether herbicides (21). This compound isspecifically selective on cotton and is highly effective
against the main cotton weeds (Ipomea indica, spottedspurge, prickly sida and velvetleaf) at doses of
35-70g/ha. It was registered in the United States in1996 and later came to be used in Brazil and othercountries all over the world (22), (23), (24).
Pyriminobac-methyl (Hieclean) is a compound thatcame about as a result of modifying the aforementioned

94

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, JapanThe so-called one-shot herbicide that combine multiple
active ingredients in order to save labor replaced theprevious sequential applications and is currently usedon most rice fields today. However, although one-shot
herbicides reduce the number of applications necessary,
they also contain two to five types of active ingredients,
so there is high demand among rice producers forformulations that use fewer ingredients to suppress
weeds. Another major problem is that 90% of one-shot
formulations contain SU, repeated use of which has
resulted in a build-up of resistance to it since around
1995.
Pyrimisulfan is highly effective against annual weeds
such as barnyard grass (3-leaf stage) and perennial
weeds at dosages of 67g/ha. It is ground-breaking inthat it can achieve in a standalone ingredient what used
to take a combination of two to five existing ingredients.
It is also consistently effective against weeds that havebecome resistant to SU, such as Monocholia vaginalis,

Monochoria korsakowii, Scirpus juncoides andSagittaria trifolia. While it is effective in submerged
applications, its solubility in water is relatively high(114mg/L), so an improved formulation was developed
to ensure a more residual effect. Since it is very
effective in rice fields at ultra-low concentrations of
10ppb, making it into a controlled-release formulation
has helped to make the best use of this product (36).
As mentioned above, the SU herbicides discovered by
Levitt of DuPont created a market for ALS inhibitors,
which have undergone tremendous development overthe past 30 years. ALS inhibitors are the ideal herbicide:
they are very safe to mammals, as mammals do nothave the target enzyme, they also perform far better
than existing formulations at a dosage of more than two
digits less, amount, and they can be used on a diverse
range of crops. As mentioned, a number of non-SU
ALS inhibitors were developed and gained a firm
foothold among modern pesticides. Japanesecompanies played a huge role in this.
However, their popularity spread too quickly. Fromaround 1995, there were major problems with resistantweeds in areas where SU formulations were used.
Much research has been done to show that thisresistance was due to gene mutations in multiple places(37), (38). Fortunately, some ALS inhibitors such as
Propyrisulfuron and Pyrimisulfan were also effective
against resistant weeds. In any case, appropriate
measures must be taken to avoid resistance building up
where formulations are used, such as not using thesame formulation continuously. Future research anddevelopment is expected to produce new formulations
that will resolve this issue.
Cited References(1) G. Levitt et al., USP 674668; Japanese Patent No.
52-122384(2) G. Levitt, H. L. Ploeg, R. C. Weigel, Jr., D. J. Fitzgerald,
J. Agric. Food Chem. 29, p418 (1981)(3)US. EPA R.E.D. Facts EPA-738-F-05-002 (2005)
Chlorsulfuron
http://www.epa.gov/oppsrrd1/REDs/factsheets/chlorsulfuron_factsheet.pdf (accessed 17 October
2012)(4) Takahashi et al. Shin Nōyaku no Kaihatsu Tenbō[Prospects for the Development of New Pesticides],
CMC, 1997, p. 141.
(5) Hirai et al. Shin Nōyaku Kaihatsu no Saizensen [TheForefront of New Pesticide Development], CMC, 2003,
p. 135.
(6) H. Kobayashi, K. Nakanishi, M. Saeki, Y. Nakaya, Y.
Tamada and M. Katsuki: “NC-620: A New Sulfonylurea
Compound for Weed Control in Rice” 4th Pan PacificConference on Pesticide Science, Honolulu, p49 (2008)(7) Yamamoto et al. Journal of Synthetic Organic

Chemistry Vol. 52, No. 1, 1994, p. 19.
(8) Yamamoto et al. Journal of Pesticide Science, Vol. 21,
No. 2, 1996, p. 259.
(9) Sato et al. Journal of Pesticide Science, Vol. 23, No. 2,
1998, p. 184.
(10) Nissan Chemical WO2005/103044- A1 (Priority
Claim Application No.: Japanese Patent Application No.
2004-130933)(11) Yoshida. Chemical Regulation of Plants, Vol. 28, No.
1, 1993, p. 90.
(12) Murai et al. Journal of Pesticide Science, Vol. 20, No.
4, 1995, p. 453.
(13) Murai et al. Journal of Pesticide Science, Vol. 25, No.
3, 2000, p. 332.
(14) Y. Ishida, K. Ohta, T. Nakahama, S. Itoh, H. Miki, J.
Yamada, Y. Kando, K. Masumoto, T. Kamikado and Y.
Yoshikawa: Abstr.; 7th Int. Congr. Pestic.
Chem.(IUPAC), Hamburg, 01 A-46, (1990)(15) Y. Ishida, K. Ohta, S. Itoh, T. Nakahama, H. Miki, andH. Yoshikawa: J. Pestic. Sci., 18, (2) p175 (1993)(16) Ishida et al. Journal of Pesticide Science, Vol. 21, No.
2, 1996, p. 247.
(17) S. Itoh, K. Ohta, T. Yamawaki and Y. Ishida: J. Pestic.
Sci., 26, (2) p162 (2001)(18) Ota et al. Journal of Pesticide Science, Vol. 27, No. 2,
2002, p. 179.
(19) Ikeda et al. ‘Sumitomo Chemical’ Technical Review,
2011, p. 14.
(20) Tanaka et al. Journal of Weed Science and Technology,
Vol. 57, 2012, p. 56.
(21) Y. Nezu, N. Wada, Y. Saitoh, S. Takahashi, and T.
Miyazawa, J. Pesticide Sci., 21 (3) , p 293 (1996)(22) Nezu et al. Journal of Pesticide Science, Vol. 24, No.
2, 1998, p. 217.
(23) S. Takahasi, S. Shigematsu, A. Mori, Y. Nezu, J.S.
Clause, and C.S. Williams: Proc.; Brighton Crop Prot.
Conf. Weeds, p57 (1991)(24) Nezu. Nihon no Nōyaku Kaihatsu [JapanesePesticide Development], Pesticide Science Society ofJapan, 2003, p. 279.
(25) R. Hanai, K. Kawano, S. Shigematsu and M. Tamaru:
Proc. Brighton Crop Prot. Conf-Weeds, 1, p47 (1993)(26) Tamaru et al. Journal of Synthetic Organic ChemistryVol. 56, No. 10, 1998, p. 863.
(27) Tamaru et al. Journal of Pesticide Science, Vol. 27,
No. 2, 2002, p. 188.
(28) M. Yokoyama, O. Watanabe, K. Kawano, S.
Shigematsu and N. Wada: Brighton Crop Prot. Conf.
Weeds, p61 (1993)(29) K. Kobayashi et al., Proc. 15th Conf. APWSS, p211
(1995)(30) Yokoyama et al. Journal of Weed Science andTechnology, Vol. 39 (suppl.), 1994, p. 32.
(31) Watanabe et al. Journal of Weed Science andTechnology, Vol. 48, Nos. 1-2, 2003, p. 24.
(32) T. Yoshimura, M. Nakatani, S. Asakura, R. Hanai, M.
Hiraoka and S. Kuwahara: J. Pestic. Sci., 36 (2), p212
(2011)(33) Hanai. Agriculture of the Month, Vol. 52, No. 9, 2008,
p. 53.

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(34) Yoshimura. Chemistry and Biology, Vol. 50, No. 7,
2012, p. 552.
(35) Yoshimura. Fine Chemicals, Vol. 41, No. 3, 2012, p.
18.
(36) S. Asakua, M. Hiraoka, T.Sugimura, T. Yoshimura, M,
Nakatani and R. Hanai: J. Pestic. Sci., 37 (1) p62 (2012)(37) Ito. Journal of Pesticide Science, Vol. 25, No. 3, 2000,
p. 281.
(38) Uchino. Journal of Pesticide Science, Vol. 28, No. 4,
2003, p. 479.

4.20. Major Neonicotinoid Insecticide
Imidacloprid(Admire)andSubsequent
New
Japanese
Insecticides
Imidacloprid (Admire) is an insecticide invented anddeveloped by Nihon Tokushu Noyaku (now Bayer
Crop Science). It is currently the best-selling pesticidein the world. Developed first for overseas markets, it
was registered in Japan in 1992. It is called aneonicotinoid as it is based on and has the same modeof action as nicotine, a natural pesticide.
As discussed in Section 3.3.5, nicotine was used as an
insecticide before the war in the form of nicotine sulfate.
This was toxic to mammals and dropped in usage withthe appearance of more effective synthetic pesticides
after the war. By the 1990s, it had dropped to several
hundred tons in shipments and registration for it finally
lapsed in 2006. While there was little exploratory
research on new substances modeled on nicotine for along time, from around 1972, Shell started actively
focusing on this field of research, announcing its
discovery of Nithiazine, a nitromethylene compound, in1978 (1). This compound was effective against green
rice leafhoppers that had become resistant to existing
insecticides and was also safe for mammals, but its
development was not successful as it had poor lightstability. Kagabu et al. of Nihon Tokushu Noyaku
started exploratory research on related compounds in
1979, focusing on the nitromethylene structure of
Nithiazine. After a series of structural modifications,they discovered a highly active compound group that
included the 6-chloro-pyridylmethyl group, resulting in
Imidacloprid in 1985 (2), (3), (4) (Fig. 4.58).

Imidacloprid (Admire)

Nicotine

Nithiazine

Fig. 4.58. Imidacloprid, Nicotine and Nithiazine

96

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan

With insecticidal effects on green rice leafhoppers at
low concentrations of 0.32ppm, Imidacloprid is morethan 125 times more active than Nithiazine (5).
Imidacloprid is effective against a broad range of pest
insects, including Hemipterae, Coleopterae, some
Lepidopterae, Dipterae, thrips and termites, at 80-90%
lower concentrations than existing formulations. It isalso systemic in plants and has no side effects on crops,
meaning it can be used in granular form. It is also safe
to use, with low mammalian toxicity andichthyotoxicity.
Imidacloprid is used on a wide range of crops,
including rice, fruit trees, vegetables, wheat, soybeans,potatoes, cotton and maize. It can also be used tocontrol fleas on pets and to eradicate termites.
Like nicotine, its mode of action produces aninsecticidal effect by binding to the nicotinic
acetylcholine receptors (nAChRs) on the postsynaptic
side of the neuromuscular junction, causing
antagonistic stimulation (6), (7), (8).
Imidacloprid is currently the best-selling insecticide in
the world. Registered in 131 countries, this blockbuster(Note 1) dominates the insecticide market with sales
worth more than ¥100 billion. This achievement won
the company the Okochi Memorial Grand ProductPrize in 1998 for “development of the newchloronicotinyl insecticide Imidacloprid.”
The appearance of Imidacloprid opened the way for theneonicotinoids, the next major branch of insecticides
after the organophosphates and the carbamates. Once
Nihon Tokushu Noyaku disclosed its patent, othercompanies set to work exploring analogues. The
following distinctive formulations appeared as theresult of fierce patent competition (Fig. 4.59).

and silverleaf whiteflies. Thiacloprid is relatively safefor bees.
As mentioned above, neonicotinoid insecticides began
20 years ago with the invention of Imidacloprid by
Kagabu. They followed on from the synthetic
pyrethroids and are more effective than any otherinsecticide, becoming a mainstay among modern
pesticides. It is worth noting that all of theseneonicotinoids except Thiamethoxam were invented inJapan, a world-class achievement rivaling the major
corporations in the West.

Fig. 4.59. Neonicotinoid Insecticides
Acetamiprid (Mospilan; Nippon Soda, 1995)
Nitenpyram (Bestguard; Takeda Pharmaceutical, 1995)
Thiamethoxam (Actara; Chiba Geigy, 2000)
Thiacloprid (Bariard; Bayer Japan, 2001)
Clothianidin (Dantotsu; Takeda Pharmaceutical, 2001)
Dinotefuran (Starkle; Mitsui Chemicals, 2002)
Acetamiprid is highly effective against Lepidopterae
and also safe for bees. Dinotefuran is the only one tohave no halogen atom in its structure; it is widely usedon rice, fruit and vegetable plants and is effective
against a broad range of pest insects such as stink bugs

Cited References(1) S. B. Soloway, A. C. Henry, W. D. Kollmeyer, W. M.
Padgett, K. E. Powell, S. A. Roman, C. H. Tieman, R. A.
Corey, and C. A. Horne: “Advances in Pesticide Science.”
Part 2. ed. by H. Geissbühler, Oxford, Pergamon, P. p206,(1979)(2) Patent Publication No. 5-14716 (Patent No. 1807569)(3) Biosci. Bitech. Biochem., 56(2), p362, (1992)(4) Biosci. Bitech. Biochem., 56(2), p364, (1992)(5) Chemistry and Biology, Vol. 31, No. 8, 1993.
(6) D. Bai, S. C. R. Lummis, W. Leicht, H. Breer and D. B.
Sattelle: Pstic. Sci. 33, p197 (1991)(7) M. Tomizawa and I. Yamamoto: J. Psetic. Sci. 18, p91(1993)(8) Moriie. Nihon no Nōyaku Kaihatsu [JapanesePesticide Development], Pesticide Science Society ofJapan, 2003, p. 92.
(Note 1) Blockbuster originally meant a large bomb (thatcould destroy a city block). In medicine, it refers to a
product that is worth more than ¥100 billion in annual
sales.

Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

97

5. Discussion and Future Prospects
While pesticides in Japan date back to the 17th century,
the greatest change has been since the appearance of alarge number of synthetic pesticides after the war.
Social awareness of pesticides has also changed withthe times. This section discusses society’s awareness ofpesticides, the current state of the pesticide industry andthe competitive power of Japanese companies. While
there are many industries in which Japanese companies
hold their own against the major corporations in theWest, this section considers whether this competitive
power will continue in the future.

Let us take ethanol as an example. Let us suppose thatethanol has a particular effect against pest insects andestimate an acceptable daily intake of it.

5.1. Social Awareness: Safety andSecurity-

The mass media often portrays negative responses topesticides. Consumers seem to think that “pesticides arepoisons; therefore, it is concerning to have pesticide
residues in food and preferable to have pesticide-free
produce”. Along with food additives, pesticides are
becoming a source of concern to consumers.

-

As stated throughout this paper, the safety of pesticides
in use today is sufficiently guaranteed, both for the
farmers who handle them and for the consumers who
eat crops that have been treated with them. In fact, theresults of several million tests performed each year on
pesticide residues in food are conclusive that there is
negligible problem. However, like other chemical
substances, pesticides are medicinal as well as toxic.
Even medicines come with instructions: taking too
many sleeping pills could be fatal or taking certain cold
remedies can cause allergies (for example,
Stevens-Johnson syndrome). Pesticides are the same:
they can be medicinal or they can be toxic, dependingon the amount. However, there is one major difference
that is cause for concern: while people take cold
medicine of their own volition, they have no choiceover whether or not they ingest any pesticide residues in
the food they eat. To solve this issue, it must be
carefully explained that the degree of risk is so smallthat it is not a problem.
Another cause for concern about pesticides is a sense offear or anxiety about events that actually took place inthe past. The use of highly-toxic parathion to increase
food production after the war, Minamata disease,arsenic milk poisoning and the Kanemi rice oil disease
were social problems which caused a kind of social
allergic reaction to all chemical substances.
Misunderstanding about chemical substances is anotherreason for this concern. While the food products we eat

98

every day are considered to be safe (including various
chemical substances such as vitamins and spices), theidea persists that any additives not originally in the foodand any residual pesticides are toxic, irrespective of theamount. However, chemical substances, whether
natural or synthetic, are both poisons and also
medicines.

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, JapanA rat reproduction test result shows theno-observed-adverse-effect level (NOAEL)
to be 2,000mg/kg/day (1)Taking into account the differences between
species and the differences between
individuals multiplied by a safety factor of
1/100, the acceptable daily intake (ADI) is
20mg/kg/day.

Multiplying this by the average Japanese body weight(53.5kg) gives an ADI of 1,070mg/day. This isequivalent to 8.6g of Japanese sake (which contains
12.5w/w% ethanol), meaning that drinking one cup ofsake per day is equivalent to ingesting around five times
the ADI.
The WHO International Agency for Research on
Cancer (IARC) has already categorised ethanol inGroup 1 (carcinogenic to humans), meaning it would
not be allowed to be registered as a pesticide. This gives
us a sense of just how strict pesticide regulation is.
Many natural chemical substances are far more toxic
than pesticides. Conversely, there are countless
substances that are not subject to the same level ofsafety testing as pesticides are. Buying organic produce
is a personal preference. It is not the intention of thispaper to stop people believing the “myth” that natural
products are safe, but it seems that there is little
realisation that these vegetables are made up ofpesticide-like substances at 10,000 times the volume ofany possible pesticide residues.
Another reason for concern about pesticides is the issueof how they are handled by the mass media or inschools. The mass media mainly report stories that
arouse interest in people; that is, credible stories that
disturb the peace and make people feel concerned.
Viewers are not interested in hearing that all is well; ifsomething does not raise the ratings, it will not bereported. There is no media coverage of theaforementioned misunderstanding about pesticides.

Even the NHK often uses expressions indicating that a
particular food product is safe because pesticides were
not used on it. Once a misunderstanding aboutpesticides has been evoked, it is very difficult andtime-consuming to dispel it, because the sense ofunease is a personal sentiment. Schools do not provide
accurate education on safety risks and even contributeto this sense of unease about the dangers of chemical
substances. There is a pressing need to dispel this senseof unease with frank, scientific explanations.

5.2. Agricultural Environment: Poorin Structural Reforms; Future
Prospects
The pesticide industry is inseparably linked toagriculture. Before the war, agriculture was a fightagainst starvation. While Japan managed to overcome
its food crisis as synthetic pesticides emerged after thewar, there were other issues to deal with, such asenvironmental pollution. At least Japan has long sinceleft its food issues behind and entered a so-called age ofexcess. Consumers demand produce that looks andtastes good, and farmers have responded to thisdemand.
However, faced with a reduction in agricultural land, an
aging workforce and an increase in food imports, wecannot deny that agriculture structural reform isoverdue. Pressure by the WTO, FTA and TPP to free up
international trade will only increase. The Ministry ofAgriculture, Forestry and Fisheries enacted the
Sixth-Order Industrialization Act, albeit belatedly, andstarted initiatives to unite and strengthen production,
processing and distribution/sales, as well as backing up
other activities such as direct selling of local products,
providing school lunches, promoting farm stays andexporting specialty products. The hope is that otherinitiatives will also increase in future, such as enlarging
areas of high-quality farmland, encouraging larger-scale
operations, such as community farming, and increasing
horticultural establishments, such as plant factories.
Although organic farming is widely accepted by society,
it is not as popular in Japan as it is overseas. This isprobably because Japan’s hot and humid climaticconditions make it very difficult to grow crops without
pesticides or with fewer pesticides. According to
MAFF statistics, organic farming accounted for 8,500
hectares or 0.18% of Japan’s total agricultural land in2011.
Thus, the reality is that Japan’s agricultural environmentis fraught with difficulties, but there is a way for it tosurvive:high-income-earning,domestic-production-minded consumers who willpurchase fresh, safe and tasty food products even if they

are a little expensive. Meeting this demand will require
structural reform in the agriculture industry. Produce ofsuch high quality is competitive enough for exporting,creating a “made in Japan” branding for agricultural
products. Japan will need to expand this area andpromote dynamic restructuring to bring in a level ofincome that is attractive to farmers.
Cited References(1) “Rat offspring sired by males treated with alcohol.”
Alcohol. May-June: 10 (3) p237 (1993)(2) “OECD SIDS Initial Assessment Profile” Ethanol,
SIAM 19, p19, October (2004)
http://webnet.oecd.org/HPV/UI/handler.axd?id=87ae34
eb-5241-44a3-87eb-37f8ff949d99 (accessed 20
December 2012)

5.3. The Japanese Pesticide Industry:
Present and Future
As mentioned previously, the pesticide industry has
developed hand in hand with agricultural trends.
Licenced technology imports boomed during thepost-war period of increased food production, while
investments into research and development during theperiod of rapid economic growth paid off with results atleast rivalling those of the major corporations in theWest. Even with rising concerns over safety and social
problems arising from environmental impact, thepesticide industry managed to surmount these issues
and survive to the present day. Reduced acreage and aslump in the economy resulting from oil shocks and ahigh yen has meant a gradual decline in pesticide
shipments since the late 1990s, but the market is still
stable.
This section outlines the author’s own opinion on
structural changes in the pesticide industry and why
Japanese companies are equally or more competitive
than the major corporations in the West.
5.3.1. Structural Transformation in the Pesticide
Industry
The development success rate of new pesticides isdecreasing every year. There are two reasons: it is
becoming more difficult to invent potential new
pesticides and the development costs required for safety
and environmental impact evaluations have increased.
Only one compound in several tens of thousands
synthesized becomes a commercial product, meaningthat it costs ¥3-5 billion to develop a new pesticide. Thisrequires a scale of operation large enough to sustain thiscost. It is difficult to cover a wide range of researchalone, so companies have collaborated with universities
or other companies, or outsourced some of the work, atrend that is likely to continue.
Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology99

Although this study has not covered biopesticides, let us
mention here that biopesticides are on the rise. As at
2010, there were 60 types of biopesticides listed on thepesticide register. While organic and reduced-pesticide
farming are expected to expand, at present, biopesticide
shipments only amount to ¥2.2 billion, no more than
0.6% of the market. Although there are advantages tobiopesticides, such as little environmental impact, noconcerns over residual toxicity and low chances ofresistance developing, the reality is that they are notvery popular because they are not very good forcontrolling multiple simultaneous pest insect outbreaks
as has been seen in Japan, they do not offer a consistenteffect, they are expensive and they do not last.
Another structural change has been the appearance ofgenetically-modified organisms (GMOs). While only a
few of these have been permitted in Japan (such as blue
roses), in the United States, nearly all soybeans andmaize has been genetically modified. Farmers cultivate(Roundup Ready) crops resistant to non-selective
herbicides such as Glyphosate (Roundup) or
Glufosinate (Basta) and use only Glysophate to control
weeds on their fields. This has quickly become popular
due to benefits such as increasing yield size while
enabling no-till farming, thus spelling the end ofsoil-treatment herbicides. The trouble with GMOs isthat the only benefits are to the farmers. Consumers
perceive no benefit from GMOs; instead, they have asense of uneasiness about them. The current situation in
Japan is that GMOs are undergoing safety evaluations,but are not accepted by consumers.
Recently there has been a problem withRoundup-resistant weeds. This problem was largely
magnified when GMOs were developed in 1996.
Future measures to counteract this will involve using
multiple herbicides with different modes of action so as
to avoid relying on one single formulation.
While there have been some major changes in thepesticide industry, as mentioned above, new,high-performance pesticides have always been in
demand.
5.3.2. Survival of Japanese Companies: Dependent
on Continuous Creation of New Formulations
How have Japanese companies managed to fare to wellthus far despite far smaller in scale than the major
corporations in the West? Will this competitive power
continue? The following is the personal opinion of theauthor, but it may be of use as a reference despite being
an abstract explanation.
(1) Advantageous Position

Japanese companies know Japanese agriculture.
Consequently, they have an overwhelming advantage
in effective and efficient development. Overseas
companies are handicapped by the fact that although
they might have a conceptual understanding, when they
develop potential compounds for new formulations on
their own, they are influenced by policies in their own
country.
It is very important to set goals at the exploratory stage
and incorporate biological screening methods thatincorporate these goals. For instance, when conducting
exploratory research on rice blast fungicides, it is vitalto test the actual effect on rice plants actually infectedwith the disease, as some compounds are effective
against the disease in the field despite showing no
antibacterial effects in petri dish experiments. The key
to success is having a meticulous screening system inplace. There are also differences in climatic conditions,pest insects and weed outbreaks between the East andthe West, so it is necessary to develop appropriate
formulations, combination product formulations andmethods of application in accordance with regional
differences during the development stage. Rice blast
control is a classic example that requires mastery of arange of treatment methods, such as seed treatment,
spraying and submerged treatments. This requires
combination formulations for one-shot application as
well as jumbo formulations to save labor. Japanesecompanies are very good at this kind of development.
(2) Developing Small-Scale Pesticides
Japanese companies are characteristically able todevelop pesticides they have discovered even if there is
only a small market for them. When major overseas
corporations decide whether or not to invest further intodeveloping a formulation, they conduct strict market
research, calculate the net present value of theformulation and determine whether future recovery is
possible. The more countries that are involved, thegreater the development costs. It can cost as much as¥10 billion, which is higher than development carriedout in Japan alone. Meanwhile, Japanese companies
take only the domestic market into consideration anddevelop formulations even if the expected proceeds are
small. At a rough estimate, it costs around ¥1.5 billion(direct expenses) to develop a pesticide from the time aparticular candidate compound is identified. One
example is miticides. Compared with insecticides,
miticides are more prone to resistance developing andtherefore there is constant demand for new
formulations. Accordingly, formulations have a very
short life span and there is little chance of recovering
any investment. This is reason that Japanese companies
have been able to develop so many miticides.
There are even instances of candidate formulations

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Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japanabandoned by overseas corporations being acquired
and developed for the Japanese market; in a sense, thiscreates a kind of dichotomy.
(3) Making One Development into Two
All pesticide companies, whether Japanese or fromoverseas, need an array of products in development (aproduct pipeline). Since development takes a long time,
like medicine, the contents of the pipeline are a major
indicator of the company’s future business situation andalso have an effect on stock prices.
In some cases, Japanese companies have discovered apromising potential formulation for development and,using that formulation as leverage, granted overseas
development rights to an overseas manufacturer inexchange for the development rights in Japan for a
formulation held by that company. This is a win-win
relationship, in which each company benefits from thestrengths of the other. Of course, companies sometimes
make a bid for the world market on their own, but thisrequires a huge investment into development as well as
facing a number of difficulties with overseas
development. Japanese companies often use
consultants or work on developments together withoverseas companies.
In any case, Japanese companies must keep on coming
up with promising potential candidates.
(4) Manoeuvrability and Teamwork in Small
Organisations
Japanese companies are smaller in scale than theiroverseas counterparts, but there must be benefits tocarrying out research and development on a smallerscale. If we ask if the abilities of individual researchers
are any better than those in overseas corporations, or if
Japanese are inherently more intelligent, the answer
would have to be that “they are not inferior to theirrivals, who are also good at what they do, but theirrivals have the advantage both in the number of
researchers and in the budget for research anddevelopment.” However, the teamwork andmanoeuvrability found in Japanese companies is able tocompensate for any differences in scale.
Historically, Japanese research on organic synthesis has
been first-rate. Japan can be proud that out of seven
Japanese Nobel laureates in Chemistry, four of them
have been specialists in synthetic organic chemistry;
namely, Kenichi Fukui, Ryoji Noyori, Akira Suzuki andEiichi Negishi. This tradition of outstanding work insynthetic organic chemistry has evidently been put touse in the development of pesticides.

corporations combined combinatorial solid-phase
synthesis with high throughput screening (HTS) to
create an efficient system of synthesizing andevaluating large amounts (hundreds of thousands) oftest samples in a short period of time (several months).
This was an attempt to use robots to explore leadcompounds more efficiently. First used in research anddevelopment of medicines, this method drew muchattention for its suitability for pesticides. Further details
on this technology are given in the cited work (1). While
this was initially said to have caused a paradigm shift in
exploratory research, this method has not become
universal due to other issues with it, such as not having
enough diversity in its library of compounds for future
development. While the major overseas corporations
have the financial resources, they are focusing on HTS
and building up their library of compounds and havenot made any dramatic increase in their development of
new formulations. Japanese companies have adopted
this system but refined it to match their scale ofbusiness, putting some “soul” into their test samples. To
put it another way, rather than engaging in inefficient,brute-force carpet bombing, they are shooting with ahighly precise rifle with pinpoint accuracy.
Japanese companies focus on teamwork. A major
weapon in their arsenal is their attitude towards research.
Successful pesticide development requires the ability tointegrate a range of key technologies. The key tosuccess is being able to bring a range of experts
together and unite their focus. The difference with the
major overseas manufacturers is that they are hugecompanies and therefore have a greater division of labor.
A typical example is patent applications. Patentapplications by Japanese companies often have a large
number of patent applicants listed, while applications
by overseas companies often have only a few
applicants listed, even if there were more in practice.
While there may only be one or two actual inventors,
being listed on the patent application is a major
motivation incentive for all researchers involved.
(5) Serendipity
Serendipity is often cited as the reason for success in
exploratory research, not only in the area of pesticides.
However, if we look at the 20 Japanese formulations
outlined in Section 4, we see that they were notdiscovered by chance, but by determination (tenacity)
and a firm belief that “we are going to discover this by
all means.” While the modest expression “discoveredby chance” often appears in academic presentations
outlining the details of an invention, surely thisserendipity is the result of persistent concentration andhard work.
(6) Future Prospects

From the 1990s onwards, the major overseas
Hiroki OHTA; Historical Development of Pesticides in Japan
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101

Will Japanese companies continue to be competitive inthe future? The answer is yes. The reason is that there isa very good Japanese market. Despite rising pressure
for free trade, expected future increases in produce
imports from overseas and an overdue structuralreformation, Japanese agriculture will not fade out
altogether. Fresh, good quality produce with the added
value of security cannot be replaced by imports. Given
the state of the market and the major damage from pest
insects as a result of climatic conditions, pesticides willcontinue to be necessary.
However, although pesticides will remain an importantresource for production, no significant future growth
can be expected in terms of the scale of the market,
given the development of organic farming, the102

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japanemergence of biopesticides and the preference for
reduced amounts of pesticides. New pesticides will
always be in demand, although the hurdles todevelopment are getting higher, both in safetyassessments and environmental impact assessments.
Sumithion and a number of other Japanese
formulations have become world-class products. The
hope is that other major formulations will continue toappear and follow in their footsteps.
Cited References(1)
Okajima.
Konbinatoriaru
Kemisutorī“Combinatorial
Chemistry,”
Combinatorial
Chemistry Research Society (ed.), Kagakudojin,
1997.

6. Afterword and Acknowledgements
Afterword
Despite having been involved in pesticide research anddevelopment, the author’s study of the related history
had only been fragmentary. The opportunity provided
by this study was a chance to formally put together acomplete picture of the history of the pesticide industry.
I was reminded of how I used to engage in working onreal challenges and seeking solutions for future issues
rather than looking back on the past and learning frompioneers in the industry. Despite having a conceptual
understanding of the importance of learning from
history, too often the foolish choice has been made tosimply learn from experience. This study has provided,
albeit belatedly, a fresh sense of the importance ofhistory.
Several major paradigm shifts have taken placethroughout the history of the pesticide industry.
Until the late 19th century, the only means of controlling
pest insects in agriculture was the rather inconsistentand inefficient use of whale oil on fields to eradicate
leafhoppers; the only other means was by prayer.
However, overseas technology arrived in the late 19th
century and agricultural productivity rapidly improved.
The pesticide industry started to develop with inorganic
substances such as sulphur and copper as well as
natural pyrethrum and nicotine, followed by organic
mercurials. The population had hovered around 30
million from the 17th century to the mid-19th century,
but rapidly increased in the late 19th century, reaching apeak 140 years later in 2008 at 128 million, more than
3.8 times higher. One reason for this has been thegrowth in agricultural productivity. This was the firstparadigm shift.
After the war, pesticides played a role in averting a foodcrisis. Their popularity spread quickly with theappearance of synthetic organic pesticides such as DDT,
BHC and parathion. The pesticide industry thenexperienced significant growth as Japan entered aperiod of rapid economic growth. This was the second
paradigm shift. The pesticide industry became anestablished chemical industry.
The third paradigm shift had a major impact on thepesticide industry. Repeated cases of poisoning fromhighly-mammalian-toxic pesticides and long-term
residual impact on the environment turned pesticides
into a social issue. Laws and regulations were tightened,with safety assessments and environmental impact
assessments becoming mandatory, resulting in theweeding out of a number of older, problematic

pesticides. It was during this time that society branded
pesticides as a threat to food safety; this stigma and theresultant sense of unease has been hard to shift and still
lingers today, despite the problems having been
resolved.
The final paradigm shift is still under way: theappearance of ultra-high-performance pesticides. A
number of formulations have been developed that
achieve the same effect as existing formulations at only
a few grams or a few tens of grams per hectare, such as
the sulfonylurea herbicides that appeared in the 1980s.
Of course, these have no safety of environmental
impact issues.
What will the next paradigm shift be? There have beenchanges in the industry as a result of the developmentof organic pesticides, the appearance of non-chemical
pesticides such as biopesticides, the issue of reduced
effectiveness due to a build-up of resistance and theimpact of the rising spread of genetically modified
produce. However, regardless of what changes may
take place in the future, the hope is that Japanesecompanies will draw on their past successes and keepon contributing to society through the development of
new technologies.
Acknowledgements
In writing this “Systematic Examination of Pesticide
Technology”, the author received advice, guidance andvaluable resources and information from numerous
people, listed below. The author wishes to take thisopportunity to express heartfelt gratitude to thesepeople.
Izuru Yamamoto, Professor Emeritus at Tokyo
University of Agriculture
Isamu Yamaguchi, Toshio Kondo and Kenji Morita, of
the Japan Plant Protection Association
Toshimasa Matsumoto, of the Okochi Memorial
Foundation
Matazaemon Uchida and Tsuyoshi Sakamoto, of theJapan Crop Protection Association
Hitoshi Shimotori, of the Japan Chloropicrin
Manufacturers Association
Mikihiro Ishitobi, of the Iinan Town Board of
Education
Testuya Okabayashi, of Ishihara Sangyo Kaisha, Ltd.
Noriharu Umetsu, of Otsuka Chemical Co., Ltd.
Ryotaro Sato and Hiroshi Kada, of Kyowa Hakko BioCo., Ltd.
Kozo Nagayama, Jun Inoue and Takeshi Nakano, of
Kumiai Chemical Industry Co., Ltd.
Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

103Toshio Shimamura, of Sanda Mosquito Fumigation
Archives
Shigeyoshi Shibuya, of Shibuya Index Research Group
Toshiro Otsubo and Takashi Furukawa, of Sumitomo
Chemical Company, Limited
Hisashi Ueyama, Yoshio Katsuda and Noritada Matsuo,
of Dainihon Jochugiku Co., Ltd.
Kiminori Hirata, Hajime Igarashi, Eiichi Endo andAmaki Kato, of Nissan Chemical Industries, Ltd.

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Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan

Mitsuo Hattori, Takayuki Okamoto, Yoshiyuki Eguchi
and Masashi Mizoguchi, of Nippon Soda Co., Ltd.
Kazuhisa Go, Osamu Ikeda, Yoshiaki Higashino andAkira Nishimura, of Nihon Nohyaku Co., Ltd.
Isao Ueyama, formerly of Bayer CropScience K.K.
Koichi Oguni, of Mitsui Chemicals Agro, Inc.
Masaaki Mitomi, of Meiji Seika Pharma Co., Ltd.
Takeo Yoshimoto, of United Phosphorus Limited,
Japan

Insecticides

Pesticide
Environment

SocialEnvironmentYear
PeriodTaishoJapan's first synthetic
pesticide (Sankyo)

1912 Derris

1908 Lead arsenate

1910

Major technologicaldevelopment(developer)

Formulations with the same mode of action and/or
chemical structure are placed side by side

Major formulation developed by
Japanese manufacturer
Digits indicate date of registration in Japanor overseas (country name)

Major formulation developed byoverseas manufacturer
Digits indicate date of registration in Japan

1910 Nicotine sulphate

1908 Tobacco extract

1902 Spiral mosquito coils

1885 Pyrethrin

World's first mosquito‐
repelling insence(Kincho)1670 Whale oil on leafhoppers

1910 Lime sulphur

Machine oil

1600 Family Traditions on the Killing of Insects

Mushi‐oi, mushi‐okuri prayers

Meiji

1826 Eradicating Rice Pests

1731 Fūki Hōzō‐ki

1697 Nōgyō Zensho

1900

1833 Tempo famine

1782 Tenmei Famine

1732 Kyoho famine

1642 Kanei Famine

Edo

Pesticide Technology Flow Diagram
1600
1700
1800

1921 Chlorpicrin

1920

1930
Showa

1953 Malathion

1952 Parathion

Appearance of low‐toxic
organophosphates(Sumitomo Chemical)

1947BHC

1947DDT

1960

1950 Korean war procurements

1950

1959 NAC

1967 Allethrin

1967 Cartap

1968 BPMC

1966 MIPC

1965MNFA

1962CPAS,DDDS

1980

1972 Benzomate

Appearance of
METI miticides

1995 Pyriproxyfen

2001 Indoxacarb

1990 Milbemectin

Pyflubumide in
development

2008 Cyenopyrafen

2007 Cyflumetofen

2010 Lepimectin2009 Chlorantraniliprole

2007 Flubendiamide

2002 Tolfenpyrad

1999 Acequinocyl

1995 Pyrimidifen

1993 Tebufenpyrad

1991 Fenpyroximate

1991 Pyridaben

1998 Etoxazole

2010 pyrifluquinazon

2006 Flonicamid

2004 Pyridalyl

1998 Pymetrozine

2002 Dinotefuran

2001 Thiacloprid

2010 Imicyafos

2009 Metaflumizone

2001 Methoxyfenozide

1995 Nitenpyram

1995 Acetamiprid

2010

2006 Positive list system

Heisei

1999 Chromafenozide

1995 Tebufenozide

1992 Imidacloprid

1986 Phenothiocarb

1985 Hexythiazox

Appearance of insecticides
with new effects

1983 Buprofezin

1990 Teflubenzuron

1988 Chlorfluazuron

1987 Fluvalinate
1981 Diflubenzuron

Early neonicotinoid(Japan Bayer Agrochem)

Early high‐performancemiticide (Nippon Soda)

First domestically‐
produced IGR(Nippon Nohyaku)

1988 Fenpropathrin

1987 Cycloprothrin

1987 Etofenprox

1985 Permethrin

1983 Fe nvalerate

1991 Alanycarb

1992 Fosthiazate

1986 Bensultap

1983 Carbosulfan

2000

1996 pesticide exports peak at ¥445.5 billion

1991 bubble economy burst

1990

1986 Benfuracarb

1985 Plaza Accord

1981 Thiocyclam

1975 Prothiofos

1972 Isoxathion

1971 Agricultural Chemicals
Control Act amended

1971 dollar shock1970

Early synthetic pyrethroids for
agriculture (Sumitomo Chemical)

1961 Sumithion

195 Drins1948 Agricultural Chemicals Control Act enacted

1945 End of the war

1940

Pesticide Technology Flow Diagram

Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

105

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan

Pesticide
Environment

SocialEnvironmentYear
PeriodFungicides

106

Meiji

1910

Major technologicaldevelopment(developer)

Formulations with the same mode of action and/or
chemical structure are placed side by side

Major formulation developed by
Japanese manufacturer
Digits indicate date of registration in Japanor overseas (country name)

Major formulation developed byoverseas manufacturer
Digits indicate date of registration in Japan

1897 Bordeaux mixture, copper formulations

1826 Eradicating Rice Pests

1731 Fūki Hōzō‐ki

1697 Nōgyō Zensho

1900

1833 Tempo famine

1782 Tenmei Famine

1732 Kyoho famine

1642 Kanei Famine

Edo

Pesticide Technology Flow Diagram
1600
1700
1800
Taisho1921 Organomercury

1920

1930

First domestically‐produced
pesticide (Kumiai Chemical)

Showa

1960

1950 Korean war procurements

1950

Appearance ofstrobilurin fungicides

New Japanesefungicides

2000 Fenoxanil

2000 Diclocymet

2002 Cyflufenamid

2001 Cyazofamid

1998 Azoxystrobin1998 Metominostrobin

1997 Kresoxim‐methyl

Pyriofenone indevelopment

2008 Penthiopyrad2008 Amisulbrom

2007 Benthiavalicarb‐isopropyl

2012 Pyribencarb

2010 Isotianil

2006 Metconazole

2001 Simeconazole

2000 Oxpoconazole

1997 Carpropamid

2010

2006 Positive list system

Heisei2003 Tiadinil

1994 Imibenconazole

1993 Ipconazole

1989 Pefurazoate

1986 Triflumizole

1983 Triadimefon

Appearance of 3rd‐generation NBI‐D rice
blast formulations (Japan Bayer Agro)1977 Triforine

1974 Probenazole

2000

1996 pesticide exports peak at ¥445.5 billion

1991 bubble economy burst

1990

1985 Pyroquilone

1 981 Tricyclazole

1 974 Isoprothiolane

1 970 Fthalide

1969 Tachigaren

Appearance of systemic,
highly curative EBI
formulations

World's first resistance‐inducing rice
blast formulation (Meiji Seika)

Systemic, high‐performance rice blast
treatment(Nippon Nohyaku)

1985 Plaza Accord

1969 Thiophanate; 1971 Thiophanate methyl

1965 EBP; 1967 IBP

1972 Validamycin

1967 Polyoxin

1965 Kasugamycin

1962 Blasticidin S

19801971 Agricultural Chemicals
Control Act amended

1971 dollar shock1970

1959 MAS, Asozin; 1961 MAF, Neoasozin

Early 2nd‐generation MBI‐R(Kureha Chemical)

Systemic World‐Class
Product (Nippon Soda)

Non‐mercurial secret weapon
against rice blast (Kumiai Chemical)

World's first agricultural antibiotic(KAKEN, Kumiai Chemical, Nippon Nohyaku)

1 952 Seresan lime

1948 Agricultural Chemicals Control Act enacted

1945 End of the war

1940

Hiroki OHTA; Historical Development of Pesticides in Japan
Center of the History of Japanese Industrial Technology

107

Pesticide
Environment

SocialEnvironmentYear
PeriodHerbicides and Plant Growth Regulators

1900

Meiji

1826 Eradicating Rice Pests

1833 Tempo famine

1782 Tenmei Famine

1910

Major technologicaldevelopment(developer)

Formulations with the same mode of action and/or
chemical structure are placed side by side

Major formulation developed by
Japanese manufacturer
Digits indicate date of registration in Japanor overseas (country name)

Major formulation developed byoverseas manufacturer
Digits indicate date of registration in Japan1731 Fūki Hōzō‐ki

1697 Nōgyō Zensho

1732 Kyoho famine

1642 Kanei Famine

Edo

Pesticide Technology Flow Diagram
1600
1700
1800
Taisho

1920

1930
Showa

Early PPO inhibitor(Mitsui Chemicals)

Key pesticide for sequential application on rice
(fatty acid synthesis inhibitor)(Kumiai Chemical)
1984 Pretilachlor1996 Cyhalofop‐butyl

2002 Pyriftalid

1997 Bispyribac‐sodium

1996 Pyriminobac‐methyl

2010 Mesotrione

2010 Tefuryltrione

Pyroxasulfone indevelopment

Fenoxasulfone indevelopment

2010 Pyrimisulfan

2007 Penoxsulam

1996 USA: Pyrithiobac sodium2010 Propyrisulfuron

2010 Korea: Metazosulfuron

1997 Eastern Europe: Sulfosulfuron

1995 Halosulfuron

1994 Nicosulfuron

1993 Imazosulfuron

1989 Flazaslfuron

1989 Pyrazosulfuron‐ethyl

1987 Bensulfuron methyl

1982 Chlorsulfuron

1998 Clethodim

2001 Benzobicyclon

2000 Oxaziclomefone

1996 Cumyluron

2000 Fentrazamide

1999 Indanofan

1996 Cafenstrole2007 Pyraclonil

2002 Fluthiacet‐methyl

2001 Oxadiargyl

2000 Flumioxazin

1999 Carfentrazone‐ethyl

1995 Etobenzanide

1989 Quizalofop‐ethyl

1986 Fluazifop‐butyl

1985 Sethoxydim

1980 Alloxydim

1984 Glufosinate

1984 Bialaphos

1987 Benzofenap

1985 Pyrazoxyfen

1986 Bromobutide

2010

2006 Positive list system

Heisei

1999 Pyraflufen‐ethyl

1997 Pentoxazone

1993 Thenylchlor

1989 Pyributicarb

1984 Mefenacet

1980 Glysophate

Appearance of high‐performance PC
herbicides (ALS inhibitor)(Kumiai Chemical)

Appearance of high‐performance SU herbicides(ALS inhibitors)

ACCase inhibitor for grassy weeds(Nippon Soda)

1988 Clomeprop

2000

1996 pesticide exports peak at ¥445.5 billion

1991 bubble economy burst

1990

1986 Dimepiperate

1981 Chlorphthalim

1979 Naproanilide

1985 Plaza Accord

1979 Pyrazolate

1974 Daimuron

1972 Butachlor1971 Molinate

World's first herbicide producedby fermentation(Meiji Seika)

Early 4‐HPPD inhibitor(Sankyo)

Cell division inhibitor(SDS)

1973 Chlomethoxynil
1972 Oxadiazon

1969 Benthiocarb

1963 Gibberellin1965 CNP

1963 NIP

1959 MCPB

1980

1971 Agricultural Chemicals
Control Act amended

1971 dollar shock

1970

Major VLCFAE‐inhibiting herbicide(Japan Bayer Agro)1956 PCP

1953 MCPA

1950 2,4‐PA

World‐class technology with diverse
effects such as seedless grapes(Kyowa Hakko)First grassy‐weed herbicide for ricecultivation

First broadleaf herbicide for ricecultivation

1960

1950 Korean war procurements

1950

1948 Agricultural Chemicals Control Act enacted

1945 End of the war

1940

List of Candidates for Registration as Pesticide Industry Technology
No.

Year ofmanufacture

Manufacturer

FormatNaiki
MatsudaNamba
family;Kurahashiinfamily;storage
Akanahachimangū
ShrineValuable documents containing Japan's
oldest extant recorded pesticide
preparation (of five ingredients including
morning glory seeds and aconitum root)
and its use; hailed as the origin of modern
pesticides in Japan.

KinchoKishu
inFactory,
storage
KinchoThe world's first prototype wooden mouldfor mosquito‐repelling incense, forming thepyrethrum into a spiral shape for a longer
burning time. Subsequent versions are stillcommercially available.

Kishu
Factory,
KinchoMeiji‐era hydraulic machine used to
extrude incense into a noodle shape to bewound into a coil. The oldest and mostvaluable of its type in existence.

Location

Reason for selection

1

Documents
Kokumin Hōjō‐ki
and Family
1600
Traditions on
the Killing of
Insects2

Spiral mosquito
coil wooden
prototype

1895

3

Mechanicalhand‐wound
incenseextruderUsed
late
Kincho19th
century
to 1957

4

Pre‐warmosquito coilposters foroverseas

1930‐
1940

Kantaroin
KinchoUeyama storage

5

Guide toPyrethrum
Cultivation;
Japanese
Pyrethrum

1896

Eiichiroin
KinchoUeyama storage

6'KINCHO'mosquito
repelling rods

1911‐
1914

as
above

in
storage

Kincho7'KINCHO Coil'mosquito coils

1919‐
1925

as
above

in
storage

Kincho8

Woodenincenseextrudersondisplay

Sanda
Mosquito
Fumigation
Archivesondisplay

Chloropicrin is the first synthetic organic
Japan Plant
pesticide industrially produced in Japan inProtection
1921 and is still widely used today. These
Association
oldest product bottles in existence are
Museumhighly valuable.

9

108

Name

Bottledchloropicrin
fumigant

c. 1902c. 1948

unknown

Mitsui
Chemicalsinstorage

Survey Reports on the Systemization of Technologies; No. 18, March 2013
National Museum of Nature and Science, Japan

Valuable Showa‐era posters used forexporting pyrethrum products such as
mosquito coils around the world.
Languages vary by country, including
English, Chinese, Russian and Portuguese.
The earliest manual written to promote
pyrethrum cultivation; it played a part inJapan becoming the top pyrethrum
producer in the world. 24 editions were
published, but only 9 have been kept.
The oldest extant resource of its kind; theworld's first pyrethrum‐containing
mosquito repellent. 20cm in length with a40‐minute burn time.
The world's first mosquito‐repellingincense, made into a spiral shape for alonger burning time. Exported all over theworld, these are widely used today. This is
the oldest extant product of its kind.
Altar incense sticks made into mosquito
repellent; a valuable prototype prior to
Taisho‐era hydraulic mechanization. Initiallymachine‐extruded and then coiled by hand.