Clothianidin

Clothianidin
IUPAC name 1-(2-Chlor-1,3-thiazol-5-ylmethyl)-3-methyl-2-nitroguanidine
Identifiers
CAS number	210880-92-5 (E) N
PubChem	213027 (E)
ChemSpider	184723 (E) Y
KEGG	C18508 Y
MeSH	Clothianidin
ChEBI	CHEBI:39178 N
ChEMBL	CHEMBL259727 Y
Beilstein Reference	9196326, 8620724 (E)
Jmol-3D images	Image 1 Image 2
SMILES CNC(Nn(:o):o)=NCc1cnc(Cl)s1 CNC(N[N+]([O-])=O)=NCC1=CN=C(Cl)S1
InChI InChI=1S/C6H8ClN5O2S/c1-8-6(11-12(13)14)10-3-4-2-9-5(7)15-4/h2H,3H2,1H3,(H2,8,10,11) Y Key: PGOOBECODWQEAB-UHFFFAOYSA-N Y InChI=1/C6H8ClN5O2S/c1-8-6(11-12(13)14)10-3-4-2-9-5(7)15-4/h2H,3H2,1H3,(H2,8,10,11) Key: PGOOBECODWQEAB-UHFFFAOYAT
Properties
Molecular formula	C6H8ClN5O2S
Molar mass	249.68 g mol−1
Exact mass	249.008722922 g mol-1
Appearance	Colorless crystals
Density	1.61 g cm-3
Melting point	179 °C, 452 K, 354 °F
Solubility in water	327 mg dm-3 (at 20 °C)
log P	0.732
Acidity (pKa)	7.472
Basicity (pKb)	6.525
N (verify) (what is: Y/N?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Clothianidin is an insecticide developed by Takeda Chemical Industries and Bayer AG. Similar to thiamethoxam and imidacloprid, it is a neonicotinoid. Neonicotinoids are a class of insecticides that are chemically similar to nicotine, which has been used as a pesticide since the late 1700s. As with nicotine, clothianidin and other neonicotinoids act on the central nervous system of insects. Although nicotine has been used as a pesticide for over 200 years it degraded too rapidly in the environment and lacked the selectivity to be very useful in large-scale agricultural situations. However, in order to address this problem, the neonicotinoids (chloronicotinyl insecticides) were developed as a substitute of nicotine, targeting the same receptor site (AChR) and activating post-synaptic acetylcholine receptors but not inhibiting AChE. Clothianidin, like other neonicotinoids, is an agonist of acetylcholine, the neurotransmitter that stimulates the nAChR. The advantage of clothianidin and other neonicotinoids over nicotine is that they are less likely to break down in the environment. Clothianidin is an alternative to organophosphate, carbamate, and pyrethroid pesticides. It poses lower risks to mammals, including humans, when compared to organophosphates and carbamates. It also plays a key role helping to prevent the build up in insect pests of resistance to organophosphate and pyrethroid pesticides, which is a growing problem in parts of Europe.

Authorized Uses

Clothianidin is authorized for spray, dust, soil drench (for uptake via plant roots), injectable liquid (into tree limbs and trunks, sugar cane stalks etc), and seed treatment uses, in which clothianidin coats seeds that take up the pesticide via the roots as the plant grows. The chemical may be used to protect plants against a wide variety of agricultural pests in many countries, of which the following are mentioned in citable English-language sources: Australia, Austria, Belgium, Bulgaria, Canada, Czech Republic, Denmark, Estonia, France, Finland, Germany, Greece, Hungary, Italy, Ireland, Japan, Korea, Lithuania, Netherlands, New Zealand, Poland, Portugal, Serbia, Slovakia, Slovenia, Spain, UK, and the United States. Seed treatment uses of clothianidin, corn in particular, have been revoked or suspended in Germany, Italy and Slovenia. The suspensions are reflective of E.U. pesticide law and are generally associated with acute poisoning of bees from pesticide dust being blown off of treated seeds, especially corn, and onto nearby farms where bees were performing pollinator services.

Maximum Residue Limits Allowed on Food

Permissible amounts of clothianidin residue on food and animal feed vary from crop to crop and nation to nation. However, regulatory authorities around the globe emphasize that when used according to the label instructions, clothianidin residues on food are not expected to exceed safe levels (as defined by each nation’s laws and regulations).

Toxicity

Regulatory authorities describe the toxicological database for clothianidin as “extensive,” and many studies have been reviewed to support registrations around the globe for this chemical. Laboratory and field testing revealed that clothianidin shows relatively low toxicity to many test species but is highly or very highly toxic to others. Toxicity also varies depending on whether the exposure occurs on a short-term (acute) or long-term (chronic) basis.

Effects on Humans

Using laboratory test animals as surrogates for humans and dosages much higher than are expected from exposure related to actual use, rats showed low short-term oral, dermal, and inhalation toxicity to clothianidin. For mice, acute oral toxicity was moderate to high. Rabbits showed little to no skin or eye irritation when exposed to clothianidin, and the skin of guinea pigs was not sensitized by it. When extrapolated to humans, these results suggest that clothianidin is moderately toxic through oral exposure, but toxicity is low through skin contact or inhalation. While clothianidin may cause slight eye irritation, it is not expected to be a skin sensitizer or irritant. Clothianidin does not damage genetic material nor is there evidence that it causes cancer in rats or mice; it is unlikely to be a human carcinogen.

Effects on Animals

Clothianidin is practically non-toxic to test bird species that were fed relatively large doses of the chemical on an acute basis. But Bobwhite quail eggshell thickness was affected when the test birds were given a diet consisting of relatively large amounts of clothianidin-treated seeds. The chemical is moderately toxic in the short-term to mammals that are eat it, and long-term ingestion may result in reproductive and/or developmental effects.

Laboratory testing also demonstrates that clothianidin is highly or very highly toxic to mysid shrimps and chironomids, as well as honey bees that come into contact with it. The Australian Pesticides and Veterinary Medicines Authority notes that clothianidin ranks “among the most highly acutely toxic insecticides to bees” through contact and oral exposure. Since clothianidin is a systemic pesticide that is taken up by the plant, there is also potential for long-term effects to bees and other pollinators from clothianidin residue in pollen and nectar. In addition to potential effects on worker bees, there are also concerns about lethal and/or sub-lethal effects in the larvae and reproductive effects in the queen from long-term exposure. However, the available data does not show conclusively that these potential long-term effects actually happen when clothianidin products are used at authorized rates.

Environmental Persistence

Laboratory and field testing shows that clothianidin is persistent and mobile in the environment, stable to hydrolysis, and has potential to leach to ground water and be transported via runoff to surface water bodies. Worst-case scenario estimates indicate that if applied at the maximum rate repeatedly over years, clothianidin has the potential to accumulate in the top 15 cm of soil. However, the Australian pesticide authority’s review of rotational crop studies determined that clothianidin generally is not taken up by crops sown in fields where treated corn seeds were planted, even when the test corn seeds were coated with an intentionally large amount of the chemical (2 mg/seed vs the authorized maximum application rate of 1.25 mg).

Data Gaps

North American and European pesticide regulatory authorities have identified specific data gaps and uncertainties for which clothianidin manufacturers must provide data. Studies required of the manufacturers will further investigate clothianidin’s:

• environmental persistence in soil and subsequent uptake in rotational crops
• availability in pollen and nectar
• long-term effects on honey bees and other pollinators
• developmental immunotoxicity
• effects on aerobic aquatic metabolism
• ability to leach from treated seeds and
• acute toxicity to freshwater invertebrates

The challenges associated with studying potential long-term effects of pesticides on honey bee colonies is well documented and includes the inability to adequately monitor individual bee health or extrapolate effects on individuals to whole hives. Behavior changes between bees and/or colonies in laboratory or field test conditions versus natural environments also add to the challenges. Studies submitted by Bayer AG to USEPA have provided some useful information about clothianidin's potential long-term effects on honey bees but outstanding questions remain. USEPA's analysis of nine pollinator field studies submitted concluded that three were invalid, so EPA did not use the data they provided in making its regulatory decision for clothianidin. EPA classified the remainder as supplemental, generally because Bayer AG conducted the studies without EPA first approving the protocols. Supplemental studies are ones that don't definitively answer uncertainties but still provide some data that might be useful in characterizing risk. Indicative of the rapid advance of regulators' understanding of pollinator science, USEPA first accepted one of the studies as sound science in 2007, then reclassified it as invalid in November 2010 only to reclassify it as supplemental one month later. The changes in EPA's classification of this study have no effect on the regulatory status for clothianidin in the U.S. because the study does not provide data with which EPA can legally justify altering its 2003 registration decision. An international group of pesticide regulators, researchers, industry representatives, and beekeepers is working to develop a study protocol that will definitively answer remaining questions about the potential long-term effects on bee colonies and other pollinators.

Risk Mitigation

Once laboratory and field data identify hazards associated with a chemical, regulatory authorities take different approaches to mitigate those hazards and bring the risks down to acceptable levels, as defined by each nation’s laws and regulations. For clothianidin, hazard mitigation includes establishing the maximum amount of the chemical that can be used (e.g. kg/acre or mg/seed), requiring buffer zones around treated fields to protect water supplies, and prohibiting the use of low-technology seed treatment methods or equipment that can send clouds of clothianidin dust or spray up into the air during seeding operations.

Clothianidin users are also required to monitor the weather and not use the chemical or seeds treated with it on windy days or when rain is forecast. Workers are protected from clothianidin exposure through requirements for personal protective gear, such as long-sleeve shirts, gloves, long pants, boots, and face mask or respirators as appropriate. To reduce the possibility that birds and small mammals might eat treated seeds, users are required to ensure that soil covers planted seeds and that any spilled seed is picked up.

Honeybees and other pollinators are particularly sensitive to clothianidin, as evidenced by the results of laboratory and field toxicity testing and demonstrated in acute poisoning incidents in France and Germany in 2008, and in Canada in 2010 associated with the planting of corn seeds treated with clothianidin. To reduce the risk to pollinators from acute exposure to clothianidin sprays and dust, including dust that results from planting treated seeds, label instructions prohibit the use of these products when crops or weeds are in bloom and pollinators are nearby. The use of sticking agents to reduce dust from treated seeds are also required or are standard practice in many countries, and Germany has stipulated that certain older, air-driven seeding equipment may not be used in corn seed planting operations.

2008 German bee-kill incident

Main article: 2008 German Beekill Incident

In July 2008, German authorities reported that more than 11,000 beehives were affected and millions of bees were killed in an agricultural chemical poisoning incident from late April to early May that year. Affected beekeepers reported 50 to 100 percent of their hives lost after pneumatic equipment used to plant corn seed blew clouds of pesticide dust into the air, which was then pushed by the wind onto neighboring canola fields in which managed bees were performing pollinator services. Laboratory testing at the Julius Kühn Institute demonstrated that 99% of the bees sampled tested positive for high levels of the neonicotinoid pesticide clothianidin, which is highly toxic to honey bees on an acute contact basis (i.e. direct contact with too much of the chemical can quickly kill bees). In providing background on the incident, the German Federal Office of Consumer Protection and Food Safety (BVL) noted that clothianidin had been authorized as a seed treatment on corn since 2004, and that “bee damage of this kind in conjunction with this product has not been observed in Germany” prior to the 2008 incident.

Possible contamination issues

A two year peer reviewed study published in 2012 showed the presence of two neonicotinoid insecticides, clothianidin and thiamethoxam, in bees found dead in and around hives situated near agricultural fields. Other bees at the hives exhibited tremors, uncoordinated movement and convulsions, all signs of insecticide poisoning. The insecticides were also consistently found at low levels in soil -- up to two years after treated seed was planted -- on nearby dandelion flowers and in corn pollen gathered by the bees. Insecticide-treated seeds are covered with a sticky substance to control its release into the environment, however they are then coated with talc to facilitate machine planting and the talc may be released into the environment in large amounts. The study found that the exhausted talc showed extremely high levels of the insecticides -- up to about 700,000 times the lethal contact dose for a bee. According to the research, "Whatever was on the seed was being exhausted into the environment. This material is so concentrated that even small amounts landing on flowering plants around a field can kill foragers or be transported to the hive in contaminated pollen. This might be why we found these insecticides in pollen that the bees had collected and brought back to their hives." Tests also showed that the corn pollen that bees were bringing back to hives tested positive for neonicotinoids at levels roughly below 100 parts per billion, an amount not acutely toxic, but enough to kill bees if sufficient amounts are consumed.