Chemistry:Azinphos-methyl

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Azinphos-methyl
Kekulé, skeletal formula of azinphos-methyl
Ball-and-stick model of the azinphos-methyl molecule
Space-filling model of the azinphos-methyl molecule
Names
Preferred IUPAC name
O,O-Dimethyl S-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl] phosphorodithioate
Other names
Guthion, azinphosmethyl, azinphos
Identifiers
3D model (JSmol)
Abbreviations AZM
280476
ChEBI
ChEMBL
ChemSpider
EC Number
  • 201-676-1
KEGG
MeSH Azinphosmethyl
RTECS number
  • TE1925000
UNII
UN number 2811
Properties
C10H12N3O3PS2
Molar mass 317.32 g·mol−1
Appearance Pale, dark orange, translucent crystals
Density 1.44 g cm−3
Melting point 73 °C; 163 °F; 346 K
Boiling point > 200 °C (392 °F; 473 K) (decomposes)
28 mg dm−3
log P 2.466
Vapor pressure 8 x 10−9 mmHg[1]
Hazards
Safety data sheet External MSDS
GHS pictograms GHS06: Toxic GHS09: Environmental hazard[2]
GHS Signal word Danger
H300, H311, H317, H330, H410[2]
P260, P264, P273, P280, P284, P301+310[2]
NFPA 704 (fire diamond)
Flammability code 2: Must be moderately heated or exposed to relatively high ambient temperature before ignition can occur. Flash point between 38 and 93 °C (100 and 200 °F). E.g. diesel fuelHealth code 3: Short exposure could cause serious temporary or residual injury. E.g. chlorine gasReactivity code 1: Normally stable, but can become unstable at elevated temperatures and pressures. E.g. calciumSpecial hazards (white): no codeNFPA 704 four-colored diamond
2
3
1
Flash point 69 °C (156 °F; 342 K)
Lethal dose or concentration (LD, LC):
16 mg/kg (rat, oral)
80 mg/kg (guinea pig, oral)
11 mg/kg (rat, oral)
13 mg/kg (rat, oral)
8.6 mg/kg (mouse, oral)
7 mg/kg (rat, oral)
8 mg/kg (mouse, oral)
10 mg/kg (dog, oral)[3]
69 mg/m3 (rat, 1 hr)
79 mg/m3 (rat, 1 hr)[3]
NIOSH (US health exposure limits):[1]
PEL (Permissible)
 TWA 0.2 mg/m3 [skin]
REL (Recommended)
 TWA 0.2 mg/m3 [skin]
IDLH (Immediate danger)
 10 mg/m3
Related compounds
Chlorpyrifos

Malathion

Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references
Tracking categories (test):

Azinphos-methyl (Guthion) (also spelled azinophos-methyl) is a broad spectrum organophosphate insecticide manufactured by Bayer CropScience, Gowan Co., and Makhteshim Agan.[4] Like other pesticides in this class, it owes its insecticidal properties (and human toxicity) to the fact that it is an acetylcholinesterase inhibitor (the same mechanism is responsible for the toxic effects of the V-series nerve agent chemical weapons). It is classified as an extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002), and is subject to strict reporting requirements by facilities which produce, store, or use it in significant quantities.[5]

History and uses

Azinphos-methyl is a neurotoxin derived from nerve agents developed during World War II.[4] It was first registered in the US in 1959 as an insecticide and is also used as active ingredient in organophosphate (OP) pesticides.[6] It is not registered for consumer or residential use. It has been linked to health problems of farmers who apply it, and the U.S. Environmental Protection Agency (EPA) considered a denial of reregistration, citing, “concern to farm workers, pesticide applicators, and aquatic ecosystems.[4] The use of AZM has been fully banned in the USA since 30 September 2013, ending a phase-out period of twelve years.[7] Azinphos-methyl has been banned in the European Union since 2006[8] and in Turkey since 2013.[6] The New Zealand Environmental Risk Management Authority made a decision to phase out azinphos-methyl over a five-year period starting from 2009.[9] In 2014, it was still used in Australia and partly in New Zealand.[6]

Available forms

AzM is often used as active ingredient in organophosphate pesticides like Guthion, Gusathion (GUS), Gusathion-M, Crysthyron, Cotnion, Cotnion-methyl, Metriltrizotion, Carfene, Bay 9027, Bay 17147, and R-1852. This is why Guthion is often used as a nickname for AzM. Studies have shown that pure AzM is less toxic than GUS. This increased toxicity can be explained by the interactions between the different compounds in the mixture.[6]

Synthesis

The synthesis (in this case, of carbon-14-labelled material) can be seen in figure 1. In the first step, o-nitroaniline (compound 1) is purified through dissolution in hot water-ethanol mixture in relation 2:1. [Activated carbon] is added and the result is filtrated for clarifying. The filtrate is chilled while kept in movement to generate crystals, usually at 4 °C, but if needed it can also be cooled to -10 °C. The crystals are then collected, washed and dried. If it is pure enough it is used for the following steps, which take place at 0 till 5 °C. To produce o-Nitrobenzonitrile-14C (compound 2), the first component o-nitroaniline and (concentrated reagent grade) hydrochloric acid are put together with ice and water. Sodium nitrite, dissolved in water, is added to this thin slurry. After the formation of a pale-yellow solution, which indicates the completion of the diazotization reaction, the pH should be adjusted to 6. After this, the solution is introduced to a mixture of cuprous cyanide and toluene. At room temperature the toluene layer is removed. The aqueous layer is washed and dried and the purified product is isolated by crystallization. The third product is Anthranilamide-14C (compound 3). It is formed out of o-Nitrobenzonitrile-14C, which is first solved in ethanol and hydrazine hydrate. The solvent is heated subsequently, treated in a well-ventilated hood with small periodic charges, smaller than 10 mg, of Raney nickel. Under nitrogen atmosphere the ethanolic solution is clarified and dried. The next step is to form 1,2,3-Benzotriazin-4(3H)-one-14C (compound 4). In water dissolved sodium nitrite is added to anthranilamide and hydrochloric acid in ice water. Because this is a diazotization reaction, the product is pale-yellow again. After this the pH is adjusted to 8,5. This causes the ring closure to form 1,2,3-Benzotriazin-4(3H)-one-14C. This results in a sodium salt slurry that can be treated with hydrochloric acid, what lowers the pH down to 2 till 4. The 1,2,3-Benzotriazin-4(3H)-one-14C is collected, washed and dried. In the following step 1,2,3-Benzotriazin-4-(3-chloromethyl)-one-14C has to be formed. Therefore, 1,2,3-Benzotriazin-4(3H)-one-14C and paraformaldehyde are added to ethylene dichloride and heated to 40 °C. Then thionyl chloride is added and the whole solvent is further heated to 65 °C. After four hours of heating the solution is cooled down to room temperature. Water is added and the solution is neutralized. The ethylene dichloride layer is removed and put together with the result of the washed aqueous layer. The solvent was filtered and dried. The last step is the actual synthesis of Azinphos methyl. Ethylene dichloride is added to the compound resulting from the fifth step, 1,2,3-Benzotriazin-4-(3-chloromethyl)-one-14C. This mixture is heated to 50 °C and sodium bicarbonate and O,O-dimethyl phosphorodithioate sodium salt in water are added. The ethylene dichloride layer is removed, reextracted with ethylene dichloride and purified by filtration. The pure filtrate is dried. This product is once again purified by recrystallization from methanol. What is left is pure azinphos-methyl in form of white crystals.[10]

Absorption

Azinphos-methyl can enter the body via inhalation, ingestion and dermal contact.[11] Ingestion of azinphos-methyl is responsible for the low-dose exposure to a large part of the population, due to their presence as residues in food and drinking water. After ingestion it can be absorbed from the digestive tract.[12] By skin contact, AzM can also enter the body through dermal cells.[11] Absorption through the skin is responsible for the occupational exposure to relatively high doses, mainly in agriculture workers.[12]

Mechanism of toxicity

Once azinphos-methyl is absorbed it can cause neurotoxic effects, like other organophosphate insecticides.[13] At high concentrations AzM itself can be toxic because it can function as an acetylcholinesterase (AChE) inhibitor. But its toxicity is mainly due to the bioactivation by a cytochrome P450 (CYP450)-mediated desulfuration to its phosphate triester or oxon(gutoxon) (see figure 2).[12] Gutoxon can react with a serine hydroxyl group at the active site of the AChE. The active site is then blocked and AChE is inactivated. Under normal circumstances acetylcholinesterase rapidly and efficiently degrades the neurotransmitter acetylcholine (ACh) and thereby terminates the biological activity of acetylcholine. Inhibition of AChE results in an immediate accumulation of free unbound ACh at the ending of all cholinergic nerves, which leads to overstimulation of the nervous system.[13]

Efficacy and side effects

Cholinergic nerves play an important role in the normal function of the central nervous, endocrine, neuromuscular, immunological, and respiratory system. As all cholinergic fibers contain high concentrations of ACh and AChE at their terminals, inhibition of AChE can impair their function. So exposure to azinphosmethyl, whereas it inhibits AChEs, may disturb a lot of important systems and may have various effects.[11][13] In the autonomic nervous system, accumulation of acetylcholine leads to the overstimulation of muscarinic receptors of the parasympathetic nervous system. This can affect exocrine glands (increased salivation, perspiration, lacrimation), the respiratory system (excessive bronchial secretions, tightness of the chest, and wheezing), the gastrointestinal tract (nausea, vomiting, diarrhea), the eyes (miosis, blurred vision) and the cardiovascular system (decrease in blood pressure, and bradycardia). Overstimulation of the nicotinic receptors in the para- or sympathetic nervous system may also cause adverse effects on the cardiovascular system, such as pallor, tachycardia and increased blood pressure. In the somatic nervous system, accumulation of acetylcholine may cause muscle fasciculation, paralysis, cramps, and flaccid or rigid tone. Overstimulation of the nerves in the central nervous system, specifically in the brain, may result in drowsiness, mental confusion and lethargy. More severe effects on the central nervous system include a state of coma without reflexes, cyanosis and depression of the respiratory centers.[14] Thus the inhibition of the enzyme AChE may have a lot of different effects.

Detoxification

To prevent the toxic effects, AzM can be biotransformed. Although AzM (in figure 2 named guthion) can be bioactivated by a cytochrome P450 (CYP450)-mediated desulfuration to its phosphate triester or oxon (gutoxon), it may also be detoxified by CYP itself (reaction 2 in figure 2).[12] CYP450 is namely able to catalyze the oxidative cleavage of the P-S-C bond in AzM to yield DMTP and MMBA. The other pathways of detoxification involves glutathione (GSH)-mediated dealkylation via cleavage of the P-O-CH3 bond, which than forms mono-demethylated AzM and GS-CH3 (reaction 3 in figure 2). This mono-demethylated AzM may be further demethylated to di-demethylated AzM and again GS-CH3 (reaction 4 in figure 2). AzM also may undergo glutathione-catalyzed dearylation which forms DMPDT and glutathione-conjugated mercaptomethyl benzazimide (reaction 5 in figure 2) Gutoxon, the compound that mainly causes AzM to be toxic, can also be detoxified. Gutoxon can again be detoxified with the help of CYP450. CYP450 catalyzes the oxidative cleavage of gutoxon, which than yields DMP and MMBA (reaction 6 in figure 2). Other detoxification pathways of gutoxon are via glutathione-mediated dealkylation, which goes via cleavage of the P-O-CH3 bond to form demethylated AzM and GS-CH3 (reaction 7 in figure 2), and via glutathione-catalyzed dearylation to yield DMTP and glutathione-conjugated mercaptomethyl benzazimide (reaction 8 in figure 2).[15][16][17]

Treatment

There are two different main mechanism of treatment for toxification with AzM. One possibility is to treat the patient before exposure to AzM and the other one is to treat the patient after poisoning. Competitive antagonists of AChE can be used for pre-treatment. They can reduce mortality, which is caused by exposure to AzM.[18] Organophosphorus AChE inhibitors can bind temporally to the catalytic site of the enzyme. Because of this binding, AzM cannot phosphorylate the enzyme anymore and the enzyme is shorter inhibited.[18] The mechanism for treatment after exposure is to block the muscarinic receptor activation. Anticonvulsants are used to control the seizures and oximes are used to reactivate the inhibited AChE.[18] Oximes remove the phosphoryl group bound to the active site of the AChE by binding to it.[19] There are a few oximes that are the most efficacious by AzM poisoning, namely oxime K-27 and physostigmine.[18] These two treatments are also used together, some patients are namely treated with atropine (a competitive antagonist of AChE) and reactivating oximes. When patients are resistant to atropine, the patients can be treated with low doses of anisodamine, a cholinergic and alpha-1 adrenergic antagonist, to achieve a shorter recovery time.[19] Treatment with a combination of different alkaloids or synergistically with atropine is safer than using high antroponine concentrations, which can be toxic. Another possibility is to use membrane bioreactor technology. When this technology is used, no other chemical compounds need to be added.[20] In general, pretreatment is much more efficient than post-treatment.[18]

Indications (biomarkers)

The most common biomarker for exposure to AzM is the inhibition of AChE. Also other esterase enzymes as CaE and BChE are inhibited by AzM. In general AzM exposure can be better detected by AChE inhibition than CaE inhibition. In amphibians and also zebrafish, AChE is a more sensitive biomarker for low AzM exposure-levels.[6] As already mentioned in paragraph 7 “detoxification”, AzM can be metabolized into nontoxic dimethylated alkylphosphates (AP), with the help of CYP450 and glutathione. These APs are: dimethylphosphate (DM), dimethylthiophosphate (DMTP) and dimethyldithiophosphate (DMDTP). These three metabolites may be excreted into the urine and can be used as reliable biomarkers of exposure to AzM. However these metabolites are not specific to AzM, because other organophosphate pesticides might also be metabolized into the three alkylphosphates. The amount of erythrocyte acetylcholinesterase (RBE-AChE) in the blood can also be used as a biomarker of effect for AzM. According to Zavon (1965) RBC-AChE is the best indicator of AChE activity at the nerve synapse, because this closely parallels the level of AChE in the CNS and PNS. A depression of RBC-AChE will correlate with effects due to a rapid depression of AChE enzymes found in other tissues, this is due to the fact that both enzymes can be inhibited by AzM.[13]

Environmental degradation

AzM is very stable when dissolved in acidic, neutral or slightly alkaline water but above pH11 it is rapidly hydrolyzed to anthranilic acid, benzamide, and other chemicals. In natural water-rich environments microorganisms and sunlight cause AzM to break down faster, the half-life is highly variable depending on the condition, from several days to several months. Under the normal conditions, biodegradation and evaporation are the main routes of disappearance, after evaporation AzM has more exposure to UV-light, which causes photodecomposition. With little bioactivity and no exposure to UV light, it can reach half-lives of roughly a year.[21]

Effect on animals

Possible effects on animals are endocrine disruption, reproductive and immune dysfunction and cancer.[22] A remarkable phenomenon that has been demonstrated in numerous animal studies is that repeated exposure to organophosphates causes the mammals to be less susceptible to the toxic effects of the AChE inhibitors, even though cholinesterase activities are not normal. This phenomenon is caused by the excess of agonists (ACh) within the synapse, ultimately leading to a down-regulation of cholinergic receptors. Consequently, a given concentration of ACh within the synapse causes fewer receptors to be available, which then causes a lower response.[13] Studies have shown that the AChEs in fish brains are more prone to organophosphates than amphibian brains. This can be explained by the affinity for AzM and rate of phosphorylation of the enzymes. Frog brain AChE has for example a lower affinity for AzM and a slower rate of phosphorylation than fish brain AChE.[6] The effects on amphibians are “reduced size, notochord bending, abnormal pigmentation, defective gut and gills, swimming in circles, body shortening, and impaired growth”.[6] In sea urchins, specifically the Paracentrotus lividus, AzM modifies the cytoskeleton assembly at high concentrations and can alter the deposition of the skeleton of the larva at low concentrations.[23] In mice, AzM causes weight loss, inhibits brain cholinesterase (ChE) and lowers the food consumption of the mice. A decrease of 45-50% of brain ChE is lethal in mice.[24] Also in earthworms and rats, AzM decreases AChE activity.[25][26]

In order to prevent stretching it too long, you may take a look at the following animal studies and their references:

  • Zebrafish[27]
  • Amphipod Hyalella curvispina, the earthworm Eisenia Andrei[28]
  • Tilapia Oreochromis mossambicus[29]
  • Frog Pseudacris regilla and salamander Ambystoma gracile[30]
  • Toad Rhinella arenarum[31]
  • Rainbow trout oncorhynchus mykiss[32]
  • Comparison between the toad Rhinella arenarum and the rainbow trout oncorhynchus mykiss[33]
  • Comparison between fish Mysidopsis bahia and Cyprinodon variegatus[34]

See also

References

  1. ↑ 1.0 1.1 NIOSH Pocket Guide to Chemical Hazards. "#0681". National Institute for Occupational Safety and Health (NIOSH). https://www.cdc.gov/niosh/npg/npgd0681.html. 
  2. ↑ 2.0 2.1 2.2 Sigma-Aldrich Co., Azinphos-methyl. Retrieved on 2022-03-17.
  3. ↑ 3.0 3.1 "Azinphos-methyl". Immediately Dangerous to Life and Health Concentrations (IDLH). National Institute for Occupational Safety and Health (NIOSH). https://www.cdc.gov/niosh/idlh/86500.html. 
  4. ↑ 4.0 4.1 4.2 EPA's Interrum Reregistration Eligibility Decision for Azinphos-methyl.. 
  5. ↑ 40 C.F.R.: Appendix A to Part 355—The List of Extremely Hazardous Substances and Their Threshold Planning Quantities (July 1, 2008 ed.). Government Printing Office. http://edocket.access.gpo.gov/cfr_2008/julqtr/pdf/40cfr355AppA.pdf. Retrieved October 29, 2011. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 Gungordu,A; Uckun, M (2014). Comparative assessment of in vitro and in vivo toxicity of azinphos methyl and its commercial formulation.. Environ Toxicol. 
  7. ↑ "EPA's Azinphos-methyl Page". http://www.epa.gov/pesticides/reregistration/azm/phaseout_fs.htm.. 
  8. ↑ Scott, Alex (August 4, 2008). "Europe Rejects Appeal for Use of Azinphos-methyl Pesticide". Chemical Week. http://www.chemweek.com/envirotech/regulatory/13435.html. 
  9. ↑ ERMA - press release
  10. ↑ White, E.R. (1972). "Synthesis of carbon-14-benzenoidring-labeled Guthion.". Journal of Agricultural and Food Chemistry 20 (6): 1184–1186. doi:10.1021/jf60184a037. 
  11. ↑ 11.0 11.1 11.2 Roney.N., C.S.; Stevens. Y.W.; Quinones-Rivera.A.; Wohlers.D; Citra.M. (2008). Toxicological Profile For Guthion.. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. 
  12. ↑ 12.0 12.1 12.2 12.3 Buratti, F.M. (2003). "CYP-specific bioactivation of four organophosphorothioate pesticides by human liver microsomes.". Toxicol Appl Pharmacol 186 (3): 143–154. doi:10.1016/s0041-008x(02)00027-3. PMID 12620367. 
  13. ↑ 13.0 13.1 13.2 13.3 13.4 Carrier, G.; R.C. Brunet (1999). "A toxicokinetic model to assess the risk of azinphosmethyl exposure in humans through measures of urinary elimination of alkylphosphates.". Toxicol Sci 47 (1): 23–32. doi:10.1093/toxsci/47.1.23. PMID 10048150. 
  14. ↑ Klaassen CD; A.M., Doull J (1995). Toxic effects of pesticides, in Casarett and Doull's toxicology: The basic science of poisons.. McGraw-Hill Companies: New York.. pp. 643–689. 
  15. ↑ Levine, B.S.; S.D. Murphy (1977). "Effect of piperonyl butoxide on the metabolism of dimethyl and diethyl phosphorothionate insecticides.". Toxicol Appl Pharmacol 40 (3): 393–406. doi:10.1016/0041-008x(77)90067-9. PMID 882978. 
  16. ↑ Sultatos, L.G.; L. Woods (1988). "The role of glutathione in the detoxification of the insecticides methyl parathion and azinphos-methyl in the mouse.". Toxicol Appl Pharmacol 96 (1): 168–174. doi:10.1016/0041-008x(88)90259-1. PMID 3188022. 
  17. ↑ Motoyama N, D.W. (1972). The in vitro metabolism of azinphosmethyl by mouse liver.. Pesticide Biochemistry and Physiology. pp. 170–177. 
  18. ↑ 18.0 18.1 18.2 18.3 18.4 Petroianu, G.A (2014). Reversible cholinesterase inhibitors as pre-treatment for exposure to organophosphates: assessment using azinphos-methyl.. J Appl Toxicol. 
  19. ↑ 19.0 19.1 Iyer, R.; B. Iken; A. Leon (2015). "Developments in alternative treatments for organophosphate poisoning.". Toxicol Lett 233 (2): 200–206. doi:10.1016/j.toxlet.2015.01.007. PMID 25595305. 
  20. ↑ Ghoshdastidar, A.J. (2012). "Membrane bioreactor treatment of commonly used organophosphate pesticides.". J Environ Sci Health B 47 (7): 742–750. doi:10.1080/03601234.2012.669334. PMID 22560038. 
  21. ↑ Wauchope, R.D (1992). "The SCS/ARS/CES pesticide properties database for environmental decision-making.". Rev Environ Contam Toxicol 123: 1–155. PMID 1732992. 
  22. ↑ Cortes-Eslava, J (2013). "The role of plant metabolism in the mutagenic and cytotoxic effects of four organophosphorus insecticides in Salmonella typhimurium and in human cell lines.". Chemosphere 92 (9): 1117–1125. doi:10.1016/j.chemosphere.2013.01.058. PMID 23434078. 
  23. ↑ Buono, S. (2012). "Toxic effects of pentachlorophenol, azinphos-methyl and chlorpyrifos on the development of Paracentrotus lividus embryos.". Ecotoxicology 21 (3): 688–697. doi:10.1007/s10646-011-0827-6. PMID 22101977. 
  24. ↑ Meyers, S.M.; J.O. Wolff (1994). "Comparative toxicity of azinphos-methyl to house mice, laboratory mice, deer mice, and gray-tailed voles.". Archives of Environmental Contamination and Toxicology 26 (4): 478–482. doi:10.1007/bf00214150. PMID 8198427. 
  25. ↑ Jordaan, M.; S. Reinecke; A. Reinecke (2012). "Acute and sublethal effects of sequential exposure to the pesticide azinphos-methyl on juvenile earthworms (Eisenia andrei).". Ecotoxicology 21 (3): 649–661. doi:10.1007/s10646-011-0821-z. PMID 22086221. 
  26. ↑ Kimmerle, G. (1976). "Subchronic inhalation toxicity of azinphos-methyl in rats.". Archives of Toxicology 35 (2): 83–89. doi:10.1007/bf00372761. PMID 947316. 
  27. ↑ Kluver, N. (2009). "Toxicogenomic response of azinphos-methyl treated zebrafish embryos and implication for the development of predictive models for chronic (fish) toxicity.". Toxicology Letters 189: 94. doi:10.1016/j.toxlet.2009.06.284. 
  28. ↑ Jordaan, M.S.; S.A. Reinecke; A.J. Reinecke (2012). "Acute and sublethal effects of sequential exposure to the pesticide azinphos-methyl on juvenile earthworms (Eisenia andrei).". Ecotoxicology 21 (3): 649–661. doi:10.1007/s10646-011-0821-z. PMID 22086221. 
  29. ↑ Jordaan, M.S.; S.A. Reinecke; A.J. Reinecke (2013). "Biomarker responses and morphological effects in juvenile tilapia Oreochromis mossambicus following sequential exposure to the organophosphate azinphos-methyl.". Aquat Toxicol 144–145: 133–140. doi:10.1016/j.aquatox.2013.10.007. PMID 24177216. 
  30. ↑ Nebeker, A.V. (1998). "Impact of guthion on survival and growth of the frog Pseudacris regilla and the salamanders Ambystoma gracile and Ambystoma maculatum.". Arch Environ Contam Toxicol 35 (1): 48–51. doi:10.1007/s002449900347. PMID 9601918. 
  31. ↑ Ferrari, A (2011). "Effects of azinphos methyl and carbaryl on Rhinella arenarum larvae esterases and antioxidant enzymes.". Comp Biochem Physiol C 153 (1): 34–39. doi:10.1016/j.cbpc.2010.08.003. PMID 20709623. 
  32. ↑ Ferrari, A.; A. Venturino; A.M. Pechen de D'Angelo (2007). "Muscular and brain cholinesterase sensitivities to azinphos methyl and carbaryl in the juvenile rainbow trout Oncorhynchus mykiss.". Comp Biochem Physiol C 146 (3): 308–313. doi:10.1016/j.cbpc.2007.04.002. PMID 17509940. 
  33. ↑ Ferrari, A. (2004). "Different susceptibility of two aquatic vertebrates (Oncorhynchus mykiss and Bufo arenarum) to azinphos methyl and carbaryl.". Comp Biochem Physiol C 139 (4): 239–243. doi:10.1016/j.cca.2004.11.006. PMID 15683833. 
  34. ↑ Morton, M.G (1997). "Acute and chronic toxicity of azinphos-methyl to two estuarine species, Mysidopsis bahia and Cyprinodon variegatus.". Arch Environ Contam Toxicol 32 (4): 436–441. doi:10.1007/s002449900210. PMID 9175513. 

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