Hello! Welcome to this blog posting on Formamidines. My name is Stacey, and I picked this pesticide based on a complete lack of knowledge over it. I chose this topic at random in the hopes of learning more and sharing what I was able to find. Please be advised; the media in the content below are derived from both multimedia and published literature. Figures with numeric representation are those found in the corresponding literature, those with alphabetic representation are derived from multimedia. Enjoy the read below!
Formamidines
- Source (link here for Reference #1)
- Derived from formic acid
- Synthetic compound
- Includes amitraz and chlordimeform
- Amitraz is used as an insecticide and pesticide
- Chlordimeform was used as a pesticide, but has been removed from US markets after demonstrating carcinogenic potential (2)
3D chemical model of Formamidine (1)
- Includes amitraz and chlordimeform
- Biotransformation (link here for Reference #2)
- Toxicities associated with formamidines – specifically amitraz – are typically due to exposure by ingestion, inhalation, or dermal contact. Amitraz is classified as follows;
- Class II – moderately toxic if absorbed through skin
- Class III – slightly toxic if swallowed or inhaled
- Class IV – slightly irritating to the eyes, but not a dermal irritant or sensitizer
- Amitraz is metabolized rapidly to produce 2,4-dimethyl formanilide and active metabolite N’-(2,4-dimethylphenyl)-N-methyl-formamidine
- This rapid metabolism results in a rapid onset of symptoms
- Toxicities associated with formamidines – specifically amitraz – are typically due to exposure by ingestion, inhalation, or dermal contact. Amitraz is classified as follows;
(a)
- Toxicokinetics (2)
- ADME:
- Absorbed through skin/orally digested
- Distributed in the blood stream
- Metabolized by the kidneys
- Excreted through urine
- ADME:
- Carcinogenicity (2)
- Formamidines have demonstrated carcinogenic potential in animal species (such as mice)
- shown an increase in risk for lymphoreticular malignancies and liver adenoma/carcinomas
- Amitraz is classified as a possible carcinogen in humans
- risks of genotoxicity, oxidative stress, cell death, immunotoxicity, endocrine disruption, and developmental toxicities are currently under investigation by the FDA
- Chloridimeform has been classified as a carcinogen in humans and animals since 1977
- Formamidines have demonstrated carcinogenic potential in animal species (such as mice)
- Mechanism of Action (2)
- Agonist of a2-adrenergic receptors
- Activation of these receptors has significant systemic fallout
- Inhibition of histamine H1 receptors
- Inhibition of prostaglandin snythase
- Inhibition of monoamine oxidase
- Inhibition of calcium ion channel activation
- Inhibition of cAMP signaling via adenylyl cyclase
- Activation of these receptors has significant systemic fallout
- Agonist of a2-adrenergic receptors
- Target Organ(s) (2)
- Endocrine system (see GIF below)
(b; endocrine system)
- Signs and Symptoms of toxicity (acute and chronic) (2)
- Amitraz can cross the blood brain barrier, affecting both central and peripheral nervous systems
- Acute toxicity can cause irritation to the eyes, skin, nose, and throat
- a2-adrenergic receptor activation is depicted by the Toxic Effects Image (below) and can cause:
- Hypotension
- Bradycardia
- Miosis
- Mydriasis
- Altered mental status
- Hypothermia
- Convulsion
- Polyuria
- Gastrointestinal hypomotility
- Hyperglycemia
- a2-adrenergic receptor activation is depicted by the Toxic Effects Image (below) and can cause:
- Chronic toxicity can cause MAO inhibition
- Motor activity alterations
- Aggressiveness
- Neurodevelopmental toxicity
- Central nervous system depression has been associated with both acute and chronic exposure and is dose-dependent
- Sleepiness, drowsiness, or complete loss of consciousness
Toxic Effects (2)
- Treatments for acute and chronic (including monitoring or testing) (2)
- Testing for formamidine poisoning is typically symptom directed
- There are no supportive treatments specifically for formamidine poisoning
- The supportive care includes monitoring respirations, cardiovascular function, and CNS function
- Contaminated clothing should be removed
- Skin should be washed with soap and water
- Activated charcoal has been deemed safe for use with acute amitraz poisoning, but the clinical benefit is yet to be determined
- Chronic toxicity is treated via symptom management unique to each patients’ presentation
-
- Biomarkers (3)(image (e))
- Altered sensorium, miosis, and bradycardia are the three most common markers of formamidine poisoning
- These are easily confused with organophosphate poisoning
- Clinical indications such as hyperglycemia, hypothermia, and constipation (reduced GI motility) also support formamidine poisoning over organophosphate poisoning
- The presence of salivation, lacrimation, perspiration, and diarrhea would indicate organophosphate toxicity
- Altered sensorium, miosis, and bradycardia are the three most common markers of formamidine poisoning
(e)
- Genetic susceptibility or heritable traits (2)
- Mothers exposed to amitraz have reported toxicities in their offspring
- Developmental neurotoxicity has been reported
- Includes altered behavior, neurochemistry, neurophysiology, and gross dysmorphology of the central nervous system
- Developmental neurotoxicity has been reported
- Mothers exposed to amitraz have reported toxicities in their offspring
- Historical or unique exposures (Link here for Reference #3)
- Amitraz poisoning is complicated to identify, as the signs and symptoms are consistent with organophosphate poisoning unless specific key complaints are noted
- A semi-recent systemic review identified only 310 cases out of a wide variety of case studies
- Essentiality and deficiency
- The use of amitraz is not essential
- Amitraz deficiency is actually a good thing
(c)
Additional information can be found in this summary video below. This video specifically highlights the effects Amitraz can have on pets (d)
Information References including images:
- National Center for Biotechnology Information. PubChem Compound Summary for CID 68047, Formamidine. https://pubchem.ncbi.nlm.nih.gov/compound/Formamidine. Accessed May 17, 2022.
- Javier del Pino, Paula Viviana Moyano-Cires, Maria Jose Anadon, María Jesús Díaz, Margarita Lobo, Miguel Andrés Capo, and María Teresa Frejo
Molecular Mechanisms of Amitraz Mammalian Toxicity: A Comprehensive Review of Existing Data Chemical Research in Toxicology 2015 28 (6), 1073-1094 DOI: 10.1021/tx500534x - Dhooria S, Agarwal R. Amitraz, an underrecognized poison: A systematic review. Indian J Med Res. 2016;144(3):348-358. doi:10.4103/0971-5916.198723
Multimedia References:
(a) https://giphy.com/gifs/reaction-help-leave-t7VHWISa7iN0s. Accessed 17MAY2022
(b) https://giphy.com/gifs/science-biology-labxchange-eCNcFbev3ydP2Vf9SI. Accessed 17MAY2022
(c) http://appleshinenyc.com/too-much-of-a-good-thing-is-bad/. Accessed 17MAY2022
(d) https://www.youtube.com/watch?v=YpS6jLKrFMs. Accessed 18JULY2022
(e) https://www.roshreview.com/blog/ep-11-cholinergic-toxidrome-svc-syndrome-metabolic-acidosis-rosc-acrocyanosis-mushroom-poisoning/. Accessed 17MAY2022