Pesticide Blog Entry: Picaridin

Introduction:

Picaridin is a compound that is used to repel a variety of arthropods. Picaridin, also marketed under the name of Saltidin and Icaridin, was developed by Bayer as an alternative to DEET (1).

Figure 1: Structure of Picaridin, CAS name: 1-piperidinecarboxylic acid, 2-(2-hydroxy-ethyl), 1-methylpropylester, INCI name: hydroxy ethyl isobutyl piperidine carbamate (1).

Picaridin was specifically designed to affect the specific olfactory receptors of an arthropod in order to repel them. This compound is not found naturally, and was molecularly designed to have a maximum repellent effect (1). After health concerns about DEET were raised, Picaridin was developed as a safer alternative. After studying its safety and efficacy, it was determined that Picaridin was the best compromise of qualities in an ideal repellent (1). It was found to have the best performance in terms of efficacy (2), as well the desired attributes of safety (1). In December 2000, The WHO Pesticide Evaluation Scheme (WHOPES) working group meeting recommended Picaridin as the repellent of choice for Malaria prevention (3). Picaridin is available in many different commercial products marketed as a family safe option for insect repellent like the product below:

Figure 2: OFF Family Care Insect Repellent containing Picaridin as the main ingredient (4)

 

Picaridin repellent has been proven to effective against mosquitoes, ticks, flies, gnats, chiggers, biting midges, fleas, and sand flies (1). Because of its broad spectrum application, it plays an important role in the control of vector-borne diseases.

 

Mechanism of Action:

 

General repellents act by targeting olfactory receptor organs of insects. Electrophysiological studies on the olfactory receptor organs of insects reveal that certain cell types, which are not involved in the perception of attractive odorants, respond to Picaridin (1). When Picaridin is added together with an attractant, a new input is activated in the insects’ nervous system, which adds to the input from the other receptors activated by the attractant (1). The new overall pattern is different from what is elicited from the attractant alone, and so the insect is no longer able to detect the attractant (the person using the repellent) (1).

Figure 3: How picaridin works to mask the scent of the attractant (person) from the mosquito (9)

Picaridin specifically induced a rapid increase in the concentration of inositol triphosphate (IP3) in a dose-dependent and tissue-specific manner and other secondary messenger systems were not affected (1). This suggests that Picaridin may act via subsets of G-protein-coupled receptors (GPCRs) in sensory neurons (1). The repellent effect of the active substance starts immediately after application on the skin and develops full performance within a few minutes (2).

 

Toxicokinetics:

 

There are a few different ways to administer Picaridin:

  • Dermal application (only approved method)
  • Oral (Used to study toxicity)
  • Parenteral (Used to study toxicity)

Picaridin is applied dermally as either creams, wipes, sprays, or aerosols. Picaridin has a very limited dermal absorption (5), but is metabolized as follows:

Figure 4: Proposed metabolism of Picaridin (Icaridin) in mice (1)

Based on the available data on Picaridin, the patterns of metabolism, absorption, distribution, and excretion are similar in humans and rats (6). The kinetic studies in humans and rats clearly show there is no qualitative difference between Picaridin metabolism in rats and humans (1).  In humans, Picaridin is absorbed by the skin, and is metabolized via hydroxylation and glucuronidation, and then excreted in urine (5).

 

Toxicity:

The toxicity profile of picaridin is unremarkable. Acute toxicity is very low, regardless of route of administration (1). Picaridin is not irritating to the skin, and only slightly irritating to the eyes (1). Systemic accumulation is less likely to occur in humans because skin permeability is low, retention in the epidermis of the skin was very low, and excretion was rapid (1). At a comparable dose, humans would be expected to have extremely low systemic Picaridin levels compared to rats, and experience no toxicity, which means humans are better protected than rats due to low skin permeability and retention, rapid excretion, and a minimum of systemic accumulation (1).

 

  • Effective against a broad spectrum of insects, but is not toxic to insects
    • Acts as a repellent instead of as a pesticide
  • Acute toxicity in humans is low
    • Is not well absorbed through the skin, which is main route of exposure
    • Even through other routes of exposure, not that toxic to humans
  • No evidence of the following toxicities (1):
    • Carcinogenicity
    • Genotoxicity
    • Teratogenicity
    • Reproductive Toxicity
    • Neurotoxicity
    • Oncogenicity
  • Because Picaridin is rapidly excreted, there is not a concern for cumulative or chronic toxicity
  • Looking at the data of unintentional ingestions of Picaridin, none of the incidents were major, and only had minor toxicity associated with the few incidents (7):
    • Symptoms:
      • Ocular irritation/pain
      • Vomiting
      • Conjunctivitis
      • Oral irritation
    • Treatment
      •  Dilution
      • Irrigation
      • Wash
    • Incidents were generally managed outside of a healthcare facility because they were minor
  • If used as directed, Picaridin and Picaridin-containing formulations are deemed to be safe and effective (8).

 

Historical:

There have been no major adverse events related to Picaridin toxicity. In addition, Picaridin plays a major role in prevention of vector-borne diseases like Malaria. Picaridin is an important public health product because of its efficacy and low toxicity that make it useful for preventing outbreaks, as most people can use it without any adverse health effects.

Resources:

  1. G.K. (Ghona) Sangha, “Chapter 101 – Toxicology and Safety Evaluation of the New Insect Repellent Picaridin (Saltidin)”, Editor(s): Robert Krieger, Hayes’ Handbook of Pesticide Toxicology (Third Edition), Academic Press, 2010, Pages 2219-2230, ISBN 9780123743671
  2. Boeckh J., Breer H., Geier M.,et al. “Acylated 1,3-aminopropanols as Repellents Against Bloodsucking Arthropods”, Pestic. Sci., 48 (1996), pp. 359-37
  3. World Health Organization. (2000). Review of: IR3535; KBR3023; (RS)-Methoprene 20% EC, Pyriproxyfen 0.5% GR; and Lambda-cyhalothrxn 2.5% CS. Report of the Fourth WHOPES Working Group meeting, Geneva, 12-4,5-2000.
  4. [Photo of OFF Family Cares Insect Repellent] 2020. Retrieved from https://off.com/en/product/family-care/family-care-with-picaridin-vii
  5. Costa LG. Toxic Effects of Pesticides. In: Klaassen CD. eds. Casarett and Doull’s Toxicology: The Basic Science of Poisons, Eighth Edition New York, NY: McGraw-Hill; 2013.
  6. Ecker, W. (1997). [Hydroxyethyl-1-14C] KBR 3023: Human volunteer metabolism study after dermal application. Bayer AG Institute for Metabolism Research and Residue Analysis, Leverkusen, Germany, Report No. PF 4187, 1997-01-07.
  7. Charlton NP, Murphy LT, Parker Cote JL, Vakkalanka JP. The toxicity of picaridin containing insect repellent reported to the National Poison Data System. Clin Toxicol (Phila). 2016;54(8):655‐658
  8. Antwi  FB, Shama  LM, Peterson  RK Risk assessment for the insect repellents DEET and picaridin. Regul Toxicol Pharmacol. 2008;51:31–36.
  9. Afify, Ali, et al., “Commonly Used Insect Repellents Hide Human Odors from Anopheles Mosquitoes”, Current Biology, 2019; 29(21):3669-3680.