The biological or terminal half-life of a pesticide or drug is the time it takes to lose half of its pharmacologic or physiologic activity.  It refers to the body's cleansing (detoxification) through the function of kidneys and liver, and subsequent excretion through urine and feces to eliminate a substance from the body.  For “drug” classified pesticides (chews and other FDA-regulated products) half life is used in a medical context, describing the time it takes for the blood plasma concentration of an active ingredient to halve (plasma half-life) its “steady-state.”  

The relationship between the biological and plasma half-life may be influenced by factors of bio-accumulation in tissues (protein binding), active metabolites (see below), and receptor interactions.  Manufacturer conducted premarket clearance testing may not accommodate complications for these issues because studies are commonly brief and limited in scope.  In parallel, half-life is also used as an environmental/chemistry term: to define the persistence or length of time an active ingredient remains available for uptake in the environment.

Consumable pesticides are increasing in popularity, as the active ingredient reaches the parasites through the blood, (everywhere in the dog's body), and efficacy is independent from exposure to dirt, sun, shampooing, rain, etc., whereas topical products can be washed away, or broken down by sunlight, etc.

Comfortis® (2007) and Trifexis® (2011; class: Spinosyn; also marketed as Vethical AcuGuard® and ComboGuard®) are once-monthly beef- flavored chew-able tablets dispensed by veterinarians, aggressively marketed as a convenient and cost-effective alternative to “spot-ons.”  Consumable pest control “won't stain carpeting, upholstery or clothing.”  Moreover, the tablets appeal to parents of small children: since there would be no transferable pesticide on the dog's fur: “Family friendly: no need to isolate… you can play with your dog immediately after treatment.”  Both are produced by Elanco: the animal drug division of Eli Lilly and Co., and because they act systemically, they are classified as drugs, and as such, these products fall under the purview of the US Food & Drug Administration (FDA).   

After oral administration, Spinosad quickly binds to blood plasma and so circulates throughout the body systemically, reaching “maximum plasma level” in only 2 to 4 hours after administration, with bio-availability (>70%) increased if administered with food.  It is speedily metabolized (killing in 30 minutes) and excreted. 

As is common to many competing products, manufacturer conducted premarket clearance study indicated depression/lethargy as the primary adverse effect.  This would likely be due (but not researched) to its effect on serotonin level: the primary chemical and neurotransmitter that supports regulating cognition, mood and social behavior, appetite and digestion, sedation/sleep, memory, and sexual desire and function.  It has been hypothesized that Spinosad may deplete concentrations of important amino acids such as L-tryptophan, a biosynthetic precursor for creating serotonin.  Note that the second most-common adverse
effect is inappetence. 

Then, in descending frequency: in-coordination/(vestibular syndrome), diarrhea, itching, trembling, hyper-salivation and seizures (abnormal activity in the brain).

There is no antidote for spinosad poisoning.  Treatment consists in preventing further exposure together with supportive and symptomatic measures.

Does [Insert Name of Pesticide “Chew”]
Kill Dogs?
(Or): Failure of the Regulatory Process

As a macryocyclic lactone-class insecticide, Trifexis® works by is increasing the flow of chloride ions in the synapses of neurons, which causes hyper-polarization of the cell membranes.  This causes a general blockage of the stimulus mechanisms in the central nervous system of the insect, to which it is “selectively more toxic” than the dog (see: discussion “Sodium Ion Nerve Channels” on previous page).  Unlike most other veterinary drugs, milbemycin oxime was not developed through agricultural applications, and as such, there are no thorough studies on its environmental impact.

Peak plasma concentration (Cmax) is reached 2 to 4 hours after administration, and subsequently declines with a “half-life” of 1-3 days. Bioavailability is about 80%.

Elanco does provide safety information on its web pages, but critics note that that information is accessed only by moving through a range of sub-menu.  The company offers that Trifexis® is “rigorously tested and approved as safe by the FDA and other regulatory authorities around the world,” and that “Many veterinarians… have such confidence… that they prescribe it for their own dogs.”  The page describes that Elanco monitors “trends” in adverse reporting by consumers, and in turn, sends this information to the FDA (which federal law requires); and which is obviously conditioned by low reporting, as few consumers are even aware of or complete the reporting process (less than 10% actually report).

Elanco has faced down persistent criticism from consumers, most especially from social media outlets, and counters that: “There are many positive experiences posted, but many negative posts also appear. Unfortunately, it is often the negative information that gets attention and prompts questions, and ultimately concerns by pet owners. Readers of this information often accept what they read as factual and unbiased data.”

The resulting cerebral and cortical deficits associated with this macryocyclic lactone-class insecticide include: Ataxia (uncoordinated movements: added in 2012 to package warnings: from postmarket surveillance), hypermetria (excessive or disproportionate movement of bodily parts beyond the intended goal), disorientation, hyperesthesia (excessive reaction to tactile stimuli), tremors, mydriasis (dilatation of the pupils), recumbency (inability to rise), depression (see: discussion above), blindness (attributed to detachment of the retina), seizures (added in 2012) and coma (persistence unconsciousness).  

Further consumer reporting has included claims of pancreatitis, “fly biting,” (an air snapping behavior common in epileptic dogs), seizures, confusion or “restless wandering,” limb weakness and paralysis, sudden-onset heart disease,disease, lethargy, aggression, and vestibular syndrome. 

In dogs without the MDR-1 gene defect, the dominant poisoning symptom with macryocyclic lactone-class insecticides is mydriasis (dilatation of the pupils) together with incomplete and deregulated pupillary reflex.  Mydriasis in both eyes is the most sensitive indicator of macryocyclic lactone-class intoxication.  Because the regulatory approval process does not require long-term testing for approval, it is the consumer himself that provides this information and critics note that while many reports (including death) are “first dose,” many occurred after months or repeated dosing, suggestive of issues of bio-accumulation, or, when a dog’s immune system may eventually be exhausted and overcome, including from unrelated environmental, health, or food-related pressure.

Elanco's labeling also acknowledges that both spinosad and milbemycin oxime plasma concentrations increased over time throughout the study; this may account for adverse event reports for dogs months into treatment.

There is no antidote for milbemycin oxime poisoning.  Treatment consists in in preventing further exposure together with supportive and symptomatic measures.

Milbemycin oxime is the primary active ingredient in Sentinel® Flavor Tabs® (milbemycin oxime/lufenuron) and Sentinel® Spectrum® (Virbac/Norvartis Animal Health US, 2011: milbemycin oxime/ lufenuron/ praziquantel).  Lufenuron is a growth development inhibitor: there is no antidote for lufenuron poisoning.  Treatment consists in preventing further exposure together with supportive and symptomatic measures. 

Praziquantel is an isoquinolines-class insecticide (toxic to tapeworms), of which the molecular mode of action of is not precisely known at present. Peak plasma concentration (Cmax) is reached within the first hour after administration, although only a small portion enters systemic circulation to body organs. This is because the portal vein system brings it first to the liver where it is partly metabolized to inactive metabolites. Metabolism occurs mainly in the liver and the kidneys. Excretion is through urine at >80%, the rest through the bile to the feces; with elimination half-life at approximately 2 hours.

Transforming consumer perception:
a Pesticide becomes a “Drug”

Merck positions Bravecto® more aggressively than its competitors, asserting that it can be used as part of a treatment strategy for the control of Flea Allergy Dermatits (FAD: an allergic reaction in dogs that are hypersensitive to “intermittent exposure to flea saliva” that is injected when a flea bites), since it “controls environmental flea populations” by killing current fleas that may lay eggs over time: “the flea life cycle is broken.”

The proportions of inactive ingredients in Bravecto®
(see discussion above) is not disclosed on both US and non-US packaging, and listed as “secret” in Australian data sheets.  This is “proprietary information” and only “hazardous” ingredients over 1% and/or “carcinogenic” ingredients in concentrations above .01% are listed in the chemical composition table.  Merck’s US Material Data Safety Sheet (MDSS: a technical document which provides detailed and comprehensive information on a “controlled” product) captions only “CPBI,” (carbamoyl benzamide phenyl isoxazoline, see: above) “starch,” [quotes added] “polyethylene glycol, sucrose, and gylcerine,” with total product proportions that vary from
54.64% to 74.64%.

However, The European Medicines Agency assessment report (CVMP: 2014) indicates the excipients sucrose, maize starch, sodium lauryl sulphate, magnesium stearate, aspartame, glycerol, soya bean oil (refined), macrogol 3350 (a pig liver commercial flavouring), and a novel excipient, disodium pamoate monohydrate (INN name: disodium embonate monohydrate).

New to the market, detailed information on the toxicity and the fate of fluralaner in the dog's body (absorption>> distribution>> metabolism>>, excretion) and in the environment is sparse —(AU Material Safety Data Sheet or “MSDS”: “The toxicological properties of the mixture(s) have not been fully characterized in humans or animals.”)—but users must contemplate that since it attaches to the protein in plasma and is slowly released and distributed to fatty tissues (where it becomes available to insects), it would concentrate in kidney, liver, and muscle tissues: as the dog’s metabolic and renal systems recognize it as a toxin, and attempt to cleanse and “repair” the blood. 

According to an FDA Freedom Of Information (FOI) summary, Plasma concentrations of fluralaner confirmed systemic and continuous exposure: “Measurements and Observations: All surviving pups and adult females were euthanized between Days 50 and 71 of lactation, and adult male dogs were euthanized 1 to 6 weeks after pups were born. Gross necropsy and organ weights were assessed in all dogs, and histopathological examination (the microscopic examination of tissue in order to study the manifestations of disease)was performed on selected tissues including reproductive organs and any tissues with gross lesions. Except for histopathological evaluation , measurements and observations were conducted masked to treatment.”

Merck's premarket clearance study used small groups of healthy dogs in a laboratory setting, along with at least one study on approximately 200 client-owned animals.  During those studies, side effects included vomiting, diarrhea, bloody or mucoid stools, inappetance, itching, dry skin, and seizures. These side effects were discounted as not clinically significant or not attributable to the medication by the researchers: “there were no serious adverse reactions.”  Merck's published list of possible side effects is: “vomiting, decreased appetite, diarrhea, lethargy, polydipsia (excessive thirst), and flatulence,” and this stands as the exclusionary list that veterinarians use
(see: above). 

Not required for regulatory approval, no study was undertaken regarding the potential for “chronic/long term effects” (more than 182 days) of fluralaner severally, or concerning the inactive ingredients as they might synergize and/or amplify it or each other; nor the issues of ordinarily unknown parameters for total immune response of any particular dog that could lead to central nervous system or hepatic injury.

 

As consumer safety advocates had anticipated, less than two years later the FDA’s Center for Veterinary Medicine (CVM) had registered more than 5,300 complaints of adverse reactions to Bravecto®; more than half of which were submitted for a six month period through early January 2016; with a further 5,077 compiled by mid-October.  By August of 2017, the total had risen to 16,521.  On the latest 2017 report from the EMA (European Medicines Agency) there are now 3988 adverse event reports with 972 deaths associated with the
use of Bravecto®.

Similar to other Isoxazolines: sickness extended across violent gastrointestinal, neurological, endocrine, and renal turmoil to multi-organ toxicity/failure, blindness, euthanasia and death.  Reports also include description of mydrasis (dilated pupils), nystagmus (uncontrollable eye movement), vestibular syndrome, seizures, broad behavioral changes: particularly irritability and defensive aggression (possibly fear-induced owing to hallucinations) may accompany as the toxin accumulates in the adrenal and thryroid glands and the central nervous system.  Observers caution that the CVM database is surely incomplete: as the FDA estimates that less than 10% of adverse experiences are actually reported. 

Some reports describe reactions manifesting several months into treatment... coincidentally, according to Merck’s New Animal Drug Application (NADA 141-426): “Dogs achieved steady-state fluralaner concentrations by the third treatment period.”  Other (un-compiled/non-reported) complaints include descriptions of consumers finding dead ticks attached to their dogs more than a year after discontinuing use, and questioning— with realization that there is no antidote for fluralaner poisoning: treatment consists in preventing further exposure together with supportive and symptomatic measures — how it can ever be flushed from the system.

In 2016, as the public relations aspect of the controversy became more troublesome, Merck Animal Health (MAH) took the extraordinary step of posting a “Company Statement” on their website, with links to a surprisingly awkward (and edited) video featuring Merck’s Executive Director for its Technical Services division, adjoined to a “Bravecto®: Just the Facts” flyer for distribution to consumers… presumably from veterinarians.  Observers deemed it a public relations misfire: as aspects of the flyer in particular would seem to merely draw attention to the escalating debate, with its bold type and jarring admonishment to disregard media and AE reporting, including: “A report does not mean causation” and “Global safety surveillance of Bravecto use has provided additional compelling evidence of the safety of the product.”

In 2017, noting the potential for neurological effects, the Committee for Veterinary Medicinal Products (CVMP) of the European Medicines Agency (the government authority that approves drugs for veterinary use in the United Kingdom) advised Merck MSD that Bravecto® must have a label warning: “Special Precaution: Use with caution in dogs with pre-existing epilepsy” (The Veterinary Record, Sept. 2017, p.340).  The US version, however, does not carry this caution, even though its new “spot-on” version of fluralaner (see below) does. 

Merck: “The most frequently reported adverse reactions include vomiting or diarrhea. Other side effects that may be seen include decreased appetite, lethargy, increased thirst, and flatulance.(sic).”

In March of 2016, the CVMP granted marketing approval for Intervet/Merck's “spot-on” version of Bravecto® (although Merck eschews that too-common title for “topical”) in 5 weight-designated doses; with the US FDA following, in July.  Five months earlier, based on a benefit vs. risk analysis, the CVMP had rejected Intervet International B.V.’s (Merck) latest version (EMA/CVMP/750172/2015), which added a new target species (cats), because: “the data on user safety were unacceptable.”  
 

Immediately appealing the decision, Merck argued that “Generic/surrogate exposure modelling is an appropriate tool, and the chosen fipronil spot-on solution was an appropriate surrogate.”  CVMP ultimately agreed with Intervet’s contention that “…risk of indirect exposure via cross-contamination is usually not addressed for [regulatory approval of] topically applied antiparasitic spot-on formulations,” and that “harmonizing” was therefore appropriate.  CVMP accepted Merck's conclusion that “contamination of untreated control animals in the dog TAS study is considered most likely due to a single direct exposure to the active substance (cross-contamination) at or around the time of treatment [of the subject dogs].”  That is: Intervet employees conducting the TAS failed to control for
cross-contamination.

Consumer safety advocates already frustrated by reports of adverse effects to the chew remain alarmed by Merck's desire to backward-engineer their novel product to an existing platform.  More perplexing was the firm’s embrace of common interpretation that “the physicochemical properties of the active substance” are similar to ordinary US off-patent (non-prescription) antiparasitics: which had—at that precise moment—emerged as contentious with a rapidly growing US-based social media group monitoring the phamacovigilance process.

Also of concern were excipients (solvents/humectants/stabilizers) that are, however, specific to Bravecto® as fluralaner “topical,” such as dimethylacetamide (DMA), a category 4 acute toxicity (H332; harmful if inhaled and H312; harmful in contact with skin) and category 1B reproductive toxicity (H360D at concentration >5%, may damage the unborn child).  For that reason, a “risk characterization” for DMA would be provided in the user safety evaluation, owing to the possibility of dermal exposure to the consumer as the product is applied to the dog. 

A further risk characterisation (adverse systemic effects: acute oral exposure) for (14%; US: 13.2%) N,N-diethyl-m-toluamide (DEET) would be also be included: “A NOAEL of 75 mg/kg bw/day was reported. This NOAEL was derived from an oral capsule study in dogs terminated on day 5 due to severe (neuro)toxicity.”  Used as a topical insect repellent, DEET is a known percutaneous (through the skin) penetration enhancer.  In dogs, metabolism (oxidation) of DEET occurs in the liver, with toxicosis primarily involving the gastrointestinal tract and the central nervous system. 

A pivotal one-generation study in rats was submitted to address issues of reproductive toxicity, (in rats and rabbits) for developmental toxicity, and the assessment of the initial application for Bravecto® chewable by the CVMP was extrapolated regarding genotoxic potential and generalized safety characteritics.

Same drug...
different warnings?

Most surprisingly, Intervet/Merck’s labeling for the spot-on version of fluralaner differs, warning: “Use with caution in dogs with a history of seizures.  Seizures have been reported in dogs receiving fluralaner, even in dogs without a history of seizures.”  Consumer safety advocates are sharply critical that absent is information as to why this caution has not been extended to the already in-use chew product.

There is no antidote for fluralaner poisoning. Treatment consists in preventing further exposure together with supportive and symptomatic measures.

Ever heard the term: 
“Conscious proprioception”?

The document also discusses a “separate exploratory pharmacokinetic study” in which adverse reactions included (subsequent to an abrupt 2.5-fold rise in “plasma concentrations” after the 3rd monthly dose): vomiting/diarrhea, lethargy, anorexia, and abnormal neurological signs including ataxia (loss of muscle coordination, particularly in the extremities), tremors, disorientation, hypersalivation, diminished conscious proprioception (the ability to sense non-vision realized stimuli regarding position, motion, and equilibrium: a neuro-muscular disorder; which may be categorized as acute or chronic), and absent menace response (one form of “blink reflex”: reflexive blinking and body posture that occur in response to the rapid approach of an object, which may indicate damage to the cortical nerve).
 
The description continues: “This rise resulted ing in a Cmax (peak serum concentration) more than 7-fold higher than the mean Cmax at the maximum recommended use dose.  No cause for the sudden increase in sarolaner plasma concentrations was identified.  The dog was not treated, and was ultimately euthanized.”  There is essentially no knowledge on tolerance related to breed, age, or specific health circumstances.  Officially reported adverse effects include bloody vomiting, ataxia, convulsions and seizures, and death.

As with other Isoxazoline class ectoparasitides, ticks need to start feeding on the host (consuming sufficient blood) to become exposed to sarolaner; therefore, the transmission of infectious parasite-borne diseases cannot be excluded.  There is no antidote for Sarolaner poisoning. Treatment consists in preventing further exposure together with supportive and symptomatic measures.

Little to nothing has been published yet regarding the environmental toxicity of sarolaner.

Gastrointestinal impact and renal failure

The noted (clinically observable) adverse reactions included: weight loss, polyuria (abnormally large volume of dilute urine), diarrhea, elevated blood urea nitrogen (BUN: an indication that the kidneys are unable to remove urea from the blood normally); elevated creatinine (an indication of impaired kidney function or kidney disease); elevated potassium (symptomatic of hyperkalemia, related to kidney failure); elevated phosphorus (an electrolyte disturbance, hyperphosphatemia, indicative of kidney failure); dyspnea (labored breathing/shortness of breath); and polyphagia (excessive appetite). 

Polyphagia is suggestive of impact to the gastrointestinal system (where 80% of the dog’s immune system resides), manifest by inflammatory bowel syndrome, insulin deficiencies (the body is unable to assimilate its blood sugar, and the resulting low blood sugar levels may impact appetite) or insulin-resistant intestinal cancers. 

As with other Isoxazoline class ectoparasitides, ticks need to start feeding on the host (consuming sufficient blood) to become exposed to lotilaner; therefore, the transmission of infectious parasite-borne diseases cannot be excluded.  There is no antidote for lotilaner poisoning. Treatment consists in preventing further exposure together with supportive and symptomatic measures.

" ...The tried and true knowledge and use of herbal products by indigenous peoples have developed over millennia to safely and effectively repel, control and kill noxious insects.  Furthermore, these products cannot be patented and are far less costly than those of the multinational drug companies... that also sell to the chemical-toxic agribusiness industry. To suggest that people should use their product[s]... totally disregards the impact on beneficial insects and the birds, reptiles, bats and other wildlife who consume them.

Government legislators and municipal authorities should move to ban the sale of these kinds of products in stores across their jurisdictions. If we chose to be deaf to reason and common sense, then we will not notice or care about the silencing of this living world. Many already notice the absence of the butterflies in their yards and gardens and of once a myriad kinds of insects around night lights everywhere.

But will they understand that when the diversity of beneficial insects and insectivores is gone they will be more vulnerable to ever more insect-borne diseases?

This is in part because the most “noxious” insects—those species in part aided in their proliferation because of our ecological interferences—develop resistance to our armament of chemical warfare against them. This causes collateral damage to other harmless and beneficial species. Great economic losses for farmers ( already being experienced by almond and citrus crop growers), and famines will come when there are no bees and other pollinators for the plants, and no plant-pest killing parasitic wasps who indirectly sustain us, our economy and those diminishing other species who can barely endure the planetary infestation
and mindless onslaught of our species?

I never imagined that I would come live in a world where multinational corporations would exploit not only nature’s resources for pure profit regardless of the social and ecological costs and harmful consequences but garner the findings of the biological sciences to produce crops that manufacture their own insecticides and have resistance to herbicides, all products they sell along with their patented, genetically engineered seeds. 

But all to what end? The profit motive and the adversarial and bio-fascist attitude of corporations and of segments of society toward other living beings and the natural world will be the ultimate undoing, the nemesis of this bio-industrial epoch in human evolution, leading to the extinction of this mode of being and state of mind,
if not of Homo sapiens itself”

— Michael W. Fox, BVetMed, PHD, DsC, MRCVS; The Rachel Carson Council: 
Bayer & Merck Anti-Flea & Tick Products for Pets: Animal Health & Environmental Risks

N.B.: This essay is written for informational purposes. Our goal is to build awareness of concepts and define common terminology to stimulate discussion. We draw your attention to issues and concepts that are or may be important to the subject at hand, but do not consider that our interpretation is necessarily complete. Links are in blue & will illuminate when you pass your mouse over them. Nothing in this page is intended to be interpreted as advice or endorsement of any product. Any person who intends to rely upon or use the information contained herein in any way is solely responsible for independently verifying the information and obtaining independent expert advice if needed.