Evaluation of Flea and Tick Control Products

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Recently, Health Canada's Pest Management Regulatory Agency (PMRA) received incident reports that suggested there may be a potential for adverse reactions in cats and dogs from the use of dermally applied flea and tick control products. The majority of reported incidents involved spot-on products. Accordingly, an analysis of these products was undertaken to investigate the issue. This complex analysis involved an assessment of trends observed in the incident reports and possible correlations with toxicology information for Canadian registered products. The PMRA met with Canadian registrants of flea and tick products and engaged the United States Environmental Protection Agency (US EPA) and veterinarians throughout the analysis.

Sales data suggest that Canadian sales of spot-on pesticides are in the order of 3 million units per year. Between April 2007 and May 2009, the PMRA received 708 domestic animal incident reports (453 Canadian incidents, 255 American incidents) involving spot-on products used to control fleas and ticks. There were a total of 821 affected animals. Most of the reported Canadian incidents were classified as either minor or moderate in severity, with 14 animals exhibiting major effects and 15 animal deaths. More details about incident severity classification are available on the Health Canada web site. Spot-on incidents involving cats were reported more frequently than incidents involving dogs. Twelve percent of the animals were treated with the incorrect product based on their age, weight or species (e.g., dog product used on cat).

In general, the frequency of symptom type reported in the incidents followed a similar pattern for most spot-on products; skin effects were observed most frequently, followed by neuromuscular effects (e.g., tremors), general effects (e.g., lethargy), and gastrointestinal effects (e.g., vomiting). Skin effects were observed nearly twice as often as neuromuscular effects. Cats and dogs that died tended to weigh less than those that experienced minor or moderate effects. Dogs that died were younger than those that did not. Incident reports involved smaller breeds of dogs more often than larger, more popular breeds. Since the majority of spot-on products have a set dose for a range of companion animal weights, smaller animals (in the case of both cats and dogs) received a higher dose of product per kg body weight when compared to large animals. Typically, animals that received these higher doses experienced more serious effects compared to larger animals that received a smaller dose. The above observations do not include those incidents resulting from the misuse of a dog product on a cat. The PMRA solicited the opinions of small animal veterinarians through a survey administered by the Canadian Veterinary Medical Association. Results of this survey echo the findings from the incident reports.

Toxicology data on the active ingredient, the formulants, the end-use product as well as companion animal safety studies were examined to identify potential associations with the symptoms in the incident reports. Four active ingredients are present in spot-on products: imidacloprid, s-methoprene, pyriproxifen and permethrin. Symptoms from the incident reports were not consistent with the toxicology profiles of three of the active ingredients. For permethrin, symptoms from incident reports were consistent with the toxicology profile although it is possible that the formulants may have played a contributory role. It should be noted that permethrin was involved in a significant number of Canadian incidents. In addition, reports of misuse were most commonly associated with this active ingredient (i.e., dog products used on cats).

Given the number of skin effects in the incident reports, irritation and sensitization studies of the end use products were examined. The studies did not demonstrate sensitization potential or significant irritation potential. The dermal reactions identified in these studies were inconsistent with the skin effects reported in the incident reports. Thus, these studies were of limited predictive value in this analysis.

In 2008, there were a total of twenty formulants contained in spot-on products registered in Canada. These were assessed based on considerations such as toxicology profile, concentrations present in the products and number of incident reports. Several were highlighted as potential contributors to the symptoms reported in the incident reports. Scientific literature indicates that N-methyl-2-pyrrolidone and D-limonene can cause skin reactions; more skin effects were reported for products containing these formulants relative to products not containing these formulants. Tripropylene glycol monomethyl ether was previously identified by the PMRA as a potential concern due to reports of effects with products containing this formulant. The PMRA initiated follow-up activity with the relevant registrants, who are now working to replace this formulant. The current analysis reaffirms this concern.

Companion animal safety studies were available in support of all spot-on products with the majority conducted according to the required guideline. All were considered acceptable at the time of the original review and did not identify treatment-related effects following exposure of animals to the products at the label rate. At exaggerated doses, observed effects were generally minor in nature and were infrequently consistent with symptoms reported in incident reports. Possible connections between symptoms reported in incident reports and effects observed in companion animal safety studies were observed for one dog and two cat formulations. In light of some of the incident report findings, there are a few studies for which different conclusions could now be made. Overall, the companion animal safety study was not highly predictive of the effects noted in the incident reports. The analysis suggests the need for further improvement in the design of the companion animal safety study.

To investigate whether efficacy studies routinely provide valuable information relative to animal safety, an investigation into data available in the efficacy studies for the spot-on products was conducted. It was concluded that there was little to no value for the inclusion of efficacy studies into the animal safety assessment for the purpose of this analysis.

Key limitations were identified during this analysis. They included the following:

• questionable quality of the data reported in incidents
• under-reporting of incidents by the registrants
• limited information from sales data
• limited capability of the toxicology database to predict effects in cats and dogs
• limited power of the companion animal safety study 
• limited data on formulants and the use of alternate formulants in a registered product

An Information Update is available on Health Canada's website.

As a result of this evaluation, the PMRA has required label improvements for spot-on pesticides used on companion animals. These label improvements are outlined in Regulatory Directive DIR2010-02.