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Summary It has been estimated that between 10 and 33 percent of need to be taken into account in determining the safety of dogs and cats in the United States are fed an animal dietary animal dietary supplements. The committee was to describe supplement, with some of the same supplements also being its findings and conclusions about the safety of the three fed to horses. For the purpose of this report, the committee supplements and provide recommendations for factors to defined an animal dietary supplement as “a substance for consider in future analyses. It was made clear to the commit- oral consumption by horses, dogs, or cats, whether in/on tee that the report should address only safety and that utility feed or offered separately, intended for specific benefit to or efficacy of animal dietary supplements was not part of the the animal by means other than provision of nutrients rec- task. Thus the committee did not assess the validity of utility ognized as essential or for provision of essential nutrients or efficacy claims. for intended effect on the animal beyond normal nutritional The study was requested and sponsored by the CVM needs, but not including legally defined drugs.” The growth of FDA. The report was intended to help form the basis of in use of animal dietary supplements has raised several con- a more general framework for evaluating animal dietary cerns. Among the issues involved are the safety of specific supplement safety. The primary approach taken by the com- animal dietary supplements and the approaches that should mittee was to examine published scientific reports to assess be taken to determine the safety of animal dietary supple- whether feeding these three supplements to horses, dogs, or ments in general. The passage of the Dietary Supplement cats presents a significant adverse health effect that changes Health and Education Act (DSHEA) in 1994 amended the normal function in the animals. Additional information was way in which human dietary supplements are regulated, but also received directly from pet food and animal dietary the Center for Veterinary Medicine (CVM) of the Food and supplement industry representatives. This information was Drug Administration (FDA) indicated that the less restrictive also examined and included when appropriate. The knowl- regulatory approach of DSHEA should not apply to prod- edge gained from conducting these assessments allowed the ucts intended for animals. Thus, dietary supplements for committee to review and begin to define factors that should humans and dietary supplements for animals are subject to be considered when evaluating the safety of animal dietary regulation under two different sections of the Federal Food, supplements in general. Drug, and Cosmetic Act (FFDCA), even though they may be the same substances, given in the same manner, for the Key Findings same purpose. Currently FDA and other regulatory bodies are under pressure to resolve the public’s desire to provide A consistent finding from the study of lutein, evening these products to their animals with the restrictions that exist primrose oil, and garlic was that there are insufficient safety within the current statutory and regulatory framework. data of a quality normally required for animal drugs and animal food additives. Ideally, the committee would have liked to have the data to define a no observed adverse effect The Committee’s Task level (NOAEL), or at least a safe upper limit (SUL), for The committee’s assignment was to assess the safety each of the three supplements. With the limited data cur- of three dietary supplements (lutein, evening primrose oil, rently available, the committee could only report historical and garlic) offered for horses, dogs, and cats. During its safe intakes and estimate a presumed safe intake (PSI) for review of the data for each of the three supplements, the the three animal dietary supplements studied. The commit- committee was asked to examine general considerations that tee identified a number of data elements for consideration 

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 SAFETY OF DIETARY SUPPLEMENTS FOR HORSES, DOGS, AND CAts when constructing any framework for assessing animal documented quality assurance. The committee found it very dietary supplement safety that may be different from those difficult to evaluate the statistical power of the available routinely considered for drugs. Because most ingredients in studies to detect a significant adverse event. Assessment animal dietary supplements are not proprietary substances, of studies was hampered by such factors as poor definition it is unlikely that the amount of target animal data will ever of signals, lack of sufficient animal numbers, or failure to be sufficient for safety assessment, and research findings evaluate for a well-known adverse signal. in other species provide important evidence about safety. • The detection of an actual adverse effect is difficult. In Based on one of the specific animal dietary supplements some studies, explanatory information is lacking for adverse studied (e.g., garlic, see Chapter 8), it is clear that safety of events. Sometimes a single case report is all the evidence the same supplements in humans does not guarantee safety available for adverse events associated with an animal in animals. A number of factors were defined that might be dietary supplement. considered when selecting appropriate surrogates for horses, • Validated analytical methods and standards are often dogs, and cats. Based on an analysis of the available data for lacking. There is often lack of consensus for what the animal dietary supplement safety, the committee developed active compound actually is because “activity” is not a broad seven-point scale for assessing suitability of differ- clearly defined, making standardization by active com- ent data types. pound, required for drug studies, impossible. Even if the There is a clear need for a comprehensive adverse event active compound is known, an acceptable quality standard reporting system. Existing systems have limitations because and validated matrix-appropriate assay for quantitation may of difficulties in defining dosages, active ingredients, or not be available or used. consistent adverse signals as well as issues with respect • There are a number of challenges associated with to compliance and ease of access. Finally, the absence of defining dosage of animal dietary supplements. Supple- laws and regulations that specifically address animal dietary ments are often dosed on the basis of intended use and supplements causes considerable confusion to the industry employ units not directly correlated to putative active ingre- and the public. Clarification is required to enable a clear dients. The committee faced the dilemma that doses were differentiation between an animal dietary supplement and a neither consistent nor directly related to a common safety food additive or animal drug as well as factors that differen- endpoint and often varied considerably across studies (e.g., tiate regulation of human and animal dietary supplements. flavor vs. health benefit for garlic). The “generally recognized as safe (GRAS)” designation of • Dosage of some supplements (e.g., those not provided an ingredient is helpful but does not imply general safety for in specific dosage forms) is intrinsically different than that all species at all levels of intake. associated with drugs, which are dosed on a milligram per kilogram of body weight (BW) basis. However many supplements are incorporated as quantity per unit food. Specific Findings and recommendations Lack of knowledge of the actual dose of biologically active ingredients given in the studies evaluated by this committee Insufficient Data of Adequate Quality to Quantitatively is a major factor that has prevented defining exposure levels Establish the Safety of Lutein, Evening Primrose Oil, associated with lack of adverse events. and Garlic • Dietary supplements may be given in combination There are insufficient safety data for these supplements with other supplements or dietary constituents (e.g., mul- of a quality normally required for animal drugs and food tiple vitamin and supplement preparations), making the additives, despite the fact that exposure to target populations attribution of a specific adverse effect to one specific supple- may be greater. With the limited data currently available, ment difficult. the committee could only estimate a PSI for garlic, evening • Contaminants and adulterants are a potential issue for primrose oil, and lutein. The following factors are important all supplements. considerations when constructing any framework for assess- • Processing techniques are crucial determinants of ing animal dietary supplement safety: final composition and properties. • It is crucial to assess the quality and relevance of data Use of Nontarget Animal Data used in studies not specifically defined to detect safety. It is important to keep the purpose of the original study in mind. Because of the limited amount of data with target ani- At a minimum, studies require peer review or some level of mals, research findings in other species provide important safety signals. Based on the three specific animal dietary The report contains minor changes from the prepublication version to supplements studied, it is clear that safety of the same sup- clarify that in the United States there are currently no laws and regulations plements in humans does not guarantee safety in animals. that address animal dietary supplements as a specific group or entity. The clearest example of this is with garlic, where excess In the United States, the term GRAS has a specific legal meaning as discussed in Chapter 2. intakes may cause hemolytic anemia in horses, dogs, and

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SUMMARY  cats, which is an adverse effect not described in humans. Adverse Event Reporting System The committee has identified some factors that might There is a clear need for a comprehensive adverse event be considered when selecting appropriate surrogates for reporting system. Existing systems are deficient often for the horses, dogs, and cats: factors discussed above related to difficulty of defining dos- ages, active ingredients, or consistent adverse signals. The • Nutritional, metabolic, pharmacokinetic, and natural committee’s analysis of these supplements has not uncov- dietary patterns are important when selecting appropriate ered a system for adverse reporting that is similar to those animal model species. in place for drugs. As a committee, we believe that lack of • Supplements that are naturally occurring in a diet adverse events being reported to a manufacturer is weak evi- should be considered differently than those not natural for a dence for a lack of adverse effects having actually occurred. given species (e.g., lutein for horses vs. cats). Although major, life-threatening, adverse events will usu- • Information gleaned from a study of the evolutionary ally be reported, this may not be the case with less serious diets of wild and feral species vs. diets of domestic animals events that are not routinely tested for or could be confused may provide some indications of normal intake. with other problems. Similarly, extensive exposure without specifically monitoring biomarkers of adverse effects does Evaluation of the Suitability of Data for Assessing not necessarily demonstrate safety. Animal Dietary Supplement Safety An adverse event reporting system for animal dietary supplements would be very helpful. This system should be As a result of conducting these reviews, the committee structured to capture the details of dietary exposure (e.g., ranked the suitability of assessing acceptable and relevant dose, active ingredient, concomitant supplement, drug or data based on the following broad seven-class scale, with chemical exposure, and disease) and open to public access. class 1 providing the highest degree of confidence. Within each of these classes, it is appropriate to give more credence to data addressing several populations at risk. It should be Regulation of Animal Dietary Supplements noted, that for the three supplements assessed by this com- The absence of laws and regulations that specifically mittee, the highest rank of data found was class 2, with the address animal dietary supplements causes considerable majority of studies being in class 4, 5, or 6. The classes in confusion to the industry and the public. Clarification is the scale were defined as follows: required to differentiate clearly the regulation of human and animal dietary supplements as well as factors that dif- 1. Safety studies conducted in the target species similar ferentiate an animal dietary supplement from a food addi- to that acceptable for animal drug safety determination. tive or animal drug. Any future animal dietary supplement 2. Studies in the target species that specifically assess regulations should take into account existing standards such some marker of potential adverse effect. These studies could as those of the Association of American Feed Control Offi- include clinical, epidemiological, or defined experimental cials, Codex, and the analytical standards of United States models. Pharmacopeia. 3. Safety studies in a nontarget species closely related biologically to a target species (e.g. wolf for dog, mink for cat, donkey for horse). Lutein 4. Nonsafety (e.g., efficacy or long-term feeding) studies For horses, the PSI of lutein is 8.3 mg/kg BW when in a target species. eaten as forage or natural sources; no data exist to support 5. Documented historical or common usage in target recommendations regarding supplements. In dogs, the PSI species; case reports; adverse event database. of lutein is 1.8 mg/kg BW, with a historical safe intake of 6. Safety studies in a more distantly related species, 0.45 mg/kg BW. In cats, the PSI of lutein is 7.2 mg/kg BW, including humans. with a historical safe intake of 0.85 mg/kg BW. 7. Ex vivo/in vitro studies. The committee strongly recommends that animal dietary Evening Primrose Oil supplement efficacy studies monitor for specific adverse The PSI for evening primrose oil in horses is set at event signals. Efficacy studies should be accompanied by 400 mg/kg BW. This PSI assumes the level of total fat will reasonable attempts to identify and evaluate the risk of not exceed 23 percent of the diet by weight, including any potential adverse events. Furthermore, data that have been quantity of evening primrose oil added. For dogs, the PSI collected that support potential safety should be clearly is set at 424 mg/kg BW, which is the upper level used in described and reported. A simple statement that there were clinical trials. Most likely the upper safe intake for evening “no adverse effects/events” is of limited value. primrose oil is quite a bit higher than this in dogs. For cats,

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 SAFETY OF DIETARY SUPPLEMENTS FOR HORSES, DOGS, AND CAts the PSI is set at 391 mg/kg BW; however, it is likely that no apparent problems. Currently, however, there seems to cats could tolerate higher levels. Because evening primrose be less supportive data for the long-term feeding of cats oil does not contain adequate amounts of all the essential with garlic-supplemented feeds above this level. This lack, fatty acids (particularly arachidonic acid, α-linolenic acid, coupled with the potential for an increased susceptibility in eicosapentaenoic acid, and docosahexaenoic acid) and the cats, means that more data are needed to support the safety cat has limited Δ5- and Δ6-desaturase activities, the main of inclusion of garlic at levels above those historically used concern when feeding high concentrations of evening prim- as a flavor. For these reasons it was not possible to establish rose oil (particularly above the PSI level) is a deficiency of a PSI of garlic for cats. essential fatty acids. Conclusions Garlic The committee could not identify data on lutein, evening Although more data are needed, intake levels of 15 mg/kg primrose oil, or garlic that would allow for a quantitative BW/day of dried garlic powder on a long-term basis are upper limit of safety to be clearly defined (e.g., NOAEL or unlikely to result in a risk of an adverse event in horses SUL). This shortage of data resulted in trying to estimate under normal circumstances. Levels up to 90 mg/kg BW/day existing intake levels as those presumed to be safe. The may not be associated with any adverse events in healthy, committee believes these levels are conservative for lutein non­exercising, nonoxidatively stressed adult horses. The and evening primrose oil, but probably more on target for threshold level above which the risk of an adverse event garlic because of the reporting of adverse events. However, will increase significantly is likely to be between 15 and for all of the study limitations outlined above, a more pre- 200 mg/kg BW of dried garlic, more probably between 90 cise definition of safe intake levels would be conjecture. and 200 mg/kg BW, potentially depending on the health and Cross-species extrapolations of safety are difficult. The oxidative status of the individual horse involved. In dogs, human insensitivity to hemolytic effects of garlic clearly garlic has a long history of safe use as a supplement, with seen in horses, dogs, and cats illustrates this limitation. An mean levels of ≈ 22 mg/kg BW being reported with appar- adverse event reporting system is badly needed. The exis- ently no serious adverse events. Levels of up to 56 mg/kg tence of such a system, properly constructed, monitored, BW of garlic powder or garlic oil seem to have been included and open to public scrutiny, might have aided the commit- in foods for dogs with no apparent adverse events being tee in quantifying safe intake levels. Finally, the absence of reported. For cats, there are insufficient data to support a laws and regulations that specifically address animal dietary generic recommendation that covers all the types of garlic supplements causes considerable confusion to the industry preparations. Mean intake levels of 17 mg/kg BW have been and the public. Clear and precise regulations so that only reported with apparently no serious adverse events, which is safe animal dietary supplements are allowed on the market similar to the levels recommended for long-term use with need to be established.