Impact of concerning excipients on animal safety: insights for veterinary pharmacotherapy and regulatory considerations

Abstract

Objectives

Veterinarians and pharmacists are familiar with the efficacy and safety aspects attributed to active pharmaceutical ingredients included in medicines, but they are rarely concerned with the safety of excipients present in medicines. Although generally recognized as safe, excipients are not chemically inert and may produce adverse events in certain animal populations. This review aims to present excipients of concern to these populations and highlight their relevance for rational veterinary pharmacotherapy.

Evidence acquisition

A comprehensive review of the literature about the existence of adverse reactions in animals caused by pharmaceutical excipients was carried out based on an exploratory study. An overview of the correct conditions of use and safety of these excipients has also been provided, with information about their function, the proportion in which they are included in the different pharmaceutical dosage forms and the usual routes of administration.

Results

We identified 18 excipients considered of concern due to their potential to cause harm to the health of specific animal populations: bentonite, benzalkonium chloride, benzoic acid, benzyl alcohol, ethanol, lactose, mannitol, mineral oil, monosodium glutamate, polyethylene glycol, polysorbate, propylene glycol, sodium benzoate, sodium carboxymethylcellulose, sodium lauryl sulfate, sulfites, polyoxyethylene castor oil derivatives, and xylitol. Among the 135 manuscripts listed, only 24 referred to studies in which the substances were correctly evaluated as excipients.

Conclusions

Based on the information presented in this review, the authors hope to draw the attention of professionals involved in veterinary pharmacotherapy to the existence of excipients of concern in medicines. This information contributes to rational veterinary pharmacotherapy and supports veterinary pharmacovigilance actions. We hope to shed light on the subject and encourage studies and new manuscripts that address the safety of pharmaceutical excipients to the animal population.

Graphical Abstract

Introduction

According to the International Pharmaceutical Excipients Council (IPEC), excipients are defined as chemical substances that undergo safety evaluation and are included in pharmaceutical dosage forms for multiple purposes. These include facilitating manufacturing processes; ensuring accurate dosing; enhancing palatability through modifications in color, odor, and taste; ensuring adherence to treatment; maintaining physical, chemical, and microbiological stability; improving solubility and dissolution rates; enhancing bioavailability; and modifying drug release, among other functions [1–4].

Historically, the safety of excipients was frequently disregarded, and safety assessments were not routinely conducted for both human and animal populations. However, at present, there is recognition that the potential toxicity of excipients should not be ignored [5, 6]. In agreement with Abrantes et al. [6], the issue of excipient toxicity is complex due to the diverse chemical profiles, sources, and technological functions of these compounds in pharmaceutical dosage forms. The possibility of incompatibilities and the presence of degradation products in the excipients originating from their manufacture or improper storage must also be considered in the development of a stable and safe medicine. One example is lactose, an excipient widely used as a diluent in formulations for oral and parenteral use that can trigger the Maillard reaction [7, 8]. Jing and Kitts [9] showed the existence of cytotoxicity for the products of the Maillard reaction resulting from the reaction of lactose with molecules containing amine on cell lines of rats and humans. Therefore, the possibility of a Maillard reaction with active pharmaceutical ingredients (APIs) containing aldehydes and amines is an important issue in dosage form delineation and quality control [7, 8]. Another example is the presence of acetol as an impurity in propylene glycol and glycerin, excipients incorporated in products for topical use that may present a health risk after dermal exposure [10–12]. Despite the literature relating numerous cases of adverse effects in humans to the presence of excipients in medicines, the term “excipient” is rarely mentioned as a cause of adverse reactions in at-risk animal populations. Hence, these excipients should be considered of concern.

During the development and registration of medicines, it is essential to gather documents that provide complete information about the excipients regarding their functions in the pharmaceutical dosage forms, possible incompatibilities in formulations, proportions, and routes of administration. This evaluation is also necessary for therapeutic biological products such as monoclonal antibodies, antibody conjugates, cytokines, growth factors, enzymes, hormones, toxins, and vaccines in general [3–5, 13]. Golightly et al. [14] recommend that all pharmaceutical manufacturers disclose a comprehensive list of excipients in the package insert, making this information readily available to healthcare practitioners and drug information centers. In the case of excipients of concern, it is necessary to disclose the status of the excipient also on the labeling. This can be achieved through indications such as "sugar-free" or "sulfite-free" to inform consumers about the absence of these substances in the product. Reports of ARs for generally recognized as safe (GRAS) excipients occur especially in susceptible individuals or groups, such as neonates, patients with asthma or diabetes, and those with a history of intolerance or malabsorption [1, 3, 5, 6, 15, 16]. For certain excipients, such as sugar, ethyl alcohol, aspartame, and benzalkonium chloride, it is essential to provide detailed information about their content in the packaging insert and in the labeling of medicines intended for human use. Consequently, there is a growing awareness of the importance of carrying out safety assessments of these compounds and monitoring populations at risk for the presence of excipients of concern in medicines.

Nonetheless, as reported by Saito et al. [5], regulatory gaps exist in the legislation about excipients in various agencies worldwide, leading to scarcity of evidence-based information regarding the safety of excipients of concern to the pediatric population. Usually, the safety risks associated with these ingredients should be described in the adverse reactions (ARs), contraindications, and/or warnings and precautions sections of the package inter [5, 15–17]. According to Caballero and Quirce [19], the significant number of ARs properly diagnosed as caused by excipients emphasizes the need to include the name of all excipients included in the composition of vaccines for human use in the package inserts as a strategy to prevent future reactions in sensitized populations. This is particularly important when allergy to APIs has been ruled out. Similar observations regarding the presence of excipients in medicines used in veterinary pharmacotherapy must be the target of actions by sanitary agencies that regulate the manufacture of these products.

Regulation N^o 2377/90 of the Council of the European Communities states that the term "residues of veterinary medicines" refers to all substances in medicines, including APIs, excipients, or decomposition products, that may remain in the food [17]. When a medicine manufacturer considers using an excipient, they must ensure that exposure to it is safe for the target population [18–20]. Due to the relevance of excipients for animal health, guidelines from regulatory authorities in some countries recommend that information about the inclusion or changes in the limits of excipients in veterinary medicinal products be included in the product registration documents, together with information about quality requirements, pharmacopeial specifications, safety data and purpose of use. For new excipients, quality specifications and stability data must be provided by the manufacturer [17, 18, 20, 21]. However, there is no mention of recommendations for the inclusion of specific information about these ingredients in documents to which prescribers and the population have access, such as package inserts and labeling. In addition, no articles were found in the consulted literature that presented the opinion of regulatory agencies about excipients of concern to be included in medicines for exclusive veterinary use. Therefore, drawing attention to this topic is one of the objectives of this manuscript.

The purpose of this review article was to collect relevant information available in the literature about excipients for which there are reports of toxicity in animals, aiming to inform formulators, prescribers, and regulatory agencies about the potential that these pharmaceutical ingredients have to cause adverse effects. The manuscript highlights the importance of understanding the potential risks associated with excipients of concern, the need for proper evaluation for their inclusion in medicines, and their implications for safe and rational veterinary pharmacotherapy. In addition, gaps are pointed out in the regulatory sector of medicines for exclusive veterinary use regarding the presence of information about excipients of concern in package inserts and labeling.

Adverse reactions to pharmaceutical excipients

In veterinary clinical practice, an adverse event (AE) is any unfavorable and unintended observation in animals, regardless of causal association, that occurs after the use of a medicinal product, including both on-label and off-label usage. If there is a reasonable possibility that the observed events occur when the dose normally used in animals for prophylaxis, diagnosis, therapy, or modification of physiological function is administered, it may be possible to conclude that an adverse drug reaction (ADR) or adverse reaction has occurred [22–24]. For Bishop and Post [22, 23], there are different categories of suspected ARs in the animal population, including unexpected ADRs, off-label use of medicines for human use and for veterinary exclusive use, expected ADRs occurring with higher frequency, tolerance, or resistance issues, and ARs associated with medicinal products used within habitat enclosures. The literature reports that the main causes of poisoning or toxicosis in animals are due to the accidental ingestion of plants, foods, beverages, beauty, hygiene, and cleaning products, as well as pesticides, insecticides, and medicines [25–32].

Bishop and Post do not mention the possibility of ARs occurring in the animal population due to the presence of excipients in medicines used in veterinary pharmacotherapy [22, 23]. However, understanding the risks associated with ARs by excipients is essential for veterinary practitioners, pharmacists, regulatory agencies, and pharmaceutical manufacturers alike. Davidson [33] and Young, Royal and Davidson [34] mentioned that, along with APIs, excipients can be lethal for certain veterinary patients. Based on the results presented by Young, Royal and Davidson [34], a substantial portion of pharmacists in the United States has demonstrated inadequate capacity to accurately identify the toxic effects associated with APIs and excipients in the animal population. In agreement with the authors, the medicines intended for human use have consistently been implicated in instances of pet poisoning throughout the United States. As a result, it is of utmost importance for pharmacists to possess an understanding of which APIs and excipients should not be administered to animals due to safety concerns. Similarly, veterinarians exhibit inconsistent knowledge regarding the presence of excipients in medicines.

Contrary to what is observed for humans, especially for neonates and the pediatric population, reports of ARs due to excipients in veterinary medicines are scarce in the literature. As stated by Murphy and Coleman [35], a survey carried out by the Animal Poison Control Center (APCC) between 2001 and 2010 pointed out that xylitol was listed as an excipient incorporated in formulations of nutritional supplements and vitamins administered to animals in tablet, gum, and liquid forms. For the authors, if exposure to any of these products has occurred, the ingestion of xylitol should be considered. According to Karriker and Wiebe [36], the utilization of excipients that are well tolerated in medicines for human use as solvents and preservatives may give rise to toxic effects when employed in small animals or exotic species. However, it is crucial to consider species-specific susceptibility when formulating medicines containing these components, as there can be variations in the metabolism and excretion of these compounds among different species. Therefore, the selection of types and amounts of excipients used in formulations is a critical factor for veterinary pharmacotherapy safety. Lavergne et al. [37] documented a case of an adverse reaction in a dog with a history of hypothyroidism and mild weight gain who was receiving levothyroxine. After 19 days of treatment, the dog developed a severe skin reaction. The administration of the medicine was stopped, and the cutaneous signs improved. When reintroduced, the skin reaction reappeared. Upon reviewing the package insert, it was noted that the products contained magnesium stearate and polyvinylpyrrolidone (PVP). The authors attributed the adverse reaction to these excipients since the reaction did not occur when the dog was previously receiving a medicine without both excipients. However, it remains unclear whether one or both excipients trigger the skin reaction. The authors emphasized that the presumed adverse reaction to magnesium stearate and PVP is rare and appears to be limited to dogs with preexisting conditions exposed to these excipients. Further studies are needed to elucidate this phenomenon. Likewise, as agents that potentiate immune responses, excipients used in vaccine formulations may also cause adverse effects related to their chemical nature. Therefore, the issue of the immunogenicity of the excipients into veterinary exclusive medicines must also be highlighted [38, 39]. There are reports of immediate or delayed hypersensitivity reactions (IHRs) correlated to gelatin, polyethylene glycol (PEG) and its derivatives, polysorbates (PS), copolymers between PEG and propylene glycol (PPG) (poloxamers) and mixtures of mineral oil, paraffins, cycloparaffins and long-chain hydrocarbons used in vaccines [19, 40, 41]. Therefore, the possibility of ARs caused by the excipients of concern must be considered in veterinary clinical practice to contribute to the rational use of medicines for this population. These reactions must be identified and reported as such for pharmacovigilance purposes.

Information about the main excipients of concern to the animal population was summarized from the manuscripts found in the consulted databases: Embase, Medline, Lilacs, PubMed, and Scopus. To identify the articles, the following descriptors were used: “excipients” and “adverse events” and “adverse reactions” and “toxicosis” and “toxicity” and “intoxication” and “pharmaceutical dosage forms” and “drugs” and "medicines" and “animal population” and “veterinary pharmacotherapy”. Only articles published in English were included. No inclusion or exclusion criteria were used, and all manuscripts found were included in the review, with no publication date limit. In our review, 135 manuscripts were found that reported adverse reactions or intoxications in animals due to chemical substances used as excipients. However, only in 24 studies was the inclusion of substances as excipients properly evaluated in the animal population [35, 37, 40–61]. Excipients of concern and animal populations at risk for which toxicity has been reported are shown in Table 1. Although there is not always a precise description in the literature about the toxic concentrations of all the excipients of concern, they should be used with caution in the veterinary clinic.

Table 1.

References found in the literature that report toxicity to chemical compounds that should be considered excipients of concern to the animal population

Excipient	Population	References
Bentonite	Chickens and birds	182–192
Benzalkonium chloride (BC)	Cats and rabbits	27,42
Benzoic acid (BAC) and benzoates	Cats and birds	22,28–30,43,50,91,157–165
Benzyl alcohol (BA)	Dogs, cats, and birds	22,28–30,43,50,91,166–168
Carboxymethyl celulose sodium (NaCMC)	Bovines and equines	180,181
Ethyl alcohol (ethanol)	Dogs and cats	23,131–136
Mineral oil (MO)	Cats, dogs, horses	44,131–141
Lactose	Horses, calves, goats, lambs, sheep, dogs, and monkeys	111–120
Mannitol	Dogs	125
Monosodium glutamate (MG)	Chickens and rabbits	169–173
Polyethylene glycol (PEG)	Rabbits, monkeys	104–109
Polysorbate	Cats, dogs, rabbits, boiler chicken, and fishes	40,41,45,46,49–52,62,144–145
Polyoxyethylene derivatives	Dogs	152
Propylene glycol (PPG)	Cats, dogs, horses, llamas, guinea pigs, and chinchillas	54,56–59,92–103
Sodium lauryl sufate (SLS)	Cats and dogs	156
Sulfite	Chickens, dogs, and cats	174–179
Xylitol	Dogs, cats, ferrets, rabbits, and birds	32,62–89

Comprehensive information about the 18 excipients of concern, including the proportions in the formulations, their pharmaceutical functions, the dosage forms in which they are commonly incorporated, and the recommended routes of administration, are provided in Table 2. Data were taken from the Handbook of Pharmaceutical Excipients 9th edition [2] and from the PubChem database.

Table 2.

Information about excipients of concern compiled from the Handbook of Pharmaceutical Excipients (Sheskey et al., 2020; US FDA, 2023)

Excipient	Dosage forms	Functional category	%	Administration route
Bentonite	Solution, suspension, gel, cream, capsule, tablet, film, suppository	Adsorbent, clarifying agent, emulsion stabilizer, suspending agent, viscosity increasing agent	0.5 to 5	Oral, topical, vaginal
Benzalkonium chloride	Solution, suspension, aerosol, cream, lotion, gel, ointment	Preservative, wetting agent	0.01 to 0.02	Nasal, ophthalmic, otic, topical, pulmonary, parenteral (intramuscular)
Benzoic acid and benzoates	Solution, syrup, suspension, elixir, gum, oral paste, orally dissolving tablet, orally dispersible film, lozenge, cream, lotion, gel, ointment	Preservative	0.02 to 0.5	Oral, buccal, dental, rectal, vaginal, topical, parenteral (intramuscular, intravenous and, bolus)
Benzyl alcohol	Solution, syrup, suspension, elixir, aerosol	Preservative	Up to 2	Oral, buccal, dental, topical, vaginal, pulmonary, parenteral
Carboxymethylcellulose sodium	Solution, suspension, lozenge, gum, oral paste, orally dissolving tablet, orally dispersible film, gel, cream, lotion, capsule, tablet	Viscosity increasing agent, emulsifying agent, suspending agent, gel-forming agent, binder, disintegrant	0.1 to 6.0	Oral, buccal, dental, nasal, intra-articular, parenteral, intrabursal, intradermal, intralesional, intrasynovial
Ethyl alcohol	Solution, elixir, suspension, gel	Preservative, solvent, cosolvent, vehicle, skin enhancer, extracting solvent	Up to 90	Oral, buccal, dental, pulmonar, nasal, ophthalmic, rectal, topical, transdermal, parenteral (intramuscular, intravenous, subcutaneous)
Lactose	Powder, granule, tablet, capsule, pill, orodispersible tablet	Diluent, inhaler carrier, filler, lyophilization aid	Up to 90	Oral, buccal, sublingual, vaginal, pulmonar, parenteral (intravenous, intramuscular, subcutaneous)
Mannitol	Powder, granule, tablet, capsule, pill, lozenge, orally dissolving tablet, orally dispersible film	Tonicity agent, filler, diluent, plasticizer, sweetenner,	Up to 90	Oral, buccal, dental, sublingual, topical, ophthalmic, parenteral (intraperitoneal, subcutaneous, intramuscular, intravenous and bolus)
Mineral oil	Solution, suspension, cream, ointment, lotion, oral paste	Vehicle, diluent, emollient, lubricant, vaccine adjuvant	Up to 90	Oral, topical, ophthalmic, otic, rectal, transdermal, vaginal
Monosodium glutamate	Solution, syrup, suspension, elixir, oral paste	Flavoring agent	0.2 to 0.9	Oral, buccal, dental
Polyethylene glycol	Tablet, capsule, oral paste, lozenge, suppository, ointment, cream, lotion	Plasticizer, solvent, cosolvent, base, vehicle, emulsifier, stabilizing agent, humectant, lubricant, antiadherent, tablet polisher, plasticizer	Up to 30	Oral, buccal, dental, pulmonar, ophthalmic, otic, percutaneous, topical, rectal, vaginal, parenteral (intramuscular and intravenous)
Polysorbate and polyoxyethylene derivatives	Solution, suspension, oral paste, cream, ointment, lotion	Dispersing agent, emulsifying agent, nonionic surfactant, solubilizing agent, suspending agent, wetting agent	0.1 to 15	Oral, buccal, dental, rectal, topical, vaginal, parenteral, ophthalmic, (intramuscular, intravenous and bolus)
Propylene glycol	Solution, syrup, suspension, elixir, gum, oral paste, orally dissolving tablet, orally dispersible film, lozenge, cream, lotion, gel, ointment	Solvent, co-solvent, humectant, plasticizer, extracting solvent, preservative	Up to 80	Oral, buccal, dental, pulmonar, ophthalmic, conjunctival, otic, percutaneous, topical, rectal, vaginal, parenteral (intramuscular, intravenous and, bolus)
Sodium lauryl sulphate	Solution, emulsion, xampu, dentifrice, soap	Emulsifier, surfactant, detergent, solubilizer, lubricant, wetting	0.5 to 50	Oral, buccal, dental, topical
Sulfites	Solution, syrup, suspension, elixir, gum, oral paste, orally dissolving tablet, orally dispersible film, lozenge, cream, lotion, gel, ointment	Preservative, antioxidant	0.01 to 1	Oral, buccal, dental, topical, pulmonary, rectal, vaginal, ophthalmic, parenteral (intramuscular, intravenous and, bolus)
Xylitol	Tablet, capsule, gum, lozenge, solution, syrup, suspension, chewing gum, oral paste	Sweetenner, vehicle, solvent, humectant, coating agent, diluent, filler, stabilizing agent, isotonicity agent	Not found	Oral, buccal, dental, otic, parenteral (intravenous and bolus)

Excipients of concern to the animal population

Xylitol

Xylitol is approved for use in many toiletries (oral rinses, oral antiseptics, and toothpastes) and medicines, including over-the-counter (OTC) medicines such as chewable vitamins, lozenges, and spray solutions. The ingestion of large amounts of xylitol can cause transient gastrointestinal discomfort, and the excipient must be handled with caution, as it can be irritating to the eyes. Gloves and eye protection must be worn during xylitol handling [2].

ARs in dogs caused by xylitol ingestion are extensively reported in the literature, and cases are increasing as a result of accidental or intentional ingestion of products containing the excipient [62, 63]. Xylitol stimulates the synthesis and secretion of insulin, resulting in hyperinsulinemia and hypoglycemia [62–68]. Panagopoulou et al. [32] reported that an intake of more than 0.1 g.kg⁻¹ xylitol leads to the risk of hypoglycemia, while doses greater than 0.5 g.kg⁻¹ may be hepatotoxic. According to the authors, veterinarians should be aware that the ingestion of xylitol can have serious effects, threatening the lives of the target species that ingest it. Clinical signs of xylitol toxicosis in dogs and cats develop within a few min of ingestion (after approximately 30 min) and include vomiting, diarrhea, lethargy, abdominal pain, vocalization, exercise intolerance, ataxia, seizures, tachypnea, fasciculation, and coma. Petechiae, ecchymoses, or disseminated hemorrhages in the gastrointestinal tract have also been observed. Pathological findings include moderate to severe serum hepatic enzyme activity, hyperbilirubinemia, and hyperphosphatemia. Acute liver failure, jaundice, and prolongation of blood coagulation time (prothrombin and partial thromboplastin time) may also be noted. Necropsies performed in dogs indicate the presence of severe hepatic necrosis, and histological examinations reveal severe loss or atrophy of hepatocytes with lobular collapse [22, 69–83].

A study with 18 adult Pekingese dogs evaluated the administration of oral xylitol solutions at concentrations of 1 and 4 g.kg⁻¹. Blood analyses showed that plasma insulin concentrations increased after 20 min of xylitol administration, followed by an increase in hypoglycemia, with a decrease in glycemia after 30 min. Other biochemical alterations noted by the authors were increased activities of alanine aminotransferase and aspartate aminotransferase, hypophosphatemia, hypokalemia, and hypercalcemia [62]. In a similar study, twelve healthy adult crossbreed dogs were given oral aqueous solution at 4 g.kg⁻¹ xylitol, and the authors observed that plasmatic levels of glucagon and lactate increased, while concentrations of pyruvate decreased. An increase in plasma lactate concentration was observed approximately 1 to 2 h after administration, like that observed by Yamamoto et al. [64]. The authors noted an increase in the concentration of lactate in the blood of dogs that received intravenous infusion of xylitol solution at 0.6 g.kg⁻¹. Additionally, dogs developed coagulopathy characterized by prolonged prothrombin time, activated partial thromboplastin time, and thrombin time, with reduced fibrinogen levels, likely secondary to impaired liver function, in line with the previous study. Plasma concentrations of vitamin E, vitamin C, superoxide dismutase and glutathione peroxidase were reduced, while malondialdehyde levels increased, suggesting the existence of oxidative stress [63].

Du Hadway et al. [84] evaluated the prognosis of 192 dogs that ingested different doses of xylitol and were treated at university hospitals. The median dose of xylitol ingested by the animals was 0.32 g.kg⁻¹, and 20% of the animals showed clinical signs of intoxication. Dogs that developed clinical signs ingested a significantly higher dose of xylitol than asymptomatic dogs. In accordance with the authors, dogs ingesting xylitol should be hospitalized to monitor variations in blood glucose and observe the occurrence of liver failure.

Schmid and Hovda [85] reported a clinical case in which acute liver failure was observed in a Chihuahua dog after accidental ingestion of granular xylitol (224 g; 45 g.kg⁻¹). In addition to the increase in liver enzymes, the animal experienced episodes of hypoglycemia, with hormone levels increasing 2.5 to 7 times. Liver failure occurred approximately 8 to 12 h after xylitol ingestion. According to the authors, the use of xylitol in a variety of products intended for human consumption could lead to an increase in cases of toxicity in dogs, and veterinarians should be aware that more dogs could potentially be exposed and develop similar manifestations. The authors suggest that treatment be initiated in dogs that have ingested xylitol doses greater than 0.1 g.kg⁻¹.

Chalifoux and Carr [86] reported the case of a female dog hospitalized after consuming xylitol (estimated intake of 190 to 380 g; 5.96 to 11.91 g.kg⁻¹) used as a pure sweetener. Blood tests revealed hepatic extravasation, cholestasis, hyperlactatemia, thrombocytopenia, and prolonged prothrombin and activated partial thromboplastin time. Chest X-rays on the second day of hospitalization showed pulmonary hemorrhage. The animal developed an alternating pulse suggestive of myocardial dysfunction secondary to severe systemic inflammation, which resulted in death.

Although widely reported in dogs, adverse reactions to xylitol have also been observed in other animals. In cats, changes in nephrons and renal tubules have occurred after xylitol administration. High doses can cause severe hypovolemia [87–89]. Gardner and Mitchell [88] reported a case of acute intoxication of 29 wild cape sugarbirds (Promerops cafer) after ingestion of a homemade xylitol solution used as food. Clinical signs appeared approximately 15 min after xylitol ingestion and included incoordination, weakness, falls from perches, collapse, and death. Acute exposure of rabbits to different concentrations of xylitol in solutions administered by intravenous infusion was investigated by Wang et al. [88], who observed acute toxicity at a concentration of 50%. Increases in serum levels of serum glutamic-oxalacetic transaminase and serum lactic acid dehydrogenase were observed, along with an increase in urine volume. The lethal dose (LD₅₀) of a 50% solution infused at a rate of 87 mg.kg⁻¹.min⁻¹ has been estimated to be between 4 and 6 g xylitol.kg⁻¹ body weight. The infusion rate influenced the toxicity, correlated with the hyperosmolar effect.

Propylene glycol

Propylene glycol (PPG) is widely used in a variety of parenteral and nonparenteral dosage forms. PPG is a better solvent than glycerin and dissolves a wide variety of ingredients, including flavors, in place of ethanol, as it is nonvolatile. PPG is used in many OTC medicines for human and veterinary use [90]. In topical preparations, PPG is considered minimally irritating, although it is absorbed by the skin and mucous membranes, especially when there is damage to the barrier. Parenteral administration can cause pain or irritation when PPG is used in high concentrations [2, 91]. Upon ingestion, PPG is rapidly and completely absorbed from the gastrointestinal tract and undergoes oxidation to pyruvic acid, acetic acid, lactic acid, and propionaldehyde. Metabolites are efficiently cleared by the citric acid cycle. PPG is also rapidly converted to propionic acid, a volatile fatty acid, which is readily absorbed and converted to glucose through gluconeogenesis. However, high levels of PPG can lead to oxidative damage and reduce the lifespan of erythrocytes. Subcutaneous administration of PPG can cause irritation and result in bradycardia, respiratory problems, and central nervous system depression. ARs to PPG have also been documented in dogs, cats, guinea pigs, horses, calves, sheep, rabbits, chinchillas, and llamas. The oral LD₅₀ of PPG for dogs is 9 mL.kg⁻¹, with horses appearing to be more sensitive, experiencing poisoning at an oral LD₅₀ of approximately 6 mL.kg⁻¹ [47, 92–100]. Caution should be exercised when PPG-containing medicines are administered in these populations.

When administered to cats at both low and high dose levels, PPG drives the formation of Heinz bodies within red blood cells, which is associated with anemia. Reports have indicated increased formation of Heinz corpuscles associated with the use of products containing PPG as a vehicle. PPG toxicity can manifest as mild neurological signs, including ataxia and depression, when high doses are administered. Cardiotoxicity, seizures, and lactic acidosis have also been reported as adverse reactions to PPG. Intravascular hemolysis leading to hemoglobinuria has been observed, particularly when PPG-containing medicines are administered intravenously [92, 93].

Moon [47] conducted a study evaluating the infusion of etomidate in dogs using saline solution and PPG as a vehicle. The study found that only animals receiving etomidate dissolved in PPG experienced adverse reactions, including mild hemoglobinuria, obnubilation, bradycardia, hypothermia, and intravascular hemolysis. Clinical signs of PPG poisoning resemble those observed in ethylene glycol poisoning and include ataxia, seizures, mental alterations, metabolic acidosis, hyperosmolality, and nephrotoxicity [47, 93].

Several studies have demonstrated cases of intoxication in horses after the administration of PPG-containing products by topical and intravenous routes. The animals manifested severe depression, ataxia, halitosis, and foul-smelling stools. Other clinical signs observed included salivation, signs of pain, cyanosis and breathing problems [94–97]. The intravenous administration of different concentrations of chloramphenicol dissolved in a vehicle containing PPG as a diluent was evaluated in 30 horses that received the treatments for 5 days. One animal group received only PPG. Eleven horses died during the trial, and another 13 showed clinical signs such as changes in gastrointestinal motility, diarrhea, anorexia, and depression. Ataxia was also observed in 2 animals. Moderate to severe inflammation along the intestinal tract was noted at necropsy [98]. In a case reported by Ivany and Anderson [99], the administration of a PPG-containing gel for the treatment of ketosis caused intoxication in a llama, resulting in lethargy and dehydration. In calves, periods of cardiodepressor effects have been observed following the intravenous administration of solutions of oxytetracicline using PPG as a vehicle. Intravenous administration of PPG-based products and pure PPG cause cardiac asystole, systemic hypotension and decreased arterial and renal blood flow contrary to what was noted for the API aqueous solution administered by the same route [56, 57]. Intravenous injection of an aqueous solution of pentobarbitone sodium in 20% PPG caused hemoglobinemia and hemoglobinuria in sheep, contrary to the administration of the same anesthetic in water and in 20% glycerol, under identical conditions, demonstrating the existence of hemolytic activity from PPG. For the authors, PPG should be avoided as an excipient in solutions for IV use in these animals [58]. Pearl and Rice [59] advise that products containing PPG as a vehicle be administered cautiously to calves and sheep by the intravenous route.

PPG is used in various medications for removing earwax in animals. Laboratory studies have shown that PPG can induce chronic inflammatory changes in the middle cavity and tympanic membrane of guinea pigs and chinchillas, leading to epidermal hyperplasia, potential epidermal invasion, keratinization, and the formation of cholesteatoma. Additionally, findings such as granulation tissue, inflammation, bone thickening, osteogenesis, bulla cyst formation, fibrous adhesions, tympanic membrane perforation, fibrosis and reactive osteogenesis in the inner ear have been observed [100–102].

Finally, exposure of rabbits to aerosolized PPG caused degeneration of goblet cells present in the tracheal epithelium during an acute inhalation toxicity study. In comparison with mucolytic products used as controls, inhalation of 10% PPG caused greater alteration in ciliated cells, with a less pronounced effect on goblet cells [54].

Polyethylene glycol

As with the chemical properties of polyethylene glycols (PEGs) in formulations, both the functions and toxicity of this excipient are based on molecular weight and chain length. Topical products containing PEG should be used with caution in animals with extensive burns, open wounds, and renal insufficiency [2]. When administered to mucous membranes, PEG can cause hives or delayed allergic reactions and can cause mild, transient ocular irritation in rabbits. Rapid intravenous administration of undiluted PEG-containing products can lead to intravascular hemolysis and cardiodepressant effects. Prolonged use and high doses of PEGs can lead to water and electrolyte losses and cause nausea [103].

A study carried out to evaluate the topical exposure of rabbits to PEG-based antimicrobial cream or PEG-vehicle alone applied in induced lesions showed that seven of the eight rabbits treated with the antimicrobial cream and three of the four rabbits treated with the PEG-vehicle died during the study. All animals showed elevated total serum calcium, osmolality gap, anion gap metabolic acidosis, and renal failure. The six animals used as controls in the study survived. The authors suggested that the symptoms observed in the experimental animals resulted from systemic toxicity by the absorption of PEG, which was metabolized to acidic alcohols and diacids, which can be potentially toxic to the kidneys and skin cells [104]. Therefore, caution should be exercised when applying PEG-based products to damage skin to avoid topical absorption of the ingredient.

Groups of six dogs received PEGs intravenously at doses ranging from 2 to 3 g.kg⁻¹, and at a dose of 3 g.kg⁻¹, a gradual decline in blood pressure and periodic apnea were observed. Eventually, the animals suffered complete respiratory arrest. At necropsy, these dogs had pulmonary edema and small infarcts in the lungs [105]. Administration of vaccines containing pegylated APIs or pegylated nanocarriers may result in the generation of antibodies that specifically bind to PEG (anti-PEG antibodies) and cause adverse reactions. Extensive research into this adverse reaction is reflected in product registration applications with the US Food and Drug Administration (FDA), which require the performance of assays that measure anti-PEG antibody responses in new products containing pegylated derivatives [106]. In a study carried out by Feenstra et al. (2022), it was observed that subsequent administrations of a second and third dose of pegylated-asparaginase in seven healthy beagle dogs developed asparagine suppression accompanied by the development of antibodies against PEG and L-asparaginase [107].

Monkeys (Macaca fascicularis) were exposed to PEG 200 orally for a period of 13 weeks at dose levels of 2 to 4 mL.kg⁻¹. per day. Lesions consisting of intratubular deposition of a small number of oxalate crystals in the renal cortex were encountered, which were not associated with other clinical or pathological findings, suggesting that they were caused by PEG [108].

Lactose

Lactose is a carbohydrate-based excipient incorporated in high proportions in pharmaceutical dosage forms for oral, parenteral, and pulmonary use. When administered orally, it is hydrolyzed by the enzyme lactase into glucose and galactose, which are absorbed. As an energy source, lactose provides 4 kcal.g⁻¹ and has a low glycemic index: only small amounts of intact lactose are absorbed. Lactose is not considered toxic or harmful to healthy individuals. However, adverse effects may occur in patients with preexisting conditions such as lactase deficiency, glucose-galactose malabsorption, and diabetes mellitus. Lactose may contain traces of cow's milk proteins that can cause severe allergic reactions in patients with allergies [2, 109].

Like humans, lactose intolerance has been reported in animals; cases have been documented in calves, goats, lambs, and monkeys, where the presence of lactose in their food led to the development of primary or secondary diarrhea. These adverse reactions were attributed to the absence of lactase impairing the digestion of lactose. In addition to diarrhea, symptoms such as abdominal nausea and bloating may occur, and prolonged use of lactose-containing products can lead to weight loss [110–119]. Eadala et al. (2009) identified the presence of lactose in several medicines for oral use and quantified its proportion using high-performance liquid chromatography (HPLC) and concluded that the excipient was present in sufficient quantity to contribute to the occurrence of abdominal and systemic symptoms [120].

Mannitol

Mannitol or cordycepic acid is a polyol, similar to xylitol or sorbitol, but with a tendency to lose hydrogen ions in aqueous solutions, making them acidic. If inhaled, mannitol can cause bronchospasm and hemoptysis. When ingested orally in large doses, however, mannitol can cause osmotic diarrhea and severe hypovolemia. Clinical signs of adverse reactions to mannitol include changes in hydroelectrolytic balance; gastrointestinal effects such as nausea and vomiting; cardiovascular effects, such as pulmonary edema and tachycardia; and effects on the central nervous system (CNS), such as dizziness and headache. Excessive excretion of sodium, potassium, and chloride may also occur [121, 122]. It is used as a diluent agent in the proportion of 10 to 90% w/w, and it is preferred for the preparation of solid formulations in which the active ingredients are hygroscopic and sensitive to moisture while also providing a refreshing feeling [2].

Mannitol-induced diuresis, which can lead to electrolyte disturbances, dehydration, hypovolemia, and cardiovascular collapse, is therefore contraindicated in hypovolemic patients [28, 67, 123]. Clabots et al. [124] described an unprecedent study reporting the existence of kidney damage, seizures, and hypertonic hyponatremia secondary to mannitol intoxication in a dog, with consistent signs of mannitol overdose, initiated 36 h after the start of therapy and 12 h after the second injection of mannitol used as API. Considering that mannitol can be used as a single diluent in medicines for intravenous administration, the use of these products must be monitored, especially the increase in the osmolal gap (GP), which must be kept < 55 mOsm.kg⁻¹ to avoid complications.

Ethyl alcohol

Ethyl alcohol, also known as ethanol, is used in the pharmaceutical industry as a solvent and vehicle in personal care products and medicines in variable amounts of up to 90% of the formulations [2, 125, 126]. The metabolism of ethanol involves biotransformation into acetaldehyde by gastric alcohol dehydrogenase enzyme, followed by further conversion to acetaldehyde by liver alcohol dehydrogenase enzyme. Ethanol can also be converted to acetaldehyde by hepatic cytochrome enzymes. Changes in ethanol metabolism can occur due to alterations in the liver's redox state and neuroendocrine disturbances. These changes can lead to decreased gluconeogenesis and fatty acid oxidation as well as an increased lactate-to-pyruvate ratio. The concern with vomiting during intoxication is that the muscles that control the epiglottis are slow to react or become paralyzed, increasing the risk of aspiration. In the stomach, high levels are irritating, and in the blood, they stimulate emesis. Ethanol intoxication reduces the peripheral oxygen supply, causing mitochondrial oxidative dysfunction and potentially resulting in shock or hypoxia in acute intoxication. In the CNS, ethanol enhances the inhibitory effects of gamma-aminobutyric acid and competitively inhibits glycine binding at the N-methyl-d-aspartate receptor, interrupting excitatory glutaminergic neurotransmission. Other inhibitory neurotransmitters, such as dopamine and serotonin, are also stimulated. Hypothermia can result from multiple mechanisms. Ethyl alcohol can be absorbed through damaged skin [127–129].

Exposure to ethanol, whether through oral ingestion or skin contact, can have toxic effects on dogs and cats. In dogs, ethanol inhibits the release of vasopressin and can lead to the development of rapid tolerance. However, the LD₅₀ to ethanol in dogs can vary between 4 and 8 ml.kg⁻¹, and ingestion of such amounts can lead to death within 12 to 24 h. The symptoms commonly observed in these animals include CNS depression, respiratory arrest, incontinence, decreased heart rate, hypersalivation, and vomiting. Other clinical signs are ataxia, incoordination, loss of consciousness, drowsiness, dizziness and, in severe cases, death due to respiratory paralysis [23, 130–135]. In bovines, oral or dermal exposure to ethanol can result in CNS depression, lethargy, incoordination, urinary incontinence, bradycardia, hypersalivation, and emesis [23].

Mineral oil

Different hydrocarbons, such as solid paraffin, liquid paraffin (mineral oil), petrolatum (yellow wax), vegetable oils, butter, and waxes, are commonly used as excipients in liquid and semisolid formulations. Mineral oil (MO) is mainly employed in pharmaceutical forms for topical use and is considered a nonirritating and nontoxic excipient by this route. MO is used as an adjuvant in vaccines to stimulate the immune response [2].

In cats, the use of MO can lead to a significant adverse reaction known as exogenous lipid pneumonia (ELP) when used for the treatment of constipation and hairballs. ELP resulting from the aspiration of MO is also common in dogs and horses. Clinical signs of ELP can vary from absent to severe, depending on the amount of lipid aspirated. Absorption of MO into the intestine can lead to granulomatous reactions in the liver, spleen, and mesenteric lymph nodes. Long-term administration of MO coats the small intestine forming a waterproof film and may reduce the absorption of fat-soluble vitamins (A, D, E, and K) [136–141].

A study by Eördögh et al. [44] evaluated the ocular toxicity of different bases used in the preparation of ophthalmic drugs for cats. They prepared ointments using liquid vaseline and white petrolatum, either alone or in combination with lanolin, as well as oil-in-water and water-in-oil type creams using waxes. The study found that oily ointments composed of white petrolatum and liquid paraffin without lanolin had prolonged contact time and were difficult to eliminate, resulting in greater irritation of the mucosa compared to ointment with lanolin and creams. The authors concluded that semisolid ophthalmic products should be applied with caution, especially if needed for prolonged periods.

Polysorbates and polyoxyethylene castor oil derivatives

Polyoxyethylene sorbitan fatty acid esters (polysorbates) are a series of partial esters of sorbitol fatty acids and their anhydrides copolymerized with different proportions of ethylene oxide molecules. Polysorbates containing 20 oxyethylene units are hydrophilic nonionic surfactants used in the preparation of emulsions in proportions of up to 15%. There are reports of adverse reactions to a vitamin product containing a mixture of polysorbates 20 and 80 administered intravenously [2]. Polyoxyethylene 20 sorbitan monooleate (PS80) is present in several medicines, including formulations containing antiarrhythmic and other APIs, which are poorly soluble in water. PS80 is also used as a vehicle in preclinical studies for oral and parenteral administration [142, 143]. Several studies have reported the presence of toxicity in animals, both dose-dependent and nondose dependent, associated with PS20 and PS80 [142–148].

In a study, 22 dogs received 5 mL of intravenous infusion of polysorbate 20 at a rate of 0.2 mL.15 s⁻¹, and clinical reactions such as the symptoms of anaphylaxis were observed. Other changes included decreased blood pressure, heart rate, and plasma volume, as well as increased respiratory rate, lymph flow, and hematocrit [147]. An experiment that evaluated the application of a foam containing PS20 to 6% in the vaginal cavity of three beagle dogs once a day, 5 days a week, for 3 weeks, produced severe irritation, causing mucosal lesions characterized by redness, blistering, mucosal sloughing, and fibrous adhesions in one case [148].

The minimum lethal dose for intravenous administration of PS80 in dogs and cats was 0.5 g.kg⁻¹ [147]. Gough et al. [45] conducted a study to evaluate the influence of PS80 present in amiodarone solutions for intravenous administration in dogs and concluded that PS80 is not an inert excipient but a potent cardiac depressant. An intravenous solution of amiodarone containing 10 mg.kg⁻¹ of PS80 as a solubilizer, administered to a dog over 5 min, produced severe hypotension after the first administration, while the second injection (24 h later) caused fewer hypotensive effects [46]. Torres-Arraut, Singh and Pickoff [61] demonstrated that PS80 is a potent depressant of the cardiac conduction system in dogs, being responsible for the ARs observed to amiodarone solutions administered intravenously in anesthetized adult dogs at doses of 10 and 20 mg.kg⁻¹, equivalent to the amount of diluent present in commercial intravenous amiodarone solutions. He et al. [40] evaluated the sensitization capacity of different components present in an injectable herbal product in beagle dogs and noted that PS80 at 0.2% showed symptoms typical of anaphylactoid reactions, although there was no significant increase in serum histamine. As stated by Qiu et al. [41], the intravenous administration of pharmaceutical dosage forms containing PS80 can promote changes in pulmonary and arterial pressure, triggering cardiorespiratory depression in dogs. The authors also associated the presence of PS80 with the occurrence of a typical nonimmune allergic reaction (pseudoallergy) leading to the release of histamine and IgE antibodies. Mi et al. [51] observed that vitamin K1 injection induced the release of inflammatory factors via a non-IgE-mediated immune pathway and concluded that the trigger may be the PS80 added to the formulation as a solubilizer. Yang et al. [53] demonstrated that spontaneously formed PS80 impurities, such as peroxides and oxidized fatty acid residues, can induce anaphylactoid reactions in zebrafish, and polysorbates and other excipients characterized as complex mixtures present potential health risks. Pouliot et al. [52] evaluated the cardiovascular and cutaneous effects of PS80 administration in beagle dogs, monkeys, and minipigs as a function of the dose delivered by different routes. Dogs displayed signs of anaphylactoid reactions manifested in the form of erythema, edema, and signs of pruritus that occurred at lower doses. Increased heart rate and decreased blood pressure were observed as the PS80 dose was increased. The threshold for cardiovascular effects was less than 0.5 mg.kg⁻¹ for intravenous bolus, 0.3 mg.kg⁻¹ for intravenous infusion, 15 mg.kg⁻¹ for subcutaneous injection, and 10 mg.kg⁻¹ for oral administration. These results suggest that the reactions are dose-dependent and vary based on the administration route. Sun, Li and Zhang [48] and Sun et al. [49] conducted studies in beagle dogs and noted that the occurrence of nonimmune anaphylactic reactions due to the use of PS80 is dependent on the dose and route of administration, which corroborates the findings of Pouliot et al. [52].

Khosravinia, Manafi and Rafiei Alavi [142] provided water containing PS80 (3500 ppm) to broiler chickens and observed a significant increase in the levels of alkaline phosphatase (ALP) enzyme in their serum. Based on these findings, the persistent exposure of broiler chicks to PS80 at the studied concentration through their drinking water was found to have a negative impact on the growth performance of animals during their juvenile stage.

Another surfactant derived from polyoxyethylene is Cremophor® EL (macrogol glycerol ricinoleate), a polyethoxylated derivative of castor oil. Cremophor® is used as a solubilizer and emulsifier in oral, topical, and parenteral formulations, optimizing the bioavailability and efficacy of vitamins in animal feed and veterinary medicines [2, 149, 150]. There are reports of cardiovascular problems and nephrotoxicity in dogs byproducts that are presented in its formulation, such as polyoxyethyleneated castor oil derivatives [151].

Sodium lauryl sulfate and benzalkonium chloride

Excipients with detergent action are potentially irritating to the skin, eyes, and oral and respiratory mucous membranes, causing local and systemic reactions. The main manifestations of exposure to gastrointestinal surfactants are delayed-onset hypersalivation, vomiting, diarrhea, lack of appetite, abdominal discomfort, and hyperthermia. Occasionally, there may also be oral ulceration and glossitis (inflammation of the tongue). Respiratory complications, including coughing, abnormal lung sounds, and dyspnea, may also occur. In the eyes, they can cause conjunctival hyperemia, edema, and corneal ulceration. Topical exposure can cause erythema, inflammation, and dermatitis, and in many cases, burns, alopecia, edema, and skin peeling may occur. The severity of clinical signs depends on the type of surfactant, amount, route, and duration of contact. Anionic and nonionic surfactants are considered less toxic than cationic surfactants. Both anionic and nonionic surfactants, despite low systemic toxicity, can be irritating to the gastrointestinal tract and cause vomiting or diarrhea [152–154].

Among the most commonly used surfactants, sodium lauryl sulfate (SLS) is one of the most common and is also included in liquid and semisolid medicines. SLS should not be used in parenteral formulations [2]. SLS at a 1:10 dilution was applied to the vaginal mucosa of three beagle dogs, and no changes were noted after 24 h. The undiluted ingredient (28%) produced mild redness in two of the three dogs and diffuse tissue irritation in the third animal. ARs to detergents are more common in cats due to their grooming and licking behavior [155].

Benzalkonium chloride (BC) is a quaternary ammonium compound used as a cationic surfactant that is widely used as a detergent in personal products and as a preservative in pharmaceutical products, including those for ophthalmic and optical use [2]. Caloni et al. [27] conducted a retrospective analysis of poisoning cases in dogs and cats and reported two incidents of cat poisoning following skin exposure to BC in cleaning, cosmetic, and hygiene products. Burstein [42] found a significant increase in corneal lesions in cats and rabbits that were exposed to aqueous solutions of BC at concentrations ranging from 0.001% to 0.01%.

Benzoic acid, sodium benzoate and benzyl alcohol

Benzoic acid (BAC) and sodium benzoate are commonly used as preservatives in pharmaceutical formulations [2]. After oral and dermal uptake, benzoic acid and sodium benzoate are conjugated to glycine in the liver and excreted as hippuric acid, which is rapidly excreted in urine. Therefore, the metabolism of benzoate depletes glycine concentrations, which can alter the metabolism of other glycine-dependent substances. Another pathway involved in the metabolism of benzoic acid and sodium benzoate is glucuronidation, a route that is deficient in cats, resulting in the inability to metabolize BAC properly and causing intoxication. BAC and benzoates can accumulate in cats, which can potentially compromise the safety of using medicines containing these substances [156, 157]. The use of BAC in cats by oral route can lead to oxidative damage in red blood cells and the development of hemolytic anemia. Other symptoms include ataxia, blindness, respiratory problems, fasciculations, behavioral changes, seizures, and other central nervous system disorders, and in severe cases, it can even result in death. These effects can occur even after the administration of a single dose of medicines containing benzoic acid [158–164].

Benzyl alcohol (BA) can cause hyperkinesia in cats and neurological symptoms in dogs, sometimes leading to fatalities in both species [2, 43, 165–167]. BA is rapidly oxidized by the enzyme alcohol dehydrogenase to benzyl aldehyde, which is converted to benzoic acid. As benzoic acid is not metabolized by cats due to the deficiency in the glucuronidation pathway, similar to what happens with benzoic acid and sodium benzoate, benzyl alcohol can also cause adverse reactions in these animals [50]. Administration of BA can result in coma, respiratory failure, and death. Clinical signs of BA poisoning include difficulty walking, agitation, increased sensitivity to stimuli, and depression. Other signs associated with the administration of injectables containing BA include ataxia, hyperesthesia, spasms of the head and ear muscles, mild to severe depression, coma, respiratory failure, seizures, and death [165–167]. According to Cope [91], toxicity related to benzyl alcohol has been commonly reported in cats receiving lactate Ringer's solutions containing this excipient as a preservative. Cases of poisoning by benzoic acid and its derivatives are well documented, leading to recommendations to minimize the amounts of this excipient in pharmaceutical forms intended for feline use [22, 28–30, 161, 162].

Monosodium glutamate

Monosodium glutamate (MSG) is commonly used in oral pharmaceutical formulations as a flavor enhancer to improve the taste of bitter APIs and reduce the metallic aftertaste in formulations containing iron. It is also widely utilized as a flavor enhancer in food [2].

Elsharkawy et al. [168] conducted a study investigating the nephrotoxic and hepatotoxic effects of MSG and sodium metabisulfite (SM) in the diet of broiler chicks. The results showed increased levels of alkaline phosphatase enzyme, creatinine, malondialdehyde (indicating oxidative stress), and superoxide dismutase in the exposed group compared to the control group. Liver disorders with hydropic changes in liver cells, congestion of interstitial blood vessels, and necrobiosis of the renal tubule epithelium were also observed. Similarly, Khadiga et al. [169] conducted a similar experiment and observed adverse effects on the nervous tissue of broiler chicks. Olarotimi [170] observed that diets with MSG concentrations above 0.5 g.kg⁻¹ were detrimental to normal physiological processes in broilers, leading to renal dysfunction, coronary problems, and oxidative stress. Gbore et al. [171] analyzed the impact of various doses of MSG aqueous solution on growth performance and blood parameters in rabbits and found that even at low doses, MSG resulted in changes in body weight, hepatotoxic effects, and dyslipidemia. Okoye et al. [172] observed that the administration of MSG altered serum levels of luteinizing hormone, testosterone, cholesterol, and aspartate aminotransferase activity.

Other excipients related to adverse reactions in animals

Sulfites are excipients considered to be employed as antioxidants in many pharmaceutical dosage forms [2]. After oral ingestion, SM is oxidized to sulfate and is excreted in the urine, releasing sulfurous acid, which can result in irritation. The ingestion of large amounts can lead to symptoms such as cramps, diarrhea, dermatitis, hives, flushing, gastrointestinal symptoms, circulatory disorders, central nervous system depression, and even death. Hypersensitivity and bronchospasm may occur in animals prone to respiratory problems [2]. Thiamine deficiency (vitamin B1), resulting from the conversion of thiamine by sulfur into thiamine disulfide, has been extensively documented in dogs and cats that consumed diets containing sulfites as preservatives [173–178]. Takenaka et al. [177] evaluated the effects of long-term continuous intrapulmonary exposure to sulfite-containing aerosols in beagle dogs and observed changes throughout the extrapulmonary airway, including the posterior nasal cavity, larynx, and trachea [177]. Steel [178] reported the death of a cat due to acute thiamine deficiency caused by the presence of sulfites as preservatives in the meat used in the cat's diet for 38 days.

Sodium carboxymethylcellulose (NaCMC), also named sodium carmellose, is primarily used to increase the viscosity of liquid and semisolid formulations [2]. NaCMC has been implicated in anaphylactic reactions that occur with the administration of benzathine penicillin in cattle [179, 180]. Hypersensitivity reactions can vary in severity and may include symptoms such as itching, rash, difficulty breathing, and swelling [19, 144, 145]. These reactions are rare but should be taken into consideration when using pharmaceutical products containing NaCMC, especially in susceptible animal species.

Bentonite is a colloidal silicate that is commonly found in natural clay and contains a high proportion of montmorillonite, an aluminum silicate with the potential for magnesium and iron substitution in some aluminum and silicon atoms that can be replaced by magnesium and iron [2]. The use of bentonite in animal nutrition has demonstrated its ability to adsorb micronutrients, which can potentially impact animal health. Reports have indicated that chickens fed diets containing 0.5% to 3% w/w of bentonite experienced vitamin A deficiency. Furthermore, the inclusion of 0.5% to 2% w/w of bentonite in chicken diets resulted in decreased serum levels of zinc, copper, and manganese. Birds fed diets containing 2.5% to 5% w/w bentonite displayed a significant decrease in triiodothyronine and thyroxine hormones [181–191].

Conclusions

Excipients are essential components of medicines, and in addition to impacting the quality of products, they play a crucial role in the performance of pharmacotherapy. However, like APIs, excipients can cause adverse reactions in target animal populations, even when they are considered safe and used under the correct conditions. Although there are numerous reports of ARs to excipients in humans, especially in pediatric and neonatal populations, reports of cases in animals are scarce and are not addressed in the literature in a clear and profound way. The importance of including information about the excipients of interest in the package inserts and labeling of medicines for exclusive veterinary use is not adequately observed by health authorities and veterinary prescribers. Even though the concentrations that cause toxicity are not recognized, as well as the safe routes of administration for all animal species given the great variability of species and animal physiology, the information supports the alert about the existence of the problem. With the information reported in the article, the authors hope to alert veterinarians to greater caution in the use of pharmaceutical products that contain the excipients of concern, favoring the establishment of careful clinical reasoning and supporting a safe clinical intervention in pharmacotherapy. In addition, the information supports veterinary pharmacovigilance actions, especially in cases of adverse reactions.

Authors' contribution

All authors made substantial contributions to the acquisition of data and analysis of information. Additionally, each author actively participated in the preparation and revision of the manuscript, and provided their final approval of the version to be published.

Funding

This study was granted financial support through a collaborative announcement established between the Coordination for the Improvement of Higher Education Personnel (CAPES, Brazil) and the Espírito Santo Research and Innovation Foundation (FAPES, Brazil) [Call Notice No. 18/2020; TO 0137/2021].

Declarations

Conflict of interest

The authors declare no conflicts of interest.