A literature search was conducted of original articles, reviews and case reports addressing the safety of excipients in medicinal products for pediatric patients published between 2014 and 2025 available in English or Spanish. Study eligibility was based on the following criteria:

Inclusion criteria: (i) studies describing adverse events associated with drug excipients, along with the doses causing such AEs; (ii) studies that account for the toxicologic and pharmacokinetic mechanisms that lead to such AEs.

The following exclusion criteria were applied: (i) publications not primarily focused on pediatric patient safety; (ii) studies reporting toxicological effects associated with food rather than drug exposure; (iii) studies conducted in adult populations; (iv) articles not published in English or Spanish; and (v) studies without available full text.

A comprehensive literature search was performed using the PubMed, Web of Science, and ScienceDirect databases, complemented by searches of regulatory agency websites, including those of the European Medicines Agency (EMA),6,8 the Food and Drug Administration (FDA),9 the Spanish Agency for Medicines and Medical Devices (AEMPS),10 and the Madrid Health System (SERMAS).11 The search strategy included terms such as “excipients”, “pediatric”, “children”, “toxicity” and “safety”, along with the names and synonyms of known excipients, in combination with Boolean operators “AND” and “OR”. Additionally, 31 studies were retrieved from gray literature not indexed in the databases detailed above.

Two reviewers separately performed an evaluation of all titles and abstracts to identify potentially eligible studies. Subsequently, the two reviewers carried out full-text reading for appropriateness.

Information was collected on each excipient regarding their general use, toxicokinetics and toxicodynamics, as well as the dosage regimens recommended by the main regulatory agencies.

Around 40% of dispensed medications and 90% of newly discovered therapeutic compounds exhibit poor solubility in aqueous environments.12 This limitation is overcome through the use of co-diluents and tensioactive agents.5 The potential documented mechanisms of toxicity of some of the excipients in this category are explained in the following section:

Ethanol is a widely used excipient primarily used in oral, topic, buccal, inhalation and injectable forms. This excipient is characterized by its high gastrointestinal absorption and permeability through the blood-brain barrier.5 Ethanol binds gamma-aminobutyric acid A (GABA-A) and N-methyl-D-aspartate (NMDA), thereby triggering a propapoptotic cascade in neurons and causing excitotoxicity.13,14 Although this association has not been completely confirmed, ethanol can cause long-lasting cognitive and behavioral defects in neonates. The reason is that neuronal differentiation, myelinization and migration are not fully developed during the neonatal period.13

Ethanol toxicity in patients younger than 6 is primarily caused by alcohol dehydrogenase (ADH) enzyme deficiency, which metabolizes ethanol into acetaldehyde, a metabolite with lower toxicity. In this population, ADH activity is <20% with respect to that in adults, resulting in the accumulation of acetaldehyde and ethanol.15–17 The chronic intake of ethanol –even at low doses– is contraindicated in children younger than 6 and is limited to a maximum period of two weeks in children older than 6.15 Pediatric patients with liver disease or receiving disulfiram or metronidazole have a higher risk of toxicity.16

Propylene glycol is a multifunctional excipient used in a wide range of pediatric formulations, including oral, topic and injectable medications. Like in the case of ethanol, propylene glycol (PG) toxicity is caused by ADH and aldehyde dehydrogenase enzyme (ALDH) deficiency, which converts acetaldehyde into acetic acid, a non-toxic metabolite. The immaturity of this enzyme in infants younger than 4 contributes4,17,18 to a higher half-life of PG (10.8 to 30.5 h) as compared to adults (1.4 to 3.3 h).19,20 This long half-life favors the accumulation of toxic metabolites, thereby resulting in hepatotoxicity, nephrotoxicity and neurotoxicity,9,18 as detailed in Table 1. Additionally, when administered concomitantly with ethanol, the latter exhibits 10- to 20-fold higher affinity for ADH, thereby competitively inhibiting PG metabolism.13

Polyethylene glycol (PEG) 3350, 6000, 2000 and other agents with lower molecular weight are used as excipients in injectable and oral medications, suppositories and ointments. PEG 3350 and 4000 are used as active ingredients in colonoscopy bowel preparation medications and laxatives.32 In general terms, PEG is biologically inactive and has low oral bioavailability.16 However, evidence has been provided that PEG in cimetidine forms may extend gastric emptying time and compromise drug bioavailability. Moreover, PEG stearate induces the cytochrome-P450 enzyme, resulting in a reduced area under the curve of midazolam.33

Although the FDA approved PEG 3350 exclusively for patients older than 17 years for a period below 7 days, it is commonly found in preparations for pediatric patients. Long-term exposure could lead to low molecular weight compounds reaching toxic levels, as in the case of ethylene glycol, diethylene glycol and triethylene glycol.26,34,35 Cases have been reported of IgE-mediated hypersensitivity in mRNA COVID-19 vaccines containing the excipient PEG 2000.16,32

Glycerin is used in a diversity of pediatric formulations, including laxatives, intravenous solutions and syrups. Glycerin is generally safe at low doses; however, at high concentrations (e.g. in laxatives or intravenous solutions), it may cause electrolyte and gastrointestinal abnormalities,5,15,29 especially in children with compromised kidney function. This excipient may also affect absorption in medications such as omeprazole and loperamide.5,15,17

Polysorbates 20 and 80 are the most widely used tensioactive agents. Although the toxicokinetics of these substances are still not fully understood, they have been documented to inhibit glycoprotein P (P-gp) activity, which is an efflux pump. P-gp inhibition may influence drug bioavailability and distribution15,30; hence, careful dose adjustment and monitoring are needed in the absence of safe concentration thresholds for chronic exposure.

Table 1 details the most relevant solvents and tensioactive agents in terms of their associated adverse events in pediatric patients.

Lecithin –extracted from natural sources such as soya– acts as a biodegradable and biocompatible tensioactive agent. The European Food Safety Authority (EFSA) concluded that lecithin does not exhibit acute or chronic toxicity, nor developmental effects, even at high doses.28 As a very rare adverse event, its vegetal nature may cause allergic reactions in children with soya hypersensitivity.36

Preservatives are added to medications to prevent microorganism growth during manufacturing, storage or administration processes. The American Academy of Pediatrics does not recommend their use in children younger than 3 years due to their physiological and metabolic immaturity.5 On another note, its stability may be compromised by the presence of oxygen, a problem that is mitigated by the use of antioxidants.33 A description of the mechanisms of toxicity documented for some preservatives and antioxidants is provided in the following section.

Methylparaben, ethylparaben, propylparaben, and butylparaben are the most common parabens in oral and parenteral pharmaceutical formulations. These excipients may disrupt the endocrine system and accumulate in tissues,37,38 exerting obesogenic effects39 by increasing the number and size of adipocytes; this increase is mediated by interference with adipose tissue transcriptional regulators, particularly via peroxisome proliferator-activated receptors (PPARs).40 Additionally, evidence has raised concerns that methyl- and propylparaben may interact with estrogen receptors. Hence, propylparaben may exhibit antiandrogenic activity13,17,41 and butylparaben may cause cellular toxicity.33 This group of excipients has been documented to disturb bilirubin and albumin binding; consequently, it should be avoided in patients with jaundice.15,29 Parabens may trigger cross-hypersensitivity reactions in aspirin-allergic individuals, owing to their structural similarity to hydroxyparabenzoic acid, a paraben metabolite.5,42 Potential genotoxic effects have also been described in in vitro studies,5 raising concerns that chronic exposure to low doses in children could increase the risk of cellular changes.38,40,42

Sodium benzoate is used in multi-dose forms like syrups and oral solutions. This excipient is rapidly absorbed orally and is metabolized by the liver into benzoic acid, which conjugates with glycine to form hippuric acid, being primarily excreted in urine.43 In preterm neonates and infants younger than 4 weeks, the immaturity of glycine N-acyltransferase –an enzyme involved in the conjugation of sodium benzoate with glycine to produce hippuric acid– results in the accumulation of benzoic acid.5,17,44 This excipient may compete with bilirubin for binding sites on albumin and may trigger immediate non-immunological reactions, possibly mediated by a cholinergic mechanism.15,17 IgE- and histamine-mediated hypersensitivity reactions have been described, along with structural similarities to acetylsalicylic acid that may influence eicosanoid synthesis.16,43 Co-administration with ethanol or PG may impair hippuric acid excretion.13 At present, no safe concentration thresholds have been defined for chronic exposure in pediatric populations.

Benzyl alcohol is primarily used as a preservative and as a local analgesic and is added to injectable, topic and oral forms. The primary driver of its associated adverse events in neonates is the immaturity of benzyl alcohol metabolism.15 Excessive exposure to this excipient may overwhelm the detoxification capacity of the immature hepatic and renal systems due to deficient levels of glycine N-acyltransferase, an enzyme that converts benzoic acid into hippuric acid.15,24 Furthermore, this preservative has been shown to non-competitively inhibit ADH and ALDH, thereby promoting the accumulation of toxic metabolites when administered concomitantly with ethanol or PG.13 At present, any exposure to benzyl alcohol is contraindicated in children younger than 3 years5,45; additionally, no safe exposure thresholds have been defined for either acute or chronic use.

Sulfites and their derivatives are widely used as antioxidants and preservatives in injectable solutions, liquid formulations, and other preparations in which protection against oxidation of labile drugs is required. In acidic environments or upon exposure to oxygen, sulfites decompose to sulfur dioxide (SO₂), an irritant gas with the potential to induce epithelial injury in the respiratory tract. Accordingly, pH control during formulation is essential to limit accelerated SO₂ release. Sulfur dioxide also stimulates cholinergic receptors within the respiratory tract46 and, in rare instances, metabisulfites may behave as haptens, eliciting IgE-mediated hypersensitivity reactions.47–49 Although evidence remains limited, sulfites may generate reactive oxygen species, such as sulfur-based peroxides, which could contribute to oxidative stress and damage to proteins and DNA.50,51 No safe thresholds for chronic exposure in pediatric populations have been established, and evidence on long-term pulmonary effects is very limited.

Table 2 presents the most relevant preservatives and antioxidants and their adverse effects in pediatric patients.

Potassium sorbate, a derivative of sorbic acid, is a widely used natural preservative. Several in vitro studies, adding its use in neonatal oral formulations, support its safety, with no evidence of significant toxicity or clinically relevant allergic reactions.56 Nevertheless, at concentrations exceeding the recommended daily intake (up to 3 mg/kg), cytotoxic and genotoxic effects have been described.57

Citric acid and sodium citrate, commonly employed as acidulants and buffering agents, have not been linked to serious adverse effects in neonates,17 although dental enamel erosion has been documented.58 Tocopherols (vitamin E), used as antioxidants, are considered safe, with no evidence of significant accumulation or systemic toxicity59; however, high-dose, long-term exposure –rare in excipient use– may impair coagulation via vitamin K antagonism.60

Sweetening and coloring agents are indispensable components in the formulation of oral pediatric preparations, as they significantly enhance the flavor and color of the product, thereby ensuring acceptability.15 The following sections describe the documented mechanisms of toxicity and clinical considerations associated with prevalent sweeteners.

Sucrose is a disaccharide composed of glucose and fructose.61 Excessive or prolonged administration may cause dental damage and increase serum glucose concentrations. Unlike glucose, the hepatic metabolism of fructose promotes de novo lipogenesis, thereby contributing to childhood obesity.62 Emerging evidence suggests that, at high concentrations, fructose may be linked to the development or progression of certain malignancies. This is hypothesized to occur through the activation of various mechanistic pathways, including systemic inflammation.5,62 In children with fructosemia, enzyme aldolase B deficiency results in the intracellular accumulation of fructose-1-phosphate, causing nephrotoxicity.15

Aspartame is a synthetic dipeptide composed of aspartic acid and methylphenylalanine; the latter is toxic to patients with phenylketonuria and potentially hazardous for individuals with epileptogenic disorders.5,15 Aspartame is hydrolyzed and absorbed in the gastrointestinal tract, releasing methanol, aspartic acid, and phenylalanine. Methanol is oxidized in the liver to formaldehyde and subsequently to formic acid. These compounds may damage hepatic cells and generate superoxide anions and hydrogen peroxide, leading to protein denaturation and enzymatic changes.63 There are no conclusive studies regarding its safety during chronic exposure in childhood.

Saccharin is a non-caloric artificial sweetener derived from sulfonamide. No conclusive evidence has been provided of the carcinogenic potential of saccharin in humans. Some studies suggest a possible correlation with bladder cancer in children due to renal immaturity and the subsequent excessive accumulation of the sweetener; however, other authors, such as Debras et al.,64 find no evident connection between its consumption and cancer risk. Due to its sulfonamide structure, it may induce cross-reactivity in patients allergic to sulfonamides; this may result in dermatological reactions and cross-sensitivity with drugs within the sulfonamide group.15,61,65 Chronic consumption may reduce intestinal flora, promoting dysbiosis and insulin resistance.66,67

Sucralose is a sweetener synthesized from sucrose using thionyl chloride.61 Its absorption is minimal, and it is primarily excreted unchanged.15 This excipient increases the expression of P-glycoprotein and two cytochrome P450 isoforms. Consequently, it may alter the bioavailability of co-administered drugs. Furthermore, sucralose reduces the diversity of beneficial bacteria and promotes the growth of proinflammatory strains.68 Although it is a non-caloric excipient, it could influence levels of glucose, insulin, and glucagon-like peptide-1.5,69 There are no conclusive studies regarding its safety during chronic exposure in childhood.

Sorbitol is a sugar alcohol (polyol) characterized by limited gastrointestinal absorption. Within the intestinal lumen, this sweetener exerts an osmotic effect by attracting water, which leads to osmotic diarrhea. As a result, it may decrease the absorption of certain preparations, such as lamivudine.22 In the colon, unabsorbed sorbitol is fermented by the microbiota. This process generates gases, specifically H2 and CO2, along with short-chain fatty acids, resulting in abdominal distension.70 Children with aldolase B deficiency are unable to metabolize sorbitol, which is converted into fructose. This undesired effect leads to the accumulation of fructose-1-phosphate, causing severe metabolic complications.5,24,61 Currently, safe thresholds for long-term treatments have not been established. Additionally, there is a lack of evidence regarding how sorbitol affects the intestinal microbiota in healthy children.

Acesulfame potassium is a non-caloric artificial sweetener. Its thermal stability and resistance to extreme pH levels make it ideal for liquid and solid formulations. In vitro studies highlight its ability to promote the differentiation of preadipocytes into adipocytes, resulting in fat accumulation in children.71–74 Some studies suggest that early exposure could alter taste preferences toward sweet flavors. Additionally, it may reduce bacterial diversity67,72 and favor the growth of proinflammatory strains, although evidence for this microbial impact remains limited.67,75 Chronic consumption is believed to activate inflammatory pathways mediated by cytokines such as TNF-α and IL-6.45,76 Acesulfame potassium is contraindicated in infants with sulfonamide allergies, due to its structural similarity to sulfonamides.77 Currently, there are no longitudinal studies regarding its safety during chronic exposure in childhood.

Table 3 describes the most relevant sweeteners and colorants for their potential adverse events in pediatric patients.

Curcumin, when used either as an antioxidant or as a colorant, has demonstrated excellent tolerability in children with inflammatory diseases and epilepsy, with minimal adverse events, primarily mild tympanites, even at high doses of 4 g/day.80–83

Sulforaphane, a potent antioxidant derived from cruciferous vegetables, has demonstrated good tolerance in clinical studies involving children with autism spectrum disorder. No serious adverse effects were reported in these populations.84,85 Furthermore, a multicenter trial confirmed the safety of sulforaphane in children, although symptomatic benefits were moderate.84

Among polyalcohol sweeteners, xylitol and mannitol have established safety profiles in pediatrics. Xylitol is recognized for its dental benefits and minimal adverse events, including gastrointestinal discomfort such as excessive gas, loose stools, and diarrhea.47,86 Mannitol is a sugar alcohol (polyol) with an absorption rate of less than 20%, which confers it osmotic properties. Additionally, it accelerates intestinal transit, resulting in reduced bioavailability of co-administered drugs. Direct action on mast cells may trigger hypersensitivity reactions, although these effects are more frequent in patients with underlying allergies.5,15,33,87