The Dark Side of “Other Ingredients”: Why Common Supplement Fillers, Flow Agents & Preservatives Can Be Problematic

Dark Side of Supplement fillers

Compliance (EU/HCVO): This article discusses safety risks of excipients. It does not make health claims about any product.

Most people focus on actives. In reality, excipients often make up most of a capsule or tablet. They usually work quietly—but sometimes they bring risks. Below is a risk-first review of popular supplement fillers, highlighting the strongest negative signals from regulators, clinical reports, and preclinical data. Links are to primary sources (EFSA/FDA opinions, PubMed, journals).

Supplement Fillers & Binders

Maltodextrin

• Worst signals: In animal and mechanistic models, maltodextrin impairs intestinal mucus defenses, exacerbates colitis, and promotes biofilms of Crohn’s-associated E. coli. Human toxicity at supplement doses isn’t established—but the mechanistic data are concerning.

• Sources: mBio (AIEC/biofilm) — https://journals.asm.org/doi/10.1128/mBio.01286-14 ; gut barrier/colitis models — https://www.sciencedirect.com/science/article/pii/S0016508513005332

Dicalcium phosphate (phosphate salts)

• Worst signals: EFSA lowered the acceptable daily intake for total phosphates to 40 mg/kg/day and noted that inorganic phosphate additives can drive 30–60% of total intake, raising concern for hyperphosphatemia, especially in kidney disease.

• Sources: EFSA 2019 scientific opinion — https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2019.5808 ; EFSA news summary — https://www.efsa.europa.eu/en/press/news/190612

Microcrystalline cellulose (MCC)

• Worst signals: Direct toxicity signals are weak; the harshest discussions often involve co-excipients used alongside MCC (e.g., silica/nano fractions—see below).

Capsule Shells & Coatings

Titanium dioxide (E171) — whitener/opacifier

• Worst signals: EFSA 2021: genotoxicity cannot be ruled out → “no longer considered safe” as a food additive. Consequently banned in EU foods/supplements.

• Source: EFSA press & opinion — https://www.efsa.europa.eu/en/news/food-additive-titanium-dioxide-e171-no-longer-considered-safe

Flow Agents & Anti-caking

Silicon dioxide (E551; silica)

• Worst signals: EFSA’s re-evaluations say “no safety concern at reported uses,” but acknowledge uncertainties around nano fractions. Independent studies show oral nano-silica can accumulate in liver/spleen and cause organ changes in rodents at high exposures. If your silica isn’t tightly specified, you inherit the nano debate.

• Sources: EFSA re-evaluation — https://www.efsa.europa.eu/en/efsajournal/pub/5088 ; rodent accumulation — https://pubmed.ncbi.nlm.nih.gov/28738650/

Talc

• Worst signals: Asbestos contamination risk. Regulators stress there is no safe level of asbestos; FDA has pushed toward standardized testing (XRD/PLM/TEM). The reputational and legal risk is severe.

• Sources: FDA talc/asbestos page — https://www.fda.gov/cosmetics/cosmetic-ingredients/talc ; Reuters investigative overview — https://www.reuters.com/investigates/special-report/usa-talc-fda/

Magnesium stearate / stearic acid

• Worst signals: Hard human-risk data are sparse; in “worst-case” modeling, lubricants can alter dissolution of some actives. Not a strong indictment, but worth monitoring in tricky BCS-II formulations.

Disintegrants, Surfactants, Emulsifiers

Croscarmellose sodium / Sodium starch glycolate / Crospovidone

• Worst signals: Immediate hypersensitivity (rare) is published—including a case implicating croscarmellose as the excipient culprit.

• Source: Case report — https://pubmed.ncbi.nlm.nih.gov/27147601/

Polysorbate-80 (E433) & related emulsifiers

• Worst signals: In mice and ex-vivo human microbiota systems, emulsifiers drive microbiome shifts, low-grade intestinal inflammation, and metabolic-syndrome-like features. Human causality at supplement doses is unproven, but the model signal is consistent.

• Source: PNAS (Chassaing et al., 2015) — https://www.pnas.org/doi/10.1073/pnas.1422269112

Sodium lauryl sulfate (SLS; sodium dodecyl sulfate)

• Worst signals: A known mucosal irritant; in epithelial/Caco-2 models, SLS loosens tight junctions and increases permeability (which is partly why formulators use it). In vulnerable guts, SLS won’t help.

• Sources: Permeability/TJ studies — https://pubmed.ncbi.nlm.nih.gov/9426357/ ; https://pubmed.ncbi.nlm.nih.gov/11042342/

Polyethylene glycol (PEG; macrogol; E1521)

• Worst signals: Type-I hypersensitivity/anaphylaxis is well-documented with parenteral PEG; oral risk is much lower, but previously sensitized people can react.

• Source: Review (Clin Exp Allergy) — https://pubmed.ncbi.nlm.nih.gov/26833110/

Preservatives (especially liquids, gummies, syrups)

Sodium benzoate (E211)

• Worst signals: In acidic formulas with ascorbic acid (vitamin C) plus heat/light, trace benzene (a carcinogen) can form at ppb levels. Modern controls reduce risk, but the chemistry is real.

• Sources: FDA Q&A — https://www.fda.gov/food/chemicals/benzene-soft-drinks ; review — https://pubmed.ncbi.nlm.nih.gov/17522425/

Potassium sorbate / Sodium sorbate (E202/E201)

• Worst signals: In-vitro studies (human lymphocytes and other assays) show genotoxic signals (chromosomal aberrations, micronuclei, comet assay). Not proof of in-human harm, but these are the loudest negative findings.

• Sources: Genotox assays — https://pubmed.ncbi.nlm.nih.gov/19367690/ ; https://pubmed.ncbi.nlm.nih.gov/12822888/

The Pattern Behind the Problems

1. Nano-dimensions matter. For silica, the nano fraction is the debate. Even with reassuring overall assessments, organ accumulation and inflammation show up at high experimental exposures. Supplier specs and particle-size controls are everything. European Food Safety Authority+1

2. Irritants and permeability enhancers are a double-edged sword. SLS and certain polysorbates increase dissolution and absorption—but those same properties can mean barrier disruption and microbiome shifts in models. ScienceDirect+1

3. Preservative chemistry can backfire. Benzoate + vitamin C + heat/light = trace benzene; sorbates show in-vitro genotoxicity signals. Formulation design and storage conditions decide whether a risk is theoretical or practical. U.S. Food and Drug Administration+1

4. True allergies are rare—but devastating. Gelatin (especially with α-Gal), PEG, and certain disintegrants can trigger immediate hypersensitivity in sensitized people. Label transparency helps prevent surprises. Exploration Publishing+1

5. Regulatory direction is clear. Titanium dioxide was removed from EU foods on genotoxicity grounds; talc faces tightening asbestos testing rules. Expect more pressure on high-risk categories. European Food Safety Authority+1