A 28-Day Oral Toxicity Study in Wistar Rats for a Highly Bioavailable Curcumin Preparation, CAVACURMIN^®

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Pls see attached

Comments for author File: Comments.pdf

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This study evaluated the 28-day oral toxicity of CAVACURMIN®, a γ-cyclodextrin-based curcumin formulation, in male and female Wistar rats. No systemic toxicity, mortality, or adverse clinical, hematological, or pathological changes were observed at doses up to 3500 mg/kg/day. The findings support CAVACURMIN® as well tolerated and suitable for further assessment in a 90-day OECD 408-compliant study. Here are some comments need to address.

1. The introduction lacks a clear statement on how this study fills the gap created by regulatory scrutiny in 2024. The authors should connect the study’s objectives to the recent safety concerns and emphasize what differentiates this CAVACURMIN® study from previous curcumin toxicity studies.
2. The authors should describe statistical tests in sufficient detail (e.g., assumptions, software, p-value thresholds). Add a clear statistical methods subsection specifying how normality was tested, which tests were used for comparisons, and how outliers were handled.

3.The study interprets absence of toxicity without histopathological confirmation. Include representative histopathology data (if available) or provide stronger justification that this omission aligns with OECD dose-range finding study design and does not limit interpretation.

4. The results section is lengthy and descriptive without clear subheadings distinguishing systemic vs. local effects. The author can reorganize into structured subsections (e.g., “Local Tolerance,” “Systemic Toxicity,” “Organ Weights and Pathology,” “Clinical Chemistry”) and summarize key findings in concise tables.
5. The author can Include historical control ranges or reference values (e.g., for urea, ALT, albumin, liver weights) either in tables or supplementary materials. This will allow readers to assess whether the reported variations truly fall within non-adverse physiological limits.
6. The discussion repeatedly describes biochemical changes as “favorable.” This language risks overstating pharmacological benefit in a toxicity study. The author should revise to neutral, data-driven terminology and avoid speculative claims unless supported by prior peer-reviewed evidence.
7. Reference list includes duplicate and outdated entries (e.g., ref. 10 and 16 are identical). Verify all references, replace placeholder citations (e.g., “Food Res. Int. 2025, in press”), and ensure all statements are traceable to proper sources.

Author Response

see attached 

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

This subacute toxicity study for CAVACURMIN is a critical step for safety testing of orally administered curcumin with enhanced bioavailability. The methods are well-written, with appropriate detail. The dose and dose justification indicate sufficiently high dose was used to potentially induce toxicity and the use of both vehicle and gamma-cyclodextrin controls was essential. The results are thoroughly described. Clinical findings, body weight, organ weight, hemocytology, and blood biomarkers are critical end points and well described and contextualized. I would have liked to see a larger sample size, but the authors note this as an intentional design feature and I agree the study was better served by using both male and female rats, limiting the dose-range and duration, and focusing on key clinical markers to pave the way for chronic exposure studies. These data support the body of literature on curcumin safety and clinical effects, while expanding the field of knowledge in high-bioavailability curcumin oral toxicity. This is a valuable study and I support its publication. No suggestions for revisions.

Author Response

see attached 

Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

In short, the publication describes toxicity studies of the preparation named CAVACURMIN. It is produced by a large, publicly traded company: Wacker Chemie AG, Gisela-Stein-Straße 1, 81671 München, Germany (current market capitalization = EUR 3.42 billion), whose employee is the first and third author of the publication. I did not notice this when agreeing to review the publication. Had I noticed, I would have declined the proposal to review it for the following ethical reasons:

1. Due to the above, it can be assumed that the publication is promotional in nature and states that the preparation is safe for use. One might wonder why someone posed this question regarding a preparation that anyone can buy. Imagination suggests various possible reasons. As I checked, the preparation has not undergone full clinical trials (huge costs) because it is a food supplement.
2. One might ask whether, in any similar case, results that undermined the safety of use would be published. Logic suggests no, because this could lead to a lawsuit. Imagine someone trying to demonstrate the harmfulness of a preparation produced by a large pharmaceutical company.
3. Do we really want the advertising of commercial products in reputable scientific journals to become commonplace? I probably do not need to write about the negative consequences and abuses this will generate.

In view of the above, I cannot recommend the article for publication, even though I like it.

Author Response

see attached 

Author Response File: Author Response.pdf