Single-active oral pantothenic acid (vitamin B5) exposure × risk of new or worsened diarrhea adverse events

Required evidence, verification status and materials actually read
Item	AVerification status	BReading scope	CReview item	DCurrent findings	EWhy unverified	FRequired materials and conditions	GFurther research
1	Met	Full text not readStored summary read	N01 · Diarrhea harm · Is this table's safety-only, efficacy-not-applicable contract preserved?Is this table's safety-only, efficacy-not-applicable contract preserved?Required	The original question_type is safety, safety_only is true, and grading_status is not_applicable_safety. efficacy_grade/score are not_applicable, and the assessment's efficacy_framework_applied is false. The original grade is ?, score is an empty value, and there are no 7-axis/no_human keys.	The condition requiring the safety-only display contract and original values/absences to be preserved unchanged was verified. This does not constitute a judgment of efficacy or individual safety.	Original safety-only display and assessment contract	Compare the display fields with the boundaries on applying historical values.
2	Met	Full text not readStored summary read	N02 · Diarrhea harm · What are the separate question and its inclusion/exclusion scope?What are the separate question and its inclusion/exclusion scope?Required	The archived harm question concerns the risk of new or worsened diarrhea adverse events. The scope is oral pantothenic acid as the sole active ingredient in adults; abdominal pain, nausea, composite GI symptoms, topical/injected routes, and other molecules/combination products are distinguished. S2404	The original question and excluded exposures/outcomes were linked to their designated preserved locations.	Scope of the original claim/population/exposure/endpoint	Compare the boundaries of the separate question with adjacent questions.
3	Partly verified	Full text not readStored summary read	N03 · Diarrhea harm · Was the directly studied preparation distinguished from other B5-related substances?Was the directly studied preparation distinguished from other B5-related substances?Required	The direct data concern pantothenic acid tablets distributed by Rugby (as D-calcium pantothenate). Other related substances and combination products were not used as direct event evidence for this substance. Batch, purity, additives, and equivalent risk for other salts are unverified. S2404 S2407 S2408	The directly studied substance/distributed product and exclusion boundaries are available, but detailed composition/source/batch have not been established.	Identity of the substance/product composition/source ingredients/additives	Review whether the composition and molecule match for each product.
4	Partly verified	Full text not readStored summary read	N04 · Diarrhea harm · Is the acid/salt mass basis of the stated administered dose clear?Is the acid/salt mass basis of the stated administered dose clear?Required	The tablet label states pantothenic acid 500 mg (as D-calcium pantothenate), while the dosing table states calcium pantothenate. The pharmacokinetic section refers to 550 mg of calcium salt versus 500 mg of free base in the original text. The actual acid/salt basis and cumulative dose were not converted. S2404	The differing descriptions of the stated dose were verified, but the mass basis of the actual clinical dose cannot be established as a single value.	Original tablet label, dosing table, and evidence for the acid/salt mass basis	Compare how the same preparation's dose is stated across documents.
5	Met	Full text not readStored summary read	N05 · Diarrhea harm · How are the nominal doses in the single-dose conditions distinguished?How are the nominal doses in the single-dose conditions distinguished?Required	The preserved single-dose conditions are 500, 1,000, 2,000, 5,000 mg as reported in the paper. Fasted conditions are distinguished from the subsequent fed condition at 5,000 mg, and the acid/salt basis for each dose remains a separate gap. S2404	Only the records of nominal doses by condition were preserved. They were not elevated to verification of actual mass or risk thresholds.	Nominal dose and dosing/meal records by condition	Review the link between exposure under each condition and the AE table.
6	Met	Full text not readStored summary read	N06 · Diarrhea harm · Are repeated exposure and follow-up periods separated from single dosing?Are repeated exposure and follow-up periods separated from single dosing?Required	The repeated-dose condition was a nominal 2,000 mg/day for 14 days, and 8 participants completed the repeated-dose part. Follow-up extended to day 9 for single dosing and day 22 for repeated dosing. This record is not long-term exposure data. S2404	The preserved exposure/follow-up schedules and the attribution of the repeated-dose denominator were distinguished.	Repeated dosing, adherence, and AE follow-up schedule	Review exposure duration and observation duration as separate dimensions.
7	Partly verified	Full text not readStored summary read	N07 · Diarrhea harm · Are the directly studied population and baseline diarrhea status verified?Are the directly studied population and baseline diarrhea status verified?Required	The direct data concern healthy adults aged 18–55. Individual baseline symptoms and the distinction between new onset and worsening of existing diarrhea remain Not reported or Unverified. The detailed sex distribution is also not specified in the current summary. S2404	The population category was verified, but detailed baseline diarrhea/selection values cannot be established.	Table of inclusion/exclusion, sex, baseline diarrhea/diseases, and medications	Review limitations on applicability according to the population and baseline symptoms.
8	Partly verified	Full text not readStored summary read	N08 · Diarrhea harm · Can the 40 participants be distinguished from the single-dose and repeated-dose completion denominators?Can the 40 participants be distinguished from the single-dose and repeated-dose completion denominators?Required	Rao is a single-center open-label trial in 40 healthy participants. The single-dose part was completed by 32 participants and the separate repeated-dose part by 8 participants. The diarrhea table for each condition uses a denominator of 8 participants, and the fed condition involved the same 8 participants. The detailed allocation/completion/AE analysis flow is not complete from the current summary alone. S2404	Overall/part-specific completion counts and condition denominators are available, but the entire recruitment/missingness/analysis flow cannot be established.	Recruitment/allocation/exposure/completion/analysis flow and participant linkage by condition	Compare participant flow with the analysis denominator for each condition.
9	Conflicting information	Full text not readStored summary read	N09 · Diarrhea harm · Are the participants, sequence, and actual washout period for fed redosing consistently verified?Are the participants, sequence, and actual washout period for fed redosing consistently verified?Required	The 5,000 mg single fed dose is a subsequent condition in the same 8 participants after fasted dosing. Washout is described as 2–3 weeks in the main text and summarized as 2 weeks in the abstract. The fixed sequence/meal difference and this difference in descriptions are preserved. S2404	Because the records describe washout at different levels of specificity, they were not replaced with a single confirmed duration. This is a difference in descriptions in the materials, not a new causality judgment.	Original abstract, methods, and individual dosing sequence/washout schedule	Review differences in sequence/washout/meal status and inconsistencies in descriptions within the same family.
10	Partly verified	Full text not readStored summary read	N10 · Diarrhea harm · What are the definition and coding criteria for diarrhea?What are the definition and coding criteria for diarrhea?Required	The main study used the MedDRA 21.0 diarrhea category. A diagnostic definition based on stool frequency/form is Not reported or Unverified. GI discomfort or loose stools were not combined into new diarrhea events. S2404	The event coding term was verified, but the detailed diagnostic/observation definition has not been established.	Diarrhea AE definition, coding/diagnostic criteria, and records of stool frequency/form	Propose a review that re-extracts the original table using the same event definition.
11	Unverified	Full text not readStored summary read	N11 · Diarrhea harm · Are data available to distinguish new diarrhea from worsening of existing diarrhea?Are data available to distinguish new diarrhea from worsening of existing diarrhea?Required	The original question concerns new or worsened diarrhea. The current preserved summary leaves individual baseline symptoms and counts by new onset/worsening as Not reported or Unverified. S2404	The question covers both scopes, but data establishing which scope the actual events fall into are unavailable.	Baseline diarrhea and change criteria, and an AE table separating new/worsened cases	Review separated records based on the same ascertainment criteria.
12	Unverified	Full text not readStored summary read	N12 · Diarrhea harm · Can diarrhea collection methods, severity, and differences in detection be verified?Can diarrhea collection methods, severity, and differences in detection be verified?Required	The preserved summary provides the open-label design and MedDRA diarrhea coding. Diarrhea-specific severity, day of onset, duration, and details of collection procedures are Not reported or Unverified. S2404	The coding record cannot establish the collection system or diarrhea-specific severity.	AE collection form/questioning frequency, blinding/ascertainment, and severity table	Review collection methods and differences in detection/omission.
13	Met	Full text not readStored summary read	N13 · Diarrhea harm · Were nausea, vomiting, and abdominal discomfort kept separate from diarrhea?Were nausea, vomiting, and abdominal discomfort kept separate from diarrhea?Required	The preserved manuscripts kept nausea, vomiting, and abdominal discomfort as separate categories and did not add them to diarrhea. Overall GI discomfort/AE summaries are not added to diarrhea 1/8 or 0/8. S2404	The attribution boundary between the selected diarrhea endpoint and other GI categories was maintained.	Original AE categories by endpoint and a table of people/events	Review multiple events in the same person and different categories separately.
14	Met	Full text not readStored summary read	N14 · Diarrhea harm · What is the direct diarrhea report under the 5,000 mg fasted condition?What is the direct diarrhea report under the 5,000 mg fasted condition?Required	In Table 6, under the paper-labeled 5,000 mg fasted single-dose condition, among 8 participants, 1 reported diarrhea. This is a condition-specific signal observed in a small uncontrolled trial. S2404	The retained direct descriptive observation was linked only to the corresponding dose/fasted single-dose condition.	Original Table 6 and the relevant person's AE record	Review the link between the reported people, exposure conditions, and event definition.
15	Met	Full text not readStored summary read	N15 · Diarrhea harm · Are conditions with 0/8 reports also retained?Are conditions with 0/8 reports also retained?Required	The 500, 1,000, 2,000 mg fasted single doses and 2,000 mg/day repeated for 14 days each had reports of 0/8 participants. Subsequent fed dosing at 5,000 mg in the same 8 participants was 0/8. All are values collected and reported in a small table, not proof of no risk/prevention by fed dosing. S2404	Contrary/no-report records were retained by condition and were not elevated to an effect of 0 or a guarantee of safety.	Condition-specific Table 6 and the scope of exposure/follow-up and collection	Review reported 0 within the scope of missingness/detection and duration.
16	Partly verified	Full text not readStored summary read	N16 · Diarrhea harm · Can the reported numbers of people, repeated events, and exposure-time denominators be distinguished?Can the reported numbers of people, repeated events, and exposure-time denominators be distinguished?Required	The original record provides condition-specific reports of 1/8 or 0/8 participants and overall/partial completion counts. The number of repeated diarrhea events in the same person, individual exposure/event times, and details of losses from the denominator are not established in the current summary. S2404	Condition-specific person denominators are available, but repeated events/person-time and the complete analysis flow are unverified.	Condition-specific person/event counts, follow-up/exposure time, and missing data	Review interpretation of harm frequency with people, events, and time kept separate.
17	Unverified	Full text not readStored summary read	N17 · Diarrhea harm · Was diarrhea risk compared with an appropriate unexposed/placebo group?Was diarrhea risk compared with an appropriate unexposed/placebo group?Required	Rao is an open-label trial without a placebo group or randomized dose assignment. Redosing with food is a subsequent condition in the same people; estimation of diarrhea risk against an appropriate unexposed/placebo comparator is unverified. S2404	A comparative risk increase cannot be established solely from the uncontrolled/within-person subsequent conditions in the direct data.	Unexposed/appropriate comparator data with matching event definitions/follow-up	Review the population/confounding and sequence/meal differences in existing comparative observations.
18	Unverified	Full text not readStored summary read	N18 · Diarrhea harm · Is the temporal link between diarrhea onset/recovery and exposure verified?Is the temporal link between diarrhea onset/recovery and exposure verified?Required	The original limitations record leaves diarrhea-specific onset dates and duration as not reported or unverified. Even with a record of AE resolution by the end, diarrhea-specific recovery times and causal clues from dechallenge/rechallenge are not established. S2404	There is a reported signal after exposure, but no data establishing the diarrhea-specific time course.	Individual logs of dosing, blood sampling/meals, and diarrhea onset/recovery	Review the temporal sequence and alternative explanations for each event.
19	Partly verified	Full text not readStored summary read	N19 · Diarrhea harm · Is the investigator's wording on relatedness kept separate from established causality?Is the investigator's wording on relatedness kept separate from established causality?Required	The investigator considered the diarrhea at least possibly related. The original safety assessment retains the signal and Caution conclusion, but comparative risk and the contribution of alternative causes such as excipients, infection, and diet are unverified. This table does not create a new causality judgment or score. S2404	The qualitative signal conclusion was verified, but established causality for individual diarrhea was not verified.	The basis for individual AE relatedness assessments and records of alternative causes	Review the original wording on relatedness and the level of evidence for timing/alternative causes.
20	Partly verified	Full text not readStored summary read	N20 · Diarrhea harm · Were alternative explanations such as concurrent exposure, diet, and infection reviewed?Were alternative explanations such as concurrent exposure, diet, and infection reviewed?Required	Rao prohibited other medications and supplements but did not control dietary pantothenic acid intake. The contributions of excipients, infection, diet, and individual susceptibility are unverified. S2404	There were some restrictions on concurrent exposures, but no data ruling out all alternative explanations.	Records of medications/supplements, diet, meals, excipients, and infection/baseline symptoms	Review alternative exposures and potential confounding for the same event.
21	Partly verified	Full text not readStored summary read	N21 · Diarrhea harm · Are discontinuation/serious AE reports distinguished from detailed participant flow?Are discontinuation/serious AE reports distinguished from detailed participant flow?Required	The main study reports no deaths, serious adverse events, or discontinuations due to adverse events. In contrast to the completion records for 32 single-dose participants and 8 repeated-dose participants, the detailed flow of diarrhea-specific noncollection/missingness is not established in the current summary. S2404	A general safety summary and completion counts are available, but the complete diarrhea-specific flow and presence or absence of omissions are unverified.	Diarrhea-specific reasons for discontinuation/dropout, periods without collection, and participant flow	Review differences in event detection between completer data and those who discontinued/had missing data.
22	Unverified	Full text not readStored summary read	N22 · Diarrhea harm · Are the registration, protocol, analysis plan, and scope of prespecification verified?Are the registration, protocol, analysis plan, and scope of prespecification verified?Required	The original record leaves registration, protocol, and statistical analysis plan unverified and does not conclude that preregistration was absent. Records of registration/some metadata access failures at that time are also not actual access failures in this work. S2404	The current archived summaries alone cannot establish prespecification/changes or the scope of selective reporting.	Registration, protocol, SAP, and records of diarrhea prespecification/changes	Compare specified endpoints, collection, and public reporting against the plan for consistency.
23	Unverified	Full text not readStored summary read	N23 · Diarrhea harm · Are risk differences, risk ratios, CIs, and criteria for interpreting harm verified?Are risk differences, risk ratios, CIs, and criteria for interpreting harm verified?Required	The retained manuscript left comparative risk estimates, the background diarrhea rate, and the minimum harmful dose/duration unverified. Risk differences, risk ratios, incidence rates, CIs, P values, and NNH were not derived, and this table does not calculate them either. S2404	There are no data establishing quantitative comparative risk or harm criteria beyond the descriptive observations of 1/8 and 0/8.	Original comparative estimates, denominators, CIs/uncertainty, and clinical harm criteria	Review the scope of interpretation of estimates with the same event/comparator/duration.
24	Partly verified	Full text not readStored summary read	N24 · Diarrhea harm · What is the scope of the absence of recorded side effects in the arthritis trial?What is the scope of the absence of recorded side effects in the arthritis trial?Required	The arthritis trial summarized by SCF escalated calcium pantothenate over 8 weeks and states that no treatment side effects were recorded. The original diarrhea event table was not acquired/unverified, so this was not converted into 0 diarrhea events or an established safety denominator. S2405 is a PubMed bibliographic record without an abstract. S2402 S2405	Contrary general AE context and bibliographic information are available, but the original diarrhea-specific results and collection methods are unverified.	The original GPRG diarrhea/AE event table and dosing, population, and collection methods	Compare the general AE statement in the 2nd-hand summary against the original event definition/table.
25	Conflicting information	Full text not readStored summary read	N25 · Diarrhea harm · Are the overall and arm-specific participants and analysis denominators in the arthritis study consistently verified?Are the overall and arm-specific participants and analysis denominators in the arthritis study consistently verified?Required	In the GPRG record, the narrative total of 94 participants is inconsistent with the arm-specific counts of 47 and 46 participants (a total of 93 participants in the original record). The conflict was retained, and neither value was selected as an established diarrhea analysis denominator in this table. S2402 S2405	The inconsistent original descriptions of the same total were made explicit, and no new arithmetic/denominator correction was made.	Original participant flow, arm-specific allocation/analysis tables, and SCF's cited statement	Check each denominator's definition/location and conflicting descriptions against the original tables.
26	Partly verified	Full text not readStored summary read	N26 · Diarrhea harm · What limitations apply to the reused NIH example of 10 g/day?What limitations apply to the reused NIH example of 10 g/day?Required	The reused NIH S06 gives 10 g/day as an example of very high intake and mentions the possibility of mild diarrhea and GI discomfort. The exact number of cases, denominator, salt, and duration were not verified in this extraction. It is not a newly validated event rate, toxicity threshold, upper intake level, or individual recommended intake. S06	A retained qualitative example is available, but the identity of the original events and their denominator/exposure scope are unverified.	The relevant NIH section and underlying original cases and exposure/event data	Trace the original observation lineage, actual exposure, and endpoint evidence underlying the general discussion.
27	Partly verified	Full text not readStored summary read	N27 · Diarrhea harm · Are historical summaries of 10–20 g/day kept from being counted as independent human replications?Are historical summaries of 10–20 g/day kept from being counted as independent human replications?Required	S06, S2402, and S2406 are official/expert summary lineages of historical high-dose observations. The duration, exact formulation, and event counts/denominators in the 10–20 g/day reports are unverified. Do not count LEGACY-HIGH-DOSE-SUMMARY as one established human trial or three independent replications. S06 S2402 S2406	The overlapping summary lineages and limitations were verified, but the independence of the underlying original cases is not established.	SCF/CIR citation lineage, Elder 1987, and underlying original cases	Check repeated citations/duplication of the same original observations and whether the participants are independent.
28	Met	Full text not readStored summary read	N28 · Diarrhea harm · Is the meaning of insufficient data behind the absence of an established upper intake level preserved?Is the meaning of insufficient data behind the absence of an established upper intake level preserved?Required	FNB 1998 states that an upper intake level could not be established because reports of harm were not found. The checked EFSA version 11(2025-08) also indicates that an upper intake level for pantothenic acid could not be derived because of insufficient data. This does not mean unlimited safety or a legally permitted therapeutic dose. S2401 S2403	The retained editions and interpretation of insufficient data were linked as they stood, and no new safety/regulatory judgment was made.	The relevant official edition/harm assessment section and the basis for data insufficiency	Review the limitations on deriving a UL in each edition checked and whether it has been updated.
29	Met	Full text not readStored summary read	N29 · Diarrhea harm · Are adequate intake and high-dose diarrhea signals kept separate?Are adequate intake and high-dose diarrhea signals kept separate?Required	The reused US adequate intakes are 5 mg/day for adults, 6 mg/day during pregnancy and 7 mg/day during lactation. These indicate nutritional adequacy, not a diarrhea threshold or high-dose treatment instructions. Do not pool food intake and high-dose single-active-ingredient exposure into the same dose group. S06	The condition distinguishing the roles of AI values and clinical high-dose exposures was verified.	Populations/definitions of nutritional reference values and data on high-dose preparations	Review the purpose, target population and actual exposure scope of each reference separately.
30	Met	Full text not readStored summary read	N30 · Diarrhea harm · Is the boundary on applying the CIR cosmetic assessment to oral use preserved?Is the boundary on applying the CIR cosmetic assessment to oral use preserved?Required	S2406 is a safety review of the cosmetic use of panthenol, pantothenic acid and their derivatives. In the current evidence, it is used as a qualitative summary of historical high-dose oral observations, not converted into authorization or safety certification of single-active oral B5. S2406	The material’s actual title/review scope was distinguished from its citation role in this table.	CIR review scope, toxicology section and underlying oral-use references	Review the assessment’s jurisdiction/route, citation lineage and evidence for oral-exposure events separately.
31	Met	Full text not readStored summary read	N31 · Diarrhea harm · Are pantethine and the acne product with unestablished composition excluded?Are pantethine and the acne product with unestablished composition excluded?Required	Evans S2407 is excluded because pantethine is a different molecule. Yang S2408 provides product-level tolerability with unestablished monotherapy composition, so it is not transferred to the risk of single-active pantothenic acid. Not applicable for each n is a value indicating the exclusion role. S2407 S2408	The distinct reasons for the two current exclusions and the meaning of the denominator’s non-applicability were retained.	Identity of the product’s ingredients/formulation and historical exclusion extraction	Review substance identity, product composition and the transferability of diarrhea endpoints separately.
32	Partly verified	Full text not readStored summary read	N32 · Diarrhea harm · Is funding/conflict-of-interest attribution clear for each study/review?Is funding/conflict-of-interest attribution clear for each study/review?Required	Rao disclosed support from CoA Therapeutics and employment, consultancy and shareholdings related to development companies. Funding for the historical underlying cases is unverified, while the CIR/Personal Care Products Council support for CIR 2022 funds that review. Funding for the arthritis/excluded materials also remains unverified. S2404 S2405 S2406 S2407 S2408	Relationships have been disclosed for the main study/review, but support for the underlying cases and other families is not established.	Original Funding/COI, support/product provision and funding records for underlying cases	Review relationships relevant to data production/reporting structures and support that remains unknown.
33	Unverified	Full text not readStored summary read	N33 · Diarrhea harm · Is there direct harm evidence for long-term exposure and vulnerable populations?Is there direct harm evidence for long-term exposure and vulnerable populations?Required	The direct evidence concerns healthy people aged 18–55 undergoing single-dose or 14-day repeated exposure. Direct diarrhea risks during pregnancy/lactation, in children, older people, those with liver/kidney disease and during long-term exposure are unverified. S2404	There are no data establishing harms outside the population/duration of the direct study.	Long-term follow-up and direct diarrhea/exposure/comparator data by population	Review applicability and surveillance scope separately for each population/duration.
34	Met	Full text not readStored summary read	N34 · Diarrhea harm · Was current summary reading distinguished from historical access to original materials?Was current summary reading distinguished from historical access to original materials?Required	The actual current input is an archived summary preserving the KO/EN manuscripts, 5 evidence groups, 9 bibliographic records and assessment/metadata. All external original texts/registrations/official documents and old separate extractions were not attempted, acquired or read in this review. Historical access levels are retained only in separate fields. S06 S2401 S2402 S2403 S2404 S2405 S2406 S2407 S2408	Current local-summary reading was recorded separately from the historical/current external access for the 9 reports.	Original material types, bibliography and access/preservation receipts for each report	Compare the correspondence between bibliographic URLs and material types with actual reading/attempt events.
35	Met	Full text not readStored summary read	N35 · Diarrhea harm · Are the evidence-review date, access dates and actual server metadata distinguished?Are the evidence-review date, access dates and actual server metadata distinguished?Required	The original content reference date/verified_date is 2026-09-15, and the local review date recorded here is 2026-10-05. Each bibliographic record lacks an access-date key, so historical_access_date is empty. The original published/updated values are preserved, while the text states that an actual server publication date is unassigned. The evidence_cutoff and subclaims keys are also absent. S06 S2401 S2402 S2403 S2404 S2405 S2406 S2407 S2408	The record condition separating dates, absences and historical metadata by event was verified.	Actual access/version dates for each report and original server publication/modification receipts	Compare the different date-related events and the meaning of the original metadata.
36	Unverified	Full text not readStored summary read	N36 · Diarrhea harm · Are gaps in searches, corrections/retractions, unpublished materials and updating identified?Are gaps in searches, corrections/retractions, unpublished materials and updating identified?Required	The original review was a single-assistant self-review, with registration/some metadata-access failures remaining. It is not an independent external review or assurance that no corrections, retractions or unpublished materials exist. New comparative safety evidence, salt/labeled-dose information, corrections/regulatory changes or numerical/classification errors are reasons to update dates/history under the same ID/URL after assignment. S06 S2401 S2402 S2403 S2404 S2405 S2406 S2407 S2408	Updating principles exist, but search completeness and the current scope of corrections/unpublished materials were not checked in this review.	Actual logs of searches/selection, corrections/retractions and registration/unpublished-material checks, and new results	Review gaps in access/selection and reasons for updates by original ID/version.

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36 itemsWhat the statuses mean

Assessment scope

Stored-material review date: 2026-10-05
Original evidence date: 2026-09-15
Scope actually checked: Preserved Korean and English manuscripts and case-specific condition and application records. Full papers, supplements, registrations, plans and original data were not read.
What the dates mean: This is the date on which the preserved materials were checked, not the date of a search for the latest clinical literature.
Population: Adults exposed to oral B5 as the sole active ingredient; the direct data concern healthy adults aged 18–55. Arthritis, pediatric, pregnancy, lactation, and liver or kidney disease populations are not combined as the same population
Ingredient, formulation and route: Pantothenic acid (vitamin B5) as the sole active ingredient; the D-calcium pantothenate salt in the direct exposure data is identified separately · Oral; topical and injected routes excluded · The main study used pantothenic acid tablets distributed by Rugby (as D-calcium pantothenate). Release formulation, additives, and the actual acid/salt mass basis are unverified
Dose: The stated doses in each study are retained. The paper reports single doses of 500, 1000, 2000, 5000 mg and repeated dosing at 2000 mg/day; no acid/salt conversion or risk-threshold derivation
Comparator: Comparisons with no exposure, placebo, lower exposure, or other doses are prioritized, but an appropriate comparative estimate of diarrhea risk is unverified. The main study was an uncontrolled open-label trial; redosing after food involved the same people
Measured outcome: Diarrhea adverse events. The main study's MedDRA 21.0 diarrhea category is preserved and is not combined with abdominal pain, nausea, or composite GI symptoms; counts for new versus worsened diarrhea are Not reported
Duration: Single-dose and 14-day repeated exposures are separated. Follow-up in the main study extended to day 9 for single dosing and day 22 for repeated dosing. The minimum duration associated with risk from long-term or high-dose exposure is unverified
Questions outside this scope: Other molecules/combination products, other GI endpoints/efficacy, individual incidence/confirmed causality, prevention by taking after food, acid/salt conversion, and minimum risk thresholds/long-term safety are separate boundaries.

Evidence and sources

The links below lead to the sources. A link alone does not mean the original source was read or its latest publication status verified.

S06 · NIH Office of Dietary Supplements. Pantothenic Acid — Health Professional Fact Sheet

Source

Material type: Official NIH web explanation · historical reuse
Materials actually read: The corresponding Korean/English summaries and bibliographic records in the archived manuscripts were read. The linked external original materials were not read in this review.
Findings recorded in the stored summary: Record at preservation: The reused NIH material mentions possible mild diarrhea/GI distress with very high intake of 10 g/day. The original case count, denominator, salt and duration are unverified in this extraction. Adult/pregnancy/lactation AI values of 5/6/7 mg/day are nutritional adequacy references, not diarrhea thresholds or dosing instructions.
Record level: This is content recorded in the archived manuscripts, not the result of a new comparison against current external original materials.
Study overlap and independent replication: Independent replication is unverified.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Official NIH web full text	Unverified (no external lookup in this review)	Access not attempted	Not read	This is preserved historical identity/access information or a required material type. Its external existence/availability was not newly checked in this review. What was actually read was the relevant manuscript, evidence and bibliography in the currently preserved source archive summary. This external original text/old separate file was not read in this review. Only the historical scope pertaining to this document/extraction itself in the preserved citation is retained. It is not inherited by other underlying original materials or treated as actual full-text reading in this review. Historical access dates for each material are unverified. The archived manuscript’s review date of 2026-09-15 is not the access date of this original-material file. Historical access level of this material itself: full_text. Historical location in the reference bibliography: Table 1; Health Risks from Excessive Pantothenic Acid; Interactions with Medications Bibliographic access records are not inherited as access to separate full texts/underlying materials. This does not mean that external original materials were acquired or full texts read in this review.
Underlying oral-exposure cases/original event data	Unverified (no external lookup in this review)	Access not attempted	Not read	This is preserved historical identity/access information or a required material type. Its external existence/availability was not newly checked in this review. What was actually read was the relevant manuscript, evidence and bibliography in the currently preserved source archive summary. This external original text/old separate file was not read in this review. The historical access level of this original material itself is unverified in the current source. contextual_document_access_level is the original access metadata of the containing document/inherited extraction that mentions it; it is not inherited as full-text access to this original material. Historical access dates for each material are unverified. The archived manuscript’s review date of 2026-09-15 is not the access date of this original-material file. Historical access level of this material itself: Unverified. Historical location in the reference bibliography: Table 1; Health Risks from Excessive Pantothenic Acid; Interactions with Medications Bibliographic access records are not inherited as access to separate full texts/underlying materials. This does not mean that external original materials were acquired or full texts read in this review.

S2401 · Institute of Medicine (1998), Dietary Reference Intakes, chapter 10: Pantothenic Acid

Source

Material type: Official DRI assessment HTML · historical access
Materials actually read: The corresponding Korean/English summaries and bibliographic records in the archived manuscripts were read. The linked external original materials were not read in this review.
Findings recorded in the stored summary: Record at preservation: The US FNB 1998 states that it could not set an upper limit because it had not found reports of adverse effects. This statement of insufficient data is not interpreted as unlimited safety or a legally permitted treatment dose.
Record level: This is content recorded in the archived manuscripts, not the result of a new comparison against current external original materials.
Study overlap and independent replication: Independent replication is unverified.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Official DRI HTML assessment section	Unverified (no external lookup in this review)	Access not attempted	Not read	This is preserved historical identity/access information or a required material type. Its external existence/availability was not newly checked in this review. What was actually read was the relevant manuscript, evidence and bibliography in the currently preserved source archive summary. This external original text/old separate file was not read in this review. Only the historical scope pertaining to this document/extraction itself in the preserved citation is retained. It is not inherited by other underlying original materials or treated as actual full-text reading in this review. Historical access dates for each material are unverified. The archived manuscript’s review date of 2026-09-15 is not the access date of this original-material file. Historical access level of this material itself: official_full_html. Historical location in the reference bibliography: Printed pp. 370-371: Tolerable Upper Intake Levels / Hazard Identification / Risk Characterization Bibliographic access records are not inherited as access to separate full texts/underlying materials. This does not mean that external original materials were acquired or full texts read in this review.

S2402 · Scientific Committee on Food (2002), Tolerable Upper Intake Level of Pantothenic Acid, reprinted in 2006 compilation

Source

Material type: Official SCF assessment PDF · historical access
Materials actually read: The corresponding Korean/English summaries and bibliographic records in the archived manuscripts were read. The linked external original materials were not read in this review.
Findings recorded in the stored summary: Record at preservation: SCF summarizes the absence of recorded treatment side effects in an 8-week dose-escalation arthritis trial. The original diarrhea-event table has not been acquired, and the conflict between a narrative total of 94 people and 47/46 people (an original-record total of 93 people) is retained. Historical reports of 10–20 g/day are used only as a qualitative evidence lineage with unverified exact formulations, durations and event counts/denominators.
Record level: This is content recorded in the archived manuscripts, not the result of a new comparison against current external original materials.
Study overlap and independent replication: Independent replication is unverified.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Official SCF PDF assessment	Unverified (no external lookup in this review)	Access not attempted	Not read	This is preserved historical identity/access information or a required material type. Its external existence/availability was not newly checked in this review. What was actually read was the relevant manuscript, evidence and bibliography in the currently preserved source archive summary. This external original text/old separate file was not read in this review. Only the historical scope pertaining to this document/extraction itself in the preserved citation is retained. It is not inherited by other underlying original materials or treated as actual full-text reading in this review. Historical access dates for each material are unverified. The archived manuscript’s review date of 2026-09-15 is not the access date of this original-material file. Historical access level of this material itself: official_pdf_text_and_screenshot. Historical location in the reference bibliography: Pantothenic Acid: printed pp. 118-119, PDF pages 120-121; sections 3.2, 4, 5, 6 Bibliographic access records are not inherited as access to separate full texts/underlying materials. This does not mean that external original materials were acquired or full texts read in this review.
GPRG original paper/diarrhea-event table	Unverified (no external lookup in this review)	Access not attempted	Not read	This is preserved historical identity/access information or a required material type. Its external existence/availability was not newly checked in this review. What was actually read was the relevant manuscript, evidence and bibliography in the currently preserved source archive summary. This external original text/old separate file was not read in this review. The historical access level of this original material itself is unverified in the current source. contextual_document_access_level is the original access metadata of the containing document/inherited extraction that mentions it; it is not inherited as full-text access to this original material. Historical access dates for each material are unverified. The archived manuscript’s review date of 2026-09-15 is not the access date of this original-material file. Historical access level of this material itself: Unverified. Historical location in the reference bibliography: Pantothenic Acid: printed pp. 118-119, PDF pages 120-121; sections 3.2, 4, 5, 6 Bibliographic access records are not inherited as access to separate full texts/underlying materials. This does not mean that external original materials were acquired or full texts read in this review.
Historical original high-dose cases	Unverified (no external lookup in this review)	Access not attempted	Not read	This is preserved historical identity/access information or a required material type. Its external existence/availability was not newly checked in this review. What was actually read was the relevant manuscript, evidence and bibliography in the currently preserved source archive summary. This external original text/old separate file was not read in this review. The historical access level of this original material itself is unverified in the current source. contextual_document_access_level is the original access metadata of the containing document/inherited extraction that mentions it; it is not inherited as full-text access to this original material. Historical access dates for each material are unverified. The archived manuscript’s review date of 2026-09-15 is not the access date of this original-material file. Historical access level of this material itself: Unverified. Historical location in the reference bibliography: Pantothenic Acid: printed pp. 118-119, PDF pages 120-121; sections 3.2, 4, 5, 6 Bibliographic access records are not inherited as access to separate full texts/underlying materials. This does not mean that external original materials were acquired or full texts read in this review.

S2403 · EFSA, Summary of Tolerable Upper Intake Levels, version 11 (August 2025)

Source

Material type: Official EFSA UL summary PDF · historical access
Materials actually read: The corresponding Korean/English summaries and bibliographic records in the archived manuscripts were read. The linked external original materials were not read in this review.
Findings recorded in the stored summary: Record at preservation: The inspected version 11 (2025-08) table indicates insufficient data to derive a pantothenic acid upper limit. The URL’s 2024-05 path is not converted into an actual version date, and the latest version/regulatory changes were not looked up in this review.
Record level: This is content recorded in the archived manuscripts, not the result of a new comparison against current external original materials.
Study overlap and independent replication: Independent replication is unverified.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Official EFSA UL summary PDF	Unverified (no external lookup in this review)	Access not attempted	Not read	This is preserved historical identity/access information or a required material type. Its external existence/availability was not newly checked in this review. What was actually read was the relevant manuscript, evidence and bibliography in the currently preserved source archive summary. This external original text/old separate file was not read in this review. Only the historical scope pertaining to this document/extraction itself in the preserved citation is retained. It is not inherited by other underlying original materials or treated as actual full-text reading in this review. Historical access dates for each material are unverified. The archived manuscript’s review date of 2026-09-15 is not the access date of this original-material file. Historical access level of this material itself: official_pdf_text_and_screenshot. Historical location in the reference bibliography: Cover version/date; p. 4 Table 3, Pantothenic acid row Bibliographic access records are not inherited as access to separate full texts/underlying materials. This does not mean that external original materials were acquired or full texts read in this review.

S2404 · Rao SI et al. (2021). The Pharmacokinetics of Orally Administered Calcium Pantothenate in Healthy Adults

Source

Material type: Original-paper HTML; historical access to PDF tables is separate
Materials actually read: The corresponding Korean/English summaries and bibliographic records in the archived manuscripts were read. The linked external original materials were not read in this review.
Findings recorded in the stored summary: Record at preservation: In an open-label study of healthy people aged 18–55, 40 participants were included; 32 completed the single-dose part and 8 the repeated-dose part. The paper-labeled 5,000 mg fasted single-dose result of 1/8 people and, in the same 8 people, the subsequent fed result of 0/8 people are preserved. The 500/1,000/2,000 mg fasted single-dose conditions and 2,000 mg/day repeated for 14 days each yielded 0/8. These are MedDRA 21.0 diarrhea observations; other GI items are not added. Single-dose follow-up through Day 9/repeated-dose follow-up through Day 22, the methods’ 2–3-week versus the abstract’s 2-week washout descriptions and the limitations of acid/salt labeling are retained. The investigator’s possible-relatedness attribution and the record that all AE had resolved at the end do not establish a diarrhea-specific recovery date/definitive causality. The absence of placebo/randomized allocation, uncontrolled dietary B5 and CoA support/employment/consultancy/shareholdings are preserved. No new comparative risk, incidence, preventive effect of fed dosing or long-term safety conclusion is established.
Record level: This is content recorded in the archived manuscripts, not the result of a new comparison against current external original materials.
Study overlap and independent replication: Independent replication is unverified.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Original-paper HTML full text	Unverified (no external lookup in this review)	Access not attempted	Not read	This is preserved historical identity/access information or a required material type. Its external existence/availability was not newly checked in this review. What was actually read was the relevant manuscript, evidence and bibliography in the currently preserved source archive summary. This external original text/old separate file was not read in this review. The original citation’s primary_full_html_and_pdf_screenshots is metadata combining HTML access and screenshots of numerical PDF tables. This row is limited to the HTML portion and does not indicate external reading in this review. Historical access dates for each material are unverified. The archived manuscript’s review date of 2026-09-15 is not the access date of this original-material file. Historical access level of this material itself: Original-paper HTML full text (historical record of the HTML portion of the original access_level). Historical location in the reference bibliography: Methods pp. 2-3; Safety pp. 6-7; Table 6 pp. 7-8; Conflict of Interest p. 9 Bibliographic access records are not inherited as access to separate full texts/underlying materials. This does not mean that external original materials were acquired or full texts read in this review.
Original-paper PDF full text/original Table 6	Unverified (no external lookup in this review)	Access not attempted	Not read	This is preserved historical identity/access information or a required material type. Its external existence/availability was not newly checked in this review. What was actually read was the relevant manuscript, evidence and bibliography in the currently preserved source archive summary. This external original text/old separate file was not read in this review. The original citation records access to screenshots of numerical PDF tables. This is not expanded into verified access to the full PDF or individual AE/registration/plans. The original metadata are retained in contextual_document_access_level. Historical access dates for each material are unverified. The archived manuscript’s review date of 2026-09-15 is not the access date of this original-material file. Historical access level of this material itself: Original-paper PDF numerical-table screenshots (historical record; reading of the entire PDF full text is unverified). Historical location in the reference bibliography: Methods pp. 2-3; Safety pp. 6-7; Table 6 pp. 7-8; Conflict of Interest p. 9 Bibliographic access records are not inherited as access to separate full texts/underlying materials. This does not mean that external original materials were acquired or full texts read in this review.
Individual AE/exposure data and appendices	Unverified (no external lookup in this review)	Access not attempted	Not read	This is preserved historical identity/access information or a required material type. Its external existence/availability was not newly checked in this review. What was actually read was the relevant manuscript, evidence and bibliography in the currently preserved source archive summary. This external original text/old separate file was not read in this review. The historical access level of this original material itself is unverified in the current source. contextual_document_access_level is the original access metadata of the containing document/inherited extraction that mentions it; it is not inherited as full-text access to this original material. Historical access dates for each material are unverified. The archived manuscript’s review date of 2026-09-15 is not the access date of this original-material file. Historical access level of this material itself: Unverified. Historical location in the reference bibliography: Methods pp. 2-3; Safety pp. 6-7; Table 6 pp. 7-8; Conflict of Interest p. 9 Bibliographic access records are not inherited as access to separate full texts/underlying materials. This does not mean that external original materials were acquired or full texts read in this review.
Registration/protocol/SAP	Unverified (no external lookup in this review)	Access not attempted	Not read	This is preserved historical identity/access information or a required material type. Its external existence/availability was not newly checked in this review. What was actually read was the relevant manuscript, evidence and bibliography in the currently preserved source archive summary. This external original text/old separate file was not read in this review. The historical access level of this original material itself is unverified in the current source. contextual_document_access_level is the original access metadata of the containing document/inherited extraction that mentions it; it is not inherited as full-text access to this original material. Historical access dates for each material are unverified. The archived manuscript’s review date of 2026-09-15 is not the access date of this original-material file. Historical access level of this material itself: Unverified. Historical location in the reference bibliography: Methods pp. 2-3; Safety pp. 6-7; Table 6 pp. 7-8; Conflict of Interest p. 9 Bibliographic access records are not inherited as access to separate full texts/underlying materials. This does not mean that external original materials were acquired or full texts read in this review.

S2405 · Calcium pantothenate in arthritic conditions. A report from the General Practitioner Research Group (1980)

Source

Material type: PubMed bibliography without an abstract; historical non-acquisition of the original paper
Materials actually read: The corresponding Korean/English summaries and bibliographic records in the archived manuscripts were read. The linked external original materials were not read in this review.
Findings recorded in the stored summary: Record at preservation: The retained historical access concerns the title/journal and no-abstract bibliographic record for PMID 6988826. Clinical content is limited to the SCF 2nd-hand summary’s 8-week dose escalation, absence of recorded general treatment side effects and the conflict between 94 people and group counts of 47/46. Do not claim that the original diarrhea-event table was acquired/read or convert this into 0 diarrhea events.
Record level: This is content recorded in the archived manuscripts, not the result of a new comparison against current external original materials.
Study overlap and independent replication: Independent replication is unverified.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
PubMed bibliographic page without an abstract	Unverified (no external lookup in this review)	Access not attempted	Not read	This is preserved historical identity/access information or a required material type. Its external existence/availability was not newly checked in this review. What was actually read was the relevant manuscript, evidence and bibliography in the currently preserved source archive summary. This external original text/old separate file was not read in this review. Only the historical scope pertaining to this document/extraction itself in the preserved citation is retained. It is not inherited by other underlying original materials or treated as actual full-text reading in this review. Historical access dates for each material are unverified. The archived manuscript’s review date of 2026-09-15 is not the access date of this original-material file. Historical access level of this material itself: primary_metadata_no_abstract. Historical location in the reference bibliography: PubMed title / PMID / journal: Practitioner 1980;224(1340):208-211; No abstract available Bibliographic access records are not inherited as access to separate full texts/underlying materials. This does not mean that external original materials were acquired or full texts read in this review.
GPRG original-paper full text/diarrhea-event table	Unverified (no external lookup in this review)	Access not attempted	Not read	This is preserved historical identity/access information or a required material type. Its external existence/availability was not newly checked in this review. What was actually read was the relevant manuscript, evidence and bibliography in the currently preserved source archive summary. This external original text/old separate file was not read in this review. The historical access level of this original material itself is unverified in the current source. contextual_document_access_level is the original access metadata of the containing document/inherited extraction that mentions it; it is not inherited as full-text access to this original material. Historical access dates for each material are unverified. The archived manuscript’s review date of 2026-09-15 is not the access date of this original-material file. Historical access level of this material itself: Unverified. Historical location in the reference bibliography: PubMed title / PMID / journal: Practitioner 1980;224(1340):208-211; No abstract available Bibliographic access records are not inherited as access to separate full texts/underlying materials. This does not mean that external original materials were acquired or full texts read in this review.

S2406 · Scott LN et al. (2022). Safety Assessment of Panthenol, Pantothenic Acid, and Derivatives as Used in Cosmetics

Source

Material type: CIR cosmetic-review HTML · historical access
Materials actually read: The corresponding Korean/English summaries and bibliographic records in the archived manuscripts were read. The linked external original materials were not read in this review.
Findings recorded in the stored summary: Record at preservation: Scott 2022 is a review of the safety of panthenol, pantothenic acid and their derivatives in cosmetic use. Historical high-dose oral summaries, including Elder 1987, are limited to qualitative signals at 10–20 g/day; exact formulations, durations and event counts/denominators are unverified. CIR/Personal Care Products Council support funds this review, while funding for the underlying cases is unverified. It is not counted as authorization/safety certification of oral preparations or independent human replication.
Record level: This is content recorded in the archived manuscripts, not the result of a new comparison against current external original materials.
Study overlap and independent replication: Independent replication is unverified.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
CIR review HTML full text	Unverified (no external lookup in this review)	Access not attempted	Not read	This is preserved historical identity/access information or a required material type. Its external existence/availability was not newly checked in this review. What was actually read was the relevant manuscript, evidence and bibliography in the currently preserved source archive summary. This external original text/old separate file was not read in this review. Only the historical scope pertaining to this document/extraction itself in the preserved citation is retained. It is not inherited by other underlying original materials or treated as actual full-text reading in this review. Historical access dates for each material are unverified. The archived manuscript’s review date of 2026-09-15 is not the access date of this original-material file. Historical access level of this material itself: full_html. Historical location in the reference bibliography: Toxicological Studies first paragraph; reference 4 (Elder 1987); Funding and conflicts Bibliographic access records are not inherited as access to separate full texts/underlying materials. This does not mean that external original materials were acquired or full texts read in this review.
Elder 1987 and underlying original cases	Unverified (no external lookup in this review)	Access not attempted	Not read	This is preserved historical identity/access information or a required material type. Its external existence/availability was not newly checked in this review. What was actually read was the relevant manuscript, evidence and bibliography in the currently preserved source archive summary. This external original text/old separate file was not read in this review. The historical access level of this original material itself is unverified in the current source. contextual_document_access_level is the original access metadata of the containing document/inherited extraction that mentions it; it is not inherited as full-text access to this original material. Historical access dates for each material are unverified. The archived manuscript’s review date of 2026-09-15 is not the access date of this original-material file. Historical access level of this material itself: Unverified. Historical location in the reference bibliography: Toxicological Studies first paragraph; reference 4 (Elder 1987); Funding and conflicts Bibliographic access records are not inherited as access to separate full texts/underlying materials. This does not mean that external original materials were acquired or full texts read in this review.

S2407 · Evans et al. pantethine lipid trial, prior package exclusion record

Source

Material type: Exclusion extraction from an old package; the PMC link provides reference identity
Materials actually read: The corresponding Korean/English summaries and bibliographic records in the archived manuscripts were read. The linked external original materials were not read in this review.
Findings recorded in the stored summary: Record at preservation: The preserved old extraction classifies this as a pantethine trial and does not attribute it to diarrhea from single-active pantothenic acid. Not applicable for n indicates the exclusion role and does not mean 0 people/no risk. The old separate file and PMC full text were not read in this review.
Record level: This is content recorded in the archived manuscripts, not the result of a new comparison against current external original materials.
Study overlap and independent replication: Independent replication is unverified.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Original file of the old package’s exclusion extraction	Unverified (no external lookup in this review)	Access not attempted	Not read	This is preserved historical identity/access information or a required material type. Its external existence/availability was not newly checked in this review. What was actually read was the relevant manuscript, evidence and bibliography in the currently preserved source archive summary. This external original text/old separate file was not read in this review. Only the historical scope pertaining to this document/extraction itself in the preserved citation is retained. It is not inherited by other underlying original materials or treated as actual full-text reading in this review. Historical access dates for each material are unverified. The archived manuscript’s review date of 2026-09-15 is not the access date of this original-material file. Historical access level of this material itself: provided_prior_package_extraction. Historical location in the reference bibliography: reference/reused_TASK0022.json and legacy_366.json: pantethine, not pantothenic acid Bibliographic access records are not inherited as access to separate full texts/underlying materials. This does not mean that external original materials were acquired or full texts read in this review.
PMC original-paper link (current reference identity)	Unverified (no external lookup in this review)	Access not attempted	Not read	This is preserved historical identity/access information or a required material type. Its external existence/availability was not newly checked in this review. What was actually read was the relevant manuscript, evidence and bibliography in the currently preserved source archive summary. This external original text/old separate file was not read in this review. The historical access level of this original material itself is unverified in the current source. contextual_document_access_level is the original access metadata of the containing document/inherited extraction that mentions it; it is not inherited as full-text access to this original material. Historical access dates for each material are unverified. The archived manuscript’s review date of 2026-09-15 is not the access date of this original-material file. Historical access level of this material itself: Unverified. Historical location in the reference bibliography: reference/reused_TASK0022.json and legacy_366.json: pantethine, not pantothenic acid Bibliographic access records are not inherited as access to separate full texts/underlying materials. This does not mean that external original materials were acquired or full texts read in this review.

S2408 · Pantothenic-acid-based acne product, prior package composition assessment

Source

Material type: Composition assessment from an old package; the PMC link provides reference identity
Materials actually read: The corresponding Korean/English summaries and bibliographic records in the archived manuscripts were read. The linked external original materials were not read in this review.
Findings recorded in the stored summary: Record at preservation: Because monotherapy composition is unestablished in the preserved acne-product extraction, product-level tolerability is not transferred to the risk of single-active pantothenic acid. Not applicable for n indicates the exclusion role, not 0 people. The old separate composition file and PMC full text were not read in this review.
Record level: This is content recorded in the archived manuscripts, not the result of a new comparison against current external original materials.
Study overlap and independent replication: Independent replication is unverified.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Original file of the old package’s composition assessment	Unverified (no external lookup in this review)	Access not attempted	Not read	This is preserved historical identity/access information or a required material type. Its external existence/availability was not newly checked in this review. What was actually read was the relevant manuscript, evidence and bibliography in the currently preserved source archive summary. This external original text/old separate file was not read in this review. Only the historical scope pertaining to this document/extraction itself in the preserved citation is retained. It is not inherited by other underlying original materials or treated as actual full-text reading in this review. Historical access dates for each material are unverified. The archived manuscript’s review date of 2026-09-15 is not the access date of this original-material file. Historical access level of this material itself: provided_prior_package_extraction. Historical location in the reference bibliography: reference/reused_TASK0021.json: trial-product monotherapy not established Bibliographic access records are not inherited as access to separate full texts/underlying materials. This does not mean that external original materials were acquired or full texts read in this review.
PMC original-paper link (current reference identity)	Unverified (no external lookup in this review)	Access not attempted	Not read	This is preserved historical identity/access information or a required material type. Its external existence/availability was not newly checked in this review. What was actually read was the relevant manuscript, evidence and bibliography in the currently preserved source archive summary. This external original text/old separate file was not read in this review. The historical access level of this original material itself is unverified in the current source. contextual_document_access_level is the original access metadata of the containing document/inherited extraction that mentions it; it is not inherited as full-text access to this original material. Historical access dates for each material are unverified. The archived manuscript’s review date of 2026-09-15 is not the access date of this original-material file. Historical access level of this material itself: Unverified. Historical location in the reference bibliography: reference/reused_TASK0021.json: trial-product monotherapy not established Bibliographic access records are not inherited as access to separate full texts/underlying materials. This does not mean that external original materials were acquired or full texts read in this review.

Report counts versus independent study counts

The 5 archived evidence lineages do not represent a count of independent clinical trials or a total number of participants. RAO-2021-PK (S2404): used for the direct signal and descriptive statistics; not used for randomized/placebo comparative-risk estimates or general incidence / GPRG-1980-ARTHRITIS (S2405, S2402): counter/contextual evidence / LEGACY-HIGH-DOSE-SUMMARY (S06, S2402, S2406): used only for qualitative high-dose safety signals; review lineages are not summed as independent replications / EVANS-PANTETHINE-EXCLUDED (S2407): excluded / YANG-2014-EXCLUDED (S2408): excluded. Repeated citations of the same study and overlapping high-dose summaries are not summed as independent replications.

Review criteria

Version NGM-v3102-SOLE-ORAL-B5-DIARRHEA-SAFETY-1.1 · Criteria record date 2026-10-05. These are Chamgap's own application conditions, informed by the referenced methods. They do not constitute official assessment-tool certification or a new efficacy score.

N01 · Is this table's safety-only, efficacy-not-applicable contract preserved?

Required materials and conditions: Original safety-only display and assessment contract
Conditions for verification: Link safety_only, efficacy not_applicable, and framework false to their original locations without assigning a new score or efficacy display.
Requirement and applicability: Required
Application exceptions: The original grade ? and empty score value, and document quality B, are historical values. The absent 7-axis/no_human fields are not created.
Why this condition is needed: This is needed to avoid converting a harm signal into a numerical efficacy/risk grade.
Referenced methods: C01: Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are self-designed / C09: M04 §4.5, §4.6.3; limitations of the current material conversion reflect the user-defined scope and self-designed rules / H09: Chamgap's own interpretive boundaries. M19 principles are referenced; no formal causality tool was applied. Reason for application to the harm question: This is needed to avoid converting a harm signal into a numerical efficacy/risk grade. No formal causality/harm grading assessment or clinical certification was performed.

N02 · What are the separate question and its inclusion/exclusion scope?

Required materials and conditions: Scope of the original claim/population/exposure/endpoint
Conditions for verification: Link the original claim to adults, B5 as the sole active ingredient, oral exposure, and new/worsened diarrhea.
Requirement and applicability: Required
Application exceptions: Separate dose, meal, and duration conditions within the same question without extending it to all other harms/efficacy.
Why this condition is needed: Fix the selected question about diarrhea from an oral single-active-ingredient product rather than the safety of the ingredient as a whole.
Referenced methods: C01: Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are self-designed / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation of checks are self-designed / H09: Chamgap's own interpretive boundaries. M19 principles are referenced; no formal causality tool was applied. Reason for application to the harm question: Fix the selected question about diarrhea from an oral single-active-ingredient product rather than the safety of the ingredient as a whole. No formal causality/harm grading assessment or clinical certification was performed.

N03 · Was the directly studied preparation distinguished from other B5-related substances?

Required materials and conditions: Identity of the substance/product composition/source ingredients/additives
Conditions for verification: Explain inclusion/exclusion of the directly studied preparation and other substances/compositions.
Requirement and applicability: Required
Application exceptions: Pantethine, pantetheine, dexpanthenol/panthenol, B-complex products, and multivitamins are not combined as the same exposure.
Why this condition is needed: This is needed to avoid attributing events involving other molecules or combination products to B5 alone.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation of checks are self-designed / H05: Design considerations in M19 §19.2.2–19.2.4; detailed confounding records are self-designed. Reason for application to the harm question: This is needed to avoid attributing events involving other molecules or combination products to B5 alone. No formal causality/harm grading assessment or clinical certification was performed.

N04 · Is the acid/salt mass basis of the stated administered dose clear?

Required materials and conditions: Original tablet label, dosing table, and evidence for the acid/salt mass basis
Conditions for verification: Separate the label, dosing table, and pharmacokinetic explanation, leaving the unclear mass basis unresolved.
Requirement and applicability: Required
Application exceptions: Do not newly calculate the actual clinical dose from the explanation of 550 mg of calcium salt versus 500 mg of free base in the original text.
Why this condition is needed: This is needed to avoid converting the nominal dose into an actual acid/salt amount or toxicity threshold.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation of checks are self-designed / H04: M19 §19.1.2–19.2.4; self-adapted application. Reason for application to the harm question: This is needed to avoid converting the nominal dose into an actual acid/salt amount or toxicity threshold. No formal causality/harm grading assessment or clinical certification was performed.

N05 · How are the nominal doses in the single-dose conditions distinguished?

Required materials and conditions: Nominal dose and dosing/meal records by condition
Conditions for verification: Link the single doses and fasted/fed conditions exactly as reported in the paper.
Requirement and applicability: Required
Application exceptions: Do not interpret nominal doses as risk thresholds or recommended doses for individuals.
Why this condition is needed: This is needed to avoid combining different dose conditions into a single exposure or a minimum harmful dose.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation of checks are self-designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptation is self-designed / H02: Design-specific harm questions in M19 §19.2; details of temporal relationships are self-designed. Reason for application to the harm question: This is needed to avoid combining different dose conditions into a single exposure or a minimum harmful dose. No formal causality/harm grading assessment or clinical certification was performed.

N06 · Are repeated exposure and follow-up periods separated from single dosing?

Required materials and conditions: Repeated dosing, adherence, and AE follow-up schedule
Conditions for verification: Distinguish repeated dosing at 2,000 mg/day for 14 days from follow-up through day 9 for single dosing/day 22 for repeated dosing.
Requirement and applicability: Required
Application exceptions: Do not convert the 14-day repeated exposure and follow-up through day 22 into the same period.
Why this condition is needed: This is needed to avoid extending a short repeated-dose condition to long-term safety.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation of checks are self-designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptation is self-designed / H02: Design-specific harm questions in M19 §19.2; details of temporal relationships are self-designed. Reason for application to the harm question: This is needed to avoid extending a short repeated-dose condition to long-term safety. No formal causality/harm grading assessment or clinical certification was performed.

N07 · Are the directly studied population and baseline diarrhea status verified?

Required materials and conditions: Table of inclusion/exclusion, sex, baseline diarrhea/diseases, and medications
Conditions for verification: Distinguish the healthy population aged 18–55 from individual baseline GI/selection information.
Requirement and applicability: Required
Application exceptions: Do not convert the description of participants as healthy into proof of absence of diarrhea in individuals or safety in special populations.
Why this condition is needed: This is needed to avoid applying data from healthy people directly to all adults or to worsening of baseline diarrhea.
Referenced methods: C04: M03 §3.2.1; detailed population conditions are self-designed / H05: Design considerations in M19 §19.2.2–19.2.4; detailed confounding records are self-designed / H08: M19 §19.1.2–19.2.4; self-adapted application. Reason for application to the harm question: This is needed to avoid applying data from healthy people directly to all adults or to worsening of baseline diarrhea. No formal causality/harm grading assessment or clinical certification was performed.

N08 · Can the 40 participants be distinguished from the single-dose and repeated-dose completion denominators?

Required materials and conditions: Recruitment/allocation/exposure/completion/analysis flow and participant linkage by condition
Conditions for verification: Separately link completion by 40 participants overall, 32 in the single-dose part, and 8 in the repeated-dose part, and the report of 8 participants per condition.
Requirement and applicability: Required
Application exceptions: Fed redosing involved the same 8 participants, and the single-dose/repeated-dose conditions are not counted as independent studies.
Why this condition is needed: This is needed to avoid reusing the overall study size as the diarrhea analysis denominator for every condition.
Referenced methods: C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is self-adapted / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptation is self-designed / H04: M19 §19.1.2–19.2.4; self-adapted application / H06: M19 §19.1.2–19.2.4, M04 §4.6.3; self-adapted application. Reason for application to the harm question: This is needed to avoid reusing the overall study size as the diarrhea analysis denominator for every condition. No formal causality/harm grading assessment or clinical certification was performed.

N09 · Are the participants, sequence, and actual washout period for fed redosing consistently verified?

Required materials and conditions: Original abstract, methods, and individual dosing sequence/washout schedule
Conditions for verification: Verify the dosing sequence and actual washout schedule for the same 8 participants, and compare whether the duration descriptions in the abstract/methods are consistent. If differences in the duration descriptions or an unverified actual schedule remain, do not treat the duration as consistently verified.
Requirement and applicability: Required
Application exceptions: Do not correct 2 weeks in the abstract and 2–3 weeks in the methods to a single confirmed washout value or compare them as independent groups.
Why this condition is needed: This is needed to avoid interpreting conditions in the same people with changes in meal status and sequence as randomized control groups.
Referenced methods: C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is self-adapted / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation of checks are self-designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is self-designed / H02: Design-specific harm questions in M19 §19.2; details of temporal relationships are self-designed / H03: M19 §19.2.2–19.2.4, M03 §3.2.3; self-adapted application. Reason for application to the harm question: This is needed to avoid interpreting conditions in the same people with changes in meal status and sequence as randomized control groups. No formal causality/harm grading assessment or clinical certification was performed.

N10 · What are the definition and coding criteria for diarrhea?

Required materials and conditions: Diarrhea AE definition, coding/diagnostic criteria, and records of stool frequency/form
Conditions for verification: Distinguish the MedDRA 21.0 diarrhea category from the separate gap in diagnostic criteria.
Requirement and applicability: Required
Application exceptions: Do not equate a MedDRA term with diagnostic criteria based on stool frequency/form or with a clinical diagnosis.
Why this condition is needed: This is needed to avoid recoding general GI discomfort or loose stools as confirmed diarrhea.
Referenced methods: C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptation is self-designed / H01: M19 §19.1.2–19.2.4; detailed ascertainment is self-designed. Reason for application to the harm question: This is needed to avoid recoding general GI discomfort or loose stools as confirmed diarrhea. No formal causality/harm grading assessment or clinical certification was performed.

N11 · Are data available to distinguish new diarrhea from worsening of existing diarrhea?

Required materials and conditions: Baseline diarrhea and change criteria, and an AE table separating new/worsened cases
Conditions for verification: Link baseline symptoms with person counts and ascertainment data for new/worsened cases.
Requirement and applicability: Required
Application exceptions: Do not reclassify events that are currently unseparated as all new or all worsened.
Why this condition is needed: This is needed to examine whether the original event data actually distinguish the two scopes of the original question: occurrence and worsening.
Referenced methods: C04: M03 §3.2.1; detailed population conditions are self-designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptation is self-designed / H01: M19 §19.1.2–19.2.4; detailed ascertainment is self-designed. Reason for application to the harm question: This is needed to examine whether the original event data actually distinguish the two scopes of the original question: occurrence and worsening. No formal causality/harm grading assessment or clinical certification was performed.

N12 · Can diarrhea collection methods, severity, and differences in detection be verified?

Required materials and conditions: AE collection form/questioning frequency, blinding/ascertainment, and severity table
Conditions for verification: Verify diarrhea-specific collection tools, frequency, severity, and ascertainment methods.
Requirement and applicability: Required
Application exceptions: An open-label trial/use of MedDRA alone does not establish spontaneous versus systematic collection or blinded ascertainment.
Why this condition is needed: This is needed to avoid assuming that categorized reported values represent systematically and completely collected events.
Referenced methods: H01: M19 §19.1.2–19.2.4; detailed ascertainment is self-designed / H06: M19 §19.1.2–19.2.4, M04 §4.6.3; self-adapted application / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptation is self-designed. Reason for application to the harm question: This is needed to avoid assuming that categorized reported values represent systematically and completely collected events. No formal causality/harm grading assessment or clinical certification was performed.

N13 · Were nausea, vomiting, and abdominal discomfort kept separate from diarrhea?

Required materials and conditions: Original AE categories by endpoint and a table of people/events
Conditions for verification: Separate attribution of results for diarrhea and other GI categories.
Requirement and applicability: Required
Application exceptions: Overall AEs or composite GI symptoms do not replace diarrhea-only results.
Why this condition is needed: This is needed to avoid adding other GI events to the person count or magnitude of harm for the selected endpoint.
Referenced methods: C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptation is self-designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is self-designed / H01: M19 §19.1.2–19.2.4; detailed ascertainment is self-designed. Reason for application to the harm question: This is needed to avoid adding other GI events to the person count or magnitude of harm for the selected endpoint. No formal causality/harm grading assessment or clinical certification was performed.

N14 · What is the direct diarrhea report under the 5,000 mg fasted condition?

Required materials and conditions: Original Table 6 and the relevant person's AE record
Conditions for verification: Attribute the report in Table 6 for the paper-labeled 5,000 mg fasted single-dose condition (1/8 participants) to the specified condition.
Requirement and applicability: Required
Application exceptions: Do not convert 1/8 into a general incidence rate, risk ratio, individual probability, or minimum harmful dose.
Why this condition is needed: This is needed to acknowledge the direct signal while distinguishing reported observations from causal risk.
Referenced methods: H01: M19 §19.1.2–19.2.4; detailed distinctions were internally designed / H04: M19 §19.1.2–19.2.4; internal application / H09: Chamgap’s own interpretive boundary. References M19 principles; no formal causality tool was applied / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations were internally designed. Reason for application to the harm question: needed to acknowledge the direct signal while distinguishing reported observations from causal risk. No formal causality/harm grading or clinical certification was performed.

N15 · Are conditions with 0/8 reports also retained?

Required materials and conditions: Condition-specific Table 6 and the scope of exposure/follow-up and collection
Conditions for verification: Retain the 0/8 records for each lower single dose, repeated dosing, and subsequent fed dosing, together with their limitations.
Requirement and applicability: Required
Application exceptions: For the same 8 participants, the fed-dosing 0/8 is not a preventive effect, and the 0/8 under other doses/repeated dosing is not a safety threshold.
Why this condition is needed: Needed to avoid selecting only positive signals or converting an absence of reports into an absence of risk.
Referenced methods: C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses was internally designed / H04: M19 §19.1.2–19.2.4; internal application / H09: Chamgap’s own interpretive boundary. References M19 principles; no formal causality tool was applied. Reason for application to the harm question: needed to avoid selecting only positive signals or converting an absence of reports into an absence of risk. No formal causality/harm grading or clinical certification was performed.

N16 · Can the reported numbers of people, repeated events, and exposure-time denominators be distinguished?

Required materials and conditions: Condition-specific person/event counts, follow-up/exposure time, and missing data
Conditions for verification: Distinguish the original denominator for reported people and repeated-event/time information from values that are absent.
Requirement and applicability: Required
Application exceptions: Do not replace the 8 participants per condition with the total of 40 participants or 16 participants obtained from fed + fasted dosing.
Why this condition is needed: Needed to avoid confusing the different denominators for reports of people and event frequency/incidence rates.
Referenced methods: C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations were internally designed / H04: M19 §19.1.2–19.2.4; internal application. Reason for application to the harm question: needed to avoid confusing the different denominators for reports of people and event frequency/incidence rates. No formal causality/harm grading or clinical certification was performed.

N17 · Was diarrhea risk compared with an appropriate unexposed/placebo group?

Required materials and conditions: Unexposed/appropriate comparator data with matching event definitions/follow-up
Conditions for verification: Link the actual comparator structure to whether comparative risk can be estimated or remains unverified.
Requirement and applicability: Required
Application exceptions: Retain the signal even in the absence of comparative data. Do not substitute a randomized placebo group for fixed-sequence/redosing with food.
Why this condition is needed: Needed to avoid describing a report without a comparison as the magnitude of a risk increase.
Referenced methods: H03: M19 §19.2.2–19.2.4, M03 §3.2.3; internal application / H09: Chamgap’s own interpretive boundary. References M19 principles; no formal causality tool was applied / C05: M03 §3.2.2–3.2.3; reverse-direction markers and test adaptations were internally designed. Reason for application to the harm question: needed to avoid describing a report without a comparison as the magnitude of a risk increase. No formal causality/harm grading or clinical certification was performed.

N18 · Is the temporal link between diarrhea onset/recovery and exposure verified?

Required materials and conditions: Individual logs of dosing, blood sampling/meals, and diarrhea onset/recovery
Conditions for verification: Link diarrhea-specific onset, duration, and recovery with actual dosing times.
Requirement and applicability: Required
Application exceptions: Do not convert the record that all AEs had resolved by the end into diarrhea-specific recovery dates or evidence of positive dechallenge/rechallenge.
Why this condition is needed: Distinguish reports after exposure from specific onset/recovery and causal clues from re-exposure.
Referenced methods: C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations were internally designed / H02: design-specific harm questions in M19 §19.2; details of temporal relationships were internally designed / H09: Chamgap’s own interpretive boundary. References M19 principles; no formal causality tool was applied. Reason for application to the harm question: distinguish reports after exposure from specific onset/recovery and causal clues from re-exposure. No formal causality/harm grading or clinical certification was performed.

N19 · Is the investigator's wording on relatedness kept separate from established causality?

Required materials and conditions: The basis for individual AE relatedness assessments and records of alternative causes
Conditions for verification: Distinguish the original report's statements on relatedness from uncertainty and gaps concerning alternative causes.
Requirement and applicability: Required
Application exceptions: The Caution safety label is not confirmation of an individual’s cause or a quantitative causality score.
Why this condition is needed: Needed to retain the original relatedness assessment without extending it to formal causality certification.
Referenced methods: H05: design considerations in M19 §19.2.2–19.2.4; detailed confounding records were internally designed / H09: Chamgap’s own interpretive boundary. References M19 principles; no formal causality tool was applied / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations were internally designed. Reason for application to the harm question: needed to retain the original relatedness assessment without extending it to formal causality certification. No formal causality/harm grading or clinical certification was performed.

N20 · Were alternative explanations such as concurrent exposure, diet, and infection reviewed?

Required materials and conditions: Records of medications/supplements, diet, meals, excipients, and infection/baseline symptoms
Conditions for verification: Link medication/supplement restrictions and uncontrolled diet with gaps concerning alternative causes.
Requirement and applicability: Required
Application exceptions: Do not extend the prohibition of other medications/supplements to control of all diet, excipients, and infections.
Why this condition is needed: Needed to avoid eliminating background exposures and alternative causes solely on the basis of identification as a single-active-ingredient product.
Referenced methods: H05: design considerations in M19 §19.2.2–19.2.4; detailed confounding records were internally designed / C05: M03 §3.2.2–3.2.3; reverse-direction markers and test adaptations were internally designed. Reason for application to the harm question: needed to avoid eliminating background exposures and alternative causes solely on the basis of identification as a single-active-ingredient product. No formal causality/harm grading or clinical certification was performed.

N21 · Are discontinuation/serious AE reports distinguished from detailed participant flow?

Required materials and conditions: Diarrhea-specific reasons for discontinuation/dropout, periods without collection, and participant flow
Conditions for verification: Retain the original general safety summary separately from diarrhea-specific discontinuation/missingness and flow gaps.
Requirement and applicability: Required
Application exceptions: No deaths, serious AEs, or AE discontinuations is not proof of 0 diarrhea events or complete event collection for every participant.
Why this condition is needed: Needed to avoid converting a general safety summary into an absence of diarrhea-specific missingness or long-term safety.
Referenced methods: C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations were internally designed / H06: M19 §19.1.2–19.2.4, M04 §4.6.3; internal application / H01: M19 §19.1.2–19.2.4; detailed distinctions were internally designed. Reason for application to the harm question: needed to avoid converting a general safety summary into an absence of diarrhea-specific missingness or long-term safety. No formal causality/harm grading or clinical certification was performed.

N22 · Are the registration, protocol, analysis plan, and scope of prespecification verified?

Required materials and conditions: Registration, protocol, SAP, and records of diarrhea prespecification/changes
Conditions for verification: Distinguish the scope actually verified in the registration/protocol/SAP from what remains unverified.
Requirement and applicability: Required
Application exceptions: Do not convert current lack of verification and historical access failures into established absence of preregistration or confirmed deviation from the plan.
Why this condition is needed: Needed to review the possibility of selective reporting and the scope of prespecified/post hoc analyses.
Referenced methods: C09: M04 §4.5, §4.6.3; restrictions on the current data transformation follow the user-defined scope and internal design / H06: M19 §19.1.2–19.2.4, M04 §4.6.3; internal application. Reason for application to the harm question: needed to review the possibility of selective reporting and the scope of prespecified/post hoc analyses. No formal causality/harm grading or clinical certification was performed.

N23 · Are risk differences, risk ratios, CIs, and criteria for interpreting harm verified?

Required materials and conditions: Original comparative estimates, denominators, CIs/uncertainty, and clinical harm criteria
Conditions for verification: Distinguish reported observations from gaps in formal comparative estimates/uncertainty and harm criteria.
Requirement and applicability: Required
Application exceptions: Do not newly calculate risk differences/risk ratios, incidence rates, CIs, P, or NNH that are absent from the existing data.
Why this condition is needed: Needed to avoid converting a small descriptive report into quantitative comparative risk or a minimum harmful dose.
Referenced methods: H03: M19 §19.2.2–19.2.4, M03 §3.2.3; internal application / H04: M19 §19.1.2–19.2.4; internal application / H09: Chamgap’s own interpretive boundary. References M19 principles; no formal causality tool was applied / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations were internally designed. Reason for application to the harm question: needed to avoid converting a small descriptive report into quantitative comparative risk or a minimum harmful dose. No formal causality/harm grading or clinical certification was performed.

N24 · What is the scope of the absence of recorded side effects in the arthritis trial?

Required materials and conditions: The original GPRG diarrhea/AE event table and dosing, population, and collection methods
Conditions for verification: Separate SCF's summary of dose escalation over 8 weeks in arthritis from the access scope of the PubMed bibliographic record.
Requirement and applicability: Required
Application exceptions: The original event table not having been acquired is not a new access failure in this work, and an absence of recorded side effects is not substituted with 0 diarrhea events.
Why this condition is needed: Needed to retain contrary context without converting a 2nd-hand general side-effect statement into a diarrhea event table.
Referenced methods: C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses was internally designed / H01: M19 §19.1.2–19.2.4; detailed distinctions were internally designed / H07: M04 §4.6.1–4.6.2; adaptations for harm data were internally designed. Reason for application to the harm question: needed to retain contrary context without converting a 2nd-hand general side-effect statement into a diarrhea event table. No formal causality/harm grading or clinical certification was performed.

N25 · Are the overall and arm-specific participants and analysis denominators in the arthritis study consistently verified?

Required materials and conditions: Original participant flow, arm-specific allocation/analysis tables, and SCF's cited statement
Conditions for verification: Check whether the actual definitions and counts of overall and arm-specific allocation/completion/analysis denominators are consistently verified in the original tables. If the inconsistency between 94 participants and arm-specific counts of 47/46 participants remains, do not treat them as established denominators.
Requirement and applicability: Required
Application exceptions: 47+46=93 is historical arithmetic already present in the original summary. Do not correct the total through new calculations/selection.
Why this condition is needed: Needed to avoid arbitrarily correcting different statements of the total or using them as established analysis denominators.
Referenced methods: C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations were internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses was internally designed. Reason for application to the harm question: needed to avoid arbitrarily correcting different statements of the total or using them as established analysis denominators. No formal causality/harm grading or clinical certification was performed.

N26 · What limitations apply to the reused NIH example of 10 g/day?

Required materials and conditions: The relevant NIH section and underlying original cases and exposure/event data
Conditions for verification: Retain the example of very high intake at 10 g/day and the gaps concerning cases/formulation, duration, and denominators.
Requirement and applicability: Required
Application exceptions: Do not convert the official NIH discussion into a new clinical trial or an allowable/recommended intake of 10 g/day.
Why this condition is needed: Needed to avoid interpreting an official general safety statement as a new event rate or toxicity threshold.
Referenced methods: C03: data collection/selection principles in M04 §4.5–4.6; separation of access and reading and the hyperlink contract were internally designed / H07: M04 §4.6.1–4.6.2; adaptations for harm data were internally designed / H09: Chamgap’s own interpretive boundary. References M19 principles; no formal causality tool was applied. Reason for application to the harm question: needed to avoid interpreting an official general safety statement as a new event rate or toxicity threshold. No formal causality/harm grading or clinical certification was performed.

N27 · Are historical summaries of 10–20 g/day kept from being counted as independent human replications?

Required materials and conditions: SCF/CIR citation lineage, Elder 1987, and underlying original cases
Conditions for verification: Separate overlapping summary lineages of historical reports from the lack of verification of original cases.
Requirement and applicability: Required
Application exceptions: The number of official/expert documents and summary family_id are not the number of independent clinical cases/trials.
Why this condition is needed: Needed to avoid summing repeated citations by SCF/CIR/NIH as distinct established studies.
Referenced methods: C02: the distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an internal application / H07: M04 §4.6.1–4.6.2; adaptations for harm data were internally designed. Reason for application to the harm question: needed to avoid summing repeated citations by SCF/CIR/NIH as distinct established studies. No formal causality/harm grading or clinical certification was performed.

N28 · Is the meaning of insufficient data behind the absence of an established upper intake level preserved?

Required materials and conditions: The relevant official edition/harm assessment section and the basis for data insufficiency
Conditions for verification: Link the UL-related wording and dates in FNB 1998 and EFSA version 11(2025-08).
Requirement and applicability: Required
Application exceptions: The wording of the official assessment and the edition checked are historical in scope and do not represent a current lookup of the latest regulations in this work.
Why this condition is needed: Needed to avoid mistaking inability to derive an upper intake level for unlimited safety or a legally permitted therapeutic dose.
Referenced methods: C09: M04 §4.5, §4.6.3; restrictions on the current data transformation follow the user-defined scope and internal design / H08: M19 §19.1.2–19.2.4; internal application / H09: Chamgap’s own interpretive boundary. References M19 principles; no formal causality tool was applied. Reason for application to the harm question: needed to avoid mistaking inability to derive an upper intake level for unlimited safety or a legally permitted therapeutic dose. No formal causality/harm grading or clinical certification was performed.

N29 · Are adequate intake and high-dose diarrhea signals kept separate?

Required materials and conditions: Populations/definitions of nutritional reference values and data on high-dose preparations
Conditions for verification: Preserve the distinction between the nutritional purpose of the AI values and high-dose single-active-ingredient exposure.
Requirement and applicability: Required
Application exceptions: The values of 5 for adults, 6 for pregnancy and 7 mg/day for lactation are not risk values from the same clinical exposure group.
Why this condition is needed: Needed to avoid converting a nutritional adequacy reference into a diarrhea threshold or instructions for an individual's high-dose treatment.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse indicators and test adaptations are internally designed / H08: M19 §19.1.2–19.2.4; internally applied / H09: Chamgap’s own interpretive boundary. M19 principles are referenced; no formal causality tool was applied. Reason for application to the harm question: Needed to avoid converting nutritional adequacy references into a diarrhea threshold or personal high-dose treatment instructions. No formal causality/harm grading or clinical certification was performed.

N30 · Is the boundary on applying the CIR cosmetic assessment to oral use preserved?

Required materials and conditions: CIR review scope, toxicology section and underlying oral-use references
Conditions for verification: Distinguish CIR’s cosmetic-review scope from the role of its historical oral-use summaries.
Requirement and applicability: Required
Application exceptions: Historical oral-use reports cited in a cosmetic review do not provide grounds for authorization of all oral preparations.
Why this condition is needed: Needed to avoid converting a safety assessment with a different route/purpose into authorization/safety certification of a single-active oral preparation.
Referenced methods: C01: Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are internally designed / H07: M04 §4.6.1–4.6.2; adaptation to harm data is internally designed / H09: Chamgap’s own interpretive boundary. M19 principles are referenced; no formal causality tool was applied. Reason for application to the harm question: Needed to avoid converting a safety assessment with a different route/purpose into authorization/safety certification of a single-active oral preparation. No formal causality/harm grading or clinical certification was performed.

N31 · Are pantethine and the acne product with unestablished composition excluded?

Required materials and conditions: Identity of the product’s ingredients/formulation and historical exclusion extraction
Conditions for verification: Link the Evans record of a different molecule and the Yang record of unestablished single-active composition as separate grounds for exclusion.
Requirement and applicability: Required
Application exceptions: Not applicable is the denominator’s role within the exclusion scope; it does not mean 0 people, no risk or no human research.
Why this condition is needed: Needed to avoid transferring the tolerability of a different molecule/product into direct harm evidence for this question.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse indicators and test adaptations are internally designed / C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is internally applied / H07: M04 §4.6.1–4.6.2; adaptation to harm data is internally designed. Reason for application to the harm question: Needed to avoid transferring the tolerability of a different molecule/product into direct harm evidence for this question. No formal causality/harm grading or clinical certification was performed.

N32 · Is funding/conflict-of-interest attribution clear for each study/review?

Required materials and conditions: Original Funding/COI, support/product provision and funding records for underlying cases
Conditions for verification: Preserve Rao’s and the CIR review’s funding/relationships separately from the unverified information for original cases.
Requirement and applicability: Required
Application exceptions: Disclosed interests alone do not determine study invalidation, effect-size adjustment or a new harm grade.
Why this condition is needed: Needed to avoid hiding developer support or transferring another review’s funding to support for the original cases.
Referenced methods: C10: Chamgap’s own independence/attribution condition. The formal methods sections used in this pilot do not warrant every detail of this item / H07: M04 §4.6.1–4.6.2; adaptation to harm data is internally designed. Reason for application to the harm question: Needed to avoid hiding developer support or transferring another review’s funding to support for the original cases. No formal causality/harm grading or clinical certification was performed.

N33 · Is there direct harm evidence for long-term exposure and vulnerable populations?

Required materials and conditions: Long-term follow-up and direct diarrhea/exposure/comparator data by population
Conditions for verification: Separate the scope of healthy people aged 18–55 and short exposure from gaps for other populations/long-term exposure.
Requirement and applicability: Required
Application exceptions: Indirect documents/AI values and brief reports of 0/8 do not demonstrate absence of risk in each population.
Why this condition is needed: Needed to avoid extending a short study in healthy people to long-term safety during pregnancy/lactation, in children or in older people/those with disease.
Referenced methods: C04: M03 §3.2.1; detailed population conditions are internally designed / H08: M19 §19.1.2–19.2.4; internally applied. Reason for application to the harm question: Needed to avoid extending a short study in healthy people to long-term safety during pregnancy/lactation, in children or in older people/those with disease. No formal causality/harm grading or clinical certification was performed.

N34 · Was current summary reading distinguished from historical access to original materials?

Required materials and conditions: Original material types, bibliography and access/preservation receipts for each report
Conditions for verification: Separate each report’s physical URL and historical access_level/location from the current unread status of each material type.
Requirement and applicability: Required
Application exceptions: Historical full_text/official PDF/no access/inherited extractions do not represent the actual current read status of each material type.
Why this condition is needed: Needed to avoid upgrading this reading of local materials into a new reading of external full texts/old packages.
Referenced methods: C03: Data-collection/selection principles in M04 §4.5–4.6; the separation of access from reading and the hyperlink contract are internally designed. Reason for application to the harm question: Needed to avoid upgrading this reading of local materials into a new reading of external full texts/old packages. No formal causality/harm grading or clinical certification was performed.

N35 · Are the evidence-review date, access dates and actual server metadata distinguished?

Required materials and conditions: Actual access/version dates for each report and original server publication/modification receipts
Conditions for verification: Link the original review reference date, current review date, absence of report-specific access dates and limitations on the server publication date.
Requirement and applicability: Required
Application exceptions: Do not create absent evidence_cutoff/subclaims; retain both the original published/updated metadata and the statement in the text that an actual server publication date is unassigned.
Why this condition is needed: Needed to avoid treating a global date or package metadata as a verified access/original-binary verification date for each report.
Referenced methods: C09: M04 §4.5, §4.6.3; limitations on the current material transformation follow the user’s scope and internal design / C03: Data-collection/selection principles in M04 §4.5–4.6; the separation of access from reading and the hyperlink contract are internally designed. Reason for application to the harm question: Needed to avoid treating a global date or package metadata as a verified access/original-binary verification date for each report. No formal causality/harm grading or clinical certification was performed.

N36 · Are gaps in searches, corrections/retractions, unpublished materials and updating identified?

Required materials and conditions: Actual logs of searches/selection, corrections/retractions and registration/unpublished-material checks, and new results
Conditions for verification: Link the limits of self-review/historical access to the scope for updates under the same ID when new evidence/corrections arise.
Requirement and applicability: Required
Application exceptions: The original package’s statement that search records are preserved does not mean that the complete search logs/ZIP were opened in this review.
Why this condition is needed: Needed to avoid extending a historical self-check into independent review or assurance of worldwide absence of evidence.
Referenced methods: C09: M04 §4.5, §4.6.3; limitations on the current material transformation follow the user’s scope and internal design / H06: M19 §19.1.2–19.2.4, M04 §4.6.3; internally applied. Reason for application to the harm question: Needed to avoid extending a historical self-check into independent review or assurance of worldwide absence of evidence. No formal causality/harm grading or clinical certification was performed.

Referenced methods and the sections actually reviewed

M03 · Cochrane Handbook 6.5 (2024), chapter updated 2023-08

Official methodology · §3.1, §3.2.1–3.2.3, MECIR C5/C7/C13

Referenced principle: Clearly record the question, eligibility conditions and reasons for changes, and distinguish variations of the intervention.
Extent of review: Historical reuse of the 1585 method HTML copies (5), their actual original bytes/SHA and the principles recorded at the time; no new reading of method full texts or execution of a formal assessment/clinical certification

M04 · Cochrane Handbook 6.5.1 (2025), chapter updated 2025-03

Official methodology · §4.5, §4.6.1–4.6.3, MECIR C42

Referenced principle: Distinguish and link studies and reports; do not omit a study solely because outcomes are unreported.
Extent of review: Historical reuse of the 1585 method HTML copies (5), their actual original bytes/SHA and the principles recorded at the time; no new reading of method full texts or execution of a formal assessment/clinical certification

M08 · Cochrane Handbook 6.5 (2024), chapter updated 2019-10

Official methodology · §8.1–8.2.3, Table 8.2.a

Referenced principle: Fix the outcome and effect of interest when reviewing randomization, deviations, missingness, measurement and selective reporting.
Extent of review: Historical reuse of the 1585 method HTML copies (5), their actual original bytes/SHA and the principles recorded at the time; no new reading of method full texts or execution of a formal assessment/clinical certification

M15 · Cochrane Handbook 6.5 (2024), chapter updated 2023-08

Official methodology · §15.2.4, §15.3.1–15.3.3

Referenced principle: Distinguish effect estimates, intervals, importance and application. Sample size alone does not determine precision.
Extent of review: Historical reuse of the 1585 method HTML copies (5), their actual original bytes/SHA and the principles recorded at the time; no new reading of method full texts or execution of a formal assessment/clinical certification

M19 · Cochrane Handbook 6.5 (2024), chapter updated 2019-10

Official methodology · §19.1.2, §19.2.1–19.2.4

Referenced principle: Harm questions may require designs, populations and follow-up that differ from those for efficacy. Case reports do not establish incidence.
Extent of review: Historical reuse of the 1585 method HTML copies (5), their actual original bytes/SHA and the principles recorded at the time; no new reading of method full texts or execution of a formal assessment/clinical certification

What the statuses mean

Met: The specific narrow condition concerning identity/attribution, original values and scope/reading records is met. This does not establish efficacy, definitive causality, absence of risk or current external full-text verification.
Partly verified: Related observations are preserved, but some aspects of actual exposure/definitions, denominators, methods or comparison with original materials are unverified.
Unverified: This could not be established within the current archived materials and the scope verified at the time. It does not mean 0 risk, worldwide absence of evidence or access failure.
Not reported: Limited to non-reporting in manuscripts actually read/the stated scope of historical verification. It does not extend to the entirety of unread external full texts.
Conflicting information: Identifies inconsistent preserved descriptions of the same fact. Different exposure conditions or different roles of documents are not themselves conflicts.
Inaccessible: Used only for actual access failure in this review. As external access was not attempted in this review, historical failures are not converted into this state.
Review incomplete: Limited to the absence of current external comparison; it does not describe the entirety of the local archived-summary/model review that was actually completed.
Not applicable: Limited to the exclusion role for the specified exposure/endpoint. It is not a substitute for unverified/unread, no risk or no human data.

Change history

2026-11-02 · Public page/material version 1.0

The public display/materials were prepared from the existing 36 items. No new clinical search, verification-state change or scoring was performed.

The stored-material review date (2026-10-05) and original evidence cut-off (2026-09-15) were retained unchanged.

Researcher downloads

These materials provide the same evidence, scope and verification status as this page.

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N01 · Is this table's safety-only, efficacy-not-applicable contract preserved?

Current findings: The original question_type is safety, safety_only is true, and grading_status is not_applicable_safety. efficacy_grade/score are not_applicable, and the assessment's efficacy_framework_applied is false. The original grade is ?, score is an empty value, and there are no 7-axis/no_human keys.
Verification status: Met
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: The condition requiring the safety-only display contract and original values/absences to be preserved unchanged was verified. This does not constitute a judgment of efficacy or individual safety.
Reason for missing information: The efficacy framework does not apply.
Required materials and conditions: Original safety-only display and assessment contract
Materials to obtain first: Original safety-only display and assessment contract
Further research: Compare the display fields with the boundaries on applying historical values.
Remaining uncertainty: The efficacy framework does not apply. This verification status is limited to the scope of the specific narrow record condition. It does not mean a general incidence rate, individual risk, confirmed causality, prevention by taking after food, absence of risk, or worldwide absence of research.
Conditions for verification: Link safety_only, efficacy not_applicable, and framework false to their original locations without assigning a new score or efficacy display.
Why this condition is needed: This is needed to avoid converting a harm signal into a numerical efficacy/risk grade.
Application exceptions: The original grade ? and empty score value, and document quality B, are historical values. The absent 7-axis/no_human fields are not created.
Referenced methods: C01: Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are self-designed / C09: M04 §4.5, §4.6.3; limitations of the current material conversion reflect the user-defined scope and self-designed rules / H09: Chamgap's own interpretive boundaries. M19 principles are referenced; no formal causality tool was applied. Reason for application to the harm question: This is needed to avoid converting a harm signal into a numerical efficacy/risk grade. No formal causality/harm grading assessment or clinical certification was performed.

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N02 · What are the separate question and its inclusion/exclusion scope?

Current findings: The archived harm question concerns the risk of new or worsened diarrhea adverse events. The scope is oral pantothenic acid as the sole active ingredient in adults; abdominal pain, nausea, composite GI symptoms, topical/injected routes, and other molecules/combination products are distinguished.
Verification status: Met
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: The original question and excluded exposures/outcomes were linked to their designated preserved locations.
Reason for missing information: The probability of occurrence for an individual across the overall adult population remains separately unverified.
Required materials and conditions: Scope of the original claim/population/exposure/endpoint
Materials to obtain first: Scope of the original claim/population/exposure/endpoint
Further research: Compare the boundaries of the separate question with adjacent questions.
Remaining uncertainty: The probability of occurrence for an individual across the overall adult population remains separately unverified. This verification status is limited to the scope of the specific narrow record condition. It does not mean a general incidence rate, individual risk, confirmed causality, prevention by taking after food, absence of risk, or worldwide absence of research.
Conditions for verification: Link the original claim to adults, B5 as the sole active ingredient, oral exposure, and new/worsened diarrhea.
Why this condition is needed: Fix the selected question about diarrhea from an oral single-active-ingredient product rather than the safety of the ingredient as a whole.
Application exceptions: Separate dose, meal, and duration conditions within the same question without extending it to all other harms/efficacy.
Referenced methods: C01: Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are self-designed / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation of checks are self-designed / H09: Chamgap's own interpretive boundaries. M19 principles are referenced; no formal causality tool was applied. Reason for application to the harm question: Fix the selected question about diarrhea from an oral single-active-ingredient product rather than the safety of the ingredient as a whole. No formal causality/harm grading assessment or clinical certification was performed.

Related sources S2404

N03 · Was the directly studied preparation distinguished from other B5-related substances?

Current findings: The direct data concern pantothenic acid tablets distributed by Rugby (as D-calcium pantothenate). Other related substances and combination products were not used as direct event evidence for this substance. Batch, purity, additives, and equivalent risk for other salts are unverified.
Verification status: Partly verified
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: The directly studied substance/distributed product and exclusion boundaries are available, but detailed composition/source/batch have not been established.
Reason for missing information: Batch, purity, additives, and equivalence of other salts.
Required materials and conditions: Identity of the substance/product composition/source ingredients/additives
Materials to obtain first: Identity of the substance/product composition/source ingredients/additives
Further research: Review whether the composition and molecule match for each product.
Remaining uncertainty: Batch, purity, additives, and equivalence of other salts. This verification status is limited to the scope of the specific narrow record condition. It does not mean a general incidence rate, individual risk, confirmed causality, prevention by taking after food, absence of risk, or worldwide absence of research.
Conditions for verification: Explain inclusion/exclusion of the directly studied preparation and other substances/compositions.
Why this condition is needed: This is needed to avoid attributing events involving other molecules or combination products to B5 alone.
Application exceptions: Pantethine, pantetheine, dexpanthenol/panthenol, B-complex products, and multivitamins are not combined as the same exposure.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation of checks are self-designed / H05: Design considerations in M19 §19.2.2–19.2.4; detailed confounding records are self-designed. Reason for application to the harm question: This is needed to avoid attributing events involving other molecules or combination products to B5 alone. No formal causality/harm grading assessment or clinical certification was performed.

Related sources S2404 S2407 S2408

N04 · Is the acid/salt mass basis of the stated administered dose clear?

Current findings: The tablet label states pantothenic acid 500 mg (as D-calcium pantothenate), while the dosing table states calcium pantothenate. The pharmacokinetic section refers to 550 mg of calcium salt versus 500 mg of free base in the original text. The actual acid/salt basis and cumulative dose were not converted.
Verification status: Partly verified
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: The differing descriptions of the stated dose were verified, but the mass basis of the actual clinical dose cannot be established as a single value.
Reason for missing information: Actual salt amount, acid amount, and purity/cumulative dose.
Required materials and conditions: Original tablet label, dosing table, and evidence for the acid/salt mass basis
Materials to obtain first: Original tablet label, dosing table, and evidence for the acid/salt mass basis
Further research: Compare how the same preparation's dose is stated across documents.
Remaining uncertainty: Actual salt amount, acid amount, and purity/cumulative dose. This verification status is limited to the scope of the specific narrow record condition. It does not mean a general incidence rate, individual risk, confirmed causality, prevention by taking after food, absence of risk, or worldwide absence of research.
Conditions for verification: Separate the label, dosing table, and pharmacokinetic explanation, leaving the unclear mass basis unresolved.
Why this condition is needed: This is needed to avoid converting the nominal dose into an actual acid/salt amount or toxicity threshold.
Application exceptions: Do not newly calculate the actual clinical dose from the explanation of 550 mg of calcium salt versus 500 mg of free base in the original text.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation of checks are self-designed / H04: M19 §19.1.2–19.2.4; self-adapted application. Reason for application to the harm question: This is needed to avoid converting the nominal dose into an actual acid/salt amount or toxicity threshold. No formal causality/harm grading assessment or clinical certification was performed.

Related sources S2404

N05 · How are the nominal doses in the single-dose conditions distinguished?

Current findings: The preserved single-dose conditions are 500, 1,000, 2,000, 5,000 mg as reported in the paper. Fasted conditions are distinguished from the subsequent fed condition at 5,000 mg, and the acid/salt basis for each dose remains a separate gap.
Verification status: Met
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: Only the records of nominal doses by condition were preserved. They were not elevated to verification of actual mass or risk thresholds.
Reason for missing information: The minimum harmful dose is unverified.
Required materials and conditions: Nominal dose and dosing/meal records by condition
Materials to obtain first: Nominal dose and dosing/meal records by condition
Further research: Review the link between exposure under each condition and the AE table.
Remaining uncertainty: The minimum harmful dose is unverified. This verification status is limited to the scope of the specific narrow record condition. It does not mean a general incidence rate, individual risk, confirmed causality, prevention by taking after food, absence of risk, or worldwide absence of research.
Conditions for verification: Link the single doses and fasted/fed conditions exactly as reported in the paper.
Why this condition is needed: This is needed to avoid combining different dose conditions into a single exposure or a minimum harmful dose.
Application exceptions: Do not interpret nominal doses as risk thresholds or recommended doses for individuals.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation of checks are self-designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptation is self-designed / H02: Design-specific harm questions in M19 §19.2; details of temporal relationships are self-designed. Reason for application to the harm question: This is needed to avoid combining different dose conditions into a single exposure or a minimum harmful dose. No formal causality/harm grading assessment or clinical certification was performed.

Related sources S2404

N06 · Are repeated exposure and follow-up periods separated from single dosing?

Current findings: The repeated-dose condition was a nominal 2,000 mg/day for 14 days, and 8 participants completed the repeated-dose part. Follow-up extended to day 9 for single dosing and day 22 for repeated dosing. This record is not long-term exposure data.
Verification status: Met
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: The preserved exposure/follow-up schedules and the attribution of the repeated-dose denominator were distinguished.
Reason for missing information: Actual cumulative exposure and adherence for individuals, and long-term harms, are unverified.
Required materials and conditions: Repeated dosing, adherence, and AE follow-up schedule
Materials to obtain first: Repeated dosing, adherence, and AE follow-up schedule
Further research: Review exposure duration and observation duration as separate dimensions.
Remaining uncertainty: Actual cumulative exposure and adherence for individuals, and long-term harms, are unverified. This verification status is limited to the scope of the specific narrow record condition. It does not mean a general incidence rate, individual risk, confirmed causality, prevention by taking after food, absence of risk, or worldwide absence of research.
Conditions for verification: Distinguish repeated dosing at 2,000 mg/day for 14 days from follow-up through day 9 for single dosing/day 22 for repeated dosing.
Why this condition is needed: This is needed to avoid extending a short repeated-dose condition to long-term safety.
Application exceptions: Do not convert the 14-day repeated exposure and follow-up through day 22 into the same period.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation of checks are self-designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptation is self-designed / H02: Design-specific harm questions in M19 §19.2; details of temporal relationships are self-designed. Reason for application to the harm question: This is needed to avoid extending a short repeated-dose condition to long-term safety. No formal causality/harm grading assessment or clinical certification was performed.

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N07 · Are the directly studied population and baseline diarrhea status verified?

Current findings: The direct data concern healthy adults aged 18–55. Individual baseline symptoms and the distinction between new onset and worsening of existing diarrhea remain Not reported or Unverified. The detailed sex distribution is also not specified in the current summary.
Verification status: Partly verified
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: The population category was verified, but detailed baseline diarrhea/selection values cannot be established.
Reason for missing information: Individual baseline GI, sex/selection, and vulnerability.
Required materials and conditions: Table of inclusion/exclusion, sex, baseline diarrhea/diseases, and medications
Materials to obtain first: Table of inclusion/exclusion, sex, baseline diarrhea/diseases, and medications
Further research: Review limitations on applicability according to the population and baseline symptoms.
Remaining uncertainty: Individual baseline GI, sex/selection, and vulnerability. This verification status is limited to the scope of the specific narrow record condition. It does not mean a general incidence rate, individual risk, confirmed causality, prevention by taking after food, absence of risk, or worldwide absence of research.
Conditions for verification: Distinguish the healthy population aged 18–55 from individual baseline GI/selection information.
Why this condition is needed: This is needed to avoid applying data from healthy people directly to all adults or to worsening of baseline diarrhea.
Application exceptions: Do not convert the description of participants as healthy into proof of absence of diarrhea in individuals or safety in special populations.
Referenced methods: C04: M03 §3.2.1; detailed population conditions are self-designed / H05: Design considerations in M19 §19.2.2–19.2.4; detailed confounding records are self-designed / H08: M19 §19.1.2–19.2.4; self-adapted application. Reason for application to the harm question: This is needed to avoid applying data from healthy people directly to all adults or to worsening of baseline diarrhea. No formal causality/harm grading assessment or clinical certification was performed.

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N08 · Can the 40 participants be distinguished from the single-dose and repeated-dose completion denominators?

Current findings: Rao is a single-center open-label trial in 40 healthy participants. The single-dose part was completed by 32 participants and the separate repeated-dose part by 8 participants. The diarrhea table for each condition uses a denominator of 8 participants, and the fed condition involved the same 8 participants. The detailed allocation/completion/AE analysis flow is not complete from the current summary alone.
Verification status: Partly verified
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: Overall/part-specific completion counts and condition denominators are available, but the entire recruitment/missingness/analysis flow cannot be established.
Reason for missing information: Recruitment/allocation, attrition, and analysis flow for individual conditions.
Required materials and conditions: Recruitment/allocation/exposure/completion/analysis flow and participant linkage by condition
Materials to obtain first: Recruitment/allocation/exposure/completion/analysis flow and participant linkage by condition
Further research: Compare participant flow with the analysis denominator for each condition.
Remaining uncertainty: Recruitment/allocation, attrition, and analysis flow for individual conditions. This verification status is limited to the scope of the specific narrow record condition. It does not mean a general incidence rate, individual risk, confirmed causality, prevention by taking after food, absence of risk, or worldwide absence of research.
Conditions for verification: Separately link completion by 40 participants overall, 32 in the single-dose part, and 8 in the repeated-dose part, and the report of 8 participants per condition.
Why this condition is needed: This is needed to avoid reusing the overall study size as the diarrhea analysis denominator for every condition.
Application exceptions: Fed redosing involved the same 8 participants, and the single-dose/repeated-dose conditions are not counted as independent studies.
Referenced methods: C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is self-adapted / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptation is self-designed / H04: M19 §19.1.2–19.2.4; self-adapted application / H06: M19 §19.1.2–19.2.4, M04 §4.6.3; self-adapted application. Reason for application to the harm question: This is needed to avoid reusing the overall study size as the diarrhea analysis denominator for every condition. No formal causality/harm grading assessment or clinical certification was performed.

Related sources S2404

N09 · Are the participants, sequence, and actual washout period for fed redosing consistently verified?

Current findings: The 5,000 mg single fed dose is a subsequent condition in the same 8 participants after fasted dosing. Washout is described as 2–3 weeks in the main text and summarized as 2 weeks in the abstract. The fixed sequence/meal difference and this difference in descriptions are preserved.
Verification status: Conflicting information
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: Because the records describe washout at different levels of specificity, they were not replaced with a single confirmed duration. This is a difference in descriptions in the materials, not a new causality judgment.
Reason for missing information: Actual individual washout schedules and resolution of the difference in descriptions.
Required materials and conditions: Original abstract, methods, and individual dosing sequence/washout schedule
Materials to obtain first: Original abstract, methods, and individual dosing sequence/washout schedule
Further research: Review differences in sequence/washout/meal status and inconsistencies in descriptions within the same family.
Remaining uncertainty: Actual individual washout schedules and resolution of the difference in descriptions. This verification status is limited to the scope of the specific narrow record condition. It does not mean a general incidence rate, individual risk, confirmed causality, prevention by taking after food, absence of risk, or worldwide absence of research.
Conditions for verification: Verify the dosing sequence and actual washout schedule for the same 8 participants, and compare whether the duration descriptions in the abstract/methods are consistent. If differences in the duration descriptions or an unverified actual schedule remain, do not treat the duration as consistently verified.
Why this condition is needed: This is needed to avoid interpreting conditions in the same people with changes in meal status and sequence as randomized control groups.
Application exceptions: Do not correct 2 weeks in the abstract and 2–3 weeks in the methods to a single confirmed washout value or compare them as independent groups.
Referenced methods: C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is self-adapted / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation of checks are self-designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is self-designed / H02: Design-specific harm questions in M19 §19.2; details of temporal relationships are self-designed / H03: M19 §19.2.2–19.2.4, M03 §3.2.3; self-adapted application. Reason for application to the harm question: This is needed to avoid interpreting conditions in the same people with changes in meal status and sequence as randomized control groups. No formal causality/harm grading assessment or clinical certification was performed.

Related sources S2404

N10 · What are the definition and coding criteria for diarrhea?

Current findings: The main study used the MedDRA 21.0 diarrhea category. A diagnostic definition based on stool frequency/form is Not reported or Unverified. GI discomfort or loose stools were not combined into new diarrhea events.
Verification status: Partly verified
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: The event coding term was verified, but the detailed diagnostic/observation definition has not been established.
Reason for missing information: Detailed stool frequency/form and diagnostic/coding criteria.
Required materials and conditions: Diarrhea AE definition, coding/diagnostic criteria, and records of stool frequency/form
Materials to obtain first: Diarrhea AE definition, coding/diagnostic criteria, and records of stool frequency/form
Further research: Propose a review that re-extracts the original table using the same event definition.
Remaining uncertainty: Detailed stool frequency/form and diagnostic/coding criteria. This verification status is limited to the scope of the specific narrow record condition. It does not mean a general incidence rate, individual risk, confirmed causality, prevention by taking after food, absence of risk, or worldwide absence of research.
Conditions for verification: Distinguish the MedDRA 21.0 diarrhea category from the separate gap in diagnostic criteria.
Why this condition is needed: This is needed to avoid recoding general GI discomfort or loose stools as confirmed diarrhea.
Application exceptions: Do not equate a MedDRA term with diagnostic criteria based on stool frequency/form or with a clinical diagnosis.
Referenced methods: C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptation is self-designed / H01: M19 §19.1.2–19.2.4; detailed ascertainment is self-designed. Reason for application to the harm question: This is needed to avoid recoding general GI discomfort or loose stools as confirmed diarrhea. No formal causality/harm grading assessment or clinical certification was performed.

Related sources S2404

N11 · Are data available to distinguish new diarrhea from worsening of existing diarrhea?

Current findings: The original question concerns new or worsened diarrhea. The current preserved summary leaves individual baseline symptoms and counts by new onset/worsening as Not reported or Unverified.
Verification status: Unverified
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: The question covers both scopes, but data establishing which scope the actual events fall into are unavailable.
Reason for missing information: Distinction between new/worsened cases and each denominator/person count.
Required materials and conditions: Baseline diarrhea and change criteria, and an AE table separating new/worsened cases
Materials to obtain first: Baseline diarrhea and change criteria, and an AE table separating new/worsened cases
Further research: Review separated records based on the same ascertainment criteria.
Remaining uncertainty: Distinction between new/worsened cases and each denominator/person count. This verification status is limited to the scope of the specific narrow record condition. It does not mean a general incidence rate, individual risk, confirmed causality, prevention by taking after food, absence of risk, or worldwide absence of research.
Conditions for verification: Link baseline symptoms with person counts and ascertainment data for new/worsened cases.
Why this condition is needed: This is needed to examine whether the original event data actually distinguish the two scopes of the original question: occurrence and worsening.
Application exceptions: Do not reclassify events that are currently unseparated as all new or all worsened.
Referenced methods: C04: M03 §3.2.1; detailed population conditions are self-designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptation is self-designed / H01: M19 §19.1.2–19.2.4; detailed ascertainment is self-designed. Reason for application to the harm question: This is needed to examine whether the original event data actually distinguish the two scopes of the original question: occurrence and worsening. No formal causality/harm grading assessment or clinical certification was performed.

Related sources S2404

N12 · Can diarrhea collection methods, severity, and differences in detection be verified?

Current findings: The preserved summary provides the open-label design and MedDRA diarrhea coding. Diarrhea-specific severity, day of onset, duration, and details of collection procedures are Not reported or Unverified.
Verification status: Unverified
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: The coding record cannot establish the collection system or diarrhea-specific severity.
Reason for missing information: Collection methods, severity, and differences in detection.
Required materials and conditions: AE collection form/questioning frequency, blinding/ascertainment, and severity table
Materials to obtain first: AE collection form/questioning frequency, blinding/ascertainment, and severity table
Further research: Review collection methods and differences in detection/omission.
Remaining uncertainty: Collection methods, severity, and differences in detection. This verification status is limited to the scope of the specific narrow record condition. It does not mean a general incidence rate, individual risk, confirmed causality, prevention by taking after food, absence of risk, or worldwide absence of research.
Conditions for verification: Verify diarrhea-specific collection tools, frequency, severity, and ascertainment methods.
Why this condition is needed: This is needed to avoid assuming that categorized reported values represent systematically and completely collected events.
Application exceptions: An open-label trial/use of MedDRA alone does not establish spontaneous versus systematic collection or blinded ascertainment.
Referenced methods: H01: M19 §19.1.2–19.2.4; detailed ascertainment is self-designed / H06: M19 §19.1.2–19.2.4, M04 §4.6.3; self-adapted application / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptation is self-designed. Reason for application to the harm question: This is needed to avoid assuming that categorized reported values represent systematically and completely collected events. No formal causality/harm grading assessment or clinical certification was performed.

Related sources S2404

N13 · Were nausea, vomiting, and abdominal discomfort kept separate from diarrhea?

Current findings: The preserved manuscripts kept nausea, vomiting, and abdominal discomfort as separate categories and did not add them to diarrhea. Overall GI discomfort/AE summaries are not added to diarrhea 1/8 or 0/8.
Verification status: Met
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: The attribution boundary between the selected diarrhea endpoint and other GI categories was maintained.
Reason for missing information: Detailed values for each other category are not direct estimates in this diarrhea table.
Required materials and conditions: Original AE categories by endpoint and a table of people/events
Materials to obtain first: Original AE categories by endpoint and a table of people/events
Further research: Review multiple events in the same person and different categories separately.
Remaining uncertainty: Detailed values for each other category are not direct estimates in this diarrhea table. This verification status is limited to the scope of the specific narrow record condition. It does not mean a general incidence rate, individual risk, confirmed causality, prevention by taking after food, absence of risk, or worldwide absence of research.
Conditions for verification: Separate attribution of results for diarrhea and other GI categories.
Why this condition is needed: This is needed to avoid adding other GI events to the person count or magnitude of harm for the selected endpoint.
Application exceptions: Overall AEs or composite GI symptoms do not replace diarrhea-only results.
Referenced methods: C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptation is self-designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is self-designed / H01: M19 §19.1.2–19.2.4; detailed ascertainment is self-designed. Reason for application to the harm question: This is needed to avoid adding other GI events to the person count or magnitude of harm for the selected endpoint. No formal causality/harm grading assessment or clinical certification was performed.

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N14 · What is the direct diarrhea report under the 5,000 mg fasted condition?

Current findings: In Table 6, under the paper-labeled 5,000 mg fasted single-dose condition, among 8 participants, 1 reported diarrhea. This is a condition-specific signal observed in a small uncontrolled trial.
Verification status: Met
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: The retained direct descriptive observation was linked only to the corresponding dose/fasted single-dose condition.
Reason for missing information: The magnitude of comparative risk increase, general incidence, and causality remain separately unverified.
Required materials and conditions: Original Table 6 and the relevant person's AE record
Materials to obtain first: Original Table 6 and the relevant person's AE record
Further research: Review the link between the reported people, exposure conditions, and event definition.
Remaining uncertainty: The magnitude of comparative risk increase, general incidence, and causality remain separately unverified. This verification status is limited to the scope of the narrow record condition concerned. It does not mean general incidence, individual risk, established causality, prevention by fed dosing, absence of risk, or absence of research worldwide.
Conditions for verification: Attribute the report in Table 6 for the paper-labeled 5,000 mg fasted single-dose condition (1/8 participants) to the specified condition.
Why this condition is needed: This is needed to acknowledge the direct signal while distinguishing reported observations from causal risk.
Application exceptions: Do not convert 1/8 into a general incidence rate, risk ratio, individual probability, or minimum harmful dose.
Referenced methods: H01: M19 §19.1.2–19.2.4; detailed distinctions were internally designed / H04: M19 §19.1.2–19.2.4; internal application / H09: Chamgap’s own interpretive boundary. References M19 principles; no formal causality tool was applied / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations were internally designed. Reason for application to the harm question: needed to acknowledge the direct signal while distinguishing reported observations from causal risk. No formal causality/harm grading or clinical certification was performed.

Related sources S2404

N15 · Are conditions with 0/8 reports also retained?

Current findings: The 500, 1,000, 2,000 mg fasted single doses and 2,000 mg/day repeated for 14 days each had reports of 0/8 participants. Subsequent fed dosing at 5,000 mg in the same 8 participants was 0/8. All are values collected and reported in a small table, not proof of no risk/prevention by fed dosing.
Verification status: Met
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: Contrary/no-report records were retained by condition and were not elevated to an effect of 0 or a guarantee of safety.
Reason for missing information: The actual risk at lower doses/with fed dosing/over the long term is unverified.
Required materials and conditions: Condition-specific Table 6 and the scope of exposure/follow-up and collection
Materials to obtain first: Condition-specific Table 6 and the scope of exposure/follow-up and collection
Further research: Review reported 0 within the scope of missingness/detection and duration.
Remaining uncertainty: The actual risk at lower doses/with fed dosing/over the long term is unverified. This verification status is limited to the scope of the narrow record condition concerned. It does not mean general incidence, individual risk, established causality, prevention by fed dosing, absence of risk, or absence of research worldwide.
Conditions for verification: Retain the 0/8 records for each lower single dose, repeated dosing, and subsequent fed dosing, together with their limitations.
Why this condition is needed: Needed to avoid selecting only positive signals or converting an absence of reports into an absence of risk.
Application exceptions: For the same 8 participants, the fed-dosing 0/8 is not a preventive effect, and the 0/8 under other doses/repeated dosing is not a safety threshold.
Referenced methods: C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses was internally designed / H04: M19 §19.1.2–19.2.4; internal application / H09: Chamgap’s own interpretive boundary. References M19 principles; no formal causality tool was applied. Reason for application to the harm question: needed to avoid selecting only positive signals or converting an absence of reports into an absence of risk. No formal causality/harm grading or clinical certification was performed.

Related sources S2404

N16 · Can the reported numbers of people, repeated events, and exposure-time denominators be distinguished?

Current findings: The original record provides condition-specific reports of 1/8 or 0/8 participants and overall/partial completion counts. The number of repeated diarrhea events in the same person, individual exposure/event times, and details of losses from the denominator are not established in the current summary.
Verification status: Partly verified
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: Condition-specific person denominators are available, but repeated events/person-time and the complete analysis flow are unverified.
Reason for missing information: Repeated-event counts, person-time, and omissions/missingness.
Required materials and conditions: Condition-specific person/event counts, follow-up/exposure time, and missing data
Materials to obtain first: Condition-specific person/event counts, follow-up/exposure time, and missing data
Further research: Review interpretation of harm frequency with people, events, and time kept separate.
Remaining uncertainty: Repeated-event counts, person-time, and omissions/missingness. This verification status is limited to the scope of the narrow record condition concerned. It does not mean general incidence, individual risk, established causality, prevention by fed dosing, absence of risk, or absence of research worldwide.
Conditions for verification: Distinguish the original denominator for reported people and repeated-event/time information from values that are absent.
Why this condition is needed: Needed to avoid confusing the different denominators for reports of people and event frequency/incidence rates.
Application exceptions: Do not replace the 8 participants per condition with the total of 40 participants or 16 participants obtained from fed + fasted dosing.
Referenced methods: C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations were internally designed / H04: M19 §19.1.2–19.2.4; internal application. Reason for application to the harm question: needed to avoid confusing the different denominators for reports of people and event frequency/incidence rates. No formal causality/harm grading or clinical certification was performed.

Related sources S2404

N17 · Was diarrhea risk compared with an appropriate unexposed/placebo group?

Current findings: Rao is an open-label trial without a placebo group or randomized dose assignment. Redosing with food is a subsequent condition in the same people; estimation of diarrhea risk against an appropriate unexposed/placebo comparator is unverified.
Verification status: Unverified
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: A comparative risk increase cannot be established solely from the uncontrolled/within-person subsequent conditions in the direct data.
Reason for missing information: Unexposed/placebo risk, background diarrhea rate, and an appropriate comparative estimate.
Required materials and conditions: Unexposed/appropriate comparator data with matching event definitions/follow-up
Materials to obtain first: Unexposed/appropriate comparator data with matching event definitions/follow-up
Further research: Review the population/confounding and sequence/meal differences in existing comparative observations.
Remaining uncertainty: Unexposed/placebo risk, background diarrhea rate, and an appropriate comparative estimate. This verification status is limited to the scope of the narrow record condition concerned. It does not mean general incidence, individual risk, established causality, prevention by fed dosing, absence of risk, or absence of research worldwide.
Conditions for verification: Link the actual comparator structure to whether comparative risk can be estimated or remains unverified.
Why this condition is needed: Needed to avoid describing a report without a comparison as the magnitude of a risk increase.
Application exceptions: Retain the signal even in the absence of comparative data. Do not substitute a randomized placebo group for fixed-sequence/redosing with food.
Referenced methods: H03: M19 §19.2.2–19.2.4, M03 §3.2.3; internal application / H09: Chamgap’s own interpretive boundary. References M19 principles; no formal causality tool was applied / C05: M03 §3.2.2–3.2.3; reverse-direction markers and test adaptations were internally designed. Reason for application to the harm question: needed to avoid describing a report without a comparison as the magnitude of a risk increase. No formal causality/harm grading or clinical certification was performed.

Related sources S2404

N18 · Is the temporal link between diarrhea onset/recovery and exposure verified?

Current findings: The original limitations record leaves diarrhea-specific onset dates and duration as not reported or unverified. Even with a record of AE resolution by the end, diarrhea-specific recovery times and causal clues from dechallenge/rechallenge are not established.
Verification status: Unverified
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: There is a reported signal after exposure, but no data establishing the diarrhea-specific time course.
Reason for missing information: Diarrhea-specific onset, duration, recovery, and temporal links.
Required materials and conditions: Individual logs of dosing, blood sampling/meals, and diarrhea onset/recovery
Materials to obtain first: Individual logs of dosing, blood sampling/meals, and diarrhea onset/recovery
Further research: Review the temporal sequence and alternative explanations for each event.
Remaining uncertainty: Diarrhea-specific onset, duration, recovery, and temporal links. This verification status is limited to the scope of the narrow record condition concerned. It does not mean general incidence, individual risk, established causality, prevention by fed dosing, absence of risk, or absence of research worldwide.
Conditions for verification: Link diarrhea-specific onset, duration, and recovery with actual dosing times.
Why this condition is needed: Distinguish reports after exposure from specific onset/recovery and causal clues from re-exposure.
Application exceptions: Do not convert the record that all AEs had resolved by the end into diarrhea-specific recovery dates or evidence of positive dechallenge/rechallenge.
Referenced methods: C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations were internally designed / H02: design-specific harm questions in M19 §19.2; details of temporal relationships were internally designed / H09: Chamgap’s own interpretive boundary. References M19 principles; no formal causality tool was applied. Reason for application to the harm question: distinguish reports after exposure from specific onset/recovery and causal clues from re-exposure. No formal causality/harm grading or clinical certification was performed.

Related sources S2404

N19 · Is the investigator's wording on relatedness kept separate from established causality?

Current findings: The investigator considered the diarrhea at least possibly related. The original safety assessment retains the signal and Caution conclusion, but comparative risk and the contribution of alternative causes such as excipients, infection, and diet are unverified. This table does not create a new causality judgment or score.
Verification status: Partly verified
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: The qualitative signal conclusion was verified, but established causality for individual diarrhea was not verified.
Reason for missing information: Individual evidence of relatedness, alternative causes, and comparative risk.
Required materials and conditions: The basis for individual AE relatedness assessments and records of alternative causes
Materials to obtain first: The basis for individual AE relatedness assessments and records of alternative causes
Further research: Review the original wording on relatedness and the level of evidence for timing/alternative causes.
Remaining uncertainty: Individual evidence of relatedness, alternative causes, and comparative risk. This verification status is limited to the scope of the narrow record condition concerned. It does not mean general incidence, individual risk, established causality, prevention by fed dosing, absence of risk, or absence of research worldwide.
Conditions for verification: Distinguish the original report's statements on relatedness from uncertainty and gaps concerning alternative causes.
Why this condition is needed: Needed to retain the original relatedness assessment without extending it to formal causality certification.
Application exceptions: The Caution safety label is not confirmation of an individual’s cause or a quantitative causality score.
Referenced methods: H05: design considerations in M19 §19.2.2–19.2.4; detailed confounding records were internally designed / H09: Chamgap’s own interpretive boundary. References M19 principles; no formal causality tool was applied / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations were internally designed. Reason for application to the harm question: needed to retain the original relatedness assessment without extending it to formal causality certification. No formal causality/harm grading or clinical certification was performed.

Related sources S2404

N20 · Were alternative explanations such as concurrent exposure, diet, and infection reviewed?

Current findings: Rao prohibited other medications and supplements but did not control dietary pantothenic acid intake. The contributions of excipients, infection, diet, and individual susceptibility are unverified.
Verification status: Partly verified
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: There were some restrictions on concurrent exposures, but no data ruling out all alternative explanations.
Reason for missing information: Contributions of diet, excipients, infection, and individual susceptibility.
Required materials and conditions: Records of medications/supplements, diet, meals, excipients, and infection/baseline symptoms
Materials to obtain first: Records of medications/supplements, diet, meals, excipients, and infection/baseline symptoms
Further research: Review alternative exposures and potential confounding for the same event.
Remaining uncertainty: Contributions of diet, excipients, infection, and individual susceptibility. This verification status is limited to the scope of the narrow record condition concerned. It does not mean general incidence, individual risk, established causality, prevention by fed dosing, absence of risk, or absence of research worldwide.
Conditions for verification: Link medication/supplement restrictions and uncontrolled diet with gaps concerning alternative causes.
Why this condition is needed: Needed to avoid eliminating background exposures and alternative causes solely on the basis of identification as a single-active-ingredient product.
Application exceptions: Do not extend the prohibition of other medications/supplements to control of all diet, excipients, and infections.
Referenced methods: H05: design considerations in M19 §19.2.2–19.2.4; detailed confounding records were internally designed / C05: M03 §3.2.2–3.2.3; reverse-direction markers and test adaptations were internally designed. Reason for application to the harm question: needed to avoid eliminating background exposures and alternative causes solely on the basis of identification as a single-active-ingredient product. No formal causality/harm grading or clinical certification was performed.

Related sources S2404

N21 · Are discontinuation/serious AE reports distinguished from detailed participant flow?

Current findings: The main study reports no deaths, serious adverse events, or discontinuations due to adverse events. In contrast to the completion records for 32 single-dose participants and 8 repeated-dose participants, the detailed flow of diarrhea-specific noncollection/missingness is not established in the current summary.
Verification status: Partly verified
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: A general safety summary and completion counts are available, but the complete diarrhea-specific flow and presence or absence of omissions are unverified.
Reason for missing information: Diarrhea-specific discontinuations and missingness/noncollection flow.
Required materials and conditions: Diarrhea-specific reasons for discontinuation/dropout, periods without collection, and participant flow
Materials to obtain first: Diarrhea-specific reasons for discontinuation/dropout, periods without collection, and participant flow
Further research: Review differences in event detection between completer data and those who discontinued/had missing data.
Remaining uncertainty: Diarrhea-specific discontinuations and missingness/noncollection flow. This verification status is limited to the scope of the narrow record condition concerned. It does not mean general incidence, individual risk, established causality, prevention by fed dosing, absence of risk, or absence of research worldwide.
Conditions for verification: Retain the original general safety summary separately from diarrhea-specific discontinuation/missingness and flow gaps.
Why this condition is needed: Needed to avoid converting a general safety summary into an absence of diarrhea-specific missingness or long-term safety.
Application exceptions: No deaths, serious AEs, or AE discontinuations is not proof of 0 diarrhea events or complete event collection for every participant.
Referenced methods: C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations were internally designed / H06: M19 §19.1.2–19.2.4, M04 §4.6.3; internal application / H01: M19 §19.1.2–19.2.4; detailed distinctions were internally designed. Reason for application to the harm question: needed to avoid converting a general safety summary into an absence of diarrhea-specific missingness or long-term safety. No formal causality/harm grading or clinical certification was performed.

Related sources S2404

N22 · Are the registration, protocol, analysis plan, and scope of prespecification verified?

Current findings: The original record leaves registration, protocol, and statistical analysis plan unverified and does not conclude that preregistration was absent. Records of registration/some metadata access failures at that time are also not actual access failures in this work.
Verification status: Unverified
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: The current archived summaries alone cannot establish prespecification/changes or the scope of selective reporting.
Reason for missing information: Registration/plans, prespecification, and changes/selective reporting.
Required materials and conditions: Registration, protocol, SAP, and records of diarrhea prespecification/changes
Materials to obtain first: Registration, protocol, SAP, and records of diarrhea prespecification/changes
Further research: Compare specified endpoints, collection, and public reporting against the plan for consistency.
Remaining uncertainty: Registration/plans, prespecification, and changes/selective reporting. This verification status is limited to the scope of the narrow record condition concerned. It does not mean general incidence, individual risk, established causality, prevention by fed dosing, absence of risk, or absence of research worldwide.
Conditions for verification: Distinguish the scope actually verified in the registration/protocol/SAP from what remains unverified.
Why this condition is needed: Needed to review the possibility of selective reporting and the scope of prespecified/post hoc analyses.
Application exceptions: Do not convert current lack of verification and historical access failures into established absence of preregistration or confirmed deviation from the plan.
Referenced methods: C09: M04 §4.5, §4.6.3; restrictions on the current data transformation follow the user-defined scope and internal design / H06: M19 §19.1.2–19.2.4, M04 §4.6.3; internal application. Reason for application to the harm question: needed to review the possibility of selective reporting and the scope of prespecified/post hoc analyses. No formal causality/harm grading or clinical certification was performed.

Related sources S2404

N23 · Are risk differences, risk ratios, CIs, and criteria for interpreting harm verified?

Current findings: The retained manuscript left comparative risk estimates, the background diarrhea rate, and the minimum harmful dose/duration unverified. Risk differences, risk ratios, incidence rates, CIs, P values, and NNH were not derived, and this table does not calculate them either.
Verification status: Unverified
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: There are no data establishing quantitative comparative risk or harm criteria beyond the descriptive observations of 1/8 and 0/8.
Reason for missing information: Formal comparative estimates, CIs, background risk, and clinical criteria.
Required materials and conditions: Original comparative estimates, denominators, CIs/uncertainty, and clinical harm criteria
Materials to obtain first: Original comparative estimates, denominators, CIs/uncertainty, and clinical harm criteria
Further research: Review the scope of interpretation of estimates with the same event/comparator/duration.
Remaining uncertainty: Formal comparative estimates, CIs, background risk, and clinical criteria. This verification status is limited to the scope of the narrow record condition concerned. It does not mean general incidence, individual risk, established causality, prevention by fed dosing, absence of risk, or absence of research worldwide.
Conditions for verification: Distinguish reported observations from gaps in formal comparative estimates/uncertainty and harm criteria.
Why this condition is needed: Needed to avoid converting a small descriptive report into quantitative comparative risk or a minimum harmful dose.
Application exceptions: Do not newly calculate risk differences/risk ratios, incidence rates, CIs, P, or NNH that are absent from the existing data.
Referenced methods: H03: M19 §19.2.2–19.2.4, M03 §3.2.3; internal application / H04: M19 §19.1.2–19.2.4; internal application / H09: Chamgap’s own interpretive boundary. References M19 principles; no formal causality tool was applied / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations were internally designed. Reason for application to the harm question: needed to avoid converting a small descriptive report into quantitative comparative risk or a minimum harmful dose. No formal causality/harm grading or clinical certification was performed.

Related sources S2404

N24 · What is the scope of the absence of recorded side effects in the arthritis trial?

Current findings: The arthritis trial summarized by SCF escalated calcium pantothenate over 8 weeks and states that no treatment side effects were recorded. The original diarrhea event table was not acquired/unverified, so this was not converted into 0 diarrhea events or an established safety denominator. S2405 is a PubMed bibliographic record without an abstract.
Verification status: Partly verified
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: Contrary general AE context and bibliographic information are available, but the original diarrhea-specific results and collection methods are unverified.
Reason for missing information: The original GPRG event table, diarrhea definition/collection, and denominator.
Required materials and conditions: The original GPRG diarrhea/AE event table and dosing, population, and collection methods
Materials to obtain first: The original GPRG diarrhea/AE event table and dosing, population, and collection methods
Further research: Compare the general AE statement in the 2nd-hand summary against the original event definition/table.
Remaining uncertainty: The original GPRG event table, diarrhea definition/collection, and denominator. This verification status is limited to the scope of the narrow record condition concerned. It does not mean general incidence, individual risk, established causality, prevention by fed dosing, absence of risk, or absence of research worldwide.
Conditions for verification: Separate SCF's summary of dose escalation over 8 weeks in arthritis from the access scope of the PubMed bibliographic record.
Why this condition is needed: Needed to retain contrary context without converting a 2nd-hand general side-effect statement into a diarrhea event table.
Application exceptions: The original event table not having been acquired is not a new access failure in this work, and an absence of recorded side effects is not substituted with 0 diarrhea events.
Referenced methods: C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses was internally designed / H01: M19 §19.1.2–19.2.4; detailed distinctions were internally designed / H07: M04 §4.6.1–4.6.2; adaptations for harm data were internally designed. Reason for application to the harm question: needed to retain contrary context without converting a 2nd-hand general side-effect statement into a diarrhea event table. No formal causality/harm grading or clinical certification was performed.

Related sources S2402 S2405

N25 · Are the overall and arm-specific participants and analysis denominators in the arthritis study consistently verified?

Current findings: In the GPRG record, the narrative total of 94 participants is inconsistent with the arm-specific counts of 47 and 46 participants (a total of 93 participants in the original record). The conflict was retained, and neither value was selected as an established diarrhea analysis denominator in this table.
Verification status: Conflicting information
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: The inconsistent original descriptions of the same total were made explicit, and no new arithmetic/denominator correction was made.
Reason for missing information: Actual definitions of the total, allocation/completion, and analysis denominators.
Required materials and conditions: Original participant flow, arm-specific allocation/analysis tables, and SCF's cited statement
Materials to obtain first: Original participant flow, arm-specific allocation/analysis tables, and SCF's cited statement
Further research: Check each denominator's definition/location and conflicting descriptions against the original tables.
Remaining uncertainty: Actual definitions of the total, allocation/completion, and analysis denominators. This verification status is limited to the scope of the narrow record condition concerned. It does not mean general incidence, individual risk, established causality, prevention by fed dosing, absence of risk, or absence of research worldwide.
Conditions for verification: Check whether the actual definitions and counts of overall and arm-specific allocation/completion/analysis denominators are consistently verified in the original tables. If the inconsistency between 94 participants and arm-specific counts of 47/46 participants remains, do not treat them as established denominators.
Why this condition is needed: Needed to avoid arbitrarily correcting different statements of the total or using them as established analysis denominators.
Application exceptions: 47+46=93 is historical arithmetic already present in the original summary. Do not correct the total through new calculations/selection.
Referenced methods: C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations were internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses was internally designed. Reason for application to the harm question: needed to avoid arbitrarily correcting different statements of the total or using them as established analysis denominators. No formal causality/harm grading or clinical certification was performed.

Related sources S2402 S2405

N26 · What limitations apply to the reused NIH example of 10 g/day?

Current findings: The reused NIH S06 gives 10 g/day as an example of very high intake and mentions the possibility of mild diarrhea and GI discomfort. The exact number of cases, denominator, salt, and duration were not verified in this extraction. It is not a newly validated event rate, toxicity threshold, upper intake level, or individual recommended intake.
Verification status: Partly verified
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: A retained qualitative example is available, but the identity of the original events and their denominator/exposure scope are unverified.
Reason for missing information: Underlying cases, denominator, and exact formulation/duration.
Required materials and conditions: The relevant NIH section and underlying original cases and exposure/event data
Materials to obtain first: The relevant NIH section and underlying original cases and exposure/event data
Further research: Trace the original observation lineage, actual exposure, and endpoint evidence underlying the general discussion.
Remaining uncertainty: Underlying cases, denominator, and exact formulation/duration. This verification status is limited to the scope of the narrow record condition concerned. It does not mean general incidence, individual risk, established causality, prevention by fed dosing, absence of risk, or absence of research worldwide.
Conditions for verification: Retain the example of very high intake at 10 g/day and the gaps concerning cases/formulation, duration, and denominators.
Why this condition is needed: Needed to avoid interpreting an official general safety statement as a new event rate or toxicity threshold.
Application exceptions: Do not convert the official NIH discussion into a new clinical trial or an allowable/recommended intake of 10 g/day.
Referenced methods: C03: data collection/selection principles in M04 §4.5–4.6; separation of access and reading and the hyperlink contract were internally designed / H07: M04 §4.6.1–4.6.2; adaptations for harm data were internally designed / H09: Chamgap’s own interpretive boundary. References M19 principles; no formal causality tool was applied. Reason for application to the harm question: needed to avoid interpreting an official general safety statement as a new event rate or toxicity threshold. No formal causality/harm grading or clinical certification was performed.

Related sources S06

N27 · Are historical summaries of 10–20 g/day kept from being counted as independent human replications?

Current findings: S06, S2402, and S2406 are official/expert summary lineages of historical high-dose observations. The duration, exact formulation, and event counts/denominators in the 10–20 g/day reports are unverified. Do not count LEGACY-HIGH-DOSE-SUMMARY as one established human trial or three independent replications.
Verification status: Partly verified
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: The overlapping summary lineages and limitations were verified, but the independence of the underlying original cases is not established.
Reason for missing information: Original case identities, overlap/independence, and actual events/exposures.
Required materials and conditions: SCF/CIR citation lineage, Elder 1987, and underlying original cases
Materials to obtain first: SCF/CIR citation lineage, Elder 1987, and underlying original cases
Further research: Check repeated citations/duplication of the same original observations and whether the participants are independent.
Remaining uncertainty: Original case identities, overlap/independence, and actual events/exposures. This verification status is limited to the scope of the narrow record condition concerned. It does not mean general incidence, individual risk, established causality, prevention by fed dosing, absence of risk, or absence of research worldwide.
Conditions for verification: Separate overlapping summary lineages of historical reports from the lack of verification of original cases.
Why this condition is needed: Needed to avoid summing repeated citations by SCF/CIR/NIH as distinct established studies.
Application exceptions: The number of official/expert documents and summary family_id are not the number of independent clinical cases/trials.
Referenced methods: C02: the distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an internal application / H07: M04 §4.6.1–4.6.2; adaptations for harm data were internally designed. Reason for application to the harm question: needed to avoid summing repeated citations by SCF/CIR/NIH as distinct established studies. No formal causality/harm grading or clinical certification was performed.

Related sources S06 S2402 S2406

N28 · Is the meaning of insufficient data behind the absence of an established upper intake level preserved?

Current findings: FNB 1998 states that an upper intake level could not be established because reports of harm were not found. The checked EFSA version 11(2025-08) also indicates that an upper intake level for pantothenic acid could not be derived because of insufficient data. This does not mean unlimited safety or a legally permitted therapeutic dose.
Verification status: Met
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: The retained editions and interpretation of insufficient data were linked as they stood, and no new safety/regulatory judgment was made.
Reason for missing information: Current official editions/regulatory changes were not looked up in this work.
Required materials and conditions: The relevant official edition/harm assessment section and the basis for data insufficiency
Materials to obtain first: The relevant official edition/harm assessment section and the basis for data insufficiency
Further research: Review the limitations on deriving a UL in each edition checked and whether it has been updated.
Remaining uncertainty: Current official editions/regulatory changes were not looked up in this work. This verification status is limited to the scope of the narrow record condition concerned. It does not mean general incidence, individual risk, established causality, prevention by fed dosing, absence of risk, or absence of research worldwide.
Conditions for verification: Link the UL-related wording and dates in FNB 1998 and EFSA version 11(2025-08).
Why this condition is needed: Needed to avoid mistaking inability to derive an upper intake level for unlimited safety or a legally permitted therapeutic dose.
Application exceptions: The wording of the official assessment and the edition checked are historical in scope and do not represent a current lookup of the latest regulations in this work.
Referenced methods: C09: M04 §4.5, §4.6.3; restrictions on the current data transformation follow the user-defined scope and internal design / H08: M19 §19.1.2–19.2.4; internal application / H09: Chamgap’s own interpretive boundary. References M19 principles; no formal causality tool was applied. Reason for application to the harm question: needed to avoid mistaking inability to derive an upper intake level for unlimited safety or a legally permitted therapeutic dose. No formal causality/harm grading or clinical certification was performed.

Related sources S2401 S2403

N29 · Are adequate intake and high-dose diarrhea signals kept separate?

Current findings: The reused US adequate intakes are 5 mg/day for adults, 6 mg/day during pregnancy and 7 mg/day during lactation. These indicate nutritional adequacy, not a diarrhea threshold or high-dose treatment instructions. Do not pool food intake and high-dose single-active-ingredient exposure into the same dose group.
Verification status: Met
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: The condition distinguishing the roles of AI values and clinical high-dose exposures was verified.
Reason for missing information: These nutritional references cannot determine an individual’s probability of diarrhea/treatment dose.
Required materials and conditions: Populations/definitions of nutritional reference values and data on high-dose preparations
Materials to obtain first: Populations/definitions of nutritional reference values and data on high-dose preparations
Further research: Review the purpose, target population and actual exposure scope of each reference separately.
Remaining uncertainty: These nutritional references cannot determine an individual’s probability of diarrhea/treatment dose. This verification state is limited to the scope of the specific narrow record condition. It does not imply general incidence, individual risk, definitive causality, prevention under fed conditions, no risk or worldwide absence of research.
Conditions for verification: Preserve the distinction between the nutritional purpose of the AI values and high-dose single-active-ingredient exposure.
Why this condition is needed: Needed to avoid converting a nutritional adequacy reference into a diarrhea threshold or instructions for an individual's high-dose treatment.
Application exceptions: The values of 5 for adults, 6 for pregnancy and 7 mg/day for lactation are not risk values from the same clinical exposure group.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse indicators and test adaptations are internally designed / H08: M19 §19.1.2–19.2.4; internally applied / H09: Chamgap’s own interpretive boundary. M19 principles are referenced; no formal causality tool was applied. Reason for application to the harm question: Needed to avoid converting nutritional adequacy references into a diarrhea threshold or personal high-dose treatment instructions. No formal causality/harm grading or clinical certification was performed.

Related sources S06

N30 · Is the boundary on applying the CIR cosmetic assessment to oral use preserved?

Current findings: S2406 is a safety review of the cosmetic use of panthenol, pantothenic acid and their derivatives. In the current evidence, it is used as a qualitative summary of historical high-dose oral observations, not converted into authorization or safety certification of single-active oral B5.
Verification status: Met
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: The material’s actual title/review scope was distinguished from its citation role in this table.
Reason for missing information: Oral-product authorization and individual safety judgments are not outcomes of this review.
Required materials and conditions: CIR review scope, toxicology section and underlying oral-use references
Materials to obtain first: CIR review scope, toxicology section and underlying oral-use references
Further research: Review the assessment’s jurisdiction/route, citation lineage and evidence for oral-exposure events separately.
Remaining uncertainty: Oral-product authorization and individual safety judgments are not outcomes of this review. This verification state is limited to the scope of the specific narrow record condition. It does not imply general incidence, individual risk, definitive causality, prevention under fed conditions, no risk or worldwide absence of research.
Conditions for verification: Distinguish CIR’s cosmetic-review scope from the role of its historical oral-use summaries.
Why this condition is needed: Needed to avoid converting a safety assessment with a different route/purpose into authorization/safety certification of a single-active oral preparation.
Application exceptions: Historical oral-use reports cited in a cosmetic review do not provide grounds for authorization of all oral preparations.
Referenced methods: C01: Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are internally designed / H07: M04 §4.6.1–4.6.2; adaptation to harm data is internally designed / H09: Chamgap’s own interpretive boundary. M19 principles are referenced; no formal causality tool was applied. Reason for application to the harm question: Needed to avoid converting a safety assessment with a different route/purpose into authorization/safety certification of a single-active oral preparation. No formal causality/harm grading or clinical certification was performed.

Related sources S2406

N31 · Are pantethine and the acne product with unestablished composition excluded?

Current findings: Evans S2407 is excluded because pantethine is a different molecule. Yang S2408 provides product-level tolerability with unestablished monotherapy composition, so it is not transferred to the risk of single-active pantothenic acid. Not applicable for each n is a value indicating the exclusion role.
Verification status: Met
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: The distinct reasons for the two current exclusions and the meaning of the denominator’s non-applicability were retained.
Reason for missing information: The old separate extractions/PMC full texts and composition were not newly read in this review.
Required materials and conditions: Identity of the product’s ingredients/formulation and historical exclusion extraction
Materials to obtain first: Identity of the product’s ingredients/formulation and historical exclusion extraction
Further research: Review substance identity, product composition and the transferability of diarrhea endpoints separately.
Remaining uncertainty: The old separate extractions/PMC full texts and composition were not newly read in this review. This verification state is limited to the scope of the specific narrow record condition. It does not imply general incidence, individual risk, definitive causality, prevention under fed conditions, no risk or worldwide absence of research.
Conditions for verification: Link the Evans record of a different molecule and the Yang record of unestablished single-active composition as separate grounds for exclusion.
Why this condition is needed: Needed to avoid transferring the tolerability of a different molecule/product into direct harm evidence for this question.
Application exceptions: Not applicable is the denominator’s role within the exclusion scope; it does not mean 0 people, no risk or no human research.
Referenced methods: C05: M03 §3.2.2–3.2.3; reverse indicators and test adaptations are internally designed / C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is internally applied / H07: M04 §4.6.1–4.6.2; adaptation to harm data is internally designed. Reason for application to the harm question: Needed to avoid transferring the tolerability of a different molecule/product into direct harm evidence for this question. No formal causality/harm grading or clinical certification was performed.

Related sources S2407 S2408

N32 · Is funding/conflict-of-interest attribution clear for each study/review?

Current findings: Rao disclosed support from CoA Therapeutics and employment, consultancy and shareholdings related to development companies. Funding for the historical underlying cases is unverified, while the CIR/Personal Care Products Council support for CIR 2022 funds that review. Funding for the arthritis/excluded materials also remains unverified.
Verification status: Partly verified
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: Relationships have been disclosed for the main study/review, but support for the underlying cases and other families is not established.
Reason for missing information: Funding/product provision for underlying cases and arthritis/excluded families.
Required materials and conditions: Original Funding/COI, support/product provision and funding records for underlying cases
Materials to obtain first: Original Funding/COI, support/product provision and funding records for underlying cases
Further research: Review relationships relevant to data production/reporting structures and support that remains unknown.
Remaining uncertainty: Funding/product provision for underlying cases and arthritis/excluded families. This verification state is limited to the scope of the specific narrow record condition. It does not imply general incidence, individual risk, definitive causality, prevention under fed conditions, no risk or worldwide absence of research.
Conditions for verification: Preserve Rao’s and the CIR review’s funding/relationships separately from the unverified information for original cases.
Why this condition is needed: Needed to avoid hiding developer support or transferring another review’s funding to support for the original cases.
Application exceptions: Disclosed interests alone do not determine study invalidation, effect-size adjustment or a new harm grade.
Referenced methods: C10: Chamgap’s own independence/attribution condition. The formal methods sections used in this pilot do not warrant every detail of this item / H07: M04 §4.6.1–4.6.2; adaptation to harm data is internally designed. Reason for application to the harm question: Needed to avoid hiding developer support or transferring another review’s funding to support for the original cases. No formal causality/harm grading or clinical certification was performed.

Related sources S2404 S2405 S2406 S2407 S2408

N33 · Is there direct harm evidence for long-term exposure and vulnerable populations?

Current findings: The direct evidence concerns healthy people aged 18–55 undergoing single-dose or 14-day repeated exposure. Direct diarrhea risks during pregnancy/lactation, in children, older people, those with liver/kidney disease and during long-term exposure are unverified.
Verification status: Unverified
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: There are no data establishing harms outside the population/duration of the direct study.
Reason for missing information: Direct harm/denominators/duration for long-term exposure and vulnerable populations.
Required materials and conditions: Long-term follow-up and direct diarrhea/exposure/comparator data by population
Materials to obtain first: Long-term follow-up and direct diarrhea/exposure/comparator data by population
Further research: Review applicability and surveillance scope separately for each population/duration.
Remaining uncertainty: Direct harm/denominators/duration for long-term exposure and vulnerable populations. This verification state is limited to the scope of the specific narrow record condition. It does not imply general incidence, individual risk, definitive causality, prevention under fed conditions, no risk or worldwide absence of research.
Conditions for verification: Separate the scope of healthy people aged 18–55 and short exposure from gaps for other populations/long-term exposure.
Why this condition is needed: Needed to avoid extending a short study in healthy people to long-term safety during pregnancy/lactation, in children or in older people/those with disease.
Application exceptions: Indirect documents/AI values and brief reports of 0/8 do not demonstrate absence of risk in each population.
Referenced methods: C04: M03 §3.2.1; detailed population conditions are internally designed / H08: M19 §19.1.2–19.2.4; internally applied. Reason for application to the harm question: Needed to avoid extending a short study in healthy people to long-term safety during pregnancy/lactation, in children or in older people/those with disease. No formal causality/harm grading or clinical certification was performed.

Related sources S2404

N34 · Was current summary reading distinguished from historical access to original materials?

Current findings: The actual current input is an archived summary preserving the KO/EN manuscripts, 5 evidence groups, 9 bibliographic records and assessment/metadata. All external original texts/registrations/official documents and old separate extractions were not attempted, acquired or read in this review. Historical access levels are retained only in separate fields.
Verification status: Met
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: Current local-summary reading was recorded separately from the historical/current external access for the 9 reports.
Reason for missing information: No current comparison against external original materials was performed.
Required materials and conditions: Original material types, bibliography and access/preservation receipts for each report
Materials to obtain first: Original material types, bibliography and access/preservation receipts for each report
Further research: Compare the correspondence between bibliographic URLs and material types with actual reading/attempt events.
Remaining uncertainty: No current comparison against external original materials was performed. This verification state is limited to the scope of the specific narrow record condition. It does not imply general incidence, individual risk, definitive causality, prevention under fed conditions, no risk or worldwide absence of research.
Conditions for verification: Separate each report’s physical URL and historical access_level/location from the current unread status of each material type.
Why this condition is needed: Needed to avoid upgrading this reading of local materials into a new reading of external full texts/old packages.
Application exceptions: Historical full_text/official PDF/no access/inherited extractions do not represent the actual current read status of each material type.
Referenced methods: C03: Data-collection/selection principles in M04 §4.5–4.6; the separation of access from reading and the hyperlink contract are internally designed. Reason for application to the harm question: Needed to avoid upgrading this reading of local materials into a new reading of external full texts/old packages. No formal causality/harm grading or clinical certification was performed.

Related sources S06 S2401 S2402 S2403 S2404 S2405 S2406 S2407 S2408

N35 · Are the evidence-review date, access dates and actual server metadata distinguished?

Current findings: The original content reference date/verified_date is 2026-09-15, and the local review date recorded here is 2026-10-05. Each bibliographic record lacks an access-date key, so historical_access_date is empty. The original published/updated values are preserved, while the text states that an actual server publication date is unassigned. The evidence_cutoff and subclaims keys are also absent.
Verification status: Met
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: The record condition separating dates, absences and historical metadata by event was verified.
Reason for missing information: Actual access dates for each report, the actual server publication date and original-binary SHA were not newly verified.
Required materials and conditions: Actual access/version dates for each report and original server publication/modification receipts
Materials to obtain first: Actual access/version dates for each report and original server publication/modification receipts
Further research: Compare the different date-related events and the meaning of the original metadata.
Remaining uncertainty: Actual access dates for each report, the actual server publication date and original-binary SHA were not newly verified. This verification state is limited to the scope of the specific narrow record condition. It does not imply general incidence, individual risk, definitive causality, prevention under fed conditions, no risk or worldwide absence of research.
Conditions for verification: Link the original review reference date, current review date, absence of report-specific access dates and limitations on the server publication date.
Why this condition is needed: Needed to avoid treating a global date or package metadata as a verified access/original-binary verification date for each report.
Application exceptions: Do not create absent evidence_cutoff/subclaims; retain both the original published/updated metadata and the statement in the text that an actual server publication date is unassigned.
Referenced methods: C09: M04 §4.5, §4.6.3; limitations on the current material transformation follow the user’s scope and internal design / C03: Data-collection/selection principles in M04 §4.5–4.6; the separation of access from reading and the hyperlink contract are internally designed. Reason for application to the harm question: Needed to avoid treating a global date or package metadata as a verified access/original-binary verification date for each report. No formal causality/harm grading or clinical certification was performed.

Related sources S06 S2401 S2402 S2403 S2404 S2405 S2406 S2407 S2408

N36 · Are gaps in searches, corrections/retractions, unpublished materials and updating identified?

Current findings: The original review was a single-assistant self-review, with registration/some metadata-access failures remaining. It is not an independent external review or assurance that no corrections, retractions or unpublished materials exist. New comparative safety evidence, salt/labeled-dose information, corrections/regulatory changes or numerical/classification errors are reasons to update dates/history under the same ID/URL after assignment.
Verification status: Unverified
Materials actually read: Summary read: The specified literals in the preserved manuscripts were actually read. External material types were not attempted, acquired, or read in this review.
Why unverified: Updating principles exist, but search completeness and the current scope of corrections/unpublished materials were not checked in this review.
Reason for missing information: Search/access completeness and the current scope of corrections/retractions/unpublished materials.
Required materials and conditions: Actual logs of searches/selection, corrections/retractions and registration/unpublished-material checks, and new results
Materials to obtain first: Actual logs of searches/selection, corrections/retractions and registration/unpublished-material checks, and new results
Further research: Review gaps in access/selection and reasons for updates by original ID/version.
Remaining uncertainty: Search/access completeness and the current scope of corrections/retractions/unpublished materials. This verification state is limited to the scope of the specific narrow record condition. It does not imply general incidence, individual risk, definitive causality, prevention under fed conditions, no risk or worldwide absence of research.
Conditions for verification: Link the limits of self-review/historical access to the scope for updates under the same ID when new evidence/corrections arise.
Why this condition is needed: Needed to avoid extending a historical self-check into independent review or assurance of worldwide absence of evidence.
Application exceptions: The original package’s statement that search records are preserved does not mean that the complete search logs/ZIP were opened in this review.
Referenced methods: C09: M04 §4.5, §4.6.3; limitations on the current material transformation follow the user’s scope and internal design / H06: M19 §19.1.2–19.2.4, M04 §4.6.3; internally applied. Reason for application to the harm question: Needed to avoid extending a historical self-check into independent review or assurance of worldwide absence of evidence. No formal causality/harm grading or clinical certification was performed.

Related sources S06 S2401 S2402 S2403 S2404 S2405 S2406 S2407 S2408