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What should CTD 2.6.6 and 2.6.7 toxicology summaries contain?
Present the toxicology studies and their important findings with the material, species, dose, exposure, duration and recovery context needed to interpret them. Keep the written and tabulated conclusions consistent with the controlling reports. Distinguish observed changes from expert judgments about adversity, causality, reversibility and relevance to human use.
Before you begin
M4S sections 2.6.6 and 2.6.7. Study-category headings organize available evidence; they do not determine the testing needed for an individual product.
What you will prepare: A reconciled toxicology account that preserves consequential findings and supports the integrated nonclinical assessment.
Sections covered in this guide (2)
Establish the package and its scientific boundaries
Start with the controlled toxicology register and final reports, including amendments and relevant toxicokinetic evidence. For each study identify material, species, sex, route, duration, dose groups, recovery design, report version and source location. Verify status from the actual record rather than assuming that every report has the same GLP status.
M4S provides organization for single- and repeat-dose toxicity, genotoxicity, carcinogenicity, reproductive/developmental toxicity, local tolerance and other toxicity work. Identify which categories contain evidence, which were not conducted, and where a product-specific rationale is documented. A blank category cannot establish that a study was unnecessary.
Agree with the toxicologist which findings need connected discussion across studies. This makes the summary a usable account of the program rather than a series of disconnected report abstracts.
Preserve the context of a finding
For a material observation, record what happened, to whom, at which dose or exposure, when it appeared and whether recovery was evaluated. Preserve the difference between absent evidence of recovery and a demonstrated irreversible effect. Likewise, distinguish an observed change from the expert assessment of its adversity.
Use 2.6.7 tabulated summaries to expose key design and result information. Reconcile the tables with the written discussion and applicable M4S formats. Where a study interpretation changes in an amendment, update the corresponding table and all narrative uses of the result.
Do not invent a no-observed-adverse-effect level, causality conclusion or exposure margin to complete a standard row. If the source does not support the value, ask the scientific owner how it should be represented. Provide the downstream overview author with both the conclusion and the limitations needed to use it responsibly.
Worked example: “reversible” exceeds the study design
Fictional editorial exercise: a draft says that a histopathological finding was reversible. The source study has no recovery group; the writer inferred reversal because the finding was less frequent in a different, shorter study.
Compare study design and sampling times with the sentence. Remove the unsupported inference and state the observations separately. Ask the toxicologist whether other evidence establishes reversibility and, if so, cite that evidence with its limitations. Check the tabulated conclusion and 2.4 for the same claim.
If the proposed clinical use changes from short to chronic treatment, revisit which duration and exposure comparisons the summary supports. Do not claim that an unchanged document heading means the old interpretation remains adequate.
A finding-level review record for the toxicology author
Build one working record for each finding that materially affects the toxicology narrative. Organizing only by report can obscure recurrence across studies; organizing only by target organ can obscure different doses, durations or materials. Use both views when they help answer the scientific question.
| Review field | Record from the source | Keep distinct from |
|---|---|---|
| Observation | Nature, incidence, severity and affected groups, as reported | An inferred mechanism or causal explanation |
| Exposure context | Relevant dose and supported kinetic information | An assumed margin to a human regimen |
| Time course | Onset, treatment duration and actual recovery observations | An untested prediction of reversibility |
| Interpretation | The responsible expert’s assessment and its basis | The writer’s judgment based on a statistical flag |
| Cross-study context | Corroborating and discordant findings with study identifiers | A count that treats repeated references as independent evidence |
This is an editorial quality-control aid. The submission summaries should follow the applicable M4S organization and retain the context needed to understand the evidence, without reproducing a large internal issue log.
Wording exercise: “No adverse effect occurred” is not interchangeable with “the reported change was assessed as non-adverse under the study conditions.” The first can imply absence of findings; the second identifies an interpretation. Select wording only after checking what the report actually concludes. Likewise, “not assessed” is different from “not observed.”
Coordinate the final exposure terms with the kinetic summaries. Send the overview author the finding, supported interpretation and remaining limitation together. If a report amendment changes the adversity assessment, search all three outputs for the previous statement rather than replacing only the study table.
Your preparation checklist
0/4 checkedUse this to track your review in this visit. Checks are not saved and do not establish regulatory compliance.
Frequently asked questions
Can the writer assign a NOAEL when a report does not provide one?
No. A no-observed-adverse-effect level is a scientific interpretation, not a blank field the writer should fill independently. Ask the responsible toxicologist how the evidence should be represented and preserve the distinction between an observed effect level, an adversity assessment and any proposed exposure comparison.
Does no recovery group mean a finding is irreversible?
No. It means that recovery was not evaluated by that study design. State the available observation and its limitation. If another study supports a conclusion about recovery, identify that evidence and obtain the toxicologist’s interpretation before describing the finding as reversible or irreversible.
Should every listed toxicology category have a new study?
The M4S categories organize nonclinical information; they do not prescribe the complete testing program for every product. Explain available evidence and documented product-specific decisions about omitted or alternative work. A heading, an empty table or a generic template is not a study-requirement determination.
How can written and tabulated toxicology summaries disagree?
Common editorial causes include different report versions, inconsistent dose or exposure units, and a narrative that upgrades an observation into a broader conclusion. Compare important findings in both directions, including recovery and adversity language, and propagate scientific corrections into the nonclinical overview as well.
Sources and revisions
Requirements, source recommendations and editorial preparation advice have different roles. Review the scope and revision of the source you use.
Guidance
ICH M4S(R2): Nonclinical overview and summaries ↗Step 4, December 20, 2002; sections 2.4 and 2.6 and Appendices A/B. FDA M4S and Safety Appendices remain labeled final, August 2001; ICH R2 includes subsequent editorial changes.
Technical specification · placement only
FDA eCTD v4.0 comprehensive hierarchy ↗Version 2.2, February 2025. Section 2.6.6. A heading identifies placement, not mandatory applicability.