Toxicological Risk Assessment (TRA) for Medical Devices

ISO 10993-1 requires a risk-based biological evaluation. Authorities want to see how chemical findings translate into real‑world exposure and patient safety.

TRA answers the key questions:

• What substances were found?
• At what levels?
• How much would a patient be exposed to?
• How does this compare to toxicological thresholds?

TRA also supports:

• Root‑cause analysis when biological tests show unexpected results
• Informed decision-making early in development
• Continuous risk management throughout the product lifecycle

A TRA is only as strong as the chemical data behind it. Extraction design (solvent, temperature, time, surface area) determines which compounds appear and at what levels.

Our evaluation includes:

1. Identification of constituents from ISO 10993‑18 studies
2. Assessment of Toxicological Screening Limits (TSL)
3. Derivation of Tolerable Intake (TI) or application of Threshold of Toxicological Concern (TTC)
4. Calculation of worst‑case exposure (EEDmax)
5. Calculation of Margin of Safety (MOS)
6. Application of uncertainty factors
7. Weight‑of‑evidence risk conclusion

When exposure is below applicable thresholds, certain biological endpoints may be addressed through toxicological analysis. If elevated risk is identified, the chemical profile supports targeted mitigation measures such as material modification, cleaning adjustment or process refinement.

A TRA is typically conducted when:

• Chemical characterization identifies reportable constituents
• Estimated exposure exceeds screening thresholds
• Preparing FDA 510(k), De Novo, PMA or EU MDR submissions
• Material, supplier, sterilization or process changes alter the chemical profile
• A Biological Evaluation Plan requires toxicological justification
• A test result requires investigation of potential chemical causes

TRA supports ongoing risk management when materials, suppliers or processes change.

Analytical testing identifies chemical constituents, which must then be evaluated for relevance to patient safety.

Exposure modeling, threshold derivation and uncertainty factor application require specialized toxicology training.

ISO 10993-1 permits certain biological effects/endpoints — including systemic toxicity and, in defined contexts, genotoxicity — to be addressed through chemical characterization and toxicological evaluation when supported by exposure data.

To be considered defensible, the TRA must clearly document:

• The identified chemical constituents
• The estimated patient exposure (EEDmax)
• The applicable toxicological threshold (TSL, TI, or TTC)
• The resulting Margin of Safety (MOS)
• The rationale for concluding that additional biological testing is not required

When exposure remains below justified thresholds, and the toxicological assessment is documented, regulators may accept chemical characterization and TRA in place of separate biological testing for those endpoints.

This determination must be supported by transparent methodology and consistent application of ISO 10993-17.

Hohenstein Medical supports TRA documentation for:

• FDA 510(k), De Novo and PMA submissions
• EU MDR Technical Documentation
• Biological Evaluation Plans (BEP)
• Biological Evaluation Reports (BER)
• Material and process change assessments
• Regulatory deficiency responses

Modern analytical methods can identify very small quantities of compounds. Risk depends on how much of that substance reaches the patient and how that exposure compares to established toxicological thresholds.

Many detected compounds remain well below levels known to cause harm.

Worst-case exposure is based on conservative extraction conditions, such as elevated temperatures, extended durations or aggressive solvents. These conditions are intentionally conservative to account for uncertainty and variability in device use. By maximizing the amount of substances that could be released, they help ensure that calculated safety margins remain protective under real-world conditions, even if actual patient exposure is lower.

Toxicological risk assessment uses these conservative estimates to confirm that real-world patient exposure remains within safe limits.

When a substance cannot be fully identified, it is evaluated using conservative assumptions to protect patient safety. This includes applying approaches such as the Threshold of Toxicological Concern (TTC) and using worst-case exposure estimates.

Toxicologists estimate how much of the substance a patient could be exposed to and compare that exposure to protective thresholds based on established toxicological data. If needed, they also consider similar compounds with known toxicological profiles.

Prioritization tools, such as toxicological screening limits, help determine whether further evaluation is necessary. If exposure remains below these thresholds, the substance is not expected to present a risk. If not, further investigation may be required.

For some endpoints, such as systemic toxicity, if exposure remains below established thresholds, regulators may accept toxicological evaluation in place of additional testing.

However, acceptance depends on the endpoint, device type and regulatory pathway - and some biological tests may still be required.

Regulators now expect manufacturers to understand what substances may be released, how patients are exposed and whether that exposure is safe.

Toxicological risk assessment provides this framework and supports the interpretation of both chemical and biological data, including investigation of unexpected test results.