Systemic Toxicity Testing

Scope

Systemic toxicity testing covers in vivo evaluation of material extracts for acute systemic and pyrogenic effects. The tests are conducted on animal models using extracts prepared from the test material under conditions intended to simulate worst-case clinical exposure. Both tests are governed by the ISO 10993 series, and the extraction conditions – solvent, temperature, duration, and surface area to volume ratio – are defined per ISO 10993-12.

The testing scope includes:

• Acute Systemic Injection Test (ASIT) – mouse model; extracts in saline (IV route) and cottonseed oil (IP route) administered simultaneously; animals observed at 4, 24, 48, and 72 hours for clinical signs of toxicity; governed by ISO 10993-11 and USP <88> Biological Reactivity Tests, In Vivo
• Material-Mediated Pyrogenicity Test (MMPT) – rabbit model; saline extract administered IV; rectal temperature monitored before and at 1, 2, and 3 hours post-injection; pyrogenic response assessed against defined threshold; governed by ISO 10993-11 and USP <151> Pyrogen Test
• Extraction conditions – defined per ISO 10993-12; standard extraction vehicles include 0.9% saline and cottonseed oil; temperature typically 37°C for 24 hours or 70°C for 24 hours, depending on material and intended use

Applications

• Medical device biocompatibility – systemic toxicity and pyrogenicity are required endpoints in the ISO 10993-1 biocompatibility evaluation matrix for devices with prolonged or permanent contact with the body; ASIT and MMPT are commonly needed for implants, catheters, tubing, and fluid-contact components
• New material qualification – when a new polymer, coating, or adhesive is introduced into a medical device, systemic toxicity testing establishes that leachables from the material do not produce adverse systemic effects
• Change control and material substitution – changes in raw material supplier, processing aids, or sterilization method can alter the extractable profile; retesting confirms the updated material remains within acceptable limits
• Combination products and drug-device interfaces – components that contact drug solutions or are used in drug delivery systems require systemic toxicity data covering both the material itself and its potential interactions with the drug vehicle
• Veterinary devices and implants – systemic toxicity evaluation for materials used in veterinary medical devices where similar biocompatibility endpoints are applicable

Benefits

• Addresses the systemic endpoint that local biocompatibility tests cannot – cytotoxicity, sensitization, and irritation tests evaluate localized responses; ASIT and MMPT are the only in vivo tests that detect body-wide toxic effects from material extracts
• Both routes of exposure covered in ASIT – IV and IP injection in the same study cover both direct vascular exposure and peritoneal absorption, providing broader coverage of potential clinical exposure scenarios
• MMPT distinguishes material-mediated pyrogenicity from endotoxin – a LAL test detects endotoxin but not non-endotoxin pyrogens; MMPT detects both, making it relevant for materials where chemical pyrogens are a concern
• Internationally recognized test methods – ISO 10993-11, USP 88, and USP 151 are accepted by FDA, EMA, and other major health authorities for device submissions; data generated under these methods does not need to be repeated for different market submissions
• Supports a risk-based biocompatibility strategy – when chemical characterization data alone is insufficient to rule out systemic risk, in vivo systemic toxicity data provides the biological evidence needed to support a safety conclusion