CHemical RISk calculator (CHRIS) - Color additives

Frequently asked questions

What is the primary purpose of CHRIS?

CHRIS is a rapid screening assessment tool that aids in the determination of whether a color additive (and associated additives and impurities that may be present) should be addressed in the biocompatibility evaluation of a device. Specifically, CHRIS enables the user to predict whether a worst-case release of a color additive associated substance from a polymer will be sufficiently low to not warrant further evaluation of the substance’s impact on device biocompatibility. CHRIS facilitates this determination by comparing a device specific exposure estimate, based on a conservative transport (diffusion) model, to a provisional tolerable exposure (TE) or threshold of toxicological concern (TTC) value. The TE or TTC value is considered protective for chronic exposure durations and worst-case exposure routes (i.e., direct blood contact) other than inhalation. Because both the exposure estimate and safety threshold are conservative, a margin of safety (MOS) value (= tolerable intake / exposure) in excess of one indicates acceptable risk for the typical color additive (or associated additive or impurity) in a device that contacts the body by equivalent or less invasive routes, and further assessment of the substance will be unnecessary for systemic toxicity. When exposure is determined to exceed the conservatively derived TI or TTC value (i.e., MOS < 1), device specific evaluation of the substance should be conducted.

How can CHRIS be used in a regulatory context?

CHRIS can be an option for medical device stakeholders to determine when the impact of a color additive and its constituents on device biocompatibility can be reduced. Use of CHRIS is not required in submissions, nor are systems (i.e., colored polymers) that can be used in devices restricted to those included in CHRIS. In regulatory scenarios where a risk assessment of a system is needed, output from CHRIS can be used in lieu of extraction testing / chemical characterization to estimate exposure and/or independently derive a TE value to address systemic toxicity, genotoxicity, cancer, and/or reproductive/developmental toxicity (see next question regarding other biological endpoints). If the output of CHRIS indicates a system "passes", release of the color additive (or associated substance) will not impart systemic toxicity, genotoxicity, cancer, or reproductive/developmental toxicity concern. Thus, the color additive (or associated substance) will typically not be a factor in the decision to conduct biological tests that address these specific endpoints. If the output of CHRIS is not "pass", the impact of the substance on device biocompatibility can be further evaluated by an alternative approach, such as: (1) the exposure estimate from CHRIS could be used with an independent risk assessment (i.e., device specific TI value) for FDA to review as part of a submission; (2) the conservative TE value from CHRIS could be compared to an exposure estimate based on an extraction study that might be included in a device submission (see FDA biocompatibility guidance); (3) a completely independent risk assessment that uses no component/output of CHRIS.

Does CHRIS address all biological endpoints?

CHRIS calculator output reports biological endpoints addressed in the risk assessment. As a minimum, CHRIS addresses biological endpoints that require time consuming and/or expensive biological tests, which are systemic toxicity, genotoxicity, cancer, and/or reproductive/developmental toxicity.

How are the exposure calculations done?

Details regarding the exposure model and underlying assumptions, as well as how the model is parameterized and validated for the additive / polymer combinations listed in CHRIS have been published [1].

[1] D.M. Saylor, V. Chandrasekar, D.D. Simon, P. Turner, L.C. Markley, A.M. Hood, Strategies for rapid risk assessment of color additives used in medical devices, Toxicol. Sci. 172 (2019) 201-212. doi:10.1093/toxsci/kfz179.

Where do the color additive tolerable intake values come from?

Provisional tolerable intake values (TIs) were derived for color additives commonly used in polymeric medical device components and implemented into the CHRIS. A TI value is an estimate of the daily intake of the color additive or impurity over a period of time based on body mass and considered to be without appreciable harm to human health. The TI values are expressed in milligrams per kilogram of body mass per day (mg/kg bw/day). They are used to determine the TE value for a patient of particular weight. A comprehensive literature review of studies investigating critical health effects resulting from parenteral exposure to each color additive was reviewed and documented. The quality of the study data was evaluated by the Annapolis Accords [4] principles, and then further analyzed by the Toxicological Data Reliability Assessment Tool (ToxRTool) [5] to determine the critical study for use in derivation of the TI. The point of departure (POD) is the exposure concentration of the color additive reporting the health effect in the critical study typically presented as a no-adverse-effect-level (NOAEL) or bench mark dose (BMD) value, and represents the critical adverse health effect. The POD is extrapolated to humans by calculating a modifying factor (MF) that accounts for uncertainties in the data, such as: intraspecies variability, interspecies differences and quality/completeness of the data.

[4] Gray, G.M., et al., 2008. The Annapolis Accords on the use of Toxicology in risk assessment and decision-making: an Annapolis center workshop report. Toxicol. Method 11, 225e231.

[5] Schneider, K., et al., 2009. "ToxRTool", a new tool to assess the reliability of toxicological data. Toxicol. Lett. 189, 138e144.

How does CHRIS deal with color additive impurities?

For any impurities present, CHRIS compares the total amount of impurities to the appropriate TTC value. The user should also review and confirm compliance with the relevant Code of Federal Regulations (CFR) listings as part of the submission package, i.e. in addition to any output of CHRIS. Examples of CFR listings for color additives specifically addressed by CHRIS are given below:

NOTE: some color additives included in CHRIS do not have CFR listings as of 26 October 2021.

If the total amount of impurities exceeds the relevant CFR listing and/or TTC value, one can:

What constitutes an "impurity"?

Within CHRIS, the term impurity refers to any substance in the color additive or color concentrate other than the substance(s) intended to impart the desired color to the device component or substances intentionally added to improve manufacturability. This may include unreacted starting materials, reaction and/or degradation products, and contaminants.

What about other additives contained in a color additive or concentrate?

Many color additives and concentrates contain intentionally added substances that do not contribute to the color, such as carrier resins and metal oxides, as manufacturing aides. If the amount and identity of a particular non-color additive is known, then CHRIS can be used to assess the risk associated with the substance. In these scenarios, the user should conduct a separate assessment using the tool for each known additive in the color additive or concentrate using this approach.

What if I have suggestions for inclusion of additional CAs or polymer matrices within CHRIS or changes to the user interface?

If you have a suggestion to expand the applicability of the tool or improve the user interface, please contact Dave Saylor: