CHemical RISk calculator (CHRIS) - Color additives

Context of Use (COU)

The CHRIS - Color additives module is (proposed to be) qualified to conduct screening level risk assessments to aid in the biocompatibility evaluation of polymeric medical device components that contain color additives (CAs)1. These assessments can assist device manufacturers by providing instantaneous feedback on whether the presence of CAs or other additives and impurities associated with CAs in a device would require additional justification and/or testing to demonstrate acceptable biological risk. The output is a conservative margin of safety (MOS = toxicological safety limit ÷ exposure dose) value for a CA (and associated additives and impurities) contained within a polymeric medical device component. Based on the MOS value, the calculator determines if further assessment of one or more biocompatibility endpoints is necessary for the CA and/or associated impurities.

Because the CHRIS - color additive module only addresses CAs, a favorable outcome does not imply acceptable biological risk for the final finished form of a medical device. CHRIS is also not intended to establish device classification or identify biocompatibility requirements. However, in addition to providing guidance to device manufacturers on acceptable levels of CA in a particular device, the tool can potentially be used to:

In the absence of adequate toxicological and exposure data for a CA (or associated additives and impurities) in a polymeric matrix, a toxicological risk assessment can be conducted for systemic biocompatibility endpoints by comparing the total amount of a CA, associated additive, or impurities in the matrix to an appropriate threshold of toxicological concern (TTC). This is the approach used by CHRIS in the absence of exposure and toxicity data for a particular system. For the CAs listed below, CHRIS applies a CA-specific toxicological threshold value called a tolerable intake (TI) value. These TIs are based on available systemic (including reproductive / developmental, genotoxicity, and carcinogenicity) toxicity data. Because both the TTC and TI approaches are based on systemic toxicity, CHRIS can address acute systemic toxicity, subacute/subchronic toxicity, genotoxicity, carcinogenicity, and reproductive and developmental toxicity. It does not, however, address cytotoxicity, sensitization, irritation, hemocompatibility, material mediated pyrogenicity, or implantation. Therefore, an MOS >= 1 implies the CA will not raise a safety concern with respect to only the systemic biocompatibility endpoints, which is reflected in the output of CHRIS. Safety assessments have been performed, and TIs were derived for eleven (11) CAs commonly used in medical devices2:

The CHRIS - Color additives module provides clinically relevant, yet still conservative, exposure dose estimates using a physics-based transport model for polymeric systems where transport data are available to support the use of the model. The model applies worst-case boundary conditions for release of a substance from the polymer matrix and is based on four (4) primary assumptions:

  1. The polymer does not swell or degrade in-vivo, nor does the presence of CA impact the integrity of the polymer.
  2. The total amount of CA is present in dilute concentrations (<= 2 % m/v) within the colored component.
  3. The CA is homogeneously distributed throughout the polymer.
  4. The smallest dimension of the colored device component is much greater than the size of any color additive particles that may be present (<= 50x).

While these assumptions are typically valid for color additive containing device components, users of the tool must confirm conformance to the underlying assumptions or provide supporting justification to ensure compliance for a given system. Further, CHRIS only enables system specific exposure estimates for nineteen (19) polymeric systems that are generally biostable (non-swelling and non-degrading) and contain less than 2 % m/v of a given CA. These polymers are listed below. To estimate CA release based on the model, the diffusion coefficient of the CA in the polymer matrix must be specified. For the nineteen (19) listed polymeric systems, a worst-case (upper bound) diffusion coefficient, as a function of additive molecular weight, has been established based on data from the literature. For polymer matrices that are not included in this list, CHRIS assigns an ultra-conservative diffusion coefficient that assumes the polymer has the properties of water. Note that the worst-case diffusion coefficient is only defined over a molecular weight range of 100 to 1100 g/mol. Therefore, for substances with a molecular weight > 1100 g/mol, the value of the diffusion coefficient assuming a molecular weight of 1100 g/mol can be used as a conservative value; for substances with a molecular weight < 100 g/mol, CHRIS currently cannot be used to estimate exposure.

  1. The term “color additive”, as defined under section 201(t) of the FD&C Act, means a material which:

    1. is a dye, pigment, or other substance made by a process of synthesis or similar artifice, or extracted, isolated, or otherwise derived, with or without intermediate or final change of identity, from a vegetable, animal, mineral, or other source, and

    2. when added or applied to a food, drug, or cosmetic, or to the human body or any part thereof, is capable (alone or through reaction with other substance) of imparting color thereto; except that such term does not include any material which the Secretary [of the Department of Health and Human Services] by regulation, determines is used (or intended to be used) solely for a purpose or purposes other than coloring.

  2. 21 CFR 73, Subpart D and 21 CFR 74, Subpart D identifies all those color additives for which a color additive petition exists for use of the color in a medical device application. Not all of these color additives are included in the CHRIS calculator. Please see the instructions for how to use the calculator with a color additive other than those identified in the CHRIS calculator drop down menu.↩︎