post impurity level edits

static/COU.html

@@ -6,7 +6,7 @@
 <li>obviate the need for additional biocompatibility testing when existing biocompatibility testing is inconclusive with respect to a CA. For example, the when biocompatibility extracts are colored, yet pass the testing (note that the presence of colored extracts may give rise to additional concerns unrelated to the color additive);</li>
 <li>reduce the amount of biocompatibility testing needed for product lines with devices that are identical (<em>i.e.</em> materials and processing) with the exception of the presence and type of CA.</li>
 </ul>
-<p>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 (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 &gt;= 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 devices<a href="#fn2" class="footnote-ref" id="fnref2" role="doc-noteref"><sup>2</sup></a>:</p>
+<p>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 &gt;= 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 devices<a href="#fn2" class="footnote-ref" id="fnref2" role="doc-noteref"><sup>2</sup></a>:</p>
 <ul>
 <li>Titanium dioxide - CAS #13463-67-7</li>
 <li>Carbon black - CAS #1333-86-4</li>

static/FAQ.html

@@ -13,7 +13,7 @@
 <p>[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. http://dx.doi.org/10.1080/105172301316871626.</p>
 <p>[5] Schneider, K., et al., 2009. "ToxRTool", a new tool to assess the reliability of toxicological data. Toxicol. Lett. 189, 138e144. http://dx.doi.org/10.1016/j.toxlet.2009.05.013.</p>
 <h2 id="how-does-chris-deal-with-color-additive-impurities">How does CHRIS deal with color additive impurities?</h2>
-<p>For any impurities present, users should first conduct a separate assessment using the tool for each impurity. If the impurities are unknown, the total amount of impurities associated with the color additive can be compared to the relevant TTC value. Second, the user should 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:</p>
+<p>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:</p>
 <ul>
 <li>Titanium dioxide (CAS#:13463-67-7) - <a href="https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-73/subpart-D/section-73.3126">21 CFR 73.3126</a> (medical devices); <a href="https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-73/subpart-A/section-73.575">21 CFR 73.575</a> (foods)</li>
 <li>Carbon black (CAS#:1333-86-4) - <a href="https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-74/subpart-D/section-74.3054">21 CFR 178.3297</a> (indirect food substances); <a href="https://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-178/subpart-D/section-178.3297">21 CFR 21 CFR 74.3054</a> (medical devices)</li>

static/README.html

@@ -22,9 +22,10 @@
 <h2 id="usage">Usage</h2>
 <p>The user inputs the following information into CHRIS: (a) the identity, molecular weight (for unlisted compounds), and amount, (b) the identity, mass, and (approximate) density of the polymer matrix, and (c) three (2) medical device characteristics. The required information is described in detail below:</p>
 <h3 id="color-additive">Color additive</h3>
-<p><em>Identity</em> - Select the color additive in the component being evaluated via the pull down list. If the color additive is not explicitly listed, please choose either “Other metal oxide color additive” or “Other non-metal oxide color additive” and enter the chemical name, including CAS # if known. If “Other non-metal oxide color additive” is selected, please enter the molecular weight of the color additive in grams per mole. If you are evaluating an additive or impurity associated with a color additive please select “Other compound (non-color additive)” and enter the chemical name and molecular weight. Note that the CHRIS is limited to color additive associated substances with molecular weight between 100 and 1100 g/mol. For compounds with molecular weight &gt; 1100 g/mol, this value can be used for a conservative exposure estimate.</p>
+<p><em>Identity</em> - Select the color additive in the component being evaluated via the pull down list. If the color additive is not explicitly listed, please choose either “Other metal oxide color additive” or “Other non-metal oxide color additive” and enter the chemical name, including CAS # if known. If “Other non-metal oxide color additive” is selected, please enter the molecular weight of the color additive in grams per mole. If you are evaluating an additive associated with a color additive please select “Other compound (non-color additive)” and enter the chemical name and molecular weight. Note that the CHRIS is limited to color additive associated substances with molecular weight between 100 and 1100 g/mol. For compounds with molecular weight &gt; 1100 g/mol, this value can be used for a conservative exposure estimate.</p>
 <p><em>Molecular weight</em> - Enter the molecular weight of the substance in grams per mole.</p>
 <p><em>Amount</em> - Enter the total mass of the substance in the component being evaluated expressed in milligrams.</p>
+<p><em>Total impurity concentration</em> - If you have selected a color additive, please enter the combined concentration of all impurities associated with the color additive as a percentage (% mass/mass).</p>
 <h3 id="polymer-matrix">Polymer matrix</h3>
 <p><em>Matrix</em> - Please select your polymer matrix from the list. If your polymer is not listed below, please select “Other polymer”. For polymer mixtures/blends, co-polymers, or composites (e.g. glass fiber reinforced matrices), the component or phase that is worst-case for exposure, i.e. the softest or least glassy (lowest Tg) component can be selected if listed (which, in turn, assumes the entire system is composed of the worst-case component or phase). In these scenarios, a justification should be provided for the choice of worst-case component of the polymer system.</p>
 <p><em>Mass</em> - Enter the mass of the polymer matrix in grams.</p>
@@ -35,7 +36,7 @@
 <h3 id="conformance-to-assumptions">Conformance to Assumptions</h3>
 <p>The exposure model relies on assumptions that are typically valid for bulk solutes in polymeric device components. However, if any of the assumptions are violated the exposure calculation may not remain protective. Therefore, if the output of CHRIS is used to support a submission to CDRH, users must confirm conformance to the underlying assumptions or provide supporting justification. Examples of considerations when confirming conformance are provided below:</p>
 <p><em>Biostability of the matrix</em> - While many of the matrices listed within CHRIS will not appreciably swell or degrade in any physiological environment, this can not be generalized. For example, silicones may swell in lipid-rich environments. Chemical compatibility of the polymer matrix with the use environment can be assessed based on historical use and/or evaluation of swelling and/or degradation propensity in physiologically relevant media.</p>
-<p><em>Particle/aggregate size and distribution</em> - CHRIS relies on the color additive having a distribution that is macroscopically homogeneous within the matrix; thus, any particles or aggregates must be small relative to the component and homogeneously distributed. This can be confirmed/justified through the use of particle coatings and/or dispersants in the concentrate to prevent aggregation and promote homogeneity, macroscopic observations of color uniformity, and/or microscopic observations to evaluate the potential for surface segregation phenomena, such as blooming.</p>
+<p><em>Particle/aggregate size and distribution</em> - CHRIS relies on the color additive having a distribution that is macroscopically homogeneous within the matrix (e.g. CAs used for surface marking would be excluded); thus, any particles or aggregates must be small relative to the component and homogeneously distributed. This can be confirmed/justified through the use of particle coatings and/or dispersants in the concentrate to prevent aggregation and promote homogeneity, macroscopic observations of color uniformity, and/or microscopic observations to evaluate the potential for surface segregation phenomena, such as blooming.</p>
 <p><em>Dilute concentration</em> - The model relies on a concentration independent diffusion coefficient, which assumes any color additives are present only in dilute quantities. Confirming that the total amount of color additives present is ≤ 2 m/v % is sufficient to conform with this assumption. It may be possible to justify that the CHRIS calculation for a dilute compound will remain protective if the total concentration is in excess of 2 m/v %, if the presence of additional compound could reasonably be expected to inhibit rather than promote diffusion, e.g. second phase particulates.</p>
 <p><em>Matrix stability</em> - The model parameters/transport properties are established using worst-case values reported in the literature. However, it is unclear if the reported values account for potential degradation (e.g. during sterilization) or other physicochemical changes (e.g. excessive plasticization) that may occur during manufacturing and negatively impact these values. Polymer stability can be confirmed/justified by evidence supporting that manufacturing (including sterilization) does not alter the matrix material of the final device.</p>
 <h3 id="exposure-assessment">Exposure Assessment</h3>
@@ -44,6 +45,7 @@
 <li><p>Exposure estimation - including the model equations and parameters used in the calculation</p></li>
 <li><p>Assumptions - a summary of compliance (or lack thereof) to the assumptions underlying the exposure model.</p></li>
 <li><p>Screening level toxicological risk assessment - A summary of the screening level TRA including calculated margin of safety including any important additional considerations regarding the analysis.</p></li>
+<li><p>Color additive impurities risk assessment (if applicable) - A summary of a screening level TRA comparing the total amount of impurities to the appropriate TTC value.</p></li>
 </ol>
 <h2 id="further-information">Further information</h2>
 <p>The answers to many frequently asked questions can be found <a href="FAQ.html">here</a>. If your question is not already addressed or if you have specific issues with CHRIS, please contact Dave Saylor: <a href="mailto:david.saylor@fda.hhs.gov" class="email">david.saylor@fda.hhs.gov</a>.</p>