updated md files with header

static/COU.html

@@ -1,9 +1,14 @@
-<h1 id="context-of-use-cou">Context of Use (COU)</h1>
-<p>The Color Hazard and RISk calculator (CHRIS) 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)<a href="#fn1" class="footnote-ref" id="fnref1" role="doc-noteref"><sup>1</sup></a>. 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 of CHRIS 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.</p>
+
+<header>
+   <h1 style="text-align:center"><font color="#0070C0">C</font>olor <font color="#0070C0">H</font>azard and <font color="#0070C0">RIS</font>k calculator (CHRIS) </h1>
+</header>
+<h2 id="context-of-use-cou">Context of Use (COU)</h2>
+<p>The Color Hazard and RISk calculator (CHRIS) 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)<a href="#fn1" class="footnote-ref" id="fnref1" role="doc-noteref"><sup>1</sup></a>.<br />
+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 of CHRIS 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.</p>
 <p>Because CHRIS only addresses CAs, a favorable outcome by CHRIS 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, CHRIS can potentially be used to:</p>
 <ul>
 <li>reduce the amount of biocompatibility testing needed following a supplier or manufacturing changes related to only the presence of the CA in the device;</li>
-<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>obviate the need for additional biocompatibility testing when existing biocompatibility testing is inconclusive with respect to a CA. For example, 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, 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>

static/COU.md

@@ -1,5 +1,11 @@
+```{=html}
 
-# Context of Use (COU)
+<header>
+   <h1 style="text-align:center"><font color="#0070C0">C</font>olor <font color="#0070C0">H</font>azard and <font color="#0070C0">RIS</font>k calculator (CHRIS) </h1>
+</header>
+```
+
+## Context of Use (COU)
 
 The Color Hazard and RISk calculator (CHRIS) 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].  

static/FAQ.html

@@ -1,18 +1,22 @@
-<h1 id="frequently-asked-questions">Frequently asked questions</h1>
-<h2 id="what-is-the-primary-purpose-of-chris">What is the primary purpose of CHRIS?</h2>
+
+<header>
+   <h1 style="text-align:center"><font color="#0070C0">C</font>olor <font color="#0070C0">H</font>azard and <font color="#0070C0">RIS</font>k calculator (CHRIS) </h1>
+</header>
+<h2 id="frequently-asked-questions">Frequently asked questions</h2>
+<h3 id="what-is-the-primary-purpose-of-chris">What is the primary purpose of CHRIS?</h3>
 <p>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 &lt; 1), device specific evaluation of the substance should be conducted.</p>
-<h2 id="how-can-chris-be-used-in-a-regulatory-context">How can CHRIS be used in a regulatory context?</h2>
+<h3 id="how-can-chris-be-used-in-a-regulatory-context">How can CHRIS be used in a regulatory context?</h3>
 <p>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 <a href="https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm348890.pdf">FDA biocompatibility guidance</a>); (3) a completely independent risk assessment that uses no component/output of CHRIS.</p>
-<h2 id="does-chris-address-all-biological-endpoints">Does CHRIS address all biological endpoints?</h2>
+<h3 id="does-chris-address-all-biological-endpoints">Does CHRIS address all biological endpoints?</h3>
 <p>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.</p>
-<h2 id="how-are-the-exposure-calculations-done">How are the exposure calculations done?</h2>
+<h3 id="how-are-the-exposure-calculations-done">How are the exposure calculations done?</h3>
 <p>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].</p>
 <p>[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.</p>
-<h2 id="where-do-the-color-additive-tolerable-intake-values-come-from">Where do the color additive tolerable intake values come from?</h2>
+<h3 id="where-do-the-color-additive-tolerable-intake-values-come-from">Where do the color additive tolerable intake values come from?</h3>
 <p>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. For details on the procedures and data used to derive the TI values, the complete toxicological profiles can be found <a href="ToxProfiles.pdf">here</a>.</p>
 <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>
+<h3 id="how-does-chris-deal-with-color-additive-impurities">How does CHRIS deal with color additive impurities?</h3>
 <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>
@@ -30,7 +34,7 @@
 <li>Use information from a material supplier (e.g., certificate of analysis) or analytical chemistry to determine the level of an impurity, AND</li>
 <li>Derive a chemical-specific tolerable intake for each impurity and justify that the level in your device will be acceptable.</li>
 </ul>
-<h2 id="what-constitutes-an-impurity">What constitutes an "impurity"?</h2>
+<h3 id="what-constitutes-an-impurity">What constitutes an "impurity"?</h3>
 <p>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.</p>
-<h2 id="what-about-other-additives-contained-in-a-color-additive-or-concentrate">What about other additives contained in a color additive or concentrate?</h2>
+<h3 id="what-about-other-additives-contained-in-a-color-additive-or-concentrate">What about other additives contained in a color additive or concentrate?</h3>
 <p>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.</p>

static/FAQ.md

@@ -1,25 +1,32 @@
-# Frequently asked questions
+```{=html}
 
-## What is the primary purpose of CHRIS?
+<header>
+   <h1 style="text-align:center"><font color="#0070C0">C</font>olor <font color="#0070C0">H</font>azard and <font color="#0070C0">RIS</font>k calculator (CHRIS) </h1>
+</header>
+```
+
+## 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?
+### 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 &#34;passes&#34;, 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 &#34;pass&#34;, 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](https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm348890.pdf)); (3) a completely independent risk assessment that uses no component/output of CHRIS.
 
-## Does CHRIS address all biological endpoints? 
+### 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?
+### 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?
+### 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. For details on the procedures and data used to derive the TI values, the complete toxicological profiles can be found [here](ToxProfiles.pdf).
 
@@ -27,7 +34,7 @@ Provisional tolerable intake values (TIs) were derived for color additives commo
 
 [5] Schneider, K., et al., 2009. &#34;ToxRTool&#34;, 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.
 
-## How does CHRIS deal with color additive impurities? 
+### 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:
 
@@ -47,11 +54,11 @@ If the total amount of impurities exceeds the relevant CFR listing and/or TTC va
 * Use information from a material supplier (e.g., certificate of analysis) or analytical chemistry to determine the level of an impurity, AND
 * Derive a chemical-specific tolerable intake for each impurity and justify that the level in your device will be acceptable.
 
-## What constitutes an &#34;impurity&#34;?
+### What constitutes an &#34;impurity&#34;?
 
 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?
+### 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.  
 

static/README.html

@@ -1,4 +1,7 @@
-<h1 id="color-hazard-and-risk-calculator-chris">Color Hazard and RISk calculator (CHRIS)</h1>
+
+<header>
+   <h1 style="text-align:center"><font color="#0070C0">C</font>olor <font color="#0070C0">H</font>azard and <font color="#0070C0">RIS</font>k calculator (CHRIS) </h1>
+</header>
 <h2 id="overview">Overview</h2>
 <p>The Color Hazard and RISk calculator (CHRIS) is a tool under development within the Center for Devices and Radiological Health (CDRH) at the Food and Drug Administration (FDA). The tool enables the user to perform rapid, screening level toxicological risk assessments of color additives and additives and impurities associated with the color additive that might be released from a polymer medical device component. CHRIS applies a model that computes an exposure estimate and compares the result to a tolerable exposure (TE) or threshold of toxicological concern (TTC) value. The tool assists the user in determining (a) whether the toxicological risk of a color additive associated substance should be further assessed and/or (b) the potential impact of the substance on device biocompatibility.</p>
 <p><strong>Disclaimer: CHRIS only addresses risk associated with the presence of color additives and additives and impurities associated with the color additive. Therefore, a favorable outcome by CHRIS does not imply acceptable biological risk for the final finished form of a medical device. Further, a successful CHRIS evaluation does not address local biocompatibility endpoints, and therefore additional testing may be needed despite a positive outcome from CHRIS. Because there may be additional restrictions based on specific device guidance and code of federal regulation (CFR) listings, users should also review the relevant documents for their device type and color additive.</strong></p>

static/README.md

@@ -1,4 +1,9 @@
-# Color Hazard and RISk calculator (CHRIS)
+```{=html}
+
+<header>
+   <h1 style="text-align:center"><font color="#0070C0">C</font>olor <font color="#0070C0">H</font>azard and <font color="#0070C0">RIS</font>k calculator (CHRIS) </h1>
+</header>
+```
 
 ## Overview