updated info boxes and CoUs for v2 of the CA and bulk chemical modules

color2_module/static/COU.html

@@ -11,10 +11,10 @@
    <h1 style="text-align:center"><font color="#0070C0">CH</font>emical <font color="#0070C0">RIS</font>k calculator (CHRIS) - Color additives</h1>
 </header>
 <h2 id="context-of-use-cou">Context of Use (COU)</h2>
-<p>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)<a href="#fn1" class="footnote-ref" id="fnref1"
+<p>The CHRIS - Color additives module is intended 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
@@ -101,43 +101,20 @@ present (&lt;= 50x).</li>
 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
+specific exposure estimates for fifty (50) 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 &gt; 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 &lt; 100 g/mol, CHRIS currently
-cannot be used to estimate exposure.</p>
-<ul>
-<li>Silicone</li>
-<li>Polyethylene (density &lt;= 0.94 g/cm<sup>3</sup>)</li>
-<li>Polyethylene (density &gt; 0.94 g/cm<sup>3</sup>)</li>
-<li>Polyethylene terephthalate</li>
-<li>Polyurethane (polyether)</li>
-<li>Polycarbonate</li>
-<li>Polyoxymethylene</li>
-<li>Poly(methyl methacrylate)</li>
-<li>Acrylonitrile butadiene styrene</li>
-<li>Polyether block amide</li>
-<li>Polyamide</li>
-<li>Polystyrene</li>
-<li>Polyvinyl chloride</li>
-<li>Polytetrafluoroethylene</li>
-<li>Polypropylene</li>
-<li>Polyvinyl acetate</li>
-<li>Polybutylene terephthalate</li>
-<li>Polyetheretherketone</li>
-<li>Fluorinated ethylene propylene</li>
-</ul>
+than 2 % m/v of a given CA. To estimate CA release based on the model,
+the diffusion coefficient of the CA in the polymer matrix must be
+specified. For the fifty (50) 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 up to 1100 g/mol.
+Therefore, for substances with a molecular weight &gt; 1100 g/mol, the
+value of the diffusion coefficient assuming a molecular weight of 1100
+g/mol can be used as a conservative value.</p>
 <section id="footnotes" class="footnotes footnotes-end-of-document"
 role="doc-endnotes">
 <hr />

color2_module/static/COU.md

@@ -15,7 +15,7 @@
 
 ## Context of Use (COU)
 
-The CHRIS - Color additives module is (proposed to be) qualified to conduct screening level risk assessments 
+The CHRIS - Color additives module is intended 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 
@@ -50,27 +50,7 @@ The CHRIS - Color additives module provides clinically relevant, yet still conse
 1. The CA is homogeneously distributed throughout the polymer.
 1. 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.
-
-* Silicone
-* Polyethylene (density <= 0.94 g/cm<sup>3</sup>)
-* Polyethylene (density > 0.94 g/cm<sup>3</sup>)
-* Polyethylene terephthalate
-* Polyurethane (polyether)
-* Polycarbonate
-* Polyoxymethylene
-* Poly(methyl methacrylate)
-* Acrylonitrile butadiene styrene
-* Polyether block amide
-* Polyamide
-* Polystyrene
-* Polyvinyl chloride
-* Polytetrafluoroethylene
-* Polypropylene
-* Polyvinyl acetate
-* Polybutylene terephthalate
-* Polyetheretherketone
-* Fluorinated ethylene propylene
+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 fifty (50) polymeric systems that are generally biostable (non-swelling and non-degrading) and contain less than 2 % m/v of a given CA.  To estimate CA release based on the model, the diffusion coefficient of the CA in the polymer matrix must be specified.  For the fifty (50) 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 up 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.
 
 [^1]: The term "color additive", as defined under section 201(t) of the FD&C Act, means a material which:
  

color2_module/templates/color2_index.html

@@ -15,7 +15,7 @@
   <h1 style="text-align:center"><font color="#0070C0">CH</font>emical <font color="#0070C0">RIS</font>k calculators (CHRIS) - Color additives (v2)</h1>
 </header>
 
-<p> For details on how to use the CHRIS color additive module, please read the <a href="{{url_for('.static', filename='README.html')}}"> instructions</a> and
+<p> For details on how to use the CHRIS color additive module, please click the information icons next to each section header and read the
   <a href="{{url_for('.static', filename='COU.html')}}"> Context of Use (CoU)</a>, which includes limitations of use. Answers to frequently asked questions can be
   found <a href="{{url_for('.static', filename='FAQ.html')}}"> here</a>. For a history of updates, please see the <a href="{{url_for('.static', filename='Changelog.html')}}"> changelog</a>. </p>
 
@@ -79,9 +79,14 @@ $(window).on('pageshow', function() { caCheck(); });
       </div>
       <div class="modal-body">
         <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  "Other color additive" and ...
+          If the color additive is not explicitly listed, please choose "Other color additive".  For the latter case, two additional input fields
+          will be visible.  Please select the identifier type and enter the chemical identifier. For example, if the CAS number is known,
+          select CAS from the pull down menu and enter the CAS number in the identifier field. If the CAS number is unknown,
+          CHRIS can identify the molecular structure through the SMILES code, which can be found for many chemicals using <a href="https://pubchem.ncbi.nlm.nih.gov">PubChem</a> or generated based on
+            the molecular structure using tools such as <a href="https://cactus.nci.nih.gov/cgi-bin/osra/index.cgi">OSRA</a>.
+            Alternatively, CHRIS can attempt to identify the chemical using a common name for the chemical.
           If you are evaluating an additive associated with a color additive please select "Other color additive associated compound" and
-          enter the chemical name and molecular weight ...
+          follow the same procedure for "Other color additive".
         <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>
       </div>

exposure2_module/static/exposure_COU.html

@@ -14,16 +14,16 @@
 </header>
 <h2 id="context-of-use-cou">Context of Use (COU)</h2>
 <p>The bulk leachable module of the CHemical RISk calculator (CHRIS) is
-(proposed to be) qualified to conduct screening level risk assessments
-to aid in the biocompatibility evaluation of bulk additives and
-impurities in polymeric medical device components. These assessments can
-assist device manufacturers by providing instantaneous feedback on
-whether the presence of the bulk chemical 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 bulk chemical
-contained within a polymeric medical device component. Based on the MOS
-value, the calculator determines if further assessment of one or more
+intended to conduct screening level risk assessments to aid in the
+biocompatibility evaluation of bulk additives and impurities in
+polymeric medical device components. These assessments can assist device
+manufacturers by providing instantaneous feedback on whether the
+presence of the bulk chemical 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 bulk chemical 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 specific chemical.</p>
 <p>Because CHRIS only addresses compounds with a distribution that is
 macroscopically homogeneous within the matrix, the tool can only be used
@@ -59,43 +59,19 @@ much smaller than the smallest component dimension (&lt;= 50x).</li>
 impurities in biostable polymers, users of CHRIS 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). These polymers are listed below. To estimate chemical
-release based on the model, the diffusion coefficient of the chemical 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 molecular weight, has been established based on data from
-the literature. For polymer matrices that are not included in this list,
+only enables system specific exposure estimates for fifty (50) polymeric
+systems that are generally biostable (non-swelling and non-degrading).
+These polymers are listed below. To estimate chemical release based on
+the model, the diffusion coefficient of the chemical in the polymer
+matrix must be specified. For the fifty (50) listed polymeric systems, a
+worst-case (upper bound) diffusion coefficient, as a function of
+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
-&gt; 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 &lt; 100 g/mol, CHRIS currently
-cannot be used to estimate exposure.</p>
-<ul>
-<li>Silicone</li>
-<li>Polyethylene (density &lt;= 0.94 g/cm<sup>3</sup>)</li>
-<li>Polyethylene (density &gt; 0.94 g/cm<sup>3</sup>)</li>
-<li>Polyethylene terephthalate</li>
-<li>Polyurethane (polyether)</li>
-<li>Polycarbonate</li>
-<li>Polyoxymethylene</li>
-<li>Poly(methyl methacrylate)</li>
-<li>Acrylonitrile butadiene styrene</li>
-<li>Polyether block amide</li>
-<li>Polyamide</li>
-<li>Polystyrene</li>
-<li>Polyvinyl chloride</li>
-<li>Polytetrafluoroethylene</li>
-<li>Polypropylene</li>
-<li>Polyvinyl acetate</li>
-<li>Polybutylene terephthalate</li>
-<li>Polyetheretherketone</li>
-<li>Fluorinated ethylene propylene</li>
-</ul>
+the polymer has the properties of water. up to 1100 g/mol. Therefore,
+for substances with a molecular weight &gt; 1100 g/mol, the value of the
+diffusion coefficient assuming a molecular weight of 1100 g/mol can be
+used as a conservative value.</p>
 <p>In the absence of adequate toxicological and exposure data for a
 chemical in a polymeric matrix, a toxicological risk assessment can be
 conducted for systemic biocompatibility endpoints by comparing the

exposure2_module/static/exposure_COU.md

@@ -17,7 +17,7 @@
 
 ## Context of Use (COU)
 
-The bulk leachable module of the CHemical RISk calculator (CHRIS) is (proposed to be) qualified to conduct screening level risk assessments to aid in the biocompatibility evaluation of bulk additives and impurities in polymeric medical device components.  These assessments can assist device manufacturers by providing instantaneous feedback on whether the presence of the bulk chemical 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 bulk chemical 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 specific chemical.
+The bulk leachable module of the CHemical RISk calculator (CHRIS) is intended to conduct screening level risk assessments to aid in the biocompatibility evaluation of bulk additives and impurities in polymeric medical device components.  These assessments can assist device manufacturers by providing instantaneous feedback on whether the presence of the bulk chemical 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 bulk chemical 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 specific chemical.
 
 Because CHRIS only addresses compounds with a distribution that is macroscopically homogeneous within the matrix, the tool can only be used to assess bulk additives and impurities.  Therefore, only compounds that are introduced either intentionally or unintentionally during synthesis (e.g., residual monomers and oligomers, catalysts, initiators) or compounding (e.g., stabilizers, antioxidants, plasticizers) are within scope.  Surface residuals from processing, cleaning, and sterilization are excluded.  Also, CHRIS requires the total amount of the chemical to be established in advance, e.g., based on a certificate of analysis. Further CHRIS only addresses individual chemicals; therefore, 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.  
 
@@ -28,26 +28,6 @@ CHRIS provides clinically relevant, yet still conservative, exposure dose estima
 1. The total amount of the chemical is present in dilute concentrations (<= 2 m/v %).
 1. Any particles/aggregates of the chemical present in the polymer are much smaller than the smallest component dimension (<= 50x).
 
-While these assumptions are typically valid for bulk additives and impurities in biostable polymers, users of CHRIS 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).  These polymers are listed below.  To estimate chemical release based on the model, the diffusion coefficient of the chemical 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 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.
-
-* Silicone
-* Polyethylene (density <= 0.94 g/cm<sup>3</sup>)
-* Polyethylene (density > 0.94 g/cm<sup>3</sup>)
-* Polyethylene terephthalate
-* Polyurethane (polyether)
-* Polycarbonate
-* Polyoxymethylene
-* Poly(methyl methacrylate)
-* Acrylonitrile butadiene styrene
-* Polyether block amide
-* Polyamide
-* Polystyrene
-* Polyvinyl chloride
-* Polytetrafluoroethylene
-* Polypropylene
-* Polyvinyl acetate
-* Polybutylene terephthalate
-* Polyetheretherketone
-* Fluorinated ethylene propylene
+While these assumptions are typically valid for bulk additives and impurities in biostable polymers, users of CHRIS 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 fifty (50) polymeric systems that are generally biostable (non-swelling and non-degrading).  These polymers are listed below.  To estimate chemical release based on the model, the diffusion coefficient of the chemical in the polymer matrix must be specified.  For the fifty (50) listed polymeric systems, a worst-case (upper bound) diffusion coefficient, as a function of 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.  up 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.
 
 In the absence of adequate toxicological and exposure data for a chemical in a polymeric matrix, a toxicological risk assessment can be conducted for systemic biocompatibility endpoints by comparing the exposure estimate to an appropriate threshold of toxicological concern (TTC).  This is the approach used by CHRIS in this module. The TTC values are based on systemic toxicity, thus 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 chemical will not raise a safety concern with respect to only the systemic biocompatibility endpoints, provided the chemical is not within the cohort of concern, which is reflected in the output of CHRIS.