made assumptions consistent across pages

color2_module/static/COU.html

@@ -86,10 +86,12 @@ 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:</p>
+based on five (5) primary assumptions:</p>
 <ol type="1">
 <li>The polymer does not swell or degrade in-vivo, nor does the presence
 of CA impact the integrity of the polymer.</li>
+<li>Manufacturing processes do not impact the stability of the
+polymer.</li>
 <li>The total amount of CA is present in dilute concentrations (&lt;= 2
 % m/v) within the colored component.</li>
 <li>The CA is homogeneously distributed throughout the polymer.</li>
@@ -101,26 +103,26 @@ 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 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 &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"
+specific exposure estimates for fifty-three (53) 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-three (53) 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 class="footnotes footnotes-end-of-document"
 role="doc-endnotes">
 <hr />
 <ol>
-<li id="fn1"><p>The term “color additive”, as defined under section
-201(t) of the FD&amp;C Act, means a material which:</p>
+<li id="fn1" role="doc-endnote"><p>The term “color additive”, as defined
+under section 201(t) of the FD&amp;C Act, means a material which:</p>
 <ol type="A">
 <li><p>is a dye, pigment, or other substance made by a process of
 synthesis or similar artifice, or extracted, isolated, or otherwise
@@ -135,13 +137,13 @@ intended to be used) solely for a purpose or purposes other than
 coloring.</p></li>
 </ol>
 <a href="#fnref1" class="footnote-back" role="doc-backlink">↩︎</a></li>
-<li id="fn2"><p>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 <a
-href="README.html">instructions</a> for how to use the calculator with a
-color additive other than those identified in the CHRIS calculator drop
-down menu.<a href="#fnref2" class="footnote-back"
-role="doc-backlink">↩︎</a></p></li>
+<li id="fn2" role="doc-endnote"><p>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 <a href="README.html">instructions</a> for
+how to use the calculator with a color additive other than those
+identified in the CHRIS calculator drop down menu.<a href="#fnref2"
+class="footnote-back" role="doc-backlink">↩︎</a></p></li>
 </ol>
 </section>

color2_module/static/COU.md

@@ -44,14 +44,15 @@ In the absence of adequate toxicological and exposure data for a CA (or associat
 * Ultramarine blue - CAS #57455-37-5
 * Pigment Yellow 138 - CAS # 30125-47-4
 
-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:
+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 five (5) primary assumptions:
 
 1. The polymer does not swell or degrade in-vivo, nor does the presence of CA impact the integrity of the polymer.
+1. Manufacturing processes do not impact the stability of the polymer. 
 1. The total amount of CA is present in dilute concentrations (<= 2 % m/v) within the colored component.
 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 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.
+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-three (53) 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-three (53) 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

@@ -172,10 +172,10 @@ Density (g/cm<sup>3</sup>): <input name="density" id="density" step="any" value=
   <h3> Assumptions <button type=button class="Info_btn" data-toggle="modal" data-target="#AssumeModal">&#9432;</button> </h3>
   Check all statements below that are applicable to your color additive containing component:<br><br>
   <input type="checkbox" id="assume1" name="assume1" > The clinical use environment does not cause the polymer matrix to swell or degrade.<br>
-  <input type="checkbox" id="assume2" name="assume2" > Color additive particles/aggregates present in the polymer are much smaller than the smallest component dimension (&le; 50x). <br>
+  <input type="checkbox" id="assume2" name="assume2" > Manufacturing processes do not impact the stability of the polymer. <br>
   <input type="checkbox" id="assume3" name="assume3" > The color additive is homogeneously distributed throughout the polymer. <br>
   <input type="checkbox" id="assume4" name="assume4" > The total amount of color additive is present in dilute concentrations (&le; 2 m/v %). <br>
-  <input type="checkbox" id="assume5" name="assume5" > Manufacturing processes do not impact the stability of the polymer. <br>
+  <input type="checkbox" id="assume5" name="assume5" > Color additive particles/aggregates present in the polymer are much smaller than the smallest component dimension (&le; 50x). <br>
 
   <!-- Modal -->
 <div id="AssumeModal" class="modal fade" role="dialog">

color2_module/templates/color2_report.html

@@ -128,8 +128,7 @@ In addition to the maximum daily (day 1) release rate, it can be helpful to exam
 {% endif %}
 
 {% if not assume[1] %}
-<font color="red"> &bull; Any color additive particles/aggregates are much smaller than the smallest component dimension
-    (&le; 50x). <br> </font>
+<font color="red"> &bull; Manufacturing processes do not impact the integrity of the polymer.  <br> </font>
 {% endif %}
 
 {% if not assume[2] %}
@@ -141,9 +140,11 @@ In addition to the maximum daily (day 1) release rate, it can be helpful to exam
 {% endif %}
 
 {% if not assume[4] %}
-<font color="red"> &bull; Manufacturing processes do not impact the integrity of the polymer.  <br> </font>
+<font color="red"> &bull; Any color additive particles/aggregates are much smaller than the smallest component dimension
+    (&le; 50x). <br> </font>
 {% endif %}
 
+
 {% endif %}
 
 <h2> Screening level toxicological risk assessment </h2>

exposure2_module/static/exposure_COU.html

@@ -43,11 +43,13 @@ requirements.</p>
 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
+substance from the polymer matrix and is based on five (5) primary
 assumptions:</p>
 <ol type="1">
 <li>The clinical use environment does not cause the polymer matrix to
 swell or degrade.</li>
+<li>Manufacturing processes do not impact the stability of the
+polymer.</li>
 <li>The chemical is homogeneously distributed throughout the
 polymer.</li>
 <li>The total amount of the chemical is present in dilute concentrations
@@ -59,17 +61,18 @@ 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 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,
+only enables system specific exposure estimates for fifty-three (53)
+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-three (53) 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. CHRIS was parameterized for
-solutes up to 1100 g/mol. For substances with a molecular weight &gt;
+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>
 <p>In the absence of adequate toxicological and exposure data for a

exposure2_module/static/exposure_COU.md

@@ -21,13 +21,14 @@ The bulk leachable module of the CHemical RISk calculator (CHRIS) is intended to
 
 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.  
 
-CHRIS 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:
+CHRIS 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 five (5) primary assumptions:
 
 1. The clinical use environment does not cause the polymer matrix to swell or degrade.
+1. Manufacturing processes do not impact the stability of the polymer. 
 1. The chemical is homogeneously distributed throughout the polymer.
 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 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 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.
+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-three (53) 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-three (53) 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 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. 

exposure2_module/templates/exposure2_index.html

@@ -145,10 +145,10 @@ Density (g/cm<sup>3</sup>): <input name="density" id="density" step="any" value=
   <h3> Assumptions <button type=button class="Info_btn" data-toggle="modal" data-target="#AssumeModal">&#9432;</button> </h3>
   Check all statements below that are applicable to the component being evaluated:<br><br>
   <input type="checkbox" id="assume1" name="assume1" > The clinical use environment does not cause the polymer matrix to swell or degrade.<br>
-  <input type="checkbox" id="assume2" name="assume2" > Any particles/aggregates of the chemical present in the polymer are much smaller than the smallest component dimension (&le; 50x). <br>
+  <input type="checkbox" id="assume2" name="assume2" > Manufacturing processes do not impact the stability of the polymer. <br>
   <input type="checkbox" id="assume3" name="assume3" > The chemical is homogeneously distributed throughout the polymer. <br>
   <input type="checkbox" id="assume4" name="assume4" > The total amount of the chemical is present in dilute concentrations (&le; 2 m/v %). <br>
-  <input type="checkbox" id="assume5" name="assume5" > Manufacturing processes do not impact the stability of the polymer. <br>
+  <input type="checkbox" id="assume5" name="assume5" > Any particles/aggregates of the chemical present in the polymer are much smaller than the smallest component dimension (&le; 50x). <br>
 
   <!-- Modal -->
 <div id="AssumeModal" class="modal fade" role="dialog">

exposure2_module/templates/exposure2_report.html

@@ -124,7 +124,7 @@ In addition to the maximum daily (day 1) release rate, it can be helpful to exam
 {% endif %}
 
 {% if not assume[1] %}
-<font color="red"> &bull; Any particles/aggregates of the chemical are much smaller than the smallest component dimension (&le; 50x). <br> </font>
+<font color="red"> &bull; Manufacturing processes do not impact the integrity of the polymer.  <br> </font>
 {% endif %}
 
 {% if not assume[2] %}
@@ -136,7 +136,7 @@ In addition to the maximum daily (day 1) release rate, it can be helpful to exam
 {% endif %}
 
 {% if not assume[4] %}
-<font color="red"> &bull; Manufacturing processes do not impact the integrity of the polymer.  <br> </font>
+<font color="red"> &bull; Any particles/aggregates of the chemical are much smaller than the smallest component dimension (&le; 50x). <br> </font>
 {% endif %}
 
 {% endif %}