added color3

color3_module/__init__.py

@@ -0,0 +1,5 @@
+from flask import Blueprint
+
+blueprint = Blueprint('color3_module', __name__, template_folder='templates', static_folder='static', static_url_path='/color3_module')
+
+from . import colors

color3_module/colors.py

@@ -0,0 +1,178 @@
+import sys
+from flask import Flask, render_template, request
+import numpy as np
+from functions import SigFigs, Piringer, WilkeChang, SheetRelease, SheetRates, RatePlot
+from functions import Piecewise, PowerLaw
+from . import blueprint
+from polymers import Polymers, Polymers3
+from ChemID import ResolveChemical, ImageFromSmiles, Imageto64
+import rdkit
+from rdkit.Chem import AllChem as Chem
+
+# get additional physical properties, options are: logp, rho, mp
+#get_properties = [] # don't get any; this breaks ceramics logic
+#get_properties = ['logp','rho','mp'] # get all three
+get_properties = ['mp'] # only get mp
+# show additional physical properties
+show_properties = False
+# output additional info for physical properties
+debug = False
+
+ORGANIC_ATOM_SET = {5, 6, 7, 8, 9, 15, 16, 17, 35, 53}
+METAL_ATOM_SET = set([3,4,11,12,13] + list(range(19,31+1)) + list(range(37,50+1)) + list(range(55,84+1)) + list(range(87,114+1)) + [116])
+
+# load polymer data including Ap values
+polymers, categories, params = Polymers3()
+
+# Named color additives, TI values, and Mw
+nCA = 13
+caData = np.zeros((nCA,), dtype=[('name', 'a75'), ('TI', 'd'), ('MW', 'd'),('CAS', 'a75')])
+caData[0] = ('Titanium dioxide (CAS#:13463-67-7)', 1.0, 1100., '13463-67-7')
+caData[1] = ('Carbon black (CAS#:1333-86-4)', 2.0, 1100., '1333-86-4')
+caData[2] = ('Pigment brown 24 (CAS#:68186-90-3)', 0.5, 1100., '68186-90-3')
+caData[3] = ('Zinc Oxide (CAS#:1314-13-2)', 0.05, 1100., '1314-13-2')
+caData[4] = ('Pigment Red 101 (CAS#: 1309-37-1)', 1.0, 1100., '1309-37-1')
+caData[5] = ('Solvent violet 13 (CAS#:81-48-1)', 0.0013, 319.4, '81-48-1')
+caData[6] = ('Manganese phthalocyanine (CAS#:14325-24-7)', 0.15, 567.5, '14325-24-7')
+caData[7] = ('Pigment blue 15 (CAS#:147-14-8)', 0.15, 576.1, '147-14-8')
+caData[8] = ('Phthalocyanine green (CAS#:1328-53-6)', 0.15, 1092.8, '1328-53-6')
+caData[9] = ('Ultramarine blue (CAS#:57455-37-5)', 3.3, 1100., '57455-37-5')
+caData[10] = ('Pigment Yellow 138 (CAS#:30125-47-4)', 1.0, 693.96, '30125-47-4')
+caData[11] = ('Other color additive', 1.0, 1100.0, ' ')
+caData[12] = ('Other color additive associated compound', 1.0, 1100.0, ' ')
+
+CAs = np.zeros(nCA, dtype='object')
+caMW = np.zeros(nCA, dtype='object')
+for i in range(nCA):
+    CAs[i] = caData[i][0].decode('UTF-8')
+for i in range(nCA):
+    caMW[i] = caData[i][2]
+
+app = Flask(__name__)
+app.debug = False
+
+
+@blueprint.route('/color3', methods=['GET'])
+def colors():
+    return render_template('color3_index.html', polymers=polymers, CAs=CAs, caMW=caMW)
+
+
+@blueprint.route('/color3', methods=['POST'])
+def app_post():
+
+    amount = float(request.form["amount"])
+    mass = float(request.form["mass"])
+    density = float(request.form["density"])
+    vol = mass / density
+    polymer = request.form["polymer"]
+    pIndex = (np.where(polymers == polymer)[0])[0]
+    area = float(request.form["area"])
+    exposure = request.form["exposure"]
+    CA = request.form["CA"]
+    caIndex = (np.where(CAs == CA)[0])[0]
+
+    TI = caData[caIndex][1]
+    impurity = 1.
+    isCA = True
+    chemName = ''
+
+    if caIndex <= 10:
+        IDtype = 'CAS'
+        chemName = caData[caIndex][3].decode('UTF-8')
+        impurity = float(request.form["impurity"]) * amount * 1e-2
+        # problems:
+        # o C.I. Pigment Brown 24 = 68186-90-3, kludge "works"
+        # o Manganese(II) phthalocyanine = 14325-24-7, kludge "works"
+        # o Phthalocyanine green = 1326-53-6 -> 1328-53-6, corrected CAS works
+        # o Ultramarine blue = 57445-37-5 -> 57455-37-5, corrected CAS works
+    if caIndex > 10:
+        chemName = request.form["chemName"]
+        IDtype = request.form["IDtype"]
+        impurity = float(request.form["impurity"]) * amount * 1e-2
+    if caIndex == 12:
+        isCA = False
+
+    iupac, cas, smiles, MW, LogP, rho, mp, molImage, error = ResolveChemical(chemName, IDtype, get_properties=get_properties)
+
+    if error > 0:
+        # TODO output more useful info
+        return render_template('chemError.html')
+
+    # metals/ceramics logic
+    ceramic = False
+    mol = Chem.MolFromSmiles(smiles)
+    atom_num_list = [a.GetAtomicNum() for a in mol.GetAtoms()]
+    is_metal = set(atom_num_list) <= METAL_ATOM_SET
+    if is_metal:
+        # if all atoms are metals -> this is a metal
+        return render_template('metalError.html', show_properties=show_properties, chemName=chemName, MW=MW,
+                               LogP=LogP, rho=rho, mp=mp, iupac=iupac,
+                               cas=cas, smiles=smiles, molImage=molImage)
+    else:
+        # get number of carbon-carbon bonds
+        num_CC_bonds = sum([1 if b.GetBeginAtom().GetAtomicNum() == 6 and b.GetEndAtom().GetAtomicNum() == 6 else 0 for b in mol.GetBonds()])
+        if not num_CC_bonds and (mp is not None) and mp > 700.:
+            # if not a metal, no C-C bonds, and mp > 700 (sodium chloride has mp ~ 800), assume ceramic...
+            MW = 1100.
+            ceramic = True
+
+    # Exposure type
+    if exposure != "limited":
+        time = 24.
+    else:
+        time = float(request.form["exptime"])
+
+    if exposure != "long-term":
+        TTC = 0.12
+    else:
+        TTC = 0.0015
+
+    use_qrf = False
+    if polymer == "Other polymer":
+        polytg = request.form["polytg"]
+        if polytg == '':
+            # left blank, use old default (Wilke Chang), which is taken care of by pIndex
+            pass
+        else:
+            polytg = float(polytg)
+            use_qrf = True
+        #print('b', polytg, type(polytg), file=sys.stderr)
+
+    if use_qrf:
+        #print('using qrf', file=sys.stderr)
+        if ceramic:
+            diff,domain_extrap = QRF_Ceramic(density, polytg, quantiles=[0.03,0.5,0.97])
+        else:
+            diff,domain_extrap = QRF_Apply(density, polytg, smiles, quantiles=[0.03,0.5,0.97])
+        diff = diff[2] # upper bound
+    else:
+        ## use categories
+        category = categories[pIndex]
+        diff = Piecewise(MW, params[category])
+        domain_extrap = False
+
+    release = SheetRelease(amount, vol, area, time, diff)
+
+    if caIndex > 10:
+        MOS = TTC / release
+    else:
+        MOS = 50. * TI / release
+
+    iMOS = TTC / impurity
+
+    release = SigFigs(release, 2)
+    MOS = SigFigs(MOS, 2)
+    diff = SigFigs(diff, 2)
+    iMOS = SigFigs(iMOS, 2)
+    impurity = SigFigs(impurity, 2)
+
+    # Generate the rate plot using matplotlib
+    tarray = np.arange(1., 31., 1.)
+    rates = SheetRates(amount, vol, area, tarray, diff)
+    pngImageB64String = RatePlot(tarray, rates)
+
+    return render_template('color3_report.html', caIndex=caIndex, TI=TI, isCA=isCA, show_properties=show_properties, polymers=polymers, pIndex=pIndex, release=release,
+                           area=area, vol=vol, amount=amount, diff=diff, time=time, exposure=exposure, TTC=TTC,
+                           MOS=MOS, chemName=chemName, image=pngImageB64String, MW=MW, LogP=LogP, rho=rho, mp=mp, iupac=iupac, cas=cas, smiles=smiles, molImage=molImage,
+                           ceramic=ceramic, impurity=impurity, iMOS=iMOS, domain_extrap=domain_extrap)
+

color3_module/static/COU.html

@@ -0,0 +1,149 @@
+<!DOCTYPE html>
+<html lang="en">
+<head>
+    <title>CHRIS-COU</title>
+    <link rel="stylesheet" href="styles.css">
+    <meta charset="UTF-8">
+    
+</head>
+
+<header>
+   <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 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
+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.</p>
+<p>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:</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, 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>
+<ul>
+<li>Titanium dioxide - CAS #13463-67-7</li>
+<li>Carbon black - CAS #1333-86-4</li>
+<li>Pigment brown 24 - CAS #68186-90-3</li>
+<li>Zinc Oxide - CAS #1314-13-2</li>
+<li>Pigment Red 101 - CAS #1309-37-1</li>
+<li>Solvent violet 13 - CAS #81-48-1</li>
+<li>Manganese phthalocyanine - CAS #14325-24-7</li>
+<li>Pigment blue 15 - CAS #147-14-8</li>
+<li>Phthalocyanine green - CAS #1328-53-6</li>
+<li>Ultramarine blue - CAS #57455-37-5</li>
+<li>Pigment Yellow 138 - CAS # 30125-47-4</li>
+</ul>
+<p>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:</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>
+<li>The smallest dimension of the colored device component is much
+greater than the size of any color additive particles that may be
+present (&lt;= 50x).</li>
+</ol>
+<p>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 &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 />
+<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>
+<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
+derived, with or without intermediate or final change of identity, from
+a vegetable, animal, mineral, or other source, and</p></li>
+<li><p>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.</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>
+</ol>
+</section>

color3_module/static/COU.md

@@ -0,0 +1,63 @@
+```{=html}
+<!DOCTYPE html>
+<html lang="en">
+<head>
+    <title>CHRIS-COU</title>
+    <link rel="stylesheet" href="styles.css">
+    <meta charset="UTF-8">
+    
+</head>
+
+<header>
+   <h1 style="text-align:center"><font color="#0070C0">CH</font>emical <font color="#0070C0">RIS</font>k calculator (CHRIS) - Color additives</h1>
+</header>
+```
+
+## Context of Use (COU)
+
+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 
+safety limit &#247; 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:
+
+* reduce the amount of biocompatibility testing needed following a supplier or manufacturing changes related to only the presence of the CA in the device;
+* 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);
+* reduce the amount of biocompatibility testing needed for product lines with devices that are identical (*i.e.* materials and processing) with the exception of the presence and type of CA.
+
+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 devices[^2]:
+
+* Titanium dioxide - CAS #13463-67-7
+* Carbon black - CAS #1333-86-4
+* Pigment brown 24 - CAS #68186-90-3
+* Zinc Oxide - CAS #1314-13-2
+* Pigment Red 101 - CAS #1309-37-1
+* Solvent violet 13 - CAS #81-48-1
+* Manganese phthalocyanine - CAS #14325-24-7
+* Pigment blue 15 - CAS #147-14-8
+* Phthalocyanine green - CAS #1328-53-6
+* 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 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-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:
+ 
+	A) 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
+ 
+	B) 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](README.html) for how to use the calculator with a color additive other than those identified in the CHRIS calculator drop down menu. 

color3_module/static/Changelog.html

@@ -0,0 +1,35 @@
+<!DOCTYPE html>
+<html lang="en">
+<head>
+    <title>CHRIS-COU</title>
+    <link rel="stylesheet" href="styles.css">
+    <meta charset="UTF-8">
+    
+</head>
+
+<header>
+   <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="change-log">Change Log</h2>
+<h3 id="version-1.1.2---2022-12-07">Version 1.1.2 - 2022-12-07</h3>
+<ul>
+<li>Added impurity evaluation for non-CA additives</li>
+<li>Fixed typos</li>
+</ul>
+<h3 id="version-1.1.1---2022-12-07">Version 1.1.1 - 2022-12-07</h3>
+<ul>
+<li>Modified header of the landing page</li>
+<li>Added contact information for suggested improvements</li>
+</ul>
+<h3 id="version-1.1---2022-09-26">Version 1.1 - 2022-09-26</h3>
+<ul>
+<li>Renamed “Color Hazard RISk calculator” to “CHemical RISk
+calculator”</li>
+<li>Color additive tool is now “CHemical RISk calculator - Color
+additives”</li>
+<li>Added landing page</li>
+</ul>
+<h3 id="version-1.0---2022-08-23">Version 1.0 - 2022-08-23</h3>
+<ul>
+<li>Original release</li>
+</ul>

color3_module/static/Changelog.md

@@ -0,0 +1,33 @@
+```{=html}
+<!DOCTYPE html>
+<html lang="en">
+<head>
+    <title>CHRIS-COU</title>
+    <link rel="stylesheet" href="styles.css">
+    <meta charset="UTF-8">
+    
+</head>
+
+<header>
+   <h1 style="text-align:center"><font color="#0070C0">CH</font>emical <font color="#0070C0">RIS</font>k calculator (CHRIS) - Color additives</h1>
+</header>
+```
+## Change Log
+
+### Version 1.1.2 - 2022-12-07
+* Added impurity evaluation for non-CA additives
+* Fixed typos
+
+### Version 1.1.1 - 2022-12-07
+* Modified header of the landing page
+* Added contact information for suggested improvements
+
+### Version 1.1 - 2022-09-26
+
+* Renamed "Color Hazard RISk calculator" to "CHemical RISk calculator"
+* Color additive tool is now "CHemical RISk calculator - Color additives"
+* Added landing page
+
+### Version 1.0 - 2022-08-23
+
+* Original release

color3_module/static/FAQ.html

@@ -0,0 +1,187 @@
+<!DOCTYPE html>
+<html lang="en">
+<head>
+    <title>CHRIS-FAQ</title>
+    <link rel="stylesheet" href="styles.css">
+    <meta charset="UTF-8">
+</head>
+
+<header>
+   <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="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>
+<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>
+<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>
+<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>
+<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.</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>
+<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>
+<li>Carbon black (CAS#:1333-86-4) - <a
+href="https://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-178/subpart-D/section-178.3297">21
+CFR 178.3297</a> (indirect food substances); <a
+href="https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-74/subpart-D/section-74.3054">21
+CFR 21 CFR 74.3054</a> (medical devices)</li>
+<li>Pigment brown 24 (CAS#:68186-90-3) - <a
+href="https://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-178/subpart-D/section-178.3297">21
+CFR 178.3297</a> (indirect food substances)</li>
+<li>Zinc Oxide (CAS#:1314-13-2) - <a
+href="https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-73/subpart-B/section-73.1991">21
+CFR 73.1991</a> (drugs); <a
+href="https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-73/subpart-C/section-73.2991">21
+CFR 73.2991</a> (cosmetics)</li>
+<li>Pigment Red 101 (CAS#: 1309-37-1) - <a
+href="https://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-186/subpart-B/section-186.1374">21
+CFR 186.1374</a> (indirect food substances)</li>
+<li>Pigment blue 15 (CAS#:147-14-8) - <a
+href="https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-74/subpart-D/section-74.3045">21
+CFR 74.3045</a> (medical devices)</li>
+<li>Phthalocyanine green (CAS#:1326-53-6) - <a
+href="https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-73/subpart-D/section-73.3124">21
+CFR 73.3124</a> (medical devices)</li>
+<li>Pigment Yellow 138 (CAS#:30125-47-4) - <a
+href="https://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-178/subpart-D/section-178.3297">21
+CFR 178.3297</a> (indirect food substances)</li>
+</ul>
+<p>NOTE: some color additives included in CHRIS do not have CFR listings
+as of 26 October 2021.</p>
+<p>If the total amount of impurities exceeds the relevant CFR listing
+and/or TTC value, one can:</p>
+<ul>
+<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>
+<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>
+<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>
+<h3
+id="what-if-i-have-suggestions-for-inclusion-of-additional-cas-or-polymer-matrices-within-chris-or-changes-to-the-user-interface">What
+if I have suggestions for inclusion of additional CAs or polymer
+matrices within CHRIS or changes to the user interface?</h3>
+<p>If you have a suggestion to expand the applicability of the tool or
+improve the user interface, please contact Dave Saylor: <a
+href="mailto:david.saylor@fda.hhs.gov"
+class="email">david.saylor@fda.hhs.gov</a>.</p>

color3_module/static/FAQ.md

@@ -0,0 +1,74 @@
+```{=html}
+<!DOCTYPE html>
+<html lang="en">
+<head>
+    <title>CHRIS-FAQ</title>
+    <link rel="stylesheet" href="styles.css">
+    <meta charset="UTF-8">
+</head>
+
+<header>
+   <h1 style="text-align:center"><font color="#0070C0">CH</font>emical <font color="#0070C0">RIS</font>k calculator (CHRIS) - Color additives</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?
+
+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? 
+
+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?
+
+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?
+
+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. 
+
+[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.
+
+[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? 
+
+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:
+
+* Titanium dioxide (CAS#:13463-67-7) - [21 CFR 73.3126](https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-73/subpart-D/section-73.3126) (medical devices); [21 CFR 73.575](https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-73/subpart-A/section-73.575) (foods)
+* Carbon black (CAS#:1333-86-4) - [21 CFR 178.3297](https://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-178/subpart-D/section-178.3297) (indirect food substances); [21 CFR 21 CFR 74.3054](https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-74/subpart-D/section-74.3054) (medical devices)
+* Pigment brown 24 (CAS#:68186-90-3) - [21 CFR 178.3297](https://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-178/subpart-D/section-178.3297) (indirect food substances)
+* Zinc Oxide (CAS#:1314-13-2) - [21 CFR 73.1991](https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-73/subpart-B/section-73.1991) (drugs); [21 CFR 73.2991](https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-73/subpart-C/section-73.2991) (cosmetics)
+* Pigment Red 101 (CAS#: 1309-37-1) - [21 CFR 186.1374](https://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-186/subpart-B/section-186.1374) (indirect food substances)
+* Pigment blue 15 (CAS#:147-14-8) - [21 CFR 74.3045](https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-74/subpart-D/section-74.3045) (medical devices)
+* Phthalocyanine green (CAS#:1326-53-6) - [21 CFR 73.3124](https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-73/subpart-D/section-73.3124) (medical devices)
+* Pigment Yellow 138 (CAS#:30125-47-4) - [21 CFR 178.3297](https://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-178/subpart-D/section-178.3297) (indirect food substances)
+
+NOTE:  some color additives included in CHRIS do not have CFR listings as of 26 October 2021.
+
+If the total amount of impurities exceeds the relevant CFR listing and/or TTC value, one can:
+
+* 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;?
+
+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?
+
+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.  
+
+### What if I have suggestions for inclusion of additional CAs or polymer matrices within CHRIS or changes to the user interface?
+
+If you have a suggestion to expand the applicability of the tool or improve the user interface, please contact Dave Saylor: <david.saylor@fda.hhs.gov>.

color3_module/static/README.html

@@ -0,0 +1,185 @@
+<!DOCTYPE html>
+<html lang="en">
+<head>
+    <title>CHRIS-README</title>
+    <link rel="stylesheet" href="styles.css">
+    <meta charset="UTF-8">
+</head>
+
+<header>
+   <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="overview">Overview</h2>
+<p>The CHRIS - Color additives module 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>
+<h2 id="important-considerations">Important considerations</h2>
+<ol type="1">
+<li><p>CHRIS assists in screening the potential risk of a color additive
+associated substance in a polymer medical device component. Because
+color additives and concentrates may contain multiple distinct
+substances, e.g. impurities and carrier resins, CHRIS can be used to
+evaluate each substance present in the component individually.</p></li>
+<li><p>If a color additive associated substance is present in multiple
+polymer medical device components, CHRIS will not screen the potential
+risk of the substance from all the polymer components that contain it.
+CHRIS exposure estimates from each component may be manually summated to
+estimate total exposure to each substance and manually compared to the
+TE or TTC for that substance.</p></li>
+<li><p>If the substance levels present in the device are unknown, the
+calculator currently cannot be used to screen the risk associated with
+the respective compound(s).</p></li>
+<li><p>CHRIS cannot be used to screen the potential risk of polymer
+medical device components that contact the body by the inhalation
+route.</p></li>
+<li><p>The exposure model employed by CHRIS assumes a plane sheet
+geometry as worst-case. This assumption should be valid for most medical
+device components; however, potential exceptions exist. Specifically,
+this assumption can underestimate exposure when the geometry of the
+exposed surface area is concave, e.g., body contact is limited to the
+lumen of a catheter. When the exposed surface area is concave,
+underestimating exposure can be mitigated by assuming the patient will
+be exposed to all surfaces of the component, i.e., exposed surface area
+= total component surface area.</p></li>
+</ol>
+<h2 id="assumptions">Assumptions</h2>
+<p>In addition to plane sheet geometry, four additional assumptions were
+made in the derivation of the exposure model, which include:</p>
+<ol type="1">
+<li>The polymer does not swell or degrade in-vivo.</li>
+<li>The smallest dimension of the colored component is much greater than
+the size of any color additive particles that may be present (&gt;=
+50x).</li>
+<li>The color additive is homogeneously distributed throughout the
+polymer</li>
+<li>The total amount of color additive is present in dilute
+concentrations (&lt;= 2 %) within the colored component</li>
+</ol>
+<p>It is important that your colored polymer component complies with the
+above assumptions so that a conservative exposure estimate is
+computed.</p>
+<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 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>
+<p><em>Density</em> - Enter the estimated density of the polymer matrix
+in grams per cubic centimeter. Note that a rough estimate (e.g., +/-
+10%) is acceptable.</p>
+<h3 id="device-characteristics">Device characteristics</h3>
+<p><em>Exposed surface area</em> - Enter the patient contacting surface
+area of the color additive containing component being evaluated in
+square centimeters. This includes both direct and indirect patient
+contact.</p>
+<p><em>Exposure type</em> - Select the appropriate exposure category:
+&gt; 30 days = long-term, &gt; 24 hours - 30 days = prolonged, ≤ 24
+hours = limited. For limited exposures (≤ 24 hours), please enter the
+maximum exposure time in hours.</p>
+<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 (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>
+<p>Once the fields described have been populated for the polymeric
+component being evaluated, click the <strong>Estimate exposure</strong>
+button. The risk assessment output includes the following
+information:</p>
+<ol type="1">
+<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>

color3_module/static/README.md

@@ -0,0 +1,98 @@
+```{=html}
+<!DOCTYPE html>
+<html lang="en">
+<head>
+    <title>CHRIS-README</title>
+    <link rel="stylesheet" href="styles.css">
+    <meta charset="UTF-8">
+</head>
+
+<header>
+   <h1 style="text-align:center"><font color="#0070C0">CH</font>emical <font color="#0070C0">RIS</font>k calculator (CHRIS) - Color additives</h1>
+</header>
+```
+
+## Overview
+
+The CHRIS - Color additives module 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.
+
+## Important considerations
+
+(1) CHRIS assists in screening the potential risk of a color additive associated substance in a polymer medical device component. Because color additives and concentrates may contain multiple distinct substances, e.g. impurities and carrier resins, CHRIS can be used to evaluate each substance present in the component individually.
+
+(2) If a color additive associated substance is present in multiple polymer medical device components, CHRIS will not screen the potential risk of the substance from all the polymer components that contain it. CHRIS exposure estimates from each component may be manually summated to estimate total exposure to each substance and manually compared to the TE or TTC for that substance. 
+
+(3) If the substance levels present in the device are unknown, the calculator currently cannot be used to screen the risk associated with the respective compound(s).
+
+(4) CHRIS cannot be used to screen the potential risk of polymer medical device components that contact the body by the inhalation route.
+
+(5) The exposure model employed by CHRIS assumes a plane sheet geometry as worst-case. This assumption should be valid for most medical device components; however, potential exceptions exist. Specifically, this assumption can underestimate exposure when the geometry of the exposed surface area is concave, e.g., body contact is limited to the lumen of a catheter. When the exposed surface area is concave, underestimating exposure can be mitigated by assuming the patient will be exposed to all surfaces of the component, i.e., exposed surface area = total component surface area.
+
+## Assumptions
+
+In addition to plane sheet geometry, four additional assumptions were made in the derivation of the exposure model, which include: 
+
+1. The polymer does not swell or degrade in-vivo.
+2. The smallest dimension of the colored component is much greater than the size of any color additive particles that may be present (>= 50x).
+3. The color additive is homogeneously distributed throughout the polymer
+4. The total amount of color additive is present in dilute concentrations (<= 2 %) within the colored component
+
+It is important that your colored polymer component complies with the above assumptions so that a conservative exposure estimate is computed.
+
+## Usage
+
+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:
+
+### Color additive
+
+*Identity* - 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 > 1100 g/mol, this value can be used for a conservative exposure estimate.
+
+*Molecular weight* - Enter the molecular weight of the substance in grams per mole.
+
+*Amount* - Enter the total mass of the substance in the component being evaluated expressed in milligrams.
+
+*Total impurity concentration* - 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).
+
+### Polymer matrix
+
+*Matrix* - 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.
+
+*Mass* - Enter the mass of the polymer matrix in grams.
+
+*Density* - Enter the estimated density of the polymer matrix in grams per cubic centimeter. Note that a rough estimate (e.g., +/- 10%) is acceptable.
+
+### Device characteristics
+
+*Exposed surface area* - Enter the patient contacting surface area of the color additive containing component being evaluated in square centimeters. This includes both direct and indirect patient contact.
+
+*Exposure type* - Select the appropriate exposure category: > 30 days = long-term, > 24 hours - 30 days = prolonged, &#8804; 24 hours = limited. For limited exposures (&#8804; 24 hours), please enter the maximum exposure time in hours.
+
+### Conformance to Assumptions
+
+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:
+
+*Biostability of the matrix* - 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.
+
+*Particle/aggregate size and distribution* - 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.
+
+*Dilute concentration* - 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.
+
+*Matrix stability* - 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.
+
+### Exposure Assessment
+
+Once the fields described have been populated for the polymeric component being evaluated, click the **Estimate exposure** button. The risk assessment output includes the following information:
+
+(1) Exposure estimation - including the model equations and parameters used in the calculation
+
+(2) Assumptions - a summary of compliance (or lack thereof) to the assumptions underlying the exposure model.
+
+(3) 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.
+
+(4) 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.
+
+## Further information
+
+The answers to many frequently asked questions can be found [here](FAQ.html).  If your question is not already addressed or if you have specific issues with CHRIS, please contact Dave Saylor: <david.saylor@fda.hhs.gov>.
+
+

color3_module/static/md2html.sh

@@ -0,0 +1,7 @@
+#!/bin/bash
+
+pandoc FAQ.md > FAQ.html
+pandoc README.md > README.html
+pandoc COU.md > COU.html
+pandoc Changelog.md > Changelog.html
+

color3_module/static/styles.css

@@ -0,0 +1,42 @@
+body {font-family: Arial, Helvetica, sans-serif;}
+
+/* The Modal (background) */
+.modal {
+    display: none; /* Hidden by default */
+    position: fixed; /* Stay in place */
+    z-index: 1; /* Sit on top */
+    padding-top: 100px; /* Location of the box */
+    left: 0;
+    top: 0;
+    width: 100%; /* Full width */
+    height: 100%; /* Full height */
+    max-height: calc(100vh - 210px);
+    overflow: auto; /* Enable scroll if needed */
+    background-color: rgb(0,0,0); /* Fallback color */
+    background-color: rgba(0,0,0,0.4); /* Black w/ opacity */
+}
+
+/* Modal Content */
+.modal-content {
+    background-color: #fefefe;
+    margin: auto;
+    padding: 20px;
+    border: 1px solid #888;
+    width: 80%;
+}
+
+/* The Close Button */
+.close {
+    color: #aaaaaa;
+    float: right;
+    font-size: 28px;
+    font-weight: bold;
+}
+
+.close:hover,
+.close:focus {
+    color: #000;
+    text-decoration: none;
+    cursor: pointer;
+}
+

color3_module/templates/chemError.html

@@ -0,0 +1,24 @@
+<!DOCTYPE html>
+<html lang="en">
+<head>
+    <meta charset="UTF-8">
+    <title>CHRIS-ChemError</title>
+    <link rel= "stylesheet" type= "text/css" href= "{{ url_for('static',filename='styles.css') }}">
+
+</head>
+
+<img src="{{ url_for('static',filename='images/FDAlogo.png') }}" style="float: left;" height="100"/>
+<img src="{{ url_for('static',filename='images/FDAgraphic.png') }}" style="float: right;"  height="100"/>
+<br clear="all" />
+
+<body>
+
+<div style="font-size:5rem;text-align:center"> &#129318; </div>
+
+<p style="font-size:2rem;text-align:center">
+    Uh-oh! Something went wrong. We were unable to match your chemical.  Please return to the previous page and try a
+    different identifier.
+</p>
+
+
+</body>

color3_module/templates/color3_index.html

@@ -0,0 +1,212 @@
+<!DOCTYPE html>
+<html lang="en">
+<head>
+    <meta charset="UTF-8">
+    <title>CHRIS</title>
+  <script src="https://cdn.jsdelivr.net/npm/jquery@3.5.1/dist/jquery.slim.min.js" integrity="sha384-DfXdz2htPH0lsSSs5nCTpuj/zy4C+OGpamoFVy38MVBnE+IbbVYUew+OrCXaRkfj" crossorigin="anonymous"></script>
+  <script src="https://cdn.jsdelivr.net/npm/popper.js@1.16.1/dist/umd/popper.min.js" integrity="sha384-9/reFTGAW83EW2RDu2S0VKaIzap3H66lZH81PoYlFhbGU+6BZp6G7niu735Sk7lN" crossorigin="anonymous"></script>
+  <script src="https://cdn.jsdelivr.net/npm/bootstrap@4.6.1/dist/js/bootstrap.min.js" integrity="sha384-VHvPCCyXqtD5DqJeNxl2dtTyhF78xXNXdkwX1CZeRusQfRKp+tA7hAShOK/B/fQ2" crossorigin="anonymous"></script>
+
+  <link rel= "stylesheet" type= "text/css" href= "{{ url_for('static',filename='styles.css') }}">
+
+</head>
+
+<header>
+  <h1 style="text-align:center"><font color="#0070C0">CH</font>emical <font color="#0070C0">RIS</font>k calculators (CHRIS) - Color additives (v3)</h1>
+</header>
+
+<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>
+
+<body>
+
+<form method="POST">
+
+<!-- Color additive input section -->
+
+<h3> Color additive <button type="button" class="Info_btn" data-toggle="modal" data-target="#LeachModal" >&#9432;</button> </h3>
+
+Identity: <select name="CA" id="CA" onchange="javascript:caCheck();">
+  <option value="{{CAs[0]}}" selected>{{CAs[0]}}</option>
+  {% for CA in CAs[1:] %}
+    <option value="{{CA}}">{{CA}}</option>
+  {% endfor %}
+</select> 
+<span id="otherID" style="display:none">
+    &nbsp; &rArr; Identifier type: <select name="IDtype">
+    <option value="CAS" selected>CAS</option>
+    <option value="SMILES" >SMILES</option>
+    <option value="common" >Common name</option>
+  </select>
+  Identifier: <input name="chemName" id="chemName" type="text" value="">
+  </span> <br>
+
+Amount (mg): <input name="amount" id="amount" value="1.0" step="any" min="0.000001" type="number" required> <br>
+
+Total impurity concentration (%): <input name="impurity" id="impurity" value="0.1" step="any" min="0.000001" max='100.0' type="number" required> <br>
+
+<!-- Javascript to reveal/hide CA selection box -->
+
+<script type="text/javascript">
+
+function caCheck() {
+    var iCA = parseInt(document.getElementById("CA").selectedIndex);
+
+    document.getElementById('impurity').disabled = false;
+
+    if (iCA >= 11) {
+      document.getElementById('otherID').style.display = "inline";
+      document.getElementById('chemName').value = "";
+      document.getElementById('chemName').required = true;
+    } else {
+      document.getElementById('otherID').style.display = "none";
+      document.getElementById('chemName').required = false;
+    }
+}
+
+$(window).on('pageshow', function() { caCheck(); });
+</script>
+
+<!-- Modal -->
+<div id="LeachModal" class="modal fade" role="dialog">
+  <div class="modal-dialog">
+
+    <!-- Modal content-->
+    <div class="modal-content">
+      <div class="modal-header">
+        <h4 class="modal-title">Color additive</h4>
+      </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".  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
+          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>
+      <div class="modal-footer">
+        <button type="button" class="btn btn-default" data-dismiss="modal">Close</button>
+      </div>
+    </div>
+
+  </div>
+</div>
+
+<!-- Polymer matrix input section -->
+
+<h3> Polymer matrix <button type="button" class="Info_btn" data-toggle="modal" data-target="#PolymerModal">&#9432;</button> </h3>
+Matrix: <select name="polymer" id="polymer" onchange="javascript:polymerCheck();">
+  <option value="{{polymers[0]}}" selected>{{polymers[0]}}</option>
+  {% for polymer in polymers[1:] %}
+    <option value="{{polymer}}">{{polymer}}</option>
+  {% endfor %}
+</select> <br>
+Mass (g): <input name="mass" id="mass" step="any" value="1.0" min="0.000001" type="number" required> <br>
+Density (g/cm<sup>3</sup>): <input name="density" id="density" step="any" value="1.0" min="0.01" type="number" required>
+<span id="otherpolymer" style="visibility:hidden">
+<br>Glass transition temperature (&deg;C): <input name="polytg" id="polytg" step="any" min="-273.15" max="500" value="" type="number">
+</span>
+
+<!-- Modal -->
+<div id="PolymerModal" class="modal fade" role="dialog">
+  <div class="modal-dialog">
+
+    <!-- Modal content-->
+    <div class="modal-content">
+      <div class="modal-header">
+        <h4 class="modal-title">Polymer Matrix</h4>
+      </div>
+      <div class="modal-body">
+        <p><em>Matrix</em> - Please select your polymer matrix from the list.  If your polymer is
+        not listed below, please select &#34;Other polymer&#34;.  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 T<sub>g</sub>) 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> 
+        <p><em>Density</em> - Enter the estimated density of the polymer matrix in grams per cubic centimeter. Note that a rough estimate (e.g. +/- 10%) is acceptable.</p> 
+        <p><em>Glass transition temperature</em> - For &#34;Other polymer&#34;, optionally enter the T<sub>g</sub> of the polymer matrix in degrees Celsius to use a less conservative model. If left blank, a more conservative model is used.</p>
+      </div>
+      <div class="modal-footer">
+        <button type="button" class="btn btn-default" data-dismiss="modal">Close</button>
+      </div>
+    </div>
+
+  </div>
+</div>
+
+<!-- Device characteristics input section -->
+
+  <h3> Device characteristics <button type=button class="Info_btn" data-toggle="modal" data-target="#DeviceModal">&#9432;</button> </h3>
+  Exposed surface area (cm<sup>2</sup>):
+  <input name="area" id="area" step="any" value="5.0" min="0.001" type="number" required><br>
+  Exposure type: 
+  <input type="radio" name="exposure" id="long-term" value="long-term" onclick="javascript:exposureCheck();" checked > long-term
+  <input type="radio" name="exposure" id="prolonged" value="prolonged" onclick="javascript:exposureCheck();" > prolonged
+  <input type="radio" name="exposure" id="limited" value="limited" onclick="javascript:exposureCheck();" > limited 
+  <span id="limitedtime" style="visibility:hidden">
+    &nbsp; &rArr; Exposure time (h): <input name="exptime" id="time" step="any" min="0.001" max="24" value="24" type="number" required><br>
+  </span>
+
+<!-- Modal -->
+<div id="DeviceModal" class="modal fade" role="dialog">
+  <div class="modal-dialog">
+
+    <!-- Modal content-->
+    <div class="modal-content">
+      <div class="modal-header">
+        <h4 class="modal-title">Device characteristics</h4>
+      </div>
+      <div class="modal-body">
+        <p><em>Exposed surface area</em> - Enter the patient contacting surface area of the color additive containing component being evaluated in square centimeters.  This includes both direct and indirect patient contact.</p>
+        <p><em>Exposure type</em> - Select the appropriate exposure category: > 30 days = long-term, > 24 hours - 30 days = prolonged, &#8804; 24 hours = limited.  For limited exposures (&#8804; 24 hours), please enter the maximum exposure time in hours.</p>
+      </div>
+      <div class="modal-footer">
+        <button type="button" class="btn btn-default" data-dismiss="modal">Close</button>
+      </div>
+    </div>
+
+  </div>
+</div>
+
+<h3> Exposure assessment </h3>
+Click to screen your device: <button type="submit">Estimate exposure</button>
+
+</form>
+
+
+<p id="TestingOutput"> </p>
+
+<!-- Javascript to reveal/hide polymer input box (show/hide Tg) -->
+
+<script type="text/javascript">
+function polymerCheck() {
+    if (document.getElementById('polymer').value == 'Other polymer') {
+        document.getElementById('otherpolymer').style.visibility = 'visible';
+    } else {
+        document.getElementById('otherpolymer').style.visibility = 'hidden';
+        document.getElementById('polytg').value = '';
+    }
+}
+$(window).on('pageshow', function() { polymerCheck(); });
+</script>
+
+<!-- Javascript to reveal/hide exposure time input box (limited contact) -->
+
+<script type="text/javascript">
+function exposureCheck() {
+    if (document.getElementById('limited').checked) {
+        document.getElementById('limitedtime').style.visibility = 'visible';
+    } else {
+        document.getElementById('limitedtime').style.visibility = 'hidden';
+        document.getElementById('time').value = '24';
+    }
+}
+$(window).on('pageshow', function() { exposureCheck(); });
+</script>
+
+
+</body>
+</html>

color3_module/templates/color3_report.html

@@ -0,0 +1,218 @@
+<!DOCTYPE html>
+<html lang="en">
+<head>
+    <meta charset="UTF-8">
+    <title>CHRIS Report</title>
+
+    <script src="https://polyfill.io/v3/polyfill.min.js?features=es6"></script>
+    <script id="MathJax-script" async src="https://cdn.jsdelivr.net/npm/mathjax@3/es5/tex-mml-chtml.js"></script>
+    <link rel= "stylesheet" type= "text/css" href= "{{ url_for('static',filename='styles.css') }}">
+
+    <style>
+    * {
+      box-sizing: border-box;
+    }
+
+    /* Create two equal columns that floats next to each other */
+    .column {
+      float: left;
+      width: 50%;
+      padding: 10px;
+      vertical-align: top;
+      align: center;
+    }
+
+    /* Clear floats after the columns */
+    .row:after {
+      content: "";
+      display: table;
+      clear: both;
+    }
+    </style>
+
+</head>
+
+<header>
+   <h1 style="text-align:center"><font color="#0070C0">CH</font>emical <font color="#0070C0">RIS</font>k calculators (CHRIS) Report - Color additives (v3)</h1>
+</header>
+
+<body>
+
+<p> The following report was generated using CHRIS-Color additives v.3.0 on
+<script> document.write(new Date().toLocaleDateString()); </script>.
+</p>
+
+<h2> Compound </h2>
+
+<div class="container">
+<div class="row">
+  <div class="column">
+      Input ::  {{chemName}} <br> <br>
+      IUPAC Name ::  {{iupac}} <br> <br>
+      CAS ::  {{cas}} <br> <br>
+      Molecular weight (g/mol) :: {{'%0.4f'%MW|float}}
+      {% if ceramic %} :: ceramic detected, assume maximum Mw {% endif %}
+      <br> <br>
+      {% if show_properties %}
+      LogKow :: {{LogP}}{{LogP_origin}}<br> <br>
+      Density (g/cm<sup>3</sup>) :: {{rho}}{{rho_origin}}<br> <br>
+      Melting point (&deg;C) :: {{mp}}{{mp_origin}}<br> <br>
+      {% endif %}
+      SMILES :: {{smiles}}
+  </div>
+  <div class="column">
+      <img src="{{molImage}}"/>
+  </div>
+</div>
+</div>
+
+{% if domain_extrap %}
+<font color="red"> Warning: This polymer/solute combination is outside the model's training domain, so the predicted diffusion coefficient may not be accurate. <br> </font>
+{% endif %}
+
+<h2>Exposure </h2>
+
+<p>
+<u> Diffusion calculation for leaching from {{polymers[pIndex]}} estimates a worst case single day
+    exposure = {{release}} mg. </u>
+<p>
+
+<p>
+This estimate was derived using solutions to the conservative plane sheet model for mass release, \( M \):
+
+\[
+M(\tau)= \left\{
+  \begin{array}{cr} 
+      2 M_0 \sqrt{\tau/\pi} & \tau \leq 0.2 \\
+      M_0\left(1-8 \exp\left[-\tau \pi^2/4 \right]/\pi^2\right) & \tau > 0.2
+      \end{array} \right.
+\] 
+
+where \( \tau= D t A^2 / V^2 \) and \( A \) and \( V \) are the surface area and volume of the polymer matrix,
+    respectively, \( M_0 \) is total mass initially contained in the polymer, \( D \) is a conservative estimate of
+    the diffusion coefficient of the leachable within the polymer matrix, and \( t \) is time.  Based on the input
+    provided, the calculation was based on the following values:
+</p>
+
+<p>
+\( A \) = {{area}} cm<sup>2</sup> <br>
+\( V \) = {{vol}} cm<sup>3</sup> <br>
+\( M_0 \) = {{amount}} mg <br>
+\( D \) = {{diff}} cm<sup>2</sup>/s <br>
+\( t \) = {{time}} h <br>
+<p>
+
+<p>
+In addition to the maximum daily (day 1) release rate, it can be helpful to examine the decay in release rate over time predicted by the model,
+    which is illustrated for the first 30 days of exposure in the plot below:
+</p>
+
+<img src="{{ image }}"/>
+
+<h2> Screening level toxicological risk assessment </h2>
+
+{% if caIndex > 10 %}
+
+<p>
+The threshold for toxicological concern (TTC) for {{exposure}} contact is {{TTC}} mg.  Based on the exposure estimation
+    this results in a margin of safety (MOS) of {{MOS}}.
+</p>
+
+{% if MOS >= 1 %}
+
+<p>
+<font color="green"> The MOS based on the mutagenic TTC is greater than one; therefore, no further analysis is needed
+    for systemic biocompatibility endpoints.  </font>
+</p>
+
+<p>
+<font color="red"> *Note*: This assessment assumes that {{chemName}} is not in the cohort of concern. </font>
+</p>
+
+{% else %}
+
+<p>
+<font color="red"> The MOS based on the mutagenic TTC is less than one; therefore, further analysis is needed to
+    address systemic biocompatibility endpoints.  For example, a compound specific tolerable intake value could be
+    independently derived and compared to the exposure estimate provided above.  </font>
+</p>
+
+{% endif %}
+
+{% else %}
+
+The tolerable intake value for your color additive is {{TI}} mg/kg/day.  Assuming a 50 kg patient, the tolerable
+exposure value would be {{50*TI}} mg/day.  Based on the exposure estimation this results in a margin of safety (MOS)
+of {{MOS}}.
+
+{% if MOS >= 1 %}
+
+<p>
+<font color="green"> The MOS based on the color additive specific TI is greater than one; therefore, no further analysis
+    is needed for systemic biocompatibility endpoints.  </font>
+</p>
+
+<p>
+<font color="red"> *Note*: This calculation assumes an adult patient population with a worst-case body weight of 50 kg.
+    If the intended patient population of your device is different, please adjust the tolerable exposure calculation
+    accordingly. </font>
+</p>
+
+{% else %}
+
+<p>
+<font color="red"> The MOS based on the color additive specific TI is less than one; therefore, further analysis is
+    needed to address systemic biocompatibility endpoints.   </font>
+</p>
+
+{% endif %}
+
+{% endif %}
+
+{% if isCA == true %}
+
+<p>
+<font color="red"> *Note*: This assessment assumes that the color additive complies with all relevant medical device
+    specific guidance documents and all relevant Code of Federal Regulations (CFR) color additive listings, if they
+    exist for the color additive.  Examples of CFR listings are provided in the
+    <a href="static/FAQ.html#how-does-chris-deal-with-color-additive-impurities" >FAQ</a>.</font>
+</p>
+
+{% endif %}
+
+<h2> Impurities </h2>
+
+{% if iMOS >= 1 %}
+
+<font color="green"> The total additive impurity level is {{impurity}} mg.  When compared to TTC this results in
+    an MOS = {{iMOS}}. Therefore, no further analysis is needed for the impact of impurities on systemic
+    biocompatibility endpoints. </font>
+
+<p>
+<font color="red"> *Note*: This assessment assumes that any impurities present are not in the cohort of concern. </font>
+</p>
+
+{% if isCA == true %}
+<p>
+<font color="red"> *Note*: Users should review and confirm compliance of impurity levels with any relevant Code of
+    Federal Regulations (CFR) listings as part of the submission package, i.e. in addition to any output of CHRIS.
+    A list of relevant CFR listings is provided
+    <a href="color_module/FAQ.html#how-does-chris-deal-with-color-additive-impurities" >here</a>.</font>
+</p>
+{% endif %}
+
+{% else %}
+
+<p>
+<font color="red"> The total additive impurity level is {{impurity}} mg.  When compared to TTC this results in
+    an MOS = {{iMOS}}. Therefore, further analysis is needed to address the impact of impurities on systemic
+    biocompatibility endpoints. Guidance on alternative methods to address impurities is provided
+    <a href="color_module/FAQ.html#how-does-chris-deal-with-color-additive-impurities" >here</a>. </font>
+</p>
+
+{% endif %}
+
+<button type="button" onclick="javascript:history.back()">Back</button>
+
+</body>
+</html>

color3_module/templates/metalError.html

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+<!DOCTYPE html>
+<html lang="en">
+<head>
+    <meta charset="UTF-8">
+    <title>CHRIS-ChemError</title>
+    <link rel= "stylesheet" type= "text/css" href= "{{ url_for('static',filename='styles.css') }}">
+
+    <style>
+    * {
+      box-sizing: border-box;
+    }
+
+    /* Create two equal columns that floats next to each other */
+    .column {
+      float: left;
+      width: 50%;
+      padding: 10px;
+      vertical-align: top;
+      align: center;
+    }
+
+    /* Clear floats after the columns */
+    .row:after {
+      content: "";
+      display: table;
+      clear: both;
+    }
+    </style>
+
+</head>
+
+<img src="{{ url_for('static',filename='images/FDAlogo.png') }}" style="float: left;" height="100"/>
+<img src="{{ url_for('static',filename='images/FDAgraphic.png') }}" style="float: right;"  height="100"/>
+<br clear="all" />
+
+<body>
+
+<div style="font-size:5rem;text-align:center"> &#129318; </div>
+
+<h2> Compound </h2>
+
+<div class="container">
+<div class="row">
+  <div class="column">
+      Input ::  {{chemName}} <br> <br>
+      IUPAC Name ::  {{iupac}} <br> <br>
+      CAS ::  {{cas}} <br> <br>
+      Molecular weight (g/mol) :: {{'%0.4f'%MW|float}} <br> <br>
+      {% if show_properties %} 
+      LogKow :: {{LogP}}{{LogP_origin}} <br> <br>
+      Density (g/cm<sup>3</sup>) :: {{rho}}{{rho_origin}} <br> <br>
+      Melting point (&deg;C) :: {{mp}}{{mp_origin}} <br> <br>
+      {% endif %}
+      SMILES :: {{smiles}}
+  </div>
+  <div class="column">
+      <img src="{{molImage}}"/>
+  </div>
+</div>
+</div>
+
+<p style="font-size:2rem;text-align:center">
+    Unfortunately, CHRIS cannot be used for metals.  Please return to the previous page to evaluate
+    a different chemical.
+</p>
+
+
+</body>