Q3D(R2) ELEMENTAL IMPURITIES Guidance for Industry U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) September 2022 ICH Revision 2 Q3D(R2) ELEMENTAL IMPURITIES Guidance for Industry Additional copies are available from: Office of Communications, Division of Drug Information Center for Drug Evaluation and Research Food and Drug Administration 10001 New Hampshire Ave., Hillandale Bldg., 4th Floor Silver Spring, MD 20993-0002 Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 Email: druginfo@fda.hhs.gov https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs and/or Office of Communication, Outreach and Development Center for Biologics Evaluation and Research Food and Drug Administration 10903 New Hampshire Ave., Bldg. 71, Room 3128 Silver Spring, MD 20993-0002 Phone: 800-835-4709 or 240-402-8010 Email: ocod@fda.hhs.gov https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) September 2022 ICH Revision 2 Contains Nonbinding Recommendations FOREWORD The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) has the mission of achieving greater regulatory harmonization worldwide to ensure that safe, effective, and high-quality medicines are developed, registered, and maintained in the most resource-efficient manner. By harmonizing the regulatory expectations in regions around the world, ICH guidelines have substantially reduced duplicative clinical studies, prevented unnecessary animal studies, standardized safety reporting and marketing application submissions, and contributed to many other improvements in the quality of global drug development and manufacturing and the products available to patients. ICH is a consensus-driven process that involves technical experts from regulatory authorities and industry parties in detailed technical and science-based harmonization work that results in the development of ICH guidelines. The commitment to consistent adoption of these consensus- based guidelines by regulators around the globe is critical to realizing the benefits of safe, effective, and high-quality medicines for patients as well as for industry. As a Founding Regulatory Member of ICH, the Food and Drug Administration (FDA) plays a major role in the development of each of the ICH guidelines, which FDA then adopts and issues as guidance to industry. Contains Nonbinding Recommendations TABLE OF CONTENTS I. INTRODUCTION (1) ....................................................................................................... 1 II. SCOPE (2).......................................................................................................................... 2 III. SAFETY ASSESSMENT OF POTENTIAL ELEMENTAL IMPURITIES (3) ......... 2 A. Principles of the Safety Assessment of Elemental Impurities for Oral, Parenteral and Inhalation Routes of Administration (3.1) ................................................................................... 3 B. Other Routes of Administration (3.2) .......................................................................................... 4 C. Justification for Elemental Impurity Levels Higher Than an Established PDE (3.3) ............. 4 D. Parenteral Products (3.4) .............................................................................................................. 5 IV. ELEMENT CLASSIFICATION (4) ............................................................................... 6 V. RISK ASSESSMENT AND CONTROL OF ELEMENTAL IMPURITIES (5) ........ 7 A. General Principles (5.1) ................................................................................................................. 7 B. Potential Sources of Elemental Impurities (5.2) .......................................................................... 8 C. Identification of Potential Elemental Impurities (5.3) ................................................................ 9 D. Recommendations for Elements To Be Considered in the Risk Assessment (5.4).................. 10 E. Evaluation (5.5) ............................................................................................................................ 11 F. Summary of Risk Assessment Process (5.6) ............................................................................... 12 G. Special Considerations for Biotechnologically-Derived Products (5.7) ................................... 13 VI. Control of Elemental Impurities (6) ........................................................................................... 13 VII. Converting Between PDEs and Concentration Limits (7)........................................................ 14 VIII. Speciation and Other Considerations (8) ................................................................................... 16 IX. Analytical Procedures (9) ............................................................................................................ 17 X. Lifecycle Management (10) ......................................................................................................... 17 REFERENCES .......................................................................................................................................... 22 Appendix 1: Method for Establishing Exposure Limits ........................................................................ 23 Appendix 2: Established PDEs for Elemental Impurities ..................................................................... 26 Appendix 3: Individual Safety Assessments ........................................................................................... 28 Appendix 4: Illustrative Examples .......................................................................................................... 82 Appendix 5: Limits for Elemental Impurities by the Cutaneous and Transcutaneous Route ... 90 TABLE OF CONTENTS ........................................................................................................ 90 I. BACKGROUND (1)........................................................................................................ 91 II. SCOPE (2) ....................................................................................................................... 92 i Contains Nonbinding Recommendations III. PRINCIPLES OF SAFETY ASSESSMENT FOR CUTANEOUS PRODUCTS (3) ........................................................................................................................................... 92 A. Transcutaneous Absorption of Elemental Impurities (EI) (3.1) .............................................. 92 B. PDE for Drug Products Directly Applied to the Dermis (3.2) ................................................. 93 IV. ESTABLISHING THE CUTANEOUS PERMITTED DAILY EXPOSURE (PDE) (4) ........................................................................................................................................... 93 A. Establishing the Cutaneous Modifying Factor (CMF) (4.1)..................................................... 93 B. Cutaneous PDE (4.2).................................................................................................................... 94 4.2.1 Derivation of PDE for EI, other than Arsenic (As) and Thallium (Tl) ............................... 94 4.2.2 Derivation of PDE for Arsenic.............................................................................................. 94 4.2.3 Derivation of PDE for Thallium ........................................................................................... 95 V. CUTANEOUS CONCENTRATION LIMITS FOR NI AND CO (5) ........................ 95 VI. PRODUCT RISK ASSESSMENT (6) ........................................................................... 95 VII. CUTANEOUS PDE VALUES (7).................................................................................. 96 VIII. REFERENCES (8) ......................................................................................................... 98 ii Contains Nonbinding Recommendations 1 Q3D(R2) ELEMENTAL IMPURITIES 2 Guidance for Industry1 3 4 5 This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 6 this topic. It does not establish any rights for any person and is not binding on FDA or the public. You 7 can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. 8 To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 9 title page. 10 11 12 13 I. INTRODUCTION (1) 2 14 15 Elemental impurities in drug products may arise from several sources; they may be residual 16 catalysts that were added intentionally in synthesis or may be present as impurities (e.g., through 17 interactions with processing equipment or container/closure systems or by being present in 18 components of the drug product). Because elemental impurities do not provide any therapeutic 19 benefit to the patient, their levels in the drug product should be controlled within acceptable limits. 20 There are three parts of this guidance: 21 22 • The evaluation of the toxicity data for potential elemental impurities 23 • The establishment of a Permitted Daily Exposure (PDE) for each element of toxicological 24 concern 25 • The application of a risk-based approach to control elemental impurities in drug products 26 27 An applicant is not expected to tighten the limits based on process capability, provided that the 28 elemental impurities in drug products do not exceed the PDEs. The PDEs established in this 29 guidance are considered to be protective of public health for all patient populations. In some 30 cases, lower levels of elemental impurities may be warranted when levels below toxicity 31 thresholds have been shown to have an impact on other quality attributes of the drug product 32 (e.g., element catalyzed degradation of drug substances). In addition, for elements with high 33 PDEs, other limits may have to be considered from a pharmaceutical quality perspective and 34 other guidances should be consulted such as the ICH guidance for industry Q3A(R2) Impurities 35 in New Drug Substances (June 2008) (ICH Q3A(R2)). 3 36 1 This guidance was developed within the Quality Expert Working of the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been endorsed by the ICH Assembly at Step 4 of the ICH process, April 26, 2022. At Step 4 of the process, the final draft is recommended for adoption to the regulatory bodies of the ICH regions. 2 The numbers in parentheses reflect the organizational breakdown of the document endorsed by the ICH Assembly at Step 4 of the ICH process, April 26, 2022. 3 See the ICH guidance for industry Q3A(R2) Impurities in New Drug Substances (June 2008). We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information 1 Contains Nonbinding Recommendations 37 This guidance presents a process to assess and control elemental impurities in the drug product 38 using the principles of risk management as described in the ICH guidance for industry Q9 39 Quality Risk Management (June 2006) (ICH Q9). 4 This process provides a platform for 40 developing a risk-based control strategy to limit elemental impurities in the drug product. 41 42 The contents of this document do not have the force and effect of law and are not meant to bind 43 the public in any way, unless specifically incorporated into a contract. This document is intended 44 only to provide clarity to the public regarding existing requirements under the law. FDA 45 guidance documents, including this guidance, should be viewed only as recommendations, unless 46 specific regulatory or statutory requirements are cited. The use of the word should in Agency 47 guidance means that something is suggested or recommended, but not required. 48 49 II. SCOPE (2) 50 51 The guidance applies to new finished drug products (as defined in the ICH guidances for 52 industry Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances 53 and New Drug Products: Chemical Substances (December 2000 (ICH Q6A) and Q6B 54 Substances: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products 55 (August 1999) (ICH Q6B) 5 and new drug products containing existing drug substances. The drug 56 products containing purified proteins and polypeptides (including proteins and polypeptides 57 produced from recombinant or non-recombinant origins), their derivatives, and products of 58 which they are components (e.g., conjugates) are within the scope of this guidance, as are drug 59 products containing synthetically produced polypeptides, polynucleotides, and oligosaccharides. 60 61 This guidance does not apply to herbal products, radiopharmaceuticals, vaccines, cell metabolites, 62 DNA products, allergenic extracts, cells, whole blood, cellular blood components or blood 63 derivatives including plasma and plasma derivatives, dialysate solutions not intended for 64 systemic circulation, and elements that are intentionally included in the drug product for 65 therapeutic benefit. This guidance does not apply to products based on genes (gene therapy), cells 66 (cell therapy) and tissue (tissue engineering). In some regions, these products are known as 67 advanced therapy medicinal products. 68 69 This guidance does not apply to drug products used during clinical research stages of 70 development. As the commercial process is developed, the principles contained in this guidance 71 can be useful in evaluating elemental impurities that may be present in a new drug product. 72 73 Application of Q3D to existing products is not expected prior to 36 months after publication of 74 the guidance by ICH. 75 76 III. SAFETY ASSESSMENT OF POTENTIAL ELEMENTAL IMPURITIES (3) 4 See the ICH guidance for industry Q9 Quality Risk Management (June 2006), available on the FDA guidance web page. 5 See the ICH guidances for industry Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (December 2000) and Q6B Substances: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products (August 1999), available on the FDA guidance web page. 2 Contains Nonbinding Recommendations 77 78 A. Principles of the Safety Assessment of Elemental Impurities for Oral, Parenteral 79 and Inhalation Routes of Administration (3.1) 80 81 The method used for establishing the PDE for each elemental impurity is discussed in detail in 82 Appendix 1. Elements evaluated in this guidance were assessed by reviewing the publicly 83 available data contained in scientific journals, government research reports and studies, 84 international regulatory standards (applicable to drug products) and guidance, and regulatory 85 authority research and assessment reports. This process follows the principles described in the ICH 86 guidance for industry Q3C Impurities: Residual Solvents (December 2017) (ICH Q3C). 6 The 87 available information was reviewed to establish the oral, parenteral and inhalation PDEs. For 88 practical purposes, the PDEs to be applied to the drug product that are presented in Appendix 2 89 Table A.2.1 have been rounded to 1 or 2 significant figures. 90 91 A summary safety assessment identifying the critical study for setting a PDE for each element is 92 included in Appendix 3. There are insufficient data to set PDEs by any route of administration 93 for iridium, osmium, rhodium, and ruthenium. The PDEs for these elements were established on 94 the basis of their similarity to palladium. 95 96 The factors considered in the safety assessment for establishing the PDE are listed below in 97 approximate order of relevance: 98 • The likely oxidation state of the element in the drug product 99 • Human exposure and safety data when it provided applicable information 100 • The most relevant animal study 101 • Route of administration 102 • The relevant endpoint(s) 103 104 Standards for daily intake for some of the elemental impurities discussed in this guidance exist for 105 food, water, air, and occupational exposure. Where appropriate, these standards were considered 106 in the safety assessment and establishment of the PDEs. 107 108 The longest duration animal study was generally used to establish the PDE. When a shorter 109 duration animal study was considered the most relevant, the rationale was provided in the 110 individual safety assessment. 111 112 Inhalation studies using soluble salts (when available) were preferred over studies using 113 particulates for inhalation safety assessment and derivation of inhalation PDEs. Depending on 114 available data, inhalation PDEs were based on either local (respiratory system) or systemic 115 toxicity. For PDEs established for inhalation (and oral or parenteral routes as applicable), doses 116 were normalized to a 24-hour, 7-day exposure. 117 6 See the ICH guidance for industry Q3C Impurities: Residual Solvents (December 1997), available on the FDA web page at Q8, Q9 and Q10 Questions and Answers (R4). 3 Contains Nonbinding Recommendations 118 In the absence of data and/or where data are available but not considered sufficient for a safety 119 assessment for the parenteral and or inhalation route of administration, modifying factors based 120 on oral bioavailability were used to derive the PDE from the oral PDE: 121 • Oral bioavailability <1%: divide by a modifying factor of 100 122 • Oral bioavailability ≥ 1% and <50%: divide by a modifying factor of 10 123 • Oral bioavailability ≥50% and <90%: divide by a modifying factor of 2 124 • Oral bioavailability ≥ 90%: divide by a modifying factor of 1 125 Where oral bioavailability data or occupational inhalation exposure limits were not available, a 126 calculated PDE was used based on the oral PDE divided by a modifying factor of 100 (Ref. 1). 127 128 B. Other Routes of Administration (3.2) 129 130 PDEs were established for oral, parenteral and inhalation routes of administration. In addition, 131 PDEs for the cutaneous and transcutaneous route of administration are provided in Appendix 5. 132 When PDEs are necessary for other routes of administration, the concepts described in this 133 guidance may be used to derive PDEs. An assessment may either increase or decrease an 134 established PDE. The process of derivation of the PDE for another route of administration may 135 include the following: 136 • Consider the oral PDE in Appendix 3 as a starting point in developing a route-specific PDE. 137 Based on a scientific evaluation, the parenteral and inhalation PDEs may be a more 138 appropriate starting point. 139 • Assess if the elemental impurity is expected to have local effects when administered 140 by the intended route of administration: 141 o If local effects are expected, assess whether a modification to an established PDE is 142 necessary. 143 o Consider the doses/exposures at which these effects can be expected relative to 144 the adverse effect that was used to set an established PDE. 145 o If local effects are not expected, no adjustment to an established PDE is necessary. 146 • If available, evaluate the bioavailability of the element via the intended route of 147 administration and compare this to the bioavailability of the element by the route 148 with an established PDE: 149 o When a difference is observed, a correction factor may be applied to an 150 established PDE. For example, when no local effects are expected, if the oral 151 bioavailability of an element is 50% and the bioavailability of an element by the 152 intended route is 10%, a correction factor of 5 may be applied. 153 • If a PDE proposed for the new route is increased relative to an established PDE, 154 quality attributes may need to be considered. 155 156 C. Justification for Elemental Impurity Levels Higher Than an Established PDE 157 (3.3) 158 4 Contains Nonbinding Recommendations 159 Levels of elemental impurities higher than an established PDE (see Table A.2.1) may be 160 acceptable in certain cases. These cases could include, but are not limited to, the 161 following situations: 162 • Intermittent dosing 163 • Short term dosing (i.e., 30 days or less) 164 • Specific indications (e.g., life-threatening, unmet medical needs, rare diseases) 165 Examples of justifying an increased level of an elemental impurity using a subfactor 166 approach of a modifying factor (Ref. 2,3) are provided below. Other approaches may 167 also be used to justify an increased level. Any proposed level higher than an established 168 PDE should be justified on a case-by- case basis. 169 Example 1: Element X is present in an oral drug product. From the element X 170 monograph in Appendix 3, a No-Observed-Adverse-Effect Level (NOAEL) of 1.1 171 milligram (mg)/kilogram (kg)/day (d) was identified. Modifying factors F1-F5 have been 172 established as 5, 10, 5, 1 and 1, respectively. Using the standard approach for modifying 173 factors as described in Appendix 1, the PDE is calculated as follows: 174 PDE = 1.1 mg/kg/d x 50 kg / (5 x 10 x 5 x 1 x 1) = 220 µg/day 175 Modifying factor F2 (default = 10) can be subdivided into two subfactors, one for 176 toxicokinetics (TK) and one for toxicodynamics, each with a range from 1 to 3.16. Using 177 the plasma half-life of 5 days, the TK adjustment factor could be decreased to 1.58 for 178 once weekly administration (~1 half-life), and to 1 for administration once a month (~5 179 half-lives). Using the subfactor approach for F2, the proposed level for element X 180 administered once weekly can be calculated as follows: 181 Proposed level = 1.1 mg/kg/d x 50 kg / (5 x (1.6 x 3.16) x 5 x 1 x 1) = 440 µg/day 182 For practical purposes, this value is rounded to 400 µg/day. 183 Example 2: The TK adjustment factor approach may also be appropriate for elemental 184 impurities that were not developed using the modifying factor approach. For element Z, a 185 Minimal Risk Level (MRL) of 0.02 mg/kg/day was used to derive the oral PDE. From 186 literature sources, the plasma half-life was reported to be 4 days. This element is an 187 impurity in an oral drug product administered once every 3 weeks (~ 5 half-lives). Using 188 first-order kinetics, the established PDE of 1000 µg/day is modified as follows: 189 190 Proposed level = 0.02 mg/kg/d x 50 kg / (1/3.16) = 3.16 mg/day 191 192 For practical purposes, this value is rounded to 3000 µg/day. 193 194 D. Parenteral Products (3.4) 195 196 Parenteral drug products with maximum daily volumes up to two liters may use the 197 maximum daily volume to calculate permissible concentrations from PDEs. For products 198 whose daily volumes, as specified by labeling and/or established by clinical practice, may 5 Contains Nonbinding Recommendations 199 exceed two liters (e.g., saline, dextrose, total parenteral nutrition, solutions for irrigation), 200 a 2-liter volume may be used to calculate permissible concentrations from PDEs (Ref. 4). 201 202 IV. ELEMENT CLASSIFICATION (4) 203 204 The elements included in this guidance have been placed into three classes based on their toxicity 205 (PDE) and likelihood of occurrence in the drug product. The likelihood of occurrence is derived 206 from several factors including: probability of use in pharmaceutical processes, probability of 207 being a co-isolated impurity with other elemental impurities in materials used in pharmaceutical 208 processes, and the observed natural abundance and environmental distribution of the element. For 209 the purposes of this guidance, an element with low natural abundance refers to an element with a 210 reported natural abundance of < 1 atom/106 atoms of silicon (Ref. 5). The classification scheme is 211 intended to focus the risk assessment on those elements that are the most toxic but also have a 212 reasonable probability of inclusion in the drug product (see Table 5.1). The elemental impurity 213 classes are: 214 Class 1: The elements, As, Cd, Hg, and Pb, are human toxicants that have limited or no use in 215 the manufacture of pharmaceuticals. Their presence in drug products typically comes from 216 commonly used materials (e.g., mined excipients). Because of their unique nature, these four 217 elements require evaluation during the risk assessment, across all potential sources of elemental 218 impurities and routes of administration. The outcome of the risk assessment will determine those 219 components that may require additional controls which may in some cases include testing for 220 Class 1 elements. It is not expected that all components will require testing for Class 1 elemental 221 impurities; testing should only be applied when the risk assessment identifies it as the appropriate 222 control to ensure that the PDE will be met. 223 Class 2: Elements in this class are generally considered as route-dependent human toxicants. 224 Class 2 elements are further divided in sub-classes 2A and 2B based on their relative likelihood 225 of occurrence in the drug product. 226 • Class 2A elements have relatively high probability of occurrence in the drug 227 product and thus require risk assessment across all potential sources of 228 elemental impurities and routes of administration (as indicated). The class 2A 229 elements are: Co, Ni and V. 230 • Class 2B elements have a reduced probability of occurrence in the drug 231 product related to their low abundance and low potential to be co-isolated with 232 other materials. As a result, they may be excluded from the risk assessment 233 unless they are intentionally added during the manufacture of drug substances, 234 excipients, or other components of the drug product. The elemental impurities 235 in class 2B include: Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se and Tl. 236 237 Class 3: The elements in this class have relatively low toxicities by the oral route of administration 238 (high PDEs, generally > 500 µg/day) but may require consideration in the risk assessment for 239 inhalation and parenteral routes. For oral routes of administration, unless these elements are 240 intentionally added, they do not need to be considered during the risk assessment. For parenteral 241 and inhalation products, the potential for inclusion of these elemental impurities should be 6 Contains Nonbinding Recommendations 242 evaluated during the risk assessment, unless the route specific PDE is above 500 µg/day. The 243 elements in this class include: Ba, Cr, Cu, Li, Mo, Sb, and Sn. 244 245 Other elements: Some elemental impurities for which PDEs have not been established due to 246 their low inherent toxicity and/or differences in regional regulations are not addressed in this 247 guidance. If these elemental impurities are present or included in the drug product they are 248 addressed by other guidances and/or regional regulations and practices that may be applicable for 249 particular elements (e.g., Al for compromised renal function; Mn and Zn for patients with 250 compromised hepatic function), or quality considerations (e.g., presence of W impurities in 251 therapeutic proteins) for the final drug product. Some of the elements considered include: Al, B, 252 Ca, Fe, K, Mg, Mn, Na, W and Zn. 253 254 V. RISK ASSESSMENT AND CONTROL OF ELEMENTAL IMPURITIES (5) 255 256 In developing controls for elemental impurities in drug products, the principles of quality risk 257 management, described in ICH Q9, should be considered. The risk assessment should be based 258 on scientific knowledge and principles. It should link to safety considerations for patients with an 259 understanding of the product and its manufacturing process (ICH Q8 and Q11). In the case of 260 elemental impurities, the product risk assessment would therefore be focused on assessing the 261 levels of elemental impurities in a drug product in relation to the PDEs presented in this 262 guidance. Information for this risk assessment includes but is not limited to: data generated by 263 the applicant, information supplied by drug substance and/or excipient manufacturers and/or data 264 available in published literature. 265 The applicant should document the risk assessment and control approaches in an appropriate 266 manner. The level of effort and formality of the risk assessment should be proportional to the 267 level of risk. It is neither always appropriate nor always necessary to use a formal risk 268 management process (using recognized tools and/or formal procedures, e.g., standard operating 269 procedures.) The use of informal risk management processes (using empirical tools and/or 270 internal procedures) may also be considered acceptable. Tools to assist in the risk assessment are 271 described in ICH Q8 and Q9 and will not be presented in this guidance. 272 273 A. General Principles (5.1) 274 275 For the purposes of this guidance, the risk assessment process can be described in three steps: 276 • Identify known and potential sources of elemental impurities that may find their way 277 into the drug product. 278 • Evaluate the presence of a particular elemental impurity in the drug product by 279 determining the observed or predicted level of the impurity and comparing with the 280 established PDE. 281 • Summarize and document the risk assessment. Identify if controls built into the 282 process are sufficient or identify additional controls to be considered to limit 283 elemental impurities in the drug product. 7 Contains Nonbinding Recommendations 284 In many cases, the steps are considered simultaneously. The outcome of the risk assessment may 285 be the result of iterations to develop a final approach to ensure the potential elemental impurities 286 do not exceed the PDE. 287 288 B. Potential Sources of Elemental Impurities (5.2) 289 290 In considering the production of a drug product, there are broad categories of potential sources of 291 elemental impurities. 292 • Residual impurities resulting from elements intentionally added (e.g., catalysts) in the 293 formation of the drug substance, excipients, or other drug product components. The 294 risk assessment of the drug substance should address the potential for inclusion of 295 elemental impurities in the drug product. 296 • Elemental impurities that are not intentionally added and are potentially present in the 297 drug substance, water or excipients used in the preparation of the drug product. 298 • Elemental impurities that are potentially introduced into the drug substance and/or 299 drug product from manufacturing equipment. 300 • Elemental impurities that have the potential to be leached into the drug substance and 301 drug product from container closure systems. 302 The following diagram shows an example of typical materials, equipment and components used 303 in the production of a drug product. Each of these sources may contribute elemental impurities to 304 the drug product, through any individual or any combination of the potential sources listed 305 above. During the risk assessment, the potential contributions from each of these sources should be 306 considered to determine the overall contribution of elemental impurities to the drug product. 307 8 Contains Nonbinding Recommendations 308 Manufacturing Drug equipment * Substance Elemental impurities in drug Product Water ** Container Excipients Closure System 309 310 311 * The risk of inclusion of elemental impurities can be reduced through process understanding, equipment 312 selection, equipment qualification and Good Manufacturing Practice (GMP) processes. 313 ** The risk of inclusion of elemental impurities from water can be reduced by complying with compendial 314 (e.g., European Pharmacopoeia, Japanese Pharmacopoeia, US Pharmacopeial Convention) water quality 315 requirements, if purified water or water for injection is used in the manufacturing process(es). 316 317 C. Identification of Potential Elemental Impurities (5.3) 318 319 Potential elemental impurities derived from intentionally added catalysts and inorganic 320 reagents: If any element listed in Table 5.1 is intentionally added, it should be considered in the 321 risk assessment. For this category, the identity of the potential impurities is known and 322 techniques for controlling the elemental impurities are easily characterized and defined. 323 Potential elemental impurities that may be present in drug substances and/or excipients: 324 While not intentionally added, some elemental impurities may be present in some drug 325 substances and/or excipients. The possibility for inclusion of these elements in the drug product 326 should be reflected in the risk assessment. 327 For the oral route of administration, the risk assessment should evaluate the possibility for 328 inclusion of Class 1 and Class 2A elemental impurities in the drug product. For parenteral and 329 inhalation routes of administration, the risk assessment should evaluate the possibility for 330 inclusion of the Class 1, Class 2A and Class 3 elemental impurities as shown in Table 5.1. 331 Potential elemental impurities derived from manufacturing equipment: The contribution of 332 elemental impurities from this source may be limited and the subset of elemental impurities that 333 should be considered in the risk assessment will depend on the manufacturing equipment used in 334 the production of the drug product. Application of process knowledge, selection of equipment, 335 equipment qualification and GMP controls ensure a low contribution from manufacturing 9 Contains Nonbinding Recommendations 336 equipment. The specific elemental impurities of concern should be assessed based on knowledge 337 of the composition of the components of the manufacturing equipment that come in contact with 338 components of the drug product. The risk assessment of this source of elemental impurities is 339 one that can potentially be utilized for many drug products using similar process trains and 340 processes. 341 In general, the processes used to prepare a given drug substance are considerably more 342 aggressive than processes used in preparing the drug product when assessed relative to the 343 potential to leach or remove elemental impurities from manufacturing equipment. Contributions 344 of elemental impurities from drug product processing equipment would be expected to be lower 345 than contributions observed for the drug substance. However, when this is not the case based on 346 process knowledge or understanding, the applicant should consider the potential for 347 incorporation of elemental impurities from the drug product manufacturing equipment in the risk 348 assessment (e.g., hot melt extrusion). 349 Elemental impurities leached from container closure systems: The identification of potential 350 elemental impurities that may be introduced from container closure systems should be based on a 351 scientific understanding of likely interactions between a particular drug product type and its 352 packaging. When a review of the materials of construction demonstrates that the container 353 closure system does not contain elemental impurities, no additional risk assessment needs to be 354 performed. It is recognized that the probability of elemental leaching into solid dosage forms is 355 minimal and does not require further consideration in the risk assessment. For liquid and semi- 356 solid dosage forms there is a higher probability that elemental impurities could leach from the 357 container closure system during the shelf-life of the product. Studies to understand potential 358 leachables from the container closure system (after washing, sterilization, irradiation, etc.) 359 should be performed. This source of elemental impurities will typically be addressed during 360 evaluation of the container closure system for the drug product. 361 Factors that should be considered (for liquid and semi-solid dosage forms) include but 362 are not limited to: 363 • Hydrophilicity/hydrophobicity 364 • Ionic content 365 • pH 366 • Temperature (cold chain vs room temperature and processing conditions) 367 • Contact surface area 368 • Container/component composition 369 • Terminal sterilization 370 • Packaging process 371 • Component sterilization 372 • Duration of storage 373 374 D. Recommendations for Elements to be Considered in the Risk Assessment (5.4) 375 376 The following table provides recommendations for inclusion of elemental impurities in the risk 377 assessment. This table can be applied to all sources of elemental impurities in the drug product. 10 Contains Nonbinding Recommendations 378 379 Table V.1 (5.1): Elements to be Considered in the Risk Assessment Element Class If intentionally If not intentionally added added (all routes) Oral Parenteral Inhalation Cd 1 yes yes yes yes Pb 1 yes yes yes yes As 1 yes yes yes yes Hg 1 yes yes yes yes Co 2A yes yes yes yes V 2A yes yes yes yes Ni 2A yes yes yes yes Tl 2B yes no no no Au 2B yes no no no Pd 2B yes no no no Ir 2B yes no no no Os 2B yes no no no Rh 2B yes no no no Ru 2B yes no no no Se 2B yes no no no Ag 2B yes no no no Pt 2B yes no no no Li 3 yes no yes yes Sb 3 yes no yes yes Ba 3 yes no no yes Mo 3 yes no no yes Cu 3 yes no yes yes Sn 3 yes no no yes Cr 3 yes no no yes 380 381 E. Evaluation (5.5) 382 383 As the potential elemental impurity identification process is concluded, there are two possible 384 outcomes: 385 1) The risk assessment process does not identify any potential elemental impurities. The 386 conclusion of the risk assessment and supporting information and data should be 387 documented. 388 2) The risk assessment process identifies one or more potential elemental impurities. For 389 any elemental impurities identified in the process, the risk assessment should consider 390 if there are multiple sources of the identified elemental impurity or impurities and 391 document the conclusion of the assessment and supporting information. 392 The applicant's risk assessment can be facilitated with information about the potential elemental 393 impurities provided by suppliers of drug substances, excipients, container closure systems, and 394 manufacturing equipment. The data that support this risk assessment can come from a number of 395 sources that include, but are not limited to: 396 • Prior knowledge 11 Contains Nonbinding Recommendations 397 • Published literature 398 • Data generated from similar processes 399 • Supplier information or data 400 • Testing of the components of the drug product 401 • Testing of the drug product 402 During the risk assessment, a number of factors that can influence the level of the potential 403 impurity in the drug product and should also have been considered in the risk assessment. These 404 include but are not limited to: 405 • Efficiency of removal of elemental impurities during further processing 406 • Natural abundance of elements (especially important for the categories of 407 elements which are not intentionally added) 408 • Prior knowledge of elemental impurity concentration ranges from specific 409 sources 410 • The composition of the drug product 411 412 F. Summary of Risk Assessment Process (5.6) 413 414 The risk assessment is summarized by reviewing relevant product or component specific data 415 combined with information and knowledge gained across products or processes to identify the 416 significant probable elemental impurities that may be observed in the drug product. 417 The summary should consider the significance of the observed or predicted level of the elemental 418 impurity relative to the PDE of the elemental impurity. As a measure of the significance of the 419 observed elemental impurity level, a control threshold is defined as a level that is 30% of the 420 established PDE in the drug product. The control threshold may be used to determine if additional 421 controls are warranted. 422 423 If the total elemental impurity level from all sources in the drug product is expected to be 424 consistently less than 30% of the PDE, then additional controls are not required, provided the 425 applicant has appropriately assessed the data and demonstrated adequate controls on elemental 426 impurities. 427 428 If the risk assessment fails to demonstrate that an elemental impurity level is consistently less 429 than the control threshold, controls should be established to ensure that the elemental impurity 430 level does not exceed the PDE in the drug product. (See section VI (6).) 431 432 The variability of the level of an elemental impurity should be factored into the application of the 433 control threshold to drug products. Sources of variability may include: 434 • Variability of the analytical method 435 • Variability of the elemental impurity level in the specific sources 436 • Variability of the elemental impurity level in the drug product 437 438 At the time of submission, in the absence of other justification, the level and variability of an 439 elemental impurity can be established by providing the data from three (3) representative 12 Contains Nonbinding Recommendations 440 production scale lots or six (6) representative pilot scale lots of the component or components or 441 drug product. For some components that have inherent variability (e.g., mined excipients), 442 additional data may be needed to apply the control threshold. 443 444 There are many acceptable approaches to summarizing and documenting the risk assessment that 445 may include: tables, written summaries of considerations and conclusions of the assessment. The 446 summary should identify the elemental impurities, their sources, and the controls and acceptance 447 criteria as needed. 448 449 G. Special Considerations for Biotechnologically-Derived Products (5.7) 450 451 For biotechnology-derived products, the risks of elemental impurities being present at levels that 452 raise safety concerns at the drug substance stage are considered low. This is largely because: 453 (a) Elements are not typically used as catalysts or reagents in the manufacturing of biotech 454 products. 455 (b) Elements are added at trace levels in media feeds during cell culture processes, without 456 accumulation and with significant dilution/removal during further processing. 457 (c) Typical purification schemes used in biotech manufacturing such as extraction, 458 chromatography steps and dialysis or Ultrafiltration-Diafiltration (UF/DF) have the 459 capacity to clear elements introduced in cell culture/fermentation steps or from contact 460 with manufacturing equipment to negligible levels. 461 462 As such, specific controls on elemental impurities up to the biotech drug substance are generally 463 not needed. In cases where the biotechnology-derived drug substance contains synthetic 464 structures (such as antibody-drug conjugates), appropriate controls on the small molecule 465 component for elemental impurities should be evaluated. 466 467 However, potential elemental impurity sources included in drug product manufacturing (e.g., 468 excipients) and other environmental sources should be considered for biotechnologically- 469 derived drug products. The contribution of these sources to the finished product should be 470 assessed because they are typically introduced in the drug product manufacture at a step in the 471 process where subsequent elemental impurity removal is not generally performed. Risk factors 472 that should be considered in this assessment should include the type of excipients used, the 473 processing conditions and their susceptibility to contamination by environmental factors (e.g., 474 controlled areas for sterile manufacturing and use of purified water) and overall dosing 475 frequency. 476 477 VI. Control of Elemental Impurities (6) 478 479 Control of elemental impurities is one part of the overall control strategy for a drug product that 480 assures that elemental impurities do not exceed the PDEs. When the level of an elemental 481 impurity may exceed the control threshold, additional measures should be implemented to assure 482 that the level does not exceed the PDE. Approaches that an applicant can pursue include but are 483 not limited to: 484 • Modification of the steps in the manufacturing process that result in the reduction of 13 Contains Nonbinding Recommendations 485 elemental impurities below the control threshold through specific or non-specific 486 purification steps 487 • Implementation of in-process or upstream controls, designed to limit the concentration of 488 the elemental impurity below the control threshold in the drug product 489 • Establishment of specification limits for excipients or materials (e.g., synthetic 490 intermediates) 491 • Establishment of specification limits for the drug substance 492 • Establishment of specification limits for the drug product 493 • Selection of appropriate container closure systems 494 Periodic testing may be applied to elemental impurities according to the principles described in 495 ICH Q6A. 496 497 The information on the control of elemental impurities that is provided in a regulatory 498 submission includes, but is not limited to, a summary of the risk assessment, appropriate data as 499 necessary, and a description of the controls established to limit elemental impurities. 500 501 VII. Converting Between PDEs and Concentration Limits (7) 502 503 The PDEs, reported in micrograms per day (µg/day) provided in this document give the 504 maximum permitted quantity of each element that may be contained in the maximum daily intake 505 of a drug product. Because the PDE reflects only total exposure from the drug product, it is useful 506 to convert the PDE, into concentrations as a tool in evaluating elemental impurities in drug 507 products or their components. The options listed in this section describe some acceptable 508 approaches to establishing concentrations of elemental impurities in drug products or 509 components that would assure that the drug product does not exceed the PDEs. The applicant 510 may select any of these options as long as the resulting permitted concentrations assure that the 511 drug product does not exceed the PDEs. In the choice of a specific option the applicant must have 512 knowledge of, or make assumptions about, the daily intake of the drug product. The permitted 513 concentration limits may be used: 514 • As a tool in the risk assessment to compare the observed or predicted levels to the PDE 515 • In discussions with suppliers to help establish upstream controls that would assure 516 that the product does not exceed the PDE 517 • To establish concentration targets when developing in-process controls on elemental 518 impurities 519 • To convey information regarding the controls on elemental impurities in regulatory 520 submissions 521 522 As discussed in section V.B (5.2), there are multiple sources of elemental impurities in drug 523 products. When applying any of the options described below, elemental impurities from 524 container closure systems and manufacturing equipment should be taken into account before 525 calculating the maximum permitted concentration in the remaining components (excipients and 526 drug substance). If it is determined during the risk assessment that the container closure systems 527 and manufacturing equipment do not contribute to the elemental impurity level in the drug 14 Contains Nonbinding Recommendations 528 product, they do not need to be considered. Where contributions from container closure systems 529 and manufacturing equipment exist, these contributions may be accounted for by subtracting the 530 estimated daily intake from these sources from the PDE before calculation of the allowed 531 concentration in the excipients and drug substance. 532 533 Option 1: Common permitted concentration limits of elements across drug product 534 components for drug products with daily intakes of not more than 10 grams: 535 536 This option is not intended to imply that all elements are present at the same concentration, but 537 rather provides a simplified approach to the calculations. 538 539 The option assumes the daily intake (amount) of the drug product is 10 grams or less, and that 540 elemental impurities identified in the risk assessment (the target elements) are present in all 541 components of the drug product. Using Equation 1 below, and a daily intake of ten grams of drug 542 product, this option calculates a common permissible target elemental concentration for each 543 component in the drug. This approach, for each target element, allows determination of a fixed 544 common maximum concentration in micrograms per gram in each component. The permitted 545 concentrations are provided in Appendix 2, Table A.2.2. 546 PDE ( µg / day ) 547 Concentration( µg / g ) = (1) daily amount of drug product ( g / day ) 548 549 If all the components in a drug product do not exceed the Option 1 concentrations for all target 550 elements identified in the risk assessment, then all these components may be used in any 551 proportion in the drug product. An example using this option is shown in Appendix 4, Table 552 A.4.2. If the permitted concentrations in Appendix 2, Table A.2.2 are not applied, Options 2a, 2b, 553 or 3 should be followed. 554 555 Option 2a: Common permitted concentration limits across drug product components for a 556 drug product with a specified daily intake: 557 558 This option is similar to Option 1, except that the drug daily intake is not assumed to be 10 559 grams. The common permitted concentration of each element is determined using Equation 1 and 560 the actual maximum daily intake. 561 This approach, for each target element, allows determination of a fixed common maximum 562 concentration in micrograms per gram in each component based on the actual daily intake 563 provided. An example using this option is provided in Appendix 4, Table A.4.3. 564 If all components in a drug product do not exceed the Option 2a concentrations for all target 565 elements identified in the risk assessment, then all these components may be used in any 566 proportion in the drug product. 567 568 Option 2b: Permitted concentration limits of elements in individual components of a 569 product with a specified daily intake: 570 15 Contains Nonbinding Recommendations 571 This option requires additional information that the applicant may assemble regarding the 572 potential for specific elemental impurities to be present in specific drug product components. The 573 applicant may set permitted concentrations based on the distribution of elements in the 574 components (e.g., higher concentrations in components with the presence of an element in 575 question). For each element identified as potentially present in the components of the drug 576 product, the maximum expected mass of the elemental impurity in the final drug product can be 577 calculated by multiplying the mass of each component material times the permitted concentration 578 established by the applicant in each material and summing over all components in the drug 579 product, as described in Equation 2. The total mass of the elemental impurity in the drug product 580 should comply with the PDEs given in Appendix 2, Table A.2.1. unless justified according to 581 other relevant sections of this guidance. If the risk assessment has determined that a specific 582 element is not a potential impurity in a specific component, there is no need to establish a 583 quantitative result for that element in that component. This approach allows that the maximum 584 permitted concentration of an element in certain components of the drug product may be higher 585 than the Option 1 or Option 2a limit, but this should then be compensated by lower allowable 586 concentrations in the other components of the drug product. Equation 2 may be used to 587 demonstrate that component-specific limits for each element in each component of a drug 588 product assure that the PDE will be met. 589 N 590 PDE (µg day ) ≥ ∑ C k ⋅ M k (2) k =1 591 592 k= an index for each of N components in the drug product 593 Ck = permitted concentration of the elemental impurity in component k (µg/g) 594 Mk = mass of component k in the maximum daily intake of the drug product (g) 595 596 An example using this option is provided in Appendix 4 Tables A.4.4 – A.4.5. 597 598 Option 3: Finished Product Analysis: 599 The concentration of each element may be measured in the final drug product. Equation 1 may 600 be used with the maximum total daily dose of the drug product to calculate a maximum permitted 601 concentration of the elemental impurity. An example using this option is provided in Appendix 4, 602 Table A.4.6. 603 604 VIII. Speciation and Other Considerations (8) 605 606 Speciation is defined as the distribution of elements among chemical species including isotopic 607 composition, electronic or oxidation state, and/or complex or molecular structure. When the 608 toxicities of different species of the same element are known, the PDE has been established using 609 the toxicity information on the species expected to be in the drug product. 610 When elemental impurity measurements are used in the risk assessment, total elemental impurity 611 levels in drug products may be used to assess compliance with the PDEs. The applicant is not 612 expected to provide speciation information; however, such information could be used to justify 613 lower or higher levels when the identified species is more or less toxic, respectively, than the 614 species used in the monographs in Appendix 3. 16 Contains Nonbinding Recommendations 615 When total elemental impurity levels in components are used in the risk assessment, the applicant 616 is not expected to provide information on release of an elemental impurity from the component 617 in which it is found. However, such information could be used to justify levels higher than those 618 based on the total elemental impurity content of the drug product. 619 620 IX. Analytical Procedures (9) 621 622 The determination of elemental impurities should be conducted using appropriate procedures 623 suitable for their intended purposes. Unless otherwise justified, the test should be specific for 624 each elemental impurity identified for control during the risk assessment. Pharmacopoeial 625 procedures or suitable alternative procedures for determining levels of elemental impurities 626 should be used. 627 628 X. Lifecycle Management (10) 629 630 The quality systems and management responsibilities described in ICH guidance for industry 631 Q10 Pharmaceutical Quality System (April 2009) (ICH Q10) 7 are intended to encourage the use 632 of science-based and risk-based approaches at each lifecycle stage, thereby promoting continual 633 improvement across the entire product lifecycle. Product and process knowledge should be 634 managed from development through the commercial life of the product up to and including 635 product discontinuation. 636 Knowledge gained from development combined with commercial manufacturing experience and 637 data can be used to further improve process understanding and process performance. Such 638 improvements can enhance controls on elemental impurities. It is recognized that the elemental 639 impurity data available for some components is somewhat limited at the date of publication of 640 this guidance, which may direct the applicant to a specific set of controls. Additional data, if 641 developed, may lead to modifications of the controls. 642 643 If changes to the drug product or components have the potential to change the elemental impurity 644 content of the drug product, the risk assessment, including established controls for elemental 645 impurities, should be re-evaluated. Such changes could include, but are not limited to: changes in 646 synthetic routes, excipient suppliers, raw materials, processes, equipment, container closure 647 systems or facilities. All changes are subject to internal change management process (ICH 648 Q10) and if needed appropriate regional regulatory requirements. 649 7 The ICH guidance for industry Q10 Pharmaceutical Quality System (April 2009) is available on the FDA guidance web page. 17 Contains Nonbinding Recommendations 650 GLOSSARY 651 ACGIH: American Conference of Governmental Industrial Hygienists. 652 ATSDR: Agency for Toxic Substances and Disease Registry. 653 CEC: Commission of the European Community. 654 CFR: Code of Federal Regulations. (USA) 655 Change Management: A systematic approach to proposing, evaluating, approving, 656 implementing, and reviewing changes. (ICH Q10) 657 CICAD: Concise International Chemical Assessment Documents. (WHO) 658 Container Closure System: The sum of packaging components that together contain 659 and protect the dosage form. This includes primary packaging components and 660 secondary packaging components, if the latter are intended to provide additional 661 protection to the drug product. A packaging system is equivalent to a container 662 closure system. (ICH Q1A) 663 Control Strategy: A planned set of controls, derived from current product and 664 process understanding, that assures process performance and product quality. The 665 controls can include parameters and attributes related to drug substance and drug 666 product materials and components, facility and equipment operating conditions, in- 667 process controls, finished product specifications, and the associated methods and 668 frequency of monitoring and control. (ICH Q10) 669 Control Threshold: A limit that is applied during the assessment of elemental 670 impurities to determine if additional control elements may be required to ensure that 671 the PDE is not exceeded in the drug product. The limit is defined as 30% of the PDE 672 of the specific elemental impurity under consideration. 673 Daily Dose: The total mass of drug product that is consumed by a patient on a daily 674 basis. 675 EFSA: European Food Safety Agency. 676 EHC: Environmental Health Criteria. (IPCS, WHO) 677 EU SCOEL: European Scientific Committee on Occupational Exposure Limits. 678 EU SEG: European Union Scientific Expert Group. 679 Herbal Products: Medicinal products containing, exclusively, plant material and/or 680 vegetable drug preparations as active ingredients. In some traditions, materials of 681 inorganic or animal origin can also be present. 682 IARC: International Agency for Research on Cancer. 683 Inhalation Unit Risk: The upper-bound excess lifetime cancer risk estimated to result 684 from continuous exposure to an agent at a concentration of 1 µg/L in water, or 1 685 µg/m3 in air. The interpretation of inhalation unit risk would be as follows: if unit risk 18 Contains Nonbinding Recommendations 686 = 2 x 10-6 per µg/L, 2 excess cancer cases (upper bound estimate) are expected to 687 develop per 1,000,000 people if exposed daily for a lifetime to 1 µg of the chemical in 688 1 liter of drinking water. (US EPA) 689 IPCS: International Programme for Chemical Safety. 690 IUPAC: International Union of Pure and Applied Chemistry. 691 IRIS: Integrated Risk Identification System, United States Environmental Protection 692 Agency. 693 LOAEL: Lowest-Observed-Adverse-Effect Level: Lowest concentration or amount 694 of a substance (dose), found by experiment or observation, that causes an adverse 695 effect on morphology, functional capacity, growth, development, or life span of a 696 target organism distinguishable from normal (control) organisms of the same species 697 and strain under defined conditions of exposure. (IUPAC) 698 LoQ: Limit of Quantitation: The quantitation limit of an individual analytical 699 procedure is the lowest amount of analyte in a sample which can be quantitatively 700 determined with suitable precision and accuracy. The quantitation limit is a parameter 701 of quantitative assays for low levels of compounds in sample matrices, and is used 702 particularly for the determination of impurities and/or degradation products. (ICH Q2) 703 LOEL: Lowest-Observed-Effect Level: The lowest dose of substance in a study or 704 group of studies that produces biologically significant increases in frequency or 705 severity of any effects in the exposed humans or animals. 706 Modifying Factor: An individual factor determined by professional judgment of a 707 toxicologist and applied to bioassay data to relate that data to human safety. (ICH 708 Q3C) (See related term Safety Factor) 709 MRL: Minimal Risk Level: An estimate of the daily human exposure to a hazardous 710 substance that is likely to be without appreciable risk. (ATSDR) 711 NAS: National Academy of Science. (USA) 712 NOAEL: No-Observed-Adverse-Effect Level: Greatest concentration or amount of a 713 substance, found by experiment or observation, that causes no detectable adverse 714 alteration of morphology, functional capacity, growth, development, or life span of the 715 target organism under defined conditions of exposure. 716 NOEL: No-Observed-Effect Level: The highest dose of substance at which there are 717 no biologically significant increases in frequency or severity of any effects in the 718 exposed humans or animals. 719 NTP: National Toxicology Program. (USA) 720 OEHHA: Office of Environmental Health Hazard Assessment. (California, USA) 721 OELV: Occupational Exposure Limit Value. 722 OSHA: Occupational Safety and Health Administration. (USA) 19 Contains Nonbinding Recommendations 723 PEL: Permitted Exposure Limit. 724 PDE: Permitted Daily Exposure: The maximum acceptable intake of elemental 725 impurity in pharmaceutical products per day. 726 Product Lifecycle: All phases in the life of the product from the initial development 727 through marketing until the product's discontinuation. (ICH Q9) 728 Quality: The degree to which a set of inherent properties of a product, system, or 729 process fulfills requirements (see ICH Q6A definition specifically for quality of drug 730 substance and drug products). (ICH Q9) 731 Quality Risk Management: A systematic process for the assessment, control, 732 communication, and review of risks to the quality of the drug product across the 733 product lifecycle. (ICH Q9) 734 Quality System: The sum of all aspects of a system that implements quality policy 735 and ensures that quality objectives are met. (ICH Q10) 736 Risk: The combination of the probability of occurrence of harm and the severity of 737 that harm. (ISO/IEC Guide 51, ICH Q9) 738 Risk Acceptance: The decision to accept risk. (ISO Guide 73) 739 Risk Analysis: The estimation of the risk associated with the identified hazards. (ICH 740 Q9) 741 Risk Assessment: A systematic process of organizing information to support a risk 742 decision to be made within a risk management process. It consists of the identification 743 of hazards and the analysis and evaluation of risks associated with exposure to those 744 hazards. (ICH Q9) 745 Risk Control: Actions implementing risk management decisions. (ISO Guide 73) 746 Risk Identification: The systematic use of information to identify potential sources 747 of harm (hazards) referring to the risk question or problem description. (ICH Q9) 748 Risk Management: The systematic application of quality management policies, 749 procedures, and practices to the tasks of assessing, controlling, communicating, and 750 reviewing risk. (ICH Q9) 751 Safety: Practical certainty that adverse effects will not result from exposure to an 752 agent under defined circumstances (Ref. 2). 753 Safety Assessment: An approach that focuses on the scientific understanding and 754 measurement of chemical hazards as well as chemical exposures, and ultimately the 755 risks associated with them. This term is often (and in this guidance) used 756 synonymously with risk assessment (Ref. 2). 757 Safety Factor: A composite (reductive) factor applied by the risk assessment experts 758 to the NOAEL or other reference point, such as the benchmark dose or benchmark 759 dose lower confidence limit, to derive a reference dose that is considered safe or 760 without appreciable risk, such as an acceptable daily intake or tolerable daily intake 20 Contains Nonbinding Recommendations 761 (the NOAEL or other reference point is divided by the safety factor to calculate the 762 reference dose). The value of the safety factor depends on the nature of the toxic 763 effect, the size and type of population to be protected, and the quality of the 764 toxicological information available. See related terms: Assessment factor, Uncertainty 765 factor (Ref. 2). 766 Severity: A measure of the possible consequences of a hazard. (ICH Q9) 767 TLV: Threshold Limit Value: The concentration in air to which it is believed that most 768 workers can be exposed daily without an adverse effect (i.e., effectively, the threshold 769 between safe and dangerous concentrations). The values were established (and are 770 revised annually) by the ACGIH and are time- weighted concentrations (TWA) for a 771 7- or 8-hour workday and 40-hour workweek, and thus related to chronic effects. 772 (IUPAC） 773 TWA: Time Weighted Average: As defined by ACGIH, time-weighted average 774 concentration for a conventional 8-hour workday and a 40-hour workweek. (IUPAC) 775 URF: Unit Risk Factor. 776 US DoL: United States Department of Labor. 777 US EPA: United States Environmental Protection Agency. 778 WHO: World Health Organization. 779 21 Contains Nonbinding Recommendations 780 REFERENCES 781 782 1. Ball D, Blanchard J, Jacobson-Kram D, McClellan R, McGovern T, Norwood DL et al. 783 2007, Development of safety qualification thresholds and their use in orally inhaled and 784 nasal drug product evaluation, Toxicol Sci, 97(2):226-36. 785 2. IPCS. Principles and methods for the risk assessment of chemicals in food, chapter 5: dose- 786 response assessment and derivation of health based guidance values, 2009, Environmental 787 Health Criteria 240, International Programme on Chemical Safety. World Health 788 Organization, Geneva, Table 5.5. 789 3. US EPA. 0410 Boron and Compounds, 2004, Integrated Risk Management System (IRIS). 790 4. Holliday MA, Segar WE, 1957, The maintenance need for water in parenteral fluid therapy, 791 Pediatrics, 19:823-32. 792 5. Haxel GB, Hedrick JB, Orris GJ, 2005, Rare earth elements-critical resources for high 793 technology, US Geological Survey, Fact Sheet 087-02. 22 Contains Nonbinding Recommendations 794 Appendix 1: Method for Establishing Exposure Limits 795 796 For most elements, acceptable exposure levels for elemental impurities in this guidance were 797 established by calculation of PDE values according to the procedures for setting exposure limits 798 in pharmaceuticals (Ref. 1), and the method adopted by International Programme for Chemical 799 Safety (IPCS) for Assessing Human Health Risk of Chemicals (Ref. 2). These methods are 800 similar to those used by the United States Environmental Protection Agency (US EPA) Integrated 801 Risk Information System, the United States Food and Drug Administration (US FDA) (Ref. 3) 802 and others. The method is outlined here to give a better understanding of the origin of the PDE 803 values. When an MRL was used to set the PDE, no additional modifying factors were used as 804 they are incorporated into the derivation of the MRL. For carcinogenic elements unit risk factors 805 were used to set the PDE using a 1:100000 risk level; these are described in the individual 806 monographs in Appendix 3. Some PDEs for inhalation were derived using occupational exposure 807 limits, applying modifying factors, and considering any specific effects to the respiratory system. 808 The PDE is derived from the No-Observed-Effect Level (NO[A]EL), or the Lowest- 809 Observed-Effect Level (LO[A]EL) in the most relevant animal study as follows: 810 811 PDE = NO(A)EL x Mass Adjustment/[F1 x F2 x F3 x F4 x F5] (A.1.1) 812 813 The PDE is derived preferably from a NO(A)EL. If no NO(A)EL is obtained, the LO(A)EL may 814 be used. Modifying factors proposed here, for relating the data to humans, are the same kind of 815 "uncertainty factors" used in Environmental Health Criteria (Ref. 2), and "modifying factors" or 816 "safety factors" in Pharmacopeial Forum. 817 818 The modifying factors are as follows: 819 820 F1 = A factor to account for extrapolation between species 821 F1 = 1 for human data 822 F1 = 5 for extrapolation from rats to humans 823 F1 = 12 for extrapolation from mice to humans 824 F1 = 2 for extrapolation from dogs to humans 825 F1 = 2.5 for extrapolation from rabbits to humans 826 F1 = 3 for extrapolation from monkeys to humans 827 F1 = 10 for extrapolation from other animals to humans 828 F1 takes into account the comparative surface area: body mass ratios for the species concerned 829 and for man. Surface area (S) is calculated as: 830 831 S = kM0.67 (A.1.2) 832 833 in which M = body mass, and the constant k has been taken to be 10. The body masses used in 834 Equation A.1.2 are those shown below in Table A.1.1. 835 F2 = A factor of 10 to account for variability between individuals 23 Contains Nonbinding Recommendations 836 A factor of 10 is generally given for all elemental impurities, and 10 is used consistently in this 837 guidance 838 F3 = A variable factor to account for toxicity studies of short-term exposure 839 F3 = 1 for studies that last at least one half lifetime (1 year for rodents or rabbits; 7 years for cats, 840 dogs and monkeys) 841 F3 = 1 for reproductive studies in which the whole period of organogenesis is covered 842 F3 = 2 for a 6-month study in rodents, or a 3.5-year study in non-rodents 843 F3 = 5 for a 3-month study in rodents, or a 2-year study in non-rodents 844 F3 = 10 for studies of a shorter duration 845 In all cases, the higher factor has been used for study durations between the time points, e.g., a 846 factor of 2 for a 9-month rodent study. 847 F4 = A factor that may be applied in cases of severe toxicity, e.g., non-genotoxic carcinogenicity, 848 neurotoxicity or teratogenicity. In studies of reproductive toxicity, the following factors are used: 849 F4 = 1 for fetal toxicity associated with maternal toxicity F4 = 5 for fetal toxicity without 850 maternal toxicity 851 F4 = 5 for a teratogenic effect with maternal toxicity 852 F4 = 10 for a teratogenic effect without maternal toxicity 853 F5 = A variable factor that may be applied if the NOEL was not established F5 = 1 for a NOEL 854 F5 = 1-5 for a NOAEL F5 = 5-10 for a LOEL 855 F5 = 10 for a Lowest-Observed-Adverse-Effect Level (LOAEL) 856 For most elements the NOAEL was used to set the oral PDE, using a F5 of 1, as the studies did 857 not investigate the difference between a NOAEL and NOEL and the toxicities were not considered 858 "adverse" at the dose selected for determining the PDE. 859 The mass adjustment assumes an arbitrary adult human body mass for either sex of 50 kg. This 860 relatively low mass provides an additional safety factor against the standard masses of 60 kg or 70 861 kg that are often used in this type of calculation. It is recognized that some patients weigh less 862 than 50 kg; these patients are considered to be accommodated by the built-in safety factors used 863 to determine a PDE and that lifetime studies were often used. For lead, the pediatric population is 864 considered the most sensitive population, and data from this population were used to set the PDE. 865 Therefore, the PDEs are considered appropriate for pharmaceuticals intended for pediatric 866 populations. 867 As an example of the application of Equation A.1.1, consider a toxicity study of cobalt in human 868 volunteers as summarized in Tvermoes (Ref. 4). The NOAEL for polycythemia is 1 mg/day. The 869 PDE for cobalt in this study is calculated as follows: 870 PDE = 1 mg/day /(1 x 10 x 2 x 1 x 1) = 0.05 mg/day= 50 µg/day 871 In this example, 872 F1 = 1 study in humans 873 F2 = 10 to account for differences between individual humans 874 F3 = 2 because the duration of the study was 90 days 24 Contains Nonbinding Recommendations 875 F4 = 1 because no severe toxicity was encountered 876 F5 = 1 because a NOAEL was used 877 878 Table A.1.1: Values Used in the Calculations in this Document Rat body weight 425 g Mouse respiratory volume 43 L/day Pregnant rat body weight 330 g Rabbit respiratory volume 1440 L/day Mouse body weight 28 g Guinea pig respiratory volume 430 L/day Pregnant mouse body weight 30 g Human respiratory volume 28,800 L/day Guinea pig body weight 500 g Dog respiratory volume 9,000 L/day Rhesus monkey body weight 2.5 kg Monkey respiratory volume 1,150 L/day Rabbit body weight 4 kg Mouse water consumption 5 mL/day (pregnant or not) Beagle dog body weight 11.5 kg Rat water consumption 30 mL/day Rat respiratory volume 290 L/day Rat food consumption 30 g/day 879 880 881 References 882 883 United States Pharmacopeial Convention, Pharmacopeial Forum, Nov-Dec 1989. 884 IPCS. Assessing Human Health Risks of Chemicals: Derivation of Guidance Values for Health- 885 based Exposure Limits, Environmental Health Criteria 170. International Programme on 886 Chemical Safety. World Health Organization, Geneva. 1994. 887 US FDA, Guidance for Industry and Other Stakeholders: Toxicological Principles for the Safety 888 Assessment of Food Ingredients (Redbook 2000), available at 889 http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInform 890 ation/IngredientsAdditivesGRASPackaging/ucm2006826.htm. 891 Tvermoes BE, Unice KM, Paustenbach DJ, Finley BL, Otani JM, Galbraith DA. 2 0 1 4 , Effects 892 and blood concentrations of cobalt after ingestion of 1 mg/d by human volunteers for 90 d. Am J 893 Clin Nutr, 99:632-46. 894 895 25 Contains Nonbinding Recommendations 896 Appendix 2: Established PDEs for Elemental Impurities 897 898 899 Table A.2.1: Permitted Daily Exposures for Elemental Impurities1 Element Class2 Oral PDE, Parenteral PDE, Inhalation PDE, µg/day µg/day µg/day Cd 1 5 2 3 Pb 1 5 5 5 As 1 15 15 2 Hg 1 30 3 1 Co 2A 50 5 3 V 2A 100 10 1 Ni 2A 200 20 6 Tl 2B 8 8 8 Au 2B 300 300 3 Pd 2B 100 10 1 Ir 2B 100 10 1 Os 2B 100 10 1 Rh 2B 100 10 1 Ru 2B 100 10 1 Se 2B 150 80 130 Ag 2B 150 15 7 Pt 2B 100 10 1 Li 3 550 250 25 Sb 3 1200 90 20 Ba 3 1400 700 300 Mo 3 3000 1500 10 Cu 3 3000 300 30 Sn 3 6000 600 60 Cr 3 11000 1100 3 900 1 PDEs reported in this table (µg/day) have been established on the basis of safety data described in the 901 monographs in Appendix 3, and apply to new drug products. The PDEs in the monographs are not rounded. 902 For practical purposes the PDEs in this table have been rounded to 1 or 2 significant figures. PDEs less than 903 10 have 1 significant figure and are rounded to the nearest unit. PDEs greater than 10 are rounded to 1 or 2 904 significant figures as appropriate. The principles applied to rounding in this table may be applied to PDEs 905 derived for other routes of administration. 906 2 Classification as defined in section IV (4). 26 Contains Nonbinding Recommendations 907 Table A.2.2: Permitted Concentrations of Elemental Impurities for Option 1 908 The values presented in this table represent permitted concentrations in micrograms per gram for 909 elemental impurities in drug products, drug substances and excipients. These concentration 910 limits are intended to be used when Option 1 is selected to assess the elemental impurity content 911 in drug products with daily doses of not more than 10 grams per day. The numbers in this table 912 are based on Table A.2.1. 913 Element Class Oral Concentration Parenteral Inhalation µg/g Concentration Concentration µg/g µg/g Cd 1 0.5 0.2 0.3 Pb 1 0.5 0.5 0.5 As 1 1.5 1.5 0.2 Hg 1 3 0.3 0.1 Co 2A 5 0.5 0.3 V 2A 10 1 0.1 Ni 2A 20 2 0.6 Tl 2B 0.8 0.8 0.8 Au 2B 30 30 0.3 Pd 2B 10 1 0.1 Ir 2B 10 1 0.1 Os 2B 10 1 0.1 Rh 2B 10 1 0.1 Ru 2B 10 1 0.1 Se 2B 15 8 13 Ag 2B 15 1.5 0.7 Pt 2B 10 1 0.1 Li 3 55 25 2.5 Sb 3 120 9 2 Ba 3 140 70 30 Mo 3 300 150 1 Cu 3 300 30 3 Sn 3 600 60 6 Cr 3 1100 110 0.3 914 915 27 Contains Nonbinding Recommendations 916 Appendix 3: Individual Safety Assessments 917 918 ANTIMONY 919 920 Summary of PDE for Antimony Antimony (Sb) Oral Parenteral Inhalation PDE (µg/day) 1200 94 22 921 922 Introduction 923 Antimony (Sb) is a silvery white naturally occurring metalloid element that is used in various 924 manufacturing processes. Small amounts of antimony are found in the earth's crust. It exists in of 925 the +3 and +5 oxidation states. Metallic antimony and a few trivalent antimony compounds are 926 the most significant regarding exposure potential and toxicity. Some antimonials, such as 927 Antimony Potassium Tartrate (APT), have been used medicinally as parasiticides. Antimony 928 trioxide is being used as a catalyst (e.g., in the manufacturing of Polyethylene Terephthalate 929 [PET] used for container closure system components). Antimony is nutritionally not essential 930 and no metabolic function is known (ATSDR, 1992). Antimony and antimony trioxide have low 931 solubility in water whereas ATP is water soluble (WHO, 2003). 932 933 Safety Limiting Toxicity 934 APT was negative for mutagenicity in Salmonella in the presence or absence of S9 (NTP, 1992). 935 In a review of genotoxicity data, conflicting results are obtained, although it appears that Sb(3+) 936 may be positive for clastogenicity (WHO, 2003). Available studies are considered inadequate to 937 assess the risk of carcinogenicity by the oral route (Lynch et al, 1999). In humans and animals, 938 the gastrointestinal tract appears to be the primary target organ after oral exposure and can result 939 in irritation, diarrhea, and vomiting. Antimony is poorly absorbed after oral administration 940 (NTP, 1992). In subchronic studies in rats lower mean body weights and adverse liver findings 941 were the most sensitive endpoints. Inhalation of high levels of antimony over a long period can 942 cause adverse respiratory effects in both humans and animals, including carcinogenicity. In an 943 inhalation carcinogenicity study conducted by Newton et al. (1994), rats were exposed to 944 antimony trioxide for 12 months, followed by a 12-month observation period. Neoplasms were 945 observed with comparable incidence among all groups. The authors conclude that Sb2O3 was not 946 carcinogenic and propose that in previous studies, positive for carcinogenicity, the tumors may 947 be the result of overload with insoluble particulates (Newton et al, 1994; WHO, 2003). 948 949 PDE – Oral Exposure 950 Limited oral data on antimony exposure is available in mice and rats (Schroeder et al., 1968; 951 Schroeder et al, 1970; Poon et al, 1998). The National Toxicology Program (NTP) conducted a 952 14-day study in rats and mice where APT was administered in the drinking water. In this study 953 APT was found to be relatively nontoxic by this route (NTP, 1992). Reevaluating the data of 954 Poon et al. (1998), Lynch et al. concluded that a NOAEL from a 90-day drinking water study in 28 Contains Nonbinding Recommendations 955 rats using 0.5 to 500 ppm APT was 50 ppm based on lower mean body weight and reduced food 956 consumption at the highest dose (Lynch et al, 1999). This finding is consistent with the earlier 957 reports from Schroeder et al. (1970). Thus, the PDE for oral exposure was determined on the 958 basis of the lowest NOAEL, i.e., 50 ppm (equivalent to 6.0 mg Sb/kg/day). 959 Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral PDE is 960 calculated as below: 961 962 PDE = 6000 µg/kg/d x 50 kg / (5 x 10 x 5 x 1 x 1) = 1200 µg/day 963 964 PDE – Parenteral Exposure 965 Adverse liver findings (liver capsule inflammation, liver cell necrosis, and liver degeneration.) 966 were the most sensitive endpoint in rats after repeated intraperitoneal administration. Thus, the 967 parenteral PDE was determined on the basis of the lowest NOAEL, i.e., 3.0 mg APT/kg/day 968 (equivalent to 1.1 mg Sb/kg/d). This value was obtained from a 90-day study in rats (based on 969 adverse liver findings at 6 mg/kg in male rats exposed to APT via intraperitoneal injection) (NTP, 970 1992). No systemic effects were observed at this dose. 971 Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), and correcting 972 for continuous dosing from 3 days per week (factor of 3/7), the parenteral PDE is calculated as 973 below: 974 975 PDE = 1100 µg/kg/d x 3/7 x 50 kg / (5 x 10 x 5 x 1 x 1) = 94 µg/day 976 977 PDE – Inhalation Exposure 978 Sub chronic and chronic inhalation rat studies have been conducted. The lung effects observed 979 across these studies were consistent. Using the data from a 13-week inhalation rat study using 980 antimony trioxide dust at exposure levels of 0.25, 1.08, 4.92 and 23.46 mg/m3, (Newton et al, 981 1994), a NOAEL of 1.08 mg/m3 was used to determine the inhalation PDE (~83% Sb). At higher 982 dose levels an increase in mean absolute and relative lung weights were observed, a finding not 983 seen in the one-year oncogenicity study using exposure levels of 0.06, 0.51 and 4.5 mg/m3. 984 Carcinogenicity was not observed in this study. No adverse effects on hematology or clinical 985 chemistry were seen in either study. 986 Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the 987 inhalation PDE is calculated as: 988 989 For continuous dosing = 0.9 mg/m3 x 6 h/d x 5 d/wk = 0.16 mg/m3 = 0.00016 mg/L 990 24 h/d x 7 d/wk 1000 L/m3 991 992 Daily dose = 0.00016 mg/L x 290 L/d = 0.11 mg/kg/day 993 0.425 kg bw 994 995 PDE = 0.11 mg/kg/d x 50 kg / (5 x 10 x 5 x 1 x 1) = 0.022 mg/d = 22 µg/day 996 29 Contains Nonbinding Recommendations 997 REFERENCES 998 ATSDR. Toxicological profile for antimony and compounds. Agency for Toxic Substances and 999 Disease Registry, Public Health Service, US Department of Health and Human Services, Atlanta, 1000 GA. 1992. 1001 Lynch BS, Capen CC, Nestmann ER, Veenstra G, Deyo JA. Review of subchronic/chronic 1002 toxicity of antimony potassium tartrate. Reg Toxicol Pharmacol 1999;30(1):9-17. 1003 Newton PE, Bolte HF, Daly IW, Pillsbury BD, Terrill JB, Drew RT et al. Subchronic and 1004 chronic inhalation toxicity of antimony trioxide in the rat. Fundam Appl Toxicol 1994;22:561- 1005 76. 1006 NTP. Technical report on toxicity studies of antimony potassium tartrate in F344/N rats and 1007 B6C3F1 mice (drinking water and intraperitoneal injection studies). National Toxicology Program, 1008 Public Health Service, U.S. Department of Health and Human Services, Research Triangle Park, 1009 NC. 1992; NTP Toxicity Report Series No. 11. 1010 Poon R, Chu I, Lecavalier P, Valli VE, Foster W, Gupta S et al. Effects of antimony on rats 1011 following 90-day exposure via drinking water. Food Chem Toxicol 1998;36:20-35. 1012 Schroeder HA, Mitchner M, Nasor AP, Balassa JJ, Kanisawa M. Zirconium, niobium, antimony 1013 and fluorine in mice: effects on growth, survival and tissue levels. J Nutr 1968;95:95-101. 1014 Schroeder HA, Mitchner M, Nasor AP. Zirconium, niobium, antimony, vanadium and lead in 1015 rats: life term studies. J. Nutr 1970;100(1):59-68. 1016 WHO. Antimony in drinking-water. Background document for development of WHO guidelines 1017 for drinking-water quality. World Health Organization, Geneva. 2003. 1018 WHO/SDE/WSH/03.04/74 1019 30 Contains Nonbinding Recommendations 1020 ARSENIC 1021 1022 Summary of PDE for Arsenic Arsenic (As) Oral Parenteral Inhalation PDE (µg/day) 15 15 1.9 1023 1024 Introduction 1025 Arsenic (As) is ubiquitous in the environment and present in food, soil, drinking water and in air. 1026 Inorganic arsenic occurs in trivalent (e.g., arsenic trioxide, sodium arsenite) or pentavalent (e.g., 1027 sodium arsenate, arsenic pentoxide, arsenic acid) forms. Arsenic has no known useful biological 1028 function in human or mammalian organisms. This assessment focuses on inorganic arsenic 1029 because this is most relevant for drug products. 1030 1031 Safety Limiting Toxicity 1032 Inorganic arsenic has shown to be genotoxic, but not mutagenic and has been acknowledged as a 1033 human carcinogen (Group 1; IARC, 2012). 1034 Due to its ubiquitous nature and toxicity profile, there have been many risk assessments 1035 conducted of arsenic and arsenic compounds, which utilize non-threshold, linear dose response 1036 approaches (Meharg and Raab, 2010). 1037 For the most part the effects of arsenic in humans have not been reproduced in animals, so the 1038 risk assessments have to rely heavily upon epidemiology data in populations with high exposure 1039 concentrations (Schuhmacher-Wolz et al., 2009). In humans, both cancer and non-cancer effects 1040 have been linked to arsenic exposure. Oral exposure has been linked to cancers of the skin, liver, 1041 lung, kidney, and bladder. Following inhalation exposure there is evidence for an increased risk 1042 of lung cancer (ATSDR, 2007; IARC, 2012; EU EFSA, 2009; WHO, 2011; US EPA, 2010). 1043 The skin (dyspigmentation, palmoplantar keratosis) and gastrointestinal tract (e.g., nausea) appear 1044 to be the most sensitive targets for non-cancer adverse effects after oral ingestion while vascular 1045 disease, reproductive effects and neurological effects are also reported as non-cancer endpoints 1046 (IARC, 2012; Schuhmacher-Wolz et al., 2009; US EPA, 2007). Oral exposure studies suggest 1047 that skin lesions may appear at levels above 0.02 mg As/kg/day; no effects were generally seen 1048 at levels from 0.0004 to 0.01 mg As/kg/day (ATSDR, 2007). There are insufficient 1049 epidemiological data to set a LOEL or NOEL for other endpoints. The regions of hyperkeratosis 1050 may evolve into skin cancers (ATSDR, 2007) and can possibly be considered predictive of skin 1051 and internal cancers and the non-cancer long-term adverse health effects (Chen et al, 2005; Hsu 1052 et al., 2013; Ahsan and Steinmaus, 2013). 1053 Studies of large populations (~40,000) exposed to arsenic concentrations in well water at 1000 1054 µg/L and higher in southwestern Chinese Taipei have been the basis of risk assessments of skin 1055 cancer, and more recently of bladder and lung cancer (US EPA, 2010). Recent meta-analyses of 1056 cancer risk have indicated no additional bladder cancer risk at low dose exposure (<100–200 1057 µg/L) (Chu and Crawford-Brown, 2006, 2007; Mink et al., 2008). This is consistent with the 1058 work of Schuhmacher-Wolz et al., (2009). 31 Contains Nonbinding Recommendations 1059 An inhalation unit risk for cancer of 0.0043 per µg/m3 has been established by the US EPA based 1060 on data from two US smelters (US EPA, 2007). The Texas Commission on Environmental 1061 Quality provided an update to the US EPA Unit Risk Factor (URF), incorporating additional 1062 years of follow-up to the US EPA data and additional data on workers from the United Kingdom 1063 and Sweden. The Commission calculated a URF of 0.0015 per µg/m3. This URF translates to an 1064 air concentration of 0.067 µg/m3 at a risk of 1 in 100,000 excess lung cancer mortality 1065 (Erraguntla et al., 2012). 1066 1067 PDE – Oral Exposure 1068 1069 The oral PDE is based on the chronic effects of arsenic to skin and sets the limit at 15 µg/day 1070 based on Agency for Toxic Substances and Disease Registry (ATSDR) MRL and US EPA limit 1071 of 0.0003 mg/kg/day (ATSDR, 2007; US EPA 2007; EU EFSA, 2009). The PDE calculated 1072 based on the ATSDR MRL is consistent with drinking water standards (WHO, 2011). 1073 PDE = 0.0003 mg/kg/d x 50 kg = 0.015 mg/d = 15 µg/day 1074 No modifying factors were applied because they are incorporated into the derivation of the MRL. 1075 1076 PDE – Parenteral Exposure 1077 The oral bioavailability of arsenic is ~95%. The most direct evidence is from a study that 1078 evaluated the 6-day elimination of arsenic in healthy humans who were given water from a high- 1079 arsenic sampling site (arsenic species not specified) and that reported approximately 95% 1080 absorption (Zheng et al., 2002). Therefore, the PDE is identical to the oral PDE. 1081 PDE = 15 µg/day 1082 1083 PDE – Inhalation Exposure 1084 Increased risk of lung cancer and other respiratory disorders have been reported following 1085 inhalation exposure to workers in the occupational setting. The rationale for using a cancer 1086 endpoint for inhalation to set the PDE is the relative lack of information on linear-dose 1087 extrapolation, as compared to the oral route. No modifying factors are needed as the URF were 1088 determined for the protection of the general public. Based on the assessment conducted by 1089 Erraguntla et al. (2012), based on the risk of 1:100.000, the inhalation PDE is: 1090 1091 PDE = 0.067 µg/m3 / 1000 L/m3 x 28800 L/d = 1.9 µg/day 1092 1093 No modifying factors were applied because the PDE is based on a URF derived from the 1094 multiplicate relative risk model described by Erraguntla et al. (2012). 1095 1096 REFERENCES 1097 Ahsan H, Steinmaus C. Invited commentary: use of arsenical skin lesions to predict risk of 1098 internal cancer-implications for prevention and future research. Am J Epidemiol 2013;177:213-6. 1099 ATSDR. Toxicological profile for arsenic. Agency for Toxic Substances and Disease Registry, 1100 Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 2007. 32 Contains Nonbinding Recommendations 1101 Chen CJ, Hsu LI, Wang CH, Shih WL, Hsu YH, Tseng MP et al. Biomarkers of exposure, effect, 1102 and susceptibility of arsenic-induced health hazards in Taiwan. Toxicol Appl Pharmacol 1103 2005;206:198-206. 1104 Chu HA, Crawford-Brown DJ. Inorganic arsenic in drinking water and bladder cancer: a 1105 metaanalysis for dose-response assessment. Int J Environ Res Public Health 2006;3:316-22. 1106 Chu HA, Crawford-Brown DJ. Inorganic arsenic in drinking water and bladder cancer: a 1107 metaanalysis for dose-response assessment. Int J Environ Res Public Health 2007;4:340-1. 1108 Erraguntla NK, Sielken RL Jr, Valdez-Flores C, Grant RL. An updated inhalation unit risk factor 1109 for arsenic and inorganic arsenic compounds based on a combined analysis of epidemiology 1110 studies. Regul Toxicol Pharmacol 2012;64:329-41. 1111 EU EFSA. Scientific opinion on arsenic in food. European Food Safety Authority. EFSA Journal 1112 2009;7(10):1351. 1113 Hsu LI, Chen GS, Lee CH, Yang TY, Chen YH, Wang YH et al. Use of arsenic-induced 1114 palmoplantar hyperkeratosis and skin cancers to predict risk of subsequent internal malignancy. 1115 Am J Epidemiol 2013;173:202-12. 1116 IARC. Arsenic, metals, fibres, and dusts: a review of human carcinogens. Monographs on the 1117 Evaluation of Carcinogenic Risks to Humans. International Agency for Research on Cancer, 1118 World Health Organization, Lyon. 2012;100C. 1119 Meharg AA, Raab A. Getting to the bottom of arsenic standards and guidelines. Environ Sci 1120 Technol 2010;44:4395-9. 1121 Mink PJ, Alexander DD, Barraj LM, Kelsh MA, Tsuji JS. Low-level arsenic exposure in 1122 drinking water and bladder cancer: a review and meta-analysis. Regul Toxicol Pharmacol 1123 2008;58:299-310. 1124 Schuhmacher-Wolz U, Dieter HH, Klein D, Schneider K. Oral exposure to inorganic arsenic: 1125 and evaluation of its carcinogenic and non-carcinogenic effects. Crit Rev Toxicol 2009;39:271- 1126 98. 1127 US EPA. Arsenic, inorganic (CASRN 7440-38-2). Integrated Risk Information System (IRIS). 1128 1998. US EPA. Inorganic arsenic. TEACH Chemical Summary. 2007. 1129 US EPA. Toxicological review of inorganic arsenic (CAS No. 7440-38-2). In support of 1130 summary information on the Integrated Risk Information System (IRIS). 2010. 1131 WHO. Arsenic in drinking-water. Background document of development of WHO Guidelines 1132 for Drinking-water quality. World Health Organization, Geneva. 2011. 1133 WHO/SDE/WSH/03.04/75/Rev/1. 1134 Zheng Y, Wu J, Ng JC, Wang G, Lian W. The absorption and excretion of fluoride and arsenic 1135 in humans. Toxicol Lett 2002;133:77-82. 1136 33 Contains Nonbinding Recommendations 1137 BARIUM 1138 1139 Summary of PDE for Barium Barium (Ba) Oral Parenteral Inhalation PDE (µg/day) 1460 730 343 1140 1141 Introduction 1142 Barium (Ba) is a dense, silver-white, soft alkaline earth metal that oxidizes readily in moist air and 1143 reacts with water. The Ba(2+) ion and the water soluble compounds of barium (chloride, nitrate, 1144 hydroxide) are toxic. The insoluble compounds of barium, such as barium sulfate, do not 1145 generate free Ba(2+) ions in the gastrointestinal tract and therefore are generally nontoxic to 1146 humans. Barium is nutritionally not essential and no metabolic function is known. Barium sulfate 1147 has multiple uses e.g., as a radiocontrast medium, a colorant in paint and in the manufacture of 1148 glass and other products (ATSDR, 2007). 1149 1150 Safety Limiting Toxicity 1151 In animals and humans, the kidney appears to be the most sensitive target of toxicity resulting 1152 from repeated ingestion of soluble barium salts. Chronic rodent studies support the evidence for 1153 an association between barium exposure and renal toxicity (NTP, 1994). The lesions were 1154 characterized by tubule dilatation, renal tubule atrophy, tubule cell regeneration, hyaline cast 1155 formation, multifocal interstitial fibrosis, and the presence of crystals, primarily in the lumen of 1156 the renal tubules. These changes were characterized as morphologically distinct from the 1157 spontaneous degenerative renal lesions commonly observed in aging mice. Effects on blood 1158 pressure may be the most sensitive endpoint observed in humans after environmental exposure 1159 (WHO, 2004). Repeated exposure to barium oxide via inhalation may cause bronchitis, including 1160 cough, phlegm, and/or shortness of breath (CICAD, 2001). 1161 1162 PDE – Oral Exposure 1163 In an evaluation conducted in two towns in Illinois, no significant differences in blood pressure or 1164 in the prevalence of cardiovascular or kidney disease was found between populations drinking 1165 water containing a mean barium concentration of 7.3 mg/L or 0.1 mg/L (WHO, 2004). Using the 1166 NOAEL of 1167 7.3 mg/L obtained from this study, and using 2 L/day as an estimation of water intake, the oral 1168 PDE can be calculated as: 1169 1170 PDE = 14.6 mg/d / (1 x 10 x 1 x 1 x 1) = 1.46 mg/d = 1460 µg/day 1171 1172 PDE – Parenteral Exposure 1173 No relevant data on parenteral exposure to barium compounds were found. The bioavailability of 1174 barium is estimated to be 20-60% in adults and infants, respectively (ATSDR, 2007). Thus, the 1175 parenteral PDE was calculated by dividing the oral PDE by a modifying factor of 2 (as described 1176 in section 3.1). 1177 PDE = 1460 µg/d / 2 = 730 µg/day 34 Contains Nonbinding Recommendations 1178 1179 PDE – Inhalation Exposure 1180 No relevant data on inhalation exposure to barium compounds were found. United States 1181 Department of Labor (US DoL, 2013) has a reported Time Weighted Average (TWA) of 0.5 1182 mg/m3 based on soluble barium salts. 1183 Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the inhalation 1184 PDE is calculated as: 1185 1186 For continuous dosing = 500 µg/ m3 x 8 hr/d x 5 d/wk = 119 µg/ m3 = 0.119 µg/L 1187 24 hr/d x 7 d/wk 1000 L/m3 1188 1189 Daily dose = 0.119 µg/L x 28800 L = 68.6 µg/kg 1190 50 kg 1191 1192 PDE = 68.6 µg/kg x 50 kg / (1 x 10 x 1 x 1 x 1) = 343 µg/day 1193 1194 REFERENCES 1195 ATSDR. Toxicological profile for barium and barium compounds. Agency for Toxic Substances 1196 and Disease Registry, Public Health Service, U.S. Department of Health and Human Services, 1197 Atlanta, GA. 2007. 1198 CICAD. Barium and barium compounds. Concise International Chemical Assessment Document 1199 33. World Health Organization, Geneva. 2001. 1200 NTP. Technical report on the toxicology and carcinogenesis studies of barium chloride dihydrate 1201 (CAS No. 10326-27-9) in F344/N rats and B6C3F1 mice (drinking water studies). National 1202 Toxicology Program, Public Health Service, U.S. Department of Health and Human Services, 1203 Research Triangle Park, NC. 1994;NTP TR 432. 1204 US DoL (OHSA). 29 CRF 1910.1000 Table Z-1. Limits for air contaminants. U.S. Department of 1205 Labor. 2013. 1206 WHO. Barium in drinking-water: Background document for development of WHO guidelines 1207 for drinking-water quality. World Health Organization, Geneva. 2004. 1208 WHO/SDE/WSH/03.04/76. 1209 35 Contains Nonbinding Recommendations 1210 CADMIUM 1211 1212 Summary of PDE for Cadmium Cadmium (Cd) Oral Parenteral Inhalation PDE (µg/day) 5.0 1.7 3.4 1213 1214 Introduction 1215 Cadmium (Cd) is a transition metal whose most abundant naturally-occurring isotope is non- 1216 radioactive. It is found in nature in mineral forms and is obtained for commercial uses principally 1217 from cadmium ore (ATSDR, 2012). Cadmium exists as a salt form in the +2 oxidation state only. 1218 Some cadmium salts such as cadmium chloride, cadmium sulfate and cadmium nitrate are water 1219 soluble; other insoluble salts can become more soluble by interaction with acids, light or oxygen. 1220 Cadmium, cadmium oxide, cadmium salts on borosilicate carrier are used as catalysts in organic 1221 synthesis. Silver cadmium alloy is used in the selective hydrogenation of carbonyl compounds. 1222 1223 Safety Limiting Toxicity 1224 Cadmium has shown to be genotoxic, but not mutagenic and has been acknowledged as a human 1225 carcinogen (Group 1; IARC, 2012). Cadmium and cadmium compounds cause cancer of the lung. 1226 Also, positive associations have been observed between exposure to cadmium and cadmium 1227 compounds and cancer of the kidney and of the prostate. 1228 A sensitive endpoint for oral exposure to cadmium and cadmium salts is renal toxicity (Buchet et 1229 al. 1990). Skeletal and renal effects are observed at similar exposure levels and are a sensitive 1230 marker of cadmium exposure (ATSDR, 2012). 1231 Evidence from numerous epidemiologic studies assessing inhalation exposures to cadmium via 1232 both occupational and environmental routes has demonstrated an increased risk of developing 1233 cancer (primarily lung) that correlates with inhalation exposure to cadmium (IARC, 2012; NTP, 1234 1995). ATSDR (2012) concluded that lung carcinogenesis due to occupational exposure was 1235 equivocal. Cadmium was clearly positive for lung tumors in rats; non-significant, non-dose 1236 dependent in mice; and not observed in hamsters. An inhalation unit risk estimate of 1237 0.0018/µg/m3 has been derived by the US EPA (1992); however, a modifying factor approach 1238 may be used for non-mutagenic carcinogens. The US Department of Labor has a reported a 1239 Permitted Exposure Level of 5 µg/m3 for cadmium (Cadmium OSHA, 2004). 1240 1241 PDE – Oral Exposure 1242 A sensitive endpoint for oral exposure to cadmium and cadmium salts is renal toxicity (Buchet et 1243 al, 1990). Skeletal and renal effects are observed at similar exposure levels and are a sensitive 1244 marker of cadmium exposure (ATSDR, 2012). A number of oral exposure studies of cadmium in 1245 rats and mice showed no evidence of carcinogenicity. Therefore, the renal toxicity endpoint was 1246 used to establish the oral PDE for cadmium, following the recommendations of ATSDR, an 1247 MRL of 0.1 µg/kg for chronic exposure is used to set the oral PDE. This is consistent with the 1248 WHO drinking water limit of 0.003 mg/L/day (WHO, 2011). 1249 1250 PDE = 0.1 µg/kg/d x 50 kg = 5.0 µg/day 36 Contains Nonbinding Recommendations 1251 1252 No modifying factors were applied because they are incorporated into the derivation of the MRL. 1253 1254 PDE – Parenteral Exposure 1255 A 12-week study in rats given daily subcutaneous injections of 0.6 mg/kg Cd, 5 days per week 1256 showed renal damage at week 7 and later (Prozialeck et al, 2009). A single dose level was used 1257 in this study. The LOAEL of this study is 0.6 mg/kg based on decreased body weight, increased 1258 urine volume and urinary biomarkers seen at this dose level. This study was used to set the 1259 parenteral PDE. In a separate single dose study where rats were administered a 0, 1, 2, 4, 8, 16 or 1260 32 µmol/kg cadmium chloride by the subcutaneous route, sarcomas were noted at the injection 1261 site at the two highest doses at the end of the 72-week observation period (Waalkes et al, 1999). 1262 It is uncertain whether the granulomas at the sites of injection over time trap an unspecified 1263 amount of the administered cadmium dose at the injection site. This phenomenon may decrease 1264 the actual parenteral cadmium dose, compared with the calculated parenteral cadmium dose. 1265 Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), and correcting for 1266 continuous dosing from 5 days to 7 days per week (factor of 5/7), the parenteral PDE is 1267 calculated as: 1268 1269 PDE = 0.6 mg/kg x 5/7 x 50 kg / (5 x 10 x 5 x 5 x 10) = 1.7 µg/day 1270 1271 A factor of five was chosen for F4 because cadmium is carcinogenic by the inhalation route and 1272 granulomas were observed by the subcutaneous route. These findings are of uncertain relevance. 1273 A factor of ten was chosen for F5 because a LOAEL was used to set the PDE. 1274 1275 PDE – Inhalation Exposure 1276 The United States Department of Labor Occupational Safety and Health Administration has 1277 developed a Permitted Exposure Level of 5 µg/m3 for cadmium. 1278 Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the inhalation 1279 PDE is calculated as: 1280 1281 For continuous dosing = 5 µg/ m3 x 8 hr/d x 5 d/wk = 1.19 µg/m3 = 0.00119 µg/L 1282 24 hr/d x 7 d/wk 1000 L/m3 1283 1284 Daily dose = 0.00119 µg/L x 28800 L = 0.685 µg/kg 1285 50 kg 1286 1287 PDE = 0.685 µg/kg x 50 kg / (1 x 10 x 1 x 1 x 1) = 3.43 µg/day 1288 1289 A modifying factor for F4 of 1 was chosen based on the potential for toxicity to be mitigated by 1290 the possible species specificity of tumorigenesis, uncertain human occupational tumorigenesis, 1291 ambient exposure levels not expected to be a health hazard, and workplace exposure levels 1292 expected to be safe. A larger factor F4 was not considered necessary as the PDE is based on a 1293 PEL. 1294 37 Contains Nonbinding Recommendations 1295 REFERENCES 1296 ATSDR. Toxicological profile of cadmium. Agency for Toxic Substances and Disease Registry, 1297 Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 2012. 1298 Buchet JP, Lauwerys R, Roels H, Bernard A, Bruaux P, Claeys F et al. Renal effects of cadmium 1299 body burden of the general population. Lancet 1990;336:699-702. 1300 Cadmium: OSHA 3136-06R, 2004. (available at 1301 https://www.osha.gov/Publications/osha3136.pdf; accessed October 10, 2017) 1302 IARC. Arsenic, metals, fibers, and dusts: a review of human carcinogens. Monographs on the 1303 Evaluation of Carcinogenic Risks to Humans. International Agency for Research on Cancer, 1304 World Health Organization, Lyon. 2012;100C. 1305 NTP. Technical report on toxicity studies of cadmium oxide (CAS No. 1306-19-0) 1306 administered by inhalation to F344/N Rats and B6C3F1 mice. National Toxicology 1307 Program, Public Health Service, U.S. Department of Health and Human Services. 1995. 1308 Prozialeck WC, Edwards JR, Vaidya VS, Bonventre JV. Preclinical evaluation of novel urinary 1309 biomarkers of cadmium nephrotoxicity. Toxicol Appl Pharmacol 2009;238:301-305. 1310 US EPA. Cadmium. Integrated Risk Information System (IRIS). 1992. 1311 Waalkes MP, Anver M, Diwan BA. Carcinogenic effects of cadmium in the Noble (NBL/Cr) rat: 1312 induction of pituitary, testicular, and injection site tumors and intraepithelial proliferative lesions 1313 of the dorsolateral prostate. Toxicol Sci 1999;52:154-161. 1314 WHO. Cadmium in drinking-water. Background document for development of WHO Guidelines 1315 for drinking-water quality. World Health Organization. 2011;WHO/SDE/WSH/03.04/80/Rev/1. 1316 38 Contains Nonbinding Recommendations 1317 CHROMIUM 1318 1319 Summary of PDE for Chromium Chromium (Cr) Oral Parenteral Inhalation PDE (µg/day) 10700 1070 2.9 1320 1321 Introduction 1322 Chromium (Cr) is found in a variety of oxidation states, the most important being Cr(0) (in 1323 stainless steel) Cr(2+), Cr(3+) and Cr(6+). Cr (2+) is readily oxidized and is used as a reducing 1324 agent in chemical synthesis. Cr(6+) is a powerful oxidant, 4 chromate, CrO 2-,2 and 7 dichromate, Cr 1325 O , being the best known oxyanions. Cr(3+), the most abundant environmental form, is an 2- 1326 essential element that plays a role in glucose metabolism. Chromium deficiency causes changes 1327 in the metabolism of glucose and lipids and may be associated with maturity-onset diabetes, 1328 cardiovascular diseases, and nervous system disorders (Anderson, 1993, 1995). Sources of 1329 chromium in pharmaceuticals may include colorants, leaching from equipment or container 1330 closure systems, and catalysts. Except when it is used as a catalyst, intake of chromium from 1331 pharmaceuticals will be in the form of metallic chromium (Cr(0)) or Cr(3+) rather than the more 1332 toxic Cr(6+); therefore, for drug products, this safety assessment is based on the known toxicity 1333 of Cr(3+) and Cr(6+) is excluded from this assessment. If Cr(6+) is used as a catalyst, then the 1334 assessment should incorporate this form. Chromium present as a colorant (e.g., chromium oxide 1335 green, chromium hydroxide green) is intentionally added and thus beyond the scope of this 1336 guidance. 1337 1338 Safety Limiting Toxicity 1339 Rats fed diets containing up to 5% Cr2O3 (equivalent to 1468 mg Cr/kg/day) for a lifetime 1340 showed no adverse effects. In a more recent dietary rat study (Anderson et al, 1997), no adverse 1341 effects were detected at 15 mg Cr(3+)/kg/day. No specific target organ toxicities have been 1342 identified for the oral intake of chromium. Generally oral intake of 1.5 mg/kg/day Cr(3+) (US 1343 EPA, 1998) is not expected to be associated with adverse health. 1344 The data was reviewed to identify the safety limiting toxicities based on routes of administration. 1345 1346 PDE – Oral Exposure 1347 The 2-year NTP studies (2010) on the carcinogenicity of Cr(3+) picolinate administered in feed 1348 to rats and mice at 2000, 10000 and 50000 ppm provided the most relevant safety information 1349 for chromium as present in drug products. The NOAEL was the low dose of 90 mg/kg Cr(3+) 1350 picolinate (11.9 weight %; 10.7 mg/kg/day Cr(3+)) in rats based on increase in the incidence of 1351 preputial gland adenoma in male rats at 460 mg/kg. This finding was not dose-dependent and was 1352 considered an equivocal finding by the study authors. This finding was not observed male mice 1353 or in the female counterpart in either species (clitoral gland). Taking into account the modifying 1354 factors (F1-F5 as discussed in Appendix 1), the oral PDE is calculated as: 1355 1356 PDE = 10.7 mg/kg/d x 50 kg / (5 x 10 x 1 x 1 x 1) = 10.7 mg/day 1357 39 Contains Nonbinding Recommendations 1358 PDE – Parenteral Exposure 1359 Recommendation for the nutritional intravenous administration of Cr(3+) vary per age group 1360 between 0.05 µg/kg/day in preterm infants and 15 µg/kg in adults (Moukazel, 2009). There is 1361 insufficient information to assess if exceeding these recommended daily doses may lead to 1362 adverse responses e.g., for the kidney especially in newborns and preterm infants. 1363 The safety review for chromium was unable to identify any significant assessments upon which 1364 to calculate a PDE for parenteral routes of exposure. On the basis of an oral bioavailability of 1365 about 10% for chromium and inorganic chromium compounds (ATSDR, 2012), the parenteral 1366 PDE was calculated by dividing the oral PDE by a modifying factor of 10 (as described in 1367 section 3.1). The recommended PDE for chromium for parenteral exposure is: 1368 1369 PDE = 10700 µg/d / 10 = 1070 µg/day 1370 1371 PDE – Inhalation Exposure 1372 The study by Derelenko et al. (1999) used inhalation of Cr(3+) sulfate particles during 13 weeks 1373 (6h/day and 5 days per week), and the predominant observed effects were chronic inflammation 1374 of the airways (mononuclear infiltrate, particular material) and local thickening of alveolar walls. 1375 The effect was observed at all doses. The LOAEL is 17 mg/m3 (3 mg Cr(3+)/m3). A lack of 1376 systemic toxicity was noted in a 13-week inhalation study in rats administered soluble or 1377 insoluble Cr(3+). Based on these data, the inhalation MRL of 0.1µg/m3 was used to set the PDE 1378 (ATSDR, 2012). 1379 1380 PDE = 0.0001 mg/m3 / 1000 m3/L x 28800 L/day = 2.9 µg/day 1381 1382 No modifying factors were applied because they are incorporated into the derivation of the MRL. 1383 1384 REFERENCES 1385 Anderson RA. Recent advances in the clinical and biochemical effects of chromium deficiency. 1386 Prog Clin Biol Res 1993;380:221-34. 1387 Anderson RA. Chromium and parenteral nutrition. Nutr 1995;11(1 suppl.):83-6. 1388 ATSDR. Toxicological profile of chromium. Agency for Toxic Substances and Disease Registry, 1389 Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 2012. 1390 Derelanko MJ, Rinehart WE, Hilaski RJ, Thompson RB, Löser E. Thirteen week subchronic rat 1391 inhalation toxicity study with a recovery phase of trivalent chromium compounds, chromic 1392 oxide, and basic chromium sulfate. Toxicol Sci 1999;52:278-88. 1393 Glaser U, Hochrainer D, Klöppel H, Oldiges H. Carcinogenicity of sodium dichromate and 1394 chromium (VI/III) oxide aerosols inhaled by male Wistar rats. Toxicology. 1986;42(2-3):219-32. 1395 Moukarzel A. Chromium in parenteral nutrition: too little or too much. Gastroenterology 1396 2009;137:S18- S28. 1397 NTP. Technical report on the toxicology and carcinogenesis studies of chromium picolinate 1398 monohydrate (CAS NO. 27882-76-4) in F344/N rats and B6C3F1 mice (feed studies). National 40 Contains Nonbinding Recommendations 1399 Toxicology Program, Public Health Service, U.S. Department of Health and Human Services. 1400 2010;NTP TR 556. 1401 US DoL (OHSA). 29 CRF 1910.1000 Table Z-1. Limits for air contaminants. U.S. Department of 1402 Labor. 2013. 1403 US EPA. Chromium (III), insoluble salts. Integrated Risk Information System (IRIS). 1998. 41 Contains Nonbinding Recommendations 1404 COBALT 1405 1406 Summary of PDE for Cobalt Cobalt (Co) Oral Parenteral Inhalation PDE (µg/day) 50 5.0 2.9 1407 1408 Introduction 1409 Cobalt (Co) is a naturally-occurring element, often combined with other elements such as oxygen, 1410 sulfur, and arsenic. Cobalt is essential in the human body because it is an integral component of 1411 Vitamin B12 and functions as a co-enzyme for several enzymes critical in the synthesis of 1412 hemoglobin and the prevention of pernicious anemia. The average person receives about 11 µg 1413 Co/day in the diet (ATSDR, 2004). The Recommended Dietary Allowance of Vitamin B12 1414 ranges from 0.7 to 2.4 µg/day (NAS, 2010), which corresponds to 0.03 to 0.1 µg of cobalt. No 1415 essential biological function of inorganic cobalt in the human body has been identified. Cobalt 1416 compounds (e.g., cobalt octanoate) are being used as catalysts in selective hydrogenation. 1417 1418 Safety Limiting Toxicity 1419 The International Agency for Research on Cancer (IARC, 2006) concluded that Cobalt sulfate and 1420 other soluble Co(2+) salts are possible human carcinogens (Group 2B). The data indicate the 1421 location of tumors is limited to the lung in rats and humans. Cobalt metal was positive for 1422 mutagenicity in vitro but negative for clastogenicity in vivo. The NTP concluded that there was 1423 clear evidence of carcinogenicity in male and female mice and rats (NTP, 2013). Human studies 1424 for carcinogenicity by inhalation are inconclusive and not classified for carcinogenicity (US 1425 EPA, 2000). Polycythemia is considered to be the most sensitive finding after repeated oral 1426 exposure to humans (ATSDR, 2004). Inhalation exposure of humans to cobalt has been 1427 associated with a severe and progressive respiratory disease known as hard-metal 1428 pneumoconiosis, as well as asthma and contact dermatitis (ATSDR, 2004; IARC, 2006). 1429 1430 PDE – Oral Exposure 1431 The oral PDE is based on the available human data. Polycythemia was a sensitive endpoint in 1432 humans after repeated oral exposure to 150 mg of cobalt chloride for 22 days (~1 mg Co/kg/day; 1433 WHO, 2006; ATSDR, 2004). Polycythemia or other effects were not observed in a study of 10 1434 human volunteers (5 men and 5 women) ingesting 1 mg/Co per day as CoCl2 for 88-90 days 1435 (Tvermoes et al, 2014). The oral PDE was determined on the basis of the NOAEL of 1 mg/day. 1436 Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral PDE is 1437 calculated as below: 1438 1439 PDE = 1 mg/d / (1 x 10 x 2 x 1 x 1) = 0.05 mg/d = 50 µg/day 1440 1441 A factor of 2 was chosen for F3 because a short-term human study was used to set the PDE. 1442 1443 PDE – Parenteral Exposure 1444 No relevant data on parenteral exposure to cobalt compounds were found. The oral 1445 bioavailability of cobalt and inorganic cobalt compounds ranges from 18-97% (ATSDR, 2004). 42 Contains Nonbinding Recommendations 1446 To account for the low oral bioavailability, the parenteral PDE was calculated by dividing the 1447 oral PDE by a modifying factor of 10 (as described in section 3.1). The PDE for cobalt for 1448 parenteral exposure is: 1449 1450 PDE = 50 µg/d / 10 = 5.0 µg/day 1451 1452 PDE – Inhalation Exposure 1453 Cobalt sulfate and other soluble Co(2+) salts are possible human carcinogens (Group 2B) that can 1454 induce lung tumors. 1455 Pneumoconiosis, asthma and contact dermatitis were the principal non-carcinogenic effects in 1456 humans after chronic inhalation. The MRL approach was considered acceptable for cobalt as the 1457 data are considered more reliable and the lack of human data for carcinogenicity cobalt sulfate. 1458 The best estimate of human cancer risk is approximately the same as the PDE derived using the 1459 MRL (WHO, 2006). For the calculation of the inhalation PDE, the chronic inhalation MRL of 1460 0.1 µg/ m3 was used (ATSDR, 2004). 1461 1462 PDE = 0.0001 mg/ m3 /1000 m3/L x 28800 L/d = 2.9 µg/day 1463 1464 No modifying factors were applied because they are incorporated into the derivation of the MRL. 1465 1466 REFERENCES 1467 ATSDR. Toxicological profile for cobalt. Agency for Toxic Substances and Disease Registry, 1468 Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 2004. 1469 IARC. Cobalt in hard metals and cobalt sulfate, gallium arsenide, indium phosphide and 1470 vanadium pentoxide. International Agency for Research on Cancer, World Health Organization, 1471 Lyon. 2003;86, updated in 2006. 1472 NAS.IOM. Food and Nutrition Board. Dietary Reference Intakes: RDA and AI for vitamins and 1473 elements. Institute of Medicine National Academies. Summary Tables, 2010. (available online at 1474 http://fnic.nal.usda.gov/dietary-guidance/dietary-reference-intakes/dri-tables; accessed May 27, 1475 2014) 1476 NTP. Technical report on the toxicology studies of cobalt metal (CAS No. 7440-48-4) in F344/N 1477 rats and B6C3F1/N mice and toxicology and carcinogenesis studies of cobalt metal in 1478 F344/NTac rats and B6C3F1/N mice (inhalation studies). National Toxicology Program, Public 1479 Health Service, U.S. Department of Health and Human Services, Research Triangle Park, NC. 1480 2013;NTP TR 581. 1481 Tvermoes BE, Unice KM, Paustenbach DJ, Finley BL, Otani JM, Galbraith DA. Effects and 1482 blood concentrations of cobalt after ingestion of 1 mg/day by human volunteers for 90 d. Am J 1483 Clin Nutr 2014;99:632-646. 1484 US EPA. Cobalt compounds: technology transfer network air toxics web site: Hazard summary. 1485 2000 (http://www.epa.gov/ttn/atw/hlthef/cobalt.html; accessed April 23, 2014). 43 Contains Nonbinding Recommendations 1486 WHO. Cobalt and inorganic cobalt compounds. Concise International Chemical Assessment 1487 Document. Inter-Organization Programme for the Sound Management of Chemicals (IOMC). 1488 World Health Organization. 2006;69. 44 Contains Nonbinding Recommendations 1489 COPPER 1490 Summary of PDE for Copper Copper (Cu) Oral Parenteral Inhalation PDE (µg/day) 3400 340 34 1491 1492 Introduction 1493 Copper (Cu) is a Group 11 element of the first transition series and has two main oxidation states, 1494 Cu(1+) and Cu(2+). It is an essential trace element in both animals and humans. Copper plays a 1495 vital role in a number of critical enzyme systems and is closely linked with normal 1496 hematopoiesis and cellular metabolism. Copper compounds (e.g., copper chromite) are being 1497 used as catalysts in hydrogenolysis and decarboxylation reactions. 1498 1499 Safety Limiting Toxicity 1500 A general review of relevant safety data for animals and humans indicates that copper can 1501 produce adverse effects to the gastrointestinal tract, liver, and kidney upon ingestion of toxic 1502 doses (Araya et al, 2003). 1503 1504 PDE – Oral Exposure 1505 Studies on cupric sulfate and copper 8-quinolinolate have been conducted in mice, rats, and dogs 1506 (IPCS, 1998). Rats were determined to be the most sensitive of these species to effects on liver 1507 and kidney. In a 13-week study in which rats were fed 500 to 8000 ppm cupric sulfate 1508 pentahydrate, the NOEL for hyperplasia and hyperkeratosis of the forestomach mucosa was 1000 1509 ppm. Hepatic and renal toxicity was observed from doses equal to and greater than 2000 ppm. 1510 The NOEL was 1000 ppm, equivalent to 64 mg CuSO4/kg/day (17 mg Cu/kg/day). (Hébert et al, 1511 1993; IPCS, 1998). Taking into account the modifying factors (F1-F5 as discussed in Appendix 1512 1), the oral PDE is calculated as: 1513 1514 PDE = 17 mg/kg/d x 50 kg / (5 x 10 x 5 x 1 x 1) = 3400 µg/day 1515 1516 PDE – Parenteral Exposure 1517 The safety review for copper was unable to identify any significant assessments upon which to 1518 calculate a PDE for parenteral routes of exposure. The human gastrointestinal system can absorb 1519 30-40% of ingested copper from the typical diets consumed in industrialized countries (Wapnir, 1520 1998). On the basis of limited oral bioavailability of 30-40% for copper and inorganic copper 1521 salts, the parenteral PDE was calculated by dividing the oral PDE by a modifying factor of 10 (as 1522 described in section 3.1). The recommended PDE for copper for parenteral exposure is: 1523 1524 PDE = 3400 µg/d / 10 = 340 µg/day 1525 1526 PDE – Inhalation Exposure 1527 The available data on the toxicity of inhaled copper were considered inadequate for derivation of 1528 acute- intermediate-, or chronic-duration inhalation MRLs (ATSDR, 2004). The inhalation 45 Contains Nonbinding Recommendations 1529 PDE was calculated by dividing the oral PDE by a modifying factor of 100 (as described in 1530 section 3.1). 1531 1532 PDE = 3400 µg/day / 100 = 34 µg/day 1533 1534 REFERENCES 1535 Araya M, Olivares M, Pizarro F, González M, Speisky H, Uauy R. Gastrointestinal symptoms and 1536 blood indicators of copper load in apparently healthy adults undergoing controlled copper 1537 exposure. Am J Clin Nutr 2003;77(3):646-50. 1538 ATSDR. Profile for copper. Agency for Toxic Substances and Disease Registry, Public Health 1539 Service, U.S. Department of Health and Human Services, Atlanta, GA. 2004. 1540 Hébert CD, Elwell MR, Travlos GS, Fitz CJ, Bucher JR. Subchronic toxicity of cupric sulfate 1541 administered in drinking water and feed to rats and mice. Fundam Appl Toxicol 1993;21:461- 1542 475. 1543 IPCS. Copper. Environmental Health Criteria 200. International Programme on Chemical Safety. 1544 World Health Organization, Geneva. 1998. 1545 Wapnir RA. Copper absorption and bioavailability. Am J Clin Nutr 1998;67(suppl):1054S-60S 1546 46 Contains Nonbinding Recommendations 1547 GOLD 1548 1549 Summary of PDE for Gold Gold (Au) Oral Parenteral Inhalation PDE (µg/day) 322 322 3.2 1550 1551 Introduction 1552 Gold (Au) exists in metallic form and in oxidation states of +1 to +5, the monovalent and trivalent 1553 forms being the most common. Elemental gold is poorly absorbed and consequently is not 1554 considered biologically active. Gold is being used on a carrier or in complexes like gold chloride 1555 and L-Au+ (where L is a phosphane, phosphite, or an arsine; Telles, 1998), as catalysts in organic 1556 synthesis. The only source for gold in drug products comes from the use as catalyst. Au(1+) salts 1557 are used therapeutically. 1558 1559 Safety Limiting Toxicity 1560 Most knowledge of gold toxicity is based on therapeutic uses of gold. Currently available 1561 therapies are gold salts of monovalent Au(1+) with a sulfur ligand (Au-S), but metallic gold has 1562 also been studied. No toxicity was seen in ten patients administered colloidal metallic gold 1563 (monoatomic gold) at 30 mg/day for one week followed by 60 mg/day the second week or the 1564 reverse schedule. The patients were continued on the trial for an additional 2 years at 30 mg/day. 1565 There was no evidence of hematologic, renal, or hepatic cytotoxicity but some improvement in 1566 clinical symptoms of rheumatoid arthritis and in cytokine parameters were noted (Abraham and 1567 Himmel, 1997). 1568 Long term animal and human data are available with gold compounds. Toxicities include renal 1569 lesions in rats administered gold compounds by injection (Payne and Saunders, 1978) and 1570 humans (Lee et al, 1965) and gastrointestinal toxicity in dogs (Payne and Arena, 1978). 1571 However, these studies have been performed with monovalent gold (Au(1+)) or forms of gold 1572 not present as pharmaceutical impurities and thus are not considered sufficiently relevant to 1573 derive a PDE for gold in pharmaceutical products. 1574 There are no relevant toxicology studies in humans or animals by the oral route of a form of gold 1575 likely to be in a pharmaceutical product to set an oral PDE of gold. Au(3+) is thought to be the 1576 more toxic form and is used in catalysis, e.g., as gold trichloride. There is only limited data on 1577 Au(3+) complexes. In one study, the Au(3+) compound [Au(en)Cl2]Cl 1578 (dichloro(ethylenediamine-aurate3+ ion) caused minimal histological changes in the kidney and 1579 liver of rats, and no renal tubular necrosis, at a dose of 32.2 mg/kg in rats administered the 1580 compound intraperitoneal for 14 days (Ahmed et al, 2012). 1581 1582 PDE – Oral Exposure 1583 The toxicologically significant endpoint for gold exposures is renal toxicity. The study in rats 1584 administered Au(3+) by the intraperitoneal route was considered acceptable in setting the oral 1585 PDE because the renal endpoint of toxicity is a sensitive endpoint of gold toxicity. Taking into 1586 account the modifying factors (F1-F5 as discussed in Appendix 1), the oral PDE is calculated as: 1587 47 Contains Nonbinding Recommendations 1588 PDE = 32.2 mg/kg x 50 kg / (5 x 10 x 10 x 1 x 10) = 322 µg/day 1589 1590 A factor of ten for F5 was chosen because the LOAEL is used to establish the PDE and the 1591 toxicological assessment was not complete. 1592 1593 PDE – Parenteral Exposure 1594 In humans, 50 mg intramuscular injections of gold sodium thiomalate resulted in >95% 1595 bioavailability (Blocka et al, 1986). In rabbits, approximately 70% of the gold sodium thiomalate 1596 was absorbed after an intramuscular injection of 2mg/kg (Melethil and Schoepp, 1987). Based on 1597 high bioavailability, and that a study by the intraperitoneal route was used to set the oral PDE, 1598 the parenteral PDE is equal to the oral PDE. 1599 1600 PDE = 322 µg/day 1601 1602 PDE – Inhalation Exposure 1603 In the absence of relevant inhalation data, including the potential local tissue toxicity of the 1604 effects of gold in lungs, the inhalation PDE was calculated by dividing the oral PDE by a 1605 modifying factor of 100 (as described in section 3.1). 1606 1607 PDE = 322 µg/d / 100 = 3.22 µg/day 1608 1609 REFERENCES 1610 Abraham GE, Himmel PB. Management of rheumatoid arthritis: rationale for the use of colloidal 1611 metallic gold. J Nutr Environ Med 1997;7:295-305. 1612 Ahmed A, Al Tamimi DM, Isab AA, Alkhawajah AMM, Shawarby MA. Histological changes in 1613 kidney and liver of rats due to gold (III) compound [Au(en)Cl2]Cl. PLoS ONE 2012;7(12):1-11. 1614 Blocka KL, Paulus HE, Furst DE. Clinical pharmacokinetics of oral and injectable gold 1615 compounds. Clin Pharmacokinet 1986;11:133-43. 1616 Lee JC, Dushkin M, Eyring EJ, Engleman EP, Hopper J Jr. Renal Lesions Associated with Gold 1617 Therapy: Light and Electron Microscopic Studies. Arthr Rheum 1965;8(5):1-13. 1618 Melethil S, Schoepp D. Pharmacokinetics of gold sodium thiomalate in rabbits. Pharm Res 1619 1987;4(4):332-6. 1620 Payne BJ, Arena E. The subacute and chronic toxicity of SK&F 36914 and SK&F D-39162 in 1621 dogs. Vet Pathol 1978;15(suppl 5): 9-12. 1622 Payne BJ, Saunders LZ. Heavy metal nephropathy of rodents. Vet Pathol 1978;15(suppl 5):51- 1623 87. 1624 Telles JH, Brode S, Chabanas M. Cationic gold (I) complexes: highly efficient catalysts for the 1625 addition of alcohols to alkynes. Angew Chem Int Ed 1998;37:1415-18 48 Contains Nonbinding Recommendations 1626 LEAD 1627 1628 Summary of PDE for Lead Lead (Pb) Oral Parenteral Inhalation PDE (µg/day) 5.0 5.0 5.0 1629 1630 Introduction 1631 Lead (Pb) occurs in organic and inorganic forms. The generally bivalent lead compounds include 1632 water- soluble salts such as lead acetate as well as insoluble salts such as lead oxides. Organic 1633 lead compounds include the gasoline additives tetramethyl- and tetraethyl-lead. Organic lead 1634 compounds undergo fairly rapid degradation in the atmosphere and form persistent inorganic 1635 lead compounds in water and soil. Lead has no known biological function in human or 1636 mammalian organisms (ATSDR, 2007). 1637 Safety Limiting Toxicity 1638 In humans and animals, exposure to lead may cause neurological, reproductive, developmental, 1639 immune, cardiovascular and renal health effects. In general, sensitivity to lead toxicity is greater 1640 when there is exposure in utero and in children compared to adults. A target blood level of 1-2 1641 µg/dL was set, and using modelling programs (US EPA, 2009) that assumed 100% 1642 bioavailability and no other exposure, a PDE was obtained. For this reason, the PDEs are the 1643 same regardless of the route of administration. 1644 1645 PDE – Oral Exposure 1646 Adverse neurobehavioral effects are considered to be the most sensitive and most relevant 1647 endpoint in humans after oral exposure. Data from epidemiological studies show that blood lead 1648 levels <5 µg/dL may be associated with neurobehavioral deficits in children (NTP, 2011). 1649 According to the US EPA model (Integrated Exposure Uptake Biokinetic (IEUBK) Model, 1994) 1650 (100% absorption, no other sources of lead), oral intake of 5 µg/day translates into a blood level 1651 of 1-2 µg/dL for children age 0-7 years (0-82 months) (US EPA, 2007, 2009). 1652 1653 PDE = 5.0 µg/day 1654 1655 PDE – Parenteral Exposure 1656 The oral effects of Pb are based on blood levels. Therefore, the parenteral PDE is equal to the oral 1657 PDE. 1658 1659 PDE = 5.0 µg/day 1660 1661 PDE – Inhalation Exposure 1662 The oral effects of Pb are based on blood levels. Therefore, the inhalation PDE is equal to the oral 1663 PDE. 1664 49 Contains Nonbinding Recommendations 1665 PDE = 5.0 µg/day 1666 1667 REFERENCES 1668 ATSDR. Toxicological profile for lead. Agency for Toxic Substances and Disease Registry, 1669 Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 2007. 1670 NTP. Monograph on health effects of low-level lead. National Toxicology Program, U.S. 1671 Department of Health and Human Services. 2012. 1672 US EPA. User's Guide for the Integrated Exposure Uptake Biokinetic Model for Lead in 1673 Children (IEUBK) Windows. 2007. 1674 US EPA. Integrated Exposure Uptake Biokinetic (IEUBK) Model for Lead. 1994, updated 2009. 1675 (http://www.epa.gov/superfund//health/contaminants/lead/products.htm; Accessed March 25, 1676 2014) 50 Contains Nonbinding Recommendations 1677 LITHIUM 1678 1679 Summary of PDE for Lithium Lithium (Li) Oral Parenteral Inhalation PDE (µg/day) 560 280 25 1680 1681 Introduction 1682 Lithium (Li) is a common metal that is present in plant and animal tissues. Lithium is being used 1683 alone or in combination with other metals as catalyst. Lithium compounds (e.g., lithium 1684 aluminum hydride) are being used as reagents in organic synthesis. Lithium exists commonly as 1685 a salt in the +1 oxidation state only. 1686 1687 Safety Limiting Toxicity 1688 Lithium is used as a human therapeutic, and extensive human data exists in the administration of 1689 lithium salts in the treatment of mania, bipolar disorder, and recurrent unipolar depression. 1690 Treatment with lithium salts requires frequent controls by the treating physician, including 1691 measurement of lithium concentrations. The therapeutic range for lithium has been established at 1692 0.6-1 mmol/L in serum, depending upon the formulation administered (Grandjean and Aubry, 1693 2009). The therapeutic margin is narrow and Li toxicity can occur at therapeutic exposures. 1694 Lithium treatment in humans is mainly associated with an increased risk of reduced urinary 1695 concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain (McKnight et al, 1696 2012). The usual recommended dose is 300- 600 mg three to four times a day (US FDA, 2011). 1697 The data was reviewed to identify the safety limiting toxicities based on routes of administration. 1698 1699 PDE – Oral Exposure 1700 Human experience with lithium was used as the point of departure for this PDE. When using the 1701 lowest human single oral dose of 300 mg lithium carbonate (56 mg Li), the oral PDE is 1702 calculated as follows: 1703 1704 PDE = 56 mg/d / (1 x 10 x 1 x 1 x 10) = 0.56 mg/d = 560 µg/day 1705 1706 A factor of ten was chosen for F5 because a LOAEL (one-third the recommended daily dose) 1707 was used to set the PDE. 1708 1709 PDE – Parenteral Exposure 1710 There are no adequate data to develop a parenteral PDE. However, based on oral bioavailability 1711 of 85% (Grandjean and Aubry, 2009), the parenteral PDE was calculated by dividing the oral 1712 PDE by a modifying factor of 2 (as described in section 3.1). 1713 1714 PDE = 560 µg/d / 2 = 280 µ/day 1715 1716 PDE – Inhalation Exposure 1717 Rabbits were exposed to lithium chloride at 0.6 and1.9 mg/m3 for 4-8 weeks, 5 days/week for 6 1718 hours/d (Johansson et al. 1988). Lungs were studied by light and electron microscopy with focus 51 Contains Nonbinding Recommendations 1719 on inflammatory changes. No significant effects were reported, so the highest dose was used to 1720 set the PDE. Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the 1721 inhalation PDE is calculated as: 1722 1723 For continuous dosing = 1.9 mg/m3 x 6 h/d x 5 d/wk = 0.34 mg/m3 = 0.00034 mg/L 1724 24 h/d x 7d/wk 1000 L/m3 1725 1726 Daily dose = 0.00034 mg/L x 1440 L/d = 122.04 µg/kg/day 1727 4 kg 1728 1729 PDE = 122.04 µg/kg/d x 50 kg / (2.5 x 10 x 10 x 1 x 1) = 25 µg/day 1730 1731 REFERENCES 1732 Grandjean EM, Aubry JM. Lithium: updated human knowledge using an evidence-based 1733 approach. Part II: Clinical pharmacology and therapeutic monitoring. CNS Drugs 1734 2009;23(4):331-49. 1735 Johansson A, Camner P, Curstedt T, Jarstrand C, Robertson B, Urban T. Rabbit lung after 1736 inhalation of lithium chloride. J Appl Toxicol 1988;8:373-5. 1737 McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR. Lithium toxicity 1738 profile: a systematic review and meta-analysis. Lancet 2012;379:721-728. 1739 US FDA. Lithium carbonate product label, 2011. (available at drugs@fda; accessed May 1, 1740 2014) 52 Contains Nonbinding Recommendations 1741 MERCURY 1742 1743 Summary of PDE for Mercury Mercury (Hg) Oral Parenteral Inhalation PDE (µg/day) 30 3.0 1.2 1744 1745 Introduction 1746 Mercury (Hg) is widely distributed in the global environment. Mercury exists in three forms: 1747 elemental mercury, inorganic mercury and organic mercury. The most likely form of residual 1748 mercury in drug products is the inorganic form. Therefore, this safety assessment is based on the 1749 relevant toxicological data of elemental or inorganic mercury. This safety assessment and derived 1750 PDEs do not apply to organic mercury. 1751 1752 Safety Limiting Toxicity 1753 There is no data to indicate that inorganic mercury is carcinogenic in human. There is limited 1754 evidence in experimental animals for the carcinogenicity of mercuric chloride. The International 1755 Agency for Research on Cancer (IARC) concluded that inorganic mercury compounds are not 1756 classifiable as to their carcinogenicity to humans (Group 3; IARC, 1997). 1757 Inorganic mercury compounds show significantly lower oral bioavailability compared to organic 1758 mercury and induce different toxicological effects including neurological, corrosive, 1759 hematopoietic, and renal effects, and cutaneous disease (acrodynia). The safety limiting toxicity 1760 for inorganic mercury and salts is renal toxicity. Direct absorption to the brain via the olfactory 1761 pathway has been reported (Shimada et al, 2005). 1762 1763 PDE – Oral Exposure 1764 There were well designed NTP studies in rats and mice of HgCl2 of up to 2 years duration. The 6- 1765 month gavage study in rats was selected because it had more detailed clinical pathology 1766 assessment and a wider range of doses (0.312 to 5 mg HgCl2/kg/5d per week) than the 2-year 1767 study. Absolute and relative (to body weight) kidney weights were increased from 0.625 mg/kg. 1768 Some changes in clinical chemistry parameters (decreased creatinine, potassium, alanine 1769 aminotransferase and aspartate aminotransferase) were noted in all dosed males. The findings did 1770 not appear dose-dependent. An increase in the incidence and severity (minimal to mild) in 1771 nephropathy was noted from 0.625 mg HgCl2. In a Joint Expert Committee for Food Additives 1772 (JECFA) assessment (JECFA, 2011) a BMDL10 of 0.06 mg Hg/kg/day (adjusted from 5 1773 days/week dosing) was derived based on adverse renal effects (weight increase) from the 6- 1774 month rat study (NTP, 1993). Using the modifying factors (F1-F5 as discussed in Appendix 1) the 1775 oral PDE is calculated as: 1776 1777 PDE = 0.06 mg/kg/d x 50 kg / (5 x 10 x 2 x 1 x 1) = 0.03 mg/d = 30 µg/day 1778 1779 F4 was set to 1 as the findings in the 6-month and 2-year studies were not considered significant 1780 at the lowest dose, and F5 was set to 1 as the BMDL10 can be considered a NOAEL (Sargent et 1781 al, 2013). 1782 53 Contains Nonbinding Recommendations 1783 PDE – Parenteral Exposure 1784 Animal studies indicate that the oral bioavailability of inorganic mercury is in the 10-30% range 1785 (ATSDR, 1999). Therefore, the parenteral PDE was calculated by dividing the oral PDE by a 1786 modifying factor of 10 (as described in Section 3.1). 1787 1788 PDE = 30 µg/d / 10 = 3.0 µg/day 1789 1790 PDE – Inhalation Exposure 1791 Neurobehavioral effects are considered to be the most sensitive endpoint following inhalation 1792 exposure in humans as shown in occupational studies at the range of air TWA levels between 14 1793 and 20 µg/m3 (US EPA, 1995; EU SCOEL, 2007). The presence of neurobehavioral effects at 1794 low-level mercury exposures (14 µg/m3) in dentists (Ngim et al. 1992) indicates that the TWA 1795 needs to be considered as a LOAEL. Taking into account the modifying factors (F1-F5 as 1796 discussed in Appendix 1), the inhalation PDE is calculated based on the long-term inhalation 1797 exposure to elemental mercury vapor: 1798 For continuous dosing = 14 µg/m3 x 8 hr/d x 6 d/wk = 4 µg/m3 = 0.004 µg/L 1799 24 hr/d x 7 d/wk 1000 L/m3 1800 1801 Daily dose = 0.004 µg/L x 28800 L = 2.30 µg/kg 1802 50 kg 1803 1804 PDE = 2.30 µg/kg x 50 kg / (1 x 10 x 1 x 1 x 10) = 1.2 µg/day 1805 1806 A factor of ten for F5 was chosen because a LOAEL was used to set the PDE and to account for 1807 the possible direct transfer of mercury to the brain through the olfactory pathway. 1808 1809 REFERENCES 1810 ATSDR. Toxicological profile for mercury. Agency for Toxic Substances and Disease Registry, 1811 Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 1999. 1812 EU SCOEL. Recommendation from the scientific committee on occupational exposure 1813 limits for elemental mercury and inorganic divalent mercury compounds. European 1814 Union Scientific Committee on Occupational Exposure Limits. 2007;SCOEL/SUM/84. 1815 IARC. Beryllium, cadmium, mercury, and exposures in the glass manufacturing industry. 1816 Monographs on the Evaluation of Carcinogenic Risks to Humans. International Agency for 1817 Research on Cancer, World Health Organization, Lyon. 1993;58, updated in 1997. 1818 JECFA. Safety evaluation of certain contaminants in food. WHO Food Additive Series 63. Joint 1819 Expert Committee on Food Additives. Rome, 2011. 1820 Ngim CH, Foo SC, Boey KW, and Jeyaratnam J. Chronic neurobehavioural effects of elemental 1821 mercury in dentists. Br J Ind Med 1992;49(11):782-90. 1822 NTP. Technical report on the toxicology and carcinogenesis studies of mercuric chloride (CAS No. 1823 7487- 94-7) in F344 rats and B6C3F1 mice (gavage studies). National Toxicology Program, 1824 Public Health Service, U.S. Department of Health and Human Services, Research Triangle Park, 1825 NC. 1993;NTP TR 408. 54 Contains Nonbinding Recommendations 1826 Sargent EV, Faria E, Pfister T, Sussman RG. Guidance on the establishment of daily exposure 1827 limits (ADE) to support risk-based manufacture of pharmaceutical products. Reg Toxicol 1828 Pharmacol 2013;65:242-250. 1829 Shimada A, Nagayama Y, Morita T et al. Localization and role of metallothioneins in the 1830 olfactory pathway after exposure to mercury vapor. Exp Toxicol Pathol 2005;57:117-125. 1831 US EPA. Mercuric chloride (HgCl2) (CASRN 7487-94-7). Integrated Risk Information System 1832 (IRIS). 1995. 55 Contains Nonbinding Recommendations 1833 MOLYBDENUM 1834 1835 Summary of PDE for Molybdenum Molybdenum (Mo) Oral Parenteral Inhalation PDE (µg/day) 3400 1700 11 1836 1837 Introduction 1838 The main oxidation states for Mo are +4 and +6, the most common forms of which are 1839 oxyanions. The predominant form of Mo occurring in soils and natural waters is the 4 molybdate 1840 ion, MoO which forms soluble compounds with a variety of cations including K+, NH4 + and 2- 1841 Ca2+. Mo exists in soil in various forms at concentration of 0.1-10 mg/kg. MoO2 and MoS2 are 1842 insoluble in water. It is widely present in vegetables, dairy products, and meats. Mo 1843 combinations (e.g., Bi-Mo, Fe-Mo, molybdenum oxide and Mo-complexes) are being used as 1844 catalysts in organic synthesis. 1845 Molybdenum is an essential element with an estimated upper-level intake range of 100-600 1846 µg/day for infants to adults, respectively (EC Scientific Committee on Food, 2000). 1847 Molybdenum deficiency is characterized by night blindness, nausea, disorientation, coma, 1848 tachycardia, and tachypnea and associated with various biochemical abnormalities including high 1849 plasma methionine. In addition, an almost undetectable serum uric acid concentration has been 1850 reported in a patient receiving total parenteral nutrition (Abumrad et al, 1981). 1851 1852 Safety Limiting Toxicity 1853 Molybdenum as the trioxide was not mutagenic (NTP, 1997) and a Ruksinstutuut Voor 1854 Volksgezondheid En Milieu (RIVM) assessment concluded that molybdenum is not genotoxic 1855 (RIVM, 2001). Carcinogenicity has not been evaluated by IARC or US EPA. Molybdenum by 1856 the oral route has low toxicity. There is some evidence of carcinogenicity in the mouse when 1857 molybdenum is administered by the inhalation route. The possible carcinogenic effects were 1858 considered the endpoint of greatest toxicological relevance for this route of exposure. 1859 1860 PDE – Oral Exposure 1861 A good laboratory practice compliant 90-day toxicology study that investigated the toxicity of 1862 sodium molybdate dehydrate administered in the diet of rats demonstrated effects at 60 mg 1863 Mo/kg/day, including effects on body weight, weight gain, food conversion efficiency, some 1864 organ weights (absolute and relative to body weight) and renal histopathology (slight diffuse 1865 hyperplasia in the proximal tubules in two females) (Murray et al, 2014). No adverse effects 1866 were noted after a 60-day recovery period, with the exception of reduced body weights in male 1867 rats. No adverse effects on reproductive organs, estrus cycles, or sperm parameters were noted. 1868 The authors conclude that the NOAEL for this study was 17 mg Mo/kg/day. No treatment-related 1869 toxicity was seen at this dose. Using modifying factors (F1-F5 as discussed in Appendix 1) the 1870 oral PDE is: 1871 1872 PDE = 17 mg/kg x 50 kg / (5 x 10 x 5 x 1 x 1) = 3.4 mg/d = 3400 µg/day 1873 56 Contains Nonbinding Recommendations 1874 PDE – Parenteral Exposure 1875 In Vyskocil and Viau (1999), it was reported that oral bioavailability in humans ranged from 28- 1876 77%. Turnland et al. (2005) report that molybdenum absorption was about 90% in healthy men. 1877 Therefore, the parenteral PDE is divided by a modifying factor of 2 (as described in section 3.1). 1878 1879 PDE= 3400 µg/day / 2 = 1700 µg/day 1880 1881 PDE – Inhalation Exposure 1882 Inhaled molybdenum trioxide was carcinogenic in male and female mice (NTP, 1997) and the 1883 weight of evidence suggests that calcium and zinc molybdates may be carcinogenic to 1884 humans (NAS, 2000). Modeling was conducted using the adenoma/carcinoma incidence data 1885 (combined) in female mice (3/50, 6/50, 8/49, and 15/49 for the 0, 10, 30 and 100 mg/m3 exposure 1886 groups, respectively) to determine a linear extrapolation, the unit risk of lung cancer is less than 1887 2.6×10−5/μg/m3 (NAS, 2000). Using a risk level of 1:100000, the inhalation PDE is calculated as 1888 follows: 1889 1890 Inhalation PDE = 1x10-5 = 0.38 µg/m3 1891 2.6 x10-5 /µg/m3 1892 1893 PDE = 0.38 µg/m3 / 1000 L/m3 x 28800 L/d = 10.9 µg/day 1894 1895 No modifying factors are used to adjust a PDE derived by the unit risk approach. 1896 1897 REFERENCES 1898 Abumrad NN, Schneider AJ, Steel D, Rogers LS. Amino acid intolerance during prolonged total 1899 parenteral nutrition reversed by molybdate therapy. Am J Clin Nutr 1981;34(11):2551-9. 1900 EC Scientific Committee on Food. Opinion of the Scientific Committee on Food on the tolerable 1901 upper intake level of molybdenum. European Commission Committee on Food, 2000 (available 1902 at ec.europa.eu/food/fs/sc/scf/out80h_en.pdf; accessed March 21, 2014). 1903 Miller RF, Price NO, Engel RW. Added dietary inorganic sulfate and its effect upon rats fed 1904 molybdenum. J Nutr 1956;60(4):539-47. 1905 Murray FJ, Sullivan FM, Tiwary AK, Carey S. 90-Day subchronic toxicity study of sodium 1906 molybdate dihydrate in rats. Regul Toxicol Pharmacol 2013: 1907 http://dx.doi.org/10.1016/j.yrtph.2013.09.003 (accessed September 29, 2014). 1908 NAS. Toxicological risks of selected flame-retardant chemicals: Subcommittee on Flame- 1909 Retardant Chemicals, Committee on Toxicology, Board on Environmental Studies and 1910 Toxicology, National Academy of Sciences National Research Council. 2000. (available at 1911 http://www.nap.edu/catalog/9841.html; accessed March 21, 2014). 1912 NTP. Toxicology and carcinogenesis studies of molybdenum trioxide (CAS No. 1313-27-5) in 1913 F344 rats and B6C3F1 mice (inhalation studies). National Toxicology Program, Public Health 1914 Service, U.S. Department of Health and Human Services. 1997. 57 Contains Nonbinding Recommendations 1915 RIVM. RIVM Report 711701025: Re-evaluation of human-toxicological maximum permissible 1916 risk levels. Ruksinstutuut Voor Volksgezondheid En Milieu (National Institute of Public Health 1917 and the Environment). 2001. 1918 Turnland JR, Keyes WR, Peiffer GL. Molybdenum absorption, excretion, and retention studied 1919 with stable isotopes in young men at five intakes of dietary molybdenum. Am J Clin Nutr 1920 1995;62:790-796. 1921 Vyskocil A, Viau C. Assessment of molybdenum toxicity in humans. J Appl Toxicol 1922 1999;19:185-192. 58 Contains Nonbinding Recommendations 1923 NICKEL 1924 1925 Summary of PDE for Nickel Nickel (Ni) Oral Parenteral Inhalation PDE (µg/day) 220 22 6.0 1926 1927 Introduction 1928 Nickel (Ni) is a Group 10 element of the first transition series. Although nickel may exist in the 1929 0, +1, +2 and +3 oxidation states, its main oxidation state is +2. Nickel is a naturally occurring 1930 metal existing in various mineral forms. In general, nickel compounds are grouped based on 1931 solubility in water, and the more soluble nickel compounds, including nickel chloride, nickel 1932 sulfate, and nickel nitrate, tend to be more toxic than less soluble forms, such as nickel oxide and 1933 nickel subsulfide (ATSDR, 2005). Nickel is nutritionally not essential for humans, but nickel 1934 deficiency may cause adverse effects in animals. Nickel as Ni-Al alloys is being used as catalyst 1935 in hydrogenation reactions. Stainless steel, which may be used in metered-dose inhaler 1936 components, is an iron-based alloy containing chromium and may also contain <1-38% nickel as 1937 an oxide (Stockmann-Juvala et al, 2013; NTP, 2006). Daily intake of nickel ranges from 100-300 1938 µg/day (US EPA, 1996). 1939 1940 Safety Limiting Toxicity 1941 Nickel is genotoxic, but not mutagenic (IARC 2012). There is no indication of carcinogenicity of 1942 Ni salts after oral administration (Heim et al, 2007). Depending on the type of salt there was an 1943 increase in tumors in some rodent inhalation studies (ATSDR, 2005; EU EFSA, 2005). The US 1944 EPA has concluded that there is sufficient evidence of carcinogenicity of nickel refinery dust (US 1945 EPA, 2012). In contrast to nickel refinery dust, no significant increase in cancer risk was found 1946 in workers in nickel alloy or stainless steel production (ATSDR, 2005). Combining all forms of 1947 nickel, IARC (2012) classified nickel as a human carcinogen (Group 1). 1948 In humans and animals, ingestion of large amounts of nickel may cause stomach pain, depression 1949 of body weight and adverse effects on blood and kidneys. Humans generally become sensitized 1950 to nickel after prolonged contact with the skin. Human data show that an oral challenge to a 1951 single dose of nickel administered in drinking water can induce dermatitis in nickel-sensitized 1952 individuals (Nielsen et al, 1999). In the derivation of the oral reference dose (US EPA, 1996) for 1953 soluble salts of nickel, individuals with nickel hypersensitivity were not taken into account. 1954 Chronic inhalation may produce adverse changes such as inflammation in lung and nasal cavity 1955 in both humans and animals; bronchitis, emphysema, fibrosis, and impaired lung function have 1956 been reported in nickel welders and foundry workers (ATSDR, 2005). The inflammatory lung 1957 lesions which developed in rats administered the soluble NiSO4 were qualitatively similar, but 1958 less severe than those occurring in rats administered the insoluble NiO (Benson, 1995). The 1959 toxicity of nickel appears greater for soluble forms, which are more rapidly absorbed from the 1960 lung (Schaumlöffel, 2012). 1961 1962 PDE – Oral Exposure 1963 In a 2-year carcinogenicity study in rats administered nickel sulfate hexahydrate at 10, 30 or 50 1964 mg/kg/day, no treatment-related tumors were observed. There was a significant exposure- 1965 response in mortality in females during weeks 0-105 at all dose levels, and a dose-dependent 59 Contains Nonbinding Recommendations 1966 decrease in body weights in both sexes at week 103 that reach significance in the 30 and 50 1967 mg/kg/day groups (Heim et al, 2007). Using the LOAEL of 10 mg/kg/day (2.2 mg Ni/kg/d), and 1968 taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral PDE is: 1969 1970 PDE = 2.2 mg/kg/d x 50 kg / (5 x 10 x 1 x 1 x 10) = 0.22 mg/d = 220 µg/day 1971 A factor of 10 was chosen for F5 because a LOAEL was used to set the PDE. 1972 PDE – Parenteral Exposure 1973 A human study using a stable nickel isotope estimated that 29-40% of the ingested label was 1974 absorbed (based on fecal excretion data) (Patriarca et al. 1997). In another study assessing the 1975 effect of food on nickel absorption, between 2-23% of an administered dose was absorbed 1976 (Nielsen et al, 1999). Therefore, on the basis of limited oral bioavailability of nickel and water- 1977 soluble nickel compounds, the parenteral PDE was calculated by dividing the oral PDE by a 1978 modifying factor of 10 (as described in section 3.1). 1979 1980 PDE = 220 µg/d / 10 = 22 µg/day 1981 1982 PDE – Inhalation Exposure 1983 For calculation of the inhalation PDE, a relevant form of nickel was selected from the available 1984 data. In 2-year studies with nickel oxide, no tumors were observed in hamsters (Wehner et al. 1985 1984) or mice (NTP, 2006). There was some evidence of carcinogenicity in rats (NTP, 2006) but 1986 no evidence of carcinogenicity with inhalation of metallic nickel (Oller et al, 2008). For nickel, 1987 the modifying factor approach was considered acceptable because the forms and levels likely to be 1988 in inhalation drug products have not shown evidence of carcinogenicity. Taking into account the 1989 modifying factors (F1-F5 as discussed in Appendix 1), the inhalation PDE is calculated based on 1990 the NOAEL in the rat study of 0.5 mg Ni/m3 /day. 1991 1992 For continuous dosing = 0.5 mg/m3 x 6 hr/d x 5 d/wk = 0.089 mg/m3 = 0.000089 mg/L 1993 24 hr/d x 7 d/wk 1000L/m3 1994 1995 Daily dose = 0.000089 mg/L x 290 L/d = 0.060 mg/kg 1996 0.425 kg bw 1997 1998 PDE = 0.060 mg/kg x 50 kg / (5 x 10 x 1 x 10 x 1) = 6.0 µg/day 1999 2000 A factor of ten was chosen for F4 because of the potential of relatively insoluble forms of Ni to 2001 accumulate in the lungs and that inflammation was observed in the lungs upon histopathology 2002 after inhalation of all forms of Ni. 2003 2004 REFERENCES 2005 ATSDR. Toxicological profile for nickel. Agency for Toxic Substances and Disease Registry, 2006 Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 2005. 2007 Benson J, Chang I-Y, Cheny YS, Hahn FF, Kennedy CH et al. Fundam Appl Toxicol 2008 1995;28:232-244. 60 Contains Nonbinding Recommendations 2009 EU EFSA. Opinion of the scientific panel on dietetic products, nutrition and allergies on a 2010 request from the Commission related to the tolerable upper intake level of nickel. European Food 2011 Safety Authority. EFSA Journal 2005;146:1-21. 2012 Haney JY, McCant DD, Sielken RL, Valdez-Flores C, Grant RL. Development of a unit risk 2013 factor for nickel and inorganic nickel compounds based on an updated carcinogenicity toxicity 2014 assessment. Reg Toxicol Pharmacol 2012;62:191-201. 2015 Heim KE, Bates HK, Rush RE, Oller AR. Oral carcinogenicity study with nickel sulphate 2016 hexahydrate in Fischer 344 rats. Toxicol Sci 2007;224:126-37. 2017 IARC. Arsenic, metals, fibres, and dusts: a review of human carcinogens. Monographs on the 2018 Evaluation of Carcinogenic Risks to Humans. International Agency for Research on Cancer, 2019 World Health Organization, Lyon. 2012;100C. 2020 Nielsen GD, Søderberg U, Jørgensen PJ, Templeton DM, Rasmussen SN, Andersen KE et al. 2021 Absorption and retention of nickel from drinking water in relation to food intake and nickel 2022 sensitivity. Toxicol Appl Pharmacol 1999;154:67-75. 2023 NTP. Toxicology and carcinogenesis studies of nickel oxide (CAS NO. 1313-99-1) in F344/N 2024 rats and B6C3F1 mice (inhalation studies). National Toxicology Program, U.S. Department of 2025 Health and Human Services. 2006;Technical Report Series No. 451. 2026 Oller AR, Kirkpatrick DT, Radovsky A, Bates HK. Inhalation carcinogenicity study with nickel 2027 metal powder in Wistar rats. Toxicol Appl Pharmacol 2008;233:262-75. 2028 Ottolenghi AD, Haseman JK, Payne WW, Falk HL, MacFarland HN. Inhalation studies of nickel 2029 sulfide in pulmonary carcinogenesis of rats. J Natl Cancer Inst 1974;54:1165-72. 2030 Patriarca M, Lyon TD, Fell GS. Nickel metabolism in humans investigated with an oral stable 2031 isotope. Am J Clin Nutr 1997;66:616-21. 2032 Schaumlöffel D. Nickel species:analysis and toxic effects. J Trace Elements Med Biol 2033 2012;26:1-6. 2034 Stockmann-Juvala H, Hedberg Y, Dhinsa NK, Griffiths DR, Brooks PN et al. Inhalation toxicity of 2035 316L stainless steel powder in relation to bioaccessibility. Human Exp Toxicol 2036 2013;32(11):1137-1154. 2037 US EPA. Nickel, soluble salts (CASRN various). Integrated Risk Information System (IRIS). 2038 1996. US EPA. Nickel refinery dust (no CASRN). Integrated Risk Information System (IRIS). 2039 2012. 2040 Wehner AP, Dagle GE, Busch RH. Pathogenicity of inhaled nickel compounds in hamsters. 2041 IARC Sci Publ 1984;(53):143-51. 61 Contains Nonbinding Recommendations 2042 PALLADIUM 2043 2044 Summary of PDE for Palladium Palladium (Pd) Oral Parenteral Inhalation PDE (µg/day) 100 10 1.0 2045 2046 Introduction 2047 Palladium (Pd) is a steel-white, ductile metallic element resembling and occurring with the other 2048 platinum group metals and nickel. It exists in three states: Pd(0) (metallic), Pd(2+) and Pd(4+). It 2049 can form organometallic compounds, only few of which have found industrial uses. Palladium 2050 (on various supports) is being used as catalyst in hydrogenation reactions. Palladium metal is 2051 stable in air and resistant to attack by most reagents except aqua regia and nitric acid. 2052 2053 Safety Limiting Toxicity 2054 In a 90-day study in male rats administered 10, 100 and 250 ng/mL palladium in drinking water, 2055 palladium was found to accumulate in the kidney but not liver, lung, spleen, or bones. 2056 Elimination was primarily through the fecal route (Iavicoli et al, 2010). Several in vitro 2057 mutagenicity tests of different palladium compounds with bacterial or mammalian cells (Ames 2058 test with Salmonella typhimurium; SOS chromotest with Escherichia coli; micronucleus test with 2059 human lymphocytes) gave negative results (IPCS, 2002; Kielhorn et al, 2002). The data was 2060 reviewed to identify the safety limiting toxicities based on routes of administration. 2061 2062 PDE – Oral Exposure 2063 Several long-term animal studies have been conducted exploring the toxicity and carcinogenicity 2064 of palladium salts. However, none to date have been executed in accordance with current 2065 guidelines for toxicological studies. The available data suggest potential NOAELs for palladium 2066 in the range of 0.8-1.5 mg/kg. A lifetime study with mice given Pd(2+) chloride in drinking- 2067 water at a dose of about 1.2 mg Pd/kg/day found a significantly higher incidence of amyloidosis 2068 in several inner organs of males and females and suppressed growth in males, but not in females 2069 (Schroeder and Mitchener, 1971; IPCS, 2002). This study also contained a signal that suggested 2070 a possible carcinogenic endpoint; however, the design of the study (single dose level, pooling of 2071 the tumor rates from male and female animals, and a significant increase in the age of the treated 2072 vs control animals) limited the utility of the data to assess the carcinogenic potential. Taking into 2073 account the modifying factors (F1-F5 as discussed in Appendix 1), the oral PDE is calculated 2074 based on the LOEL of 1.2 mg/kg/day. 2075 2076 PDE = 1.2 mg/kg/d x 50 kg / (12 x 10 x 1 x 1 x 5) = 0.1 mg/d = 100 µg/day 2077 2078 A factor of five was chosen for F5 because a LOEL was used in deriving the PDE. 2079 2080 PDE – Parenteral Exposure 2081 The safety review for palladium was unable to identify any significant assessments upon which 2082 to calculate a PDE for parenteral routes of exposure. Pd(2+) chloride (PdCl2) was poorly 2083 absorbed from the digestive tract (<0.5% of the initial oral dose in adult rats or about 5% in 62 Contains Nonbinding Recommendations 2084 suckling rats after 3-4 days). Absorption/retention in adult rats was higher following intratracheal 2085 or intravenous exposure, resulting in total body burdens of 5% or 20%, respectively, of the dose 2086 administered, 40 days after dosing (IPCS, 2002). On the basis of limited oral bioavailability of 2087 palladium, the parenteral PDE was calculated by dividing the oral PDE by a modifying factor of 2088 10 (as described in section 3.1). 2089 2090 PDE = 100 µg/d / 10 = 10 µg/day 2091 2092 PDE – Inhalation Exposure 2093 There are no adequate inhalation data on Pd. Therefore, the inhalation PDE was calculated by 2094 dividing the oral PDE by a modifying factor of 100 (as described in section 3.1). 2095 2096 PDE = 100 µg/d / 100 = 1.0 µg/day 2097 2098 REFERENCES 2099 Iavicoli I, Bocca B, Fontana L, Caimi S, Bergamaschi A, Alimonti A. Distribution and 2100 elimination of palladium in rats after 90-day oral administration. Toxicol Ind Health 2010;26. 2101 IPCS. Palladium. Environmental Health Criteria 226. International Programme on Chemical 2102 Safety. World Health Organization, Geneva. 2002. 2103 Kielhorn J, Melver C, Keller D, Mangelsdorf I. Palladium – a review of exposure and effects to 2104 human health. Int J Hyg Environ Health 2002;205:417-432. 2105 Schroeder HA, Mitchener M. Scandium, chromium (VI), gallium, yttrium, rhodium, palladium, 2106 indium in mice: Effects on growth and life span. J Nutr 1971;101:1431-8. 63 Contains Nonbinding Recommendations 2107 PLATINUM 2108 2109 Summary of PDE for Platinum Platinum (Pt) Oral Parenteral Inhalation PDE (µg/day) 108 10.8 1.4 2110 2111 Introduction 2112 Platinum (Pt) is a Group 8 element of the third transition series. It is the most important of the six 2113 heaviest of the Group 8 elements, collectively called the "platinum group metals" or 2114 "platinoids", including palladium, osmium, rhodium, ruthenium and iridium. Metallic platinum 2115 has been shown to catalyze many oxidation-reduction and decomposition reactions and the major 2116 industrial use of platinum is as a catalyst. Platinum complexes exhibiting a range of oxidation 2117 states are known, although the principal oxidation states are +2 and +4. Pt(2+) forms a tetra- 2118 coordinate aqua ion [Pt (H2O)4]2+. The most common Pt IV catalysts are chloroplatinate salts 2119 such as tetra and hexachloroplatinate ions. 2120 2121 Safety Limiting Toxicity 2122 No experimental data are available on the carcinogenicity of platinum and platinum compounds 2123 forms likely to be present in pharmaceuticals as impurities, and toxicology data are limited (US 2124 EPA, 2009). 2125 Chlorinated salts of platinum are responsible for platinum related hypersensitivity and are a 2126 major occupational health concern (US EPA, 2009). The hypersensitivity appears to be the most 2127 sensitive endpoint of chloroplatinate exposure, at least by the inhalation route. Signs include 2128 urticaria, contact dermatitis of the skin, and respiratory disorders ranging from sneezing, shortness 2129 of breath, and cyanosis to severe asthma (IPCS, 1991). Exposure reduction was effective in 2130 resolving symptoms (Merget et al, 2001). Neutral complexes and complexes without 2131 halogenated ligands do not appear allergenic (US EPA, 2009; EU SCOEL, 2011). The risk of 2132 hypersensitivity appears to be related to sensitizing dose and dose and length of exposure (IPCS, 2133 1991; US EPA, 2009; Arts et al, 2006) and cigarette smoking (US EPA, 2009; Merget et al, 2134 2000; Caverley et al, 1995). The data was reviewed to identify the safety limiting toxicities 2135 based on routes of administration 2136 2137 PDE – Oral Exposure 2138 In a study in male rats administered PtCl2 (relatively insoluble) and PtCl4 (soluble) in the diet for 2139 4 weeks, no effects were observed on hematological and clinical chemistry parameters for PtCl2. 2140 Plasma creatinine was increased and a reduction in hematocrit and erythrocyte parameters was 2141 observed in animals dosed with 50 mg Pt/kg diet for four weeks in the form of PtCl4, the highest 2142 dose tested. Platinum concentrations increased in tissues in animals dosed with either compound, 2143 particularly the kidney (Reichlmayr-Lais et al, 1992). This study was used in the determination 2144 of the PDE because toxicity is observed in the kidney with platinum compounds and was a main 2145 site of accumulation in this study. Taking into account the modifying factors (F1-F5 as discussed 2146 in Appendix 1), the oral PDE is calculated based on the NOAEL of 10 mg Pt/kg diet (4.1 mg Pt 2147 taken over 28 days; 0.146 mg/d). The body weight of the rats was 35 g at the beginning of the 64 Contains Nonbinding Recommendations 2148 study and the average weight gain over the course of the study was 235 g. A mean body weight 2149 of 135 g was used in the calculation. 2150 2151 0.146 mg/d / 0.135 kg = 1.08 mg/kg/day 2152 2153 PDE = 1.08 mg/kg/d x 50 kg / (5 x 10 x 10 x 1 x 1) = 108 µg/day 2154 2155 PDE – Parenteral Exposure 2156 The safety review for platinum identified limited assessments of platinum salt toxicity for 2157 parenteral routes of administration. The oral absorption of platinum salts is very low in rats (<1% 2158 when administered by gavage) and higher in humans (42-60% of dietary Pt; US EPA, 2009). 2159 Therefore, the oral PDE is divided by a factor of 10 (as described in section 3.1) to obtain the 2160 parenteral PDE. 2161 2162 PDE = 108 µg/d / 10 = 10.8 µg/day 2163 2164 PDE – Inhalation Exposure 2165 Due to the use of the chloroplatinates in catalytic converters, numerous animal (Biagini et al, 2166 1983) and human (Pepys et al, 1972; Pickering 1972; Merget et al, 2000; Cristaudo et al., 2007) 2167 studies have been conducted. The US EPA (1977; 2009) and the European Scientific Committee 2168 on Occupational Exposure Limits (EU SCOEL, 2011) have also examined the safety of 2169 chloroplatinates based on sensitization. The European Scientific Committee on Occupational 2170 Exposure Limits (EU SCOEL) concluded that the database does not allow for setting an 2171 occupational limit for soluble platinum salts. The US DoL (2013) has established an 2172 occupational limit for soluble platinum salts at 2 µg/m3. Taking into account the modifying 2173 factors (F1-F5 as discussed in Appendix 1), the inhalation PDE is calculated as: 2174 2175 For continuous dosing = 2 µg/m3 x 8 hr/d x 5 d/wk = 0.48 µg/m3 = 0.00048 µg/L 2176 24 hr/d x 7 d/wk 1000 m3/L 2177 2178 Daily dose = 0.00048 µg/L x 28800 L/d = 0.27 µg/kg/day 2179 50 kg 2180 2181 PDE = 0.27 µg/kg/d x 50 kg / (1 x 10 x 1 x 1 x 1) = 1.4 µg/d 2182 2183 REFERENCES 2184 Arts JHE, Mommers C, de Heer C. Dose-response relationships and threshold levels in skin and 2185 respiratory allergy. Crit Rev Toxicol 2006;36:219-51. 2186 Biagini RE, Moorman WJ, Smith RJ, Lewis TR, Bernstein IL. Pulmonary hyperreactivity in 2187 cynomolgus monkeys (Macaca fasicularis) from nose-only inhalation exposure to disodium 2188 hexachloroplatinate, Na2PtCl6. Toxicol Appl Pharmacol 1983;69:377-84. 2189 Caverley AE, Rees D, Dowdeswell RJ, Linnett PJ, Kielkowski D. Platinum salt sensitivity in 2190 refinery workers: incidence and effects of smoking and exposure. Int J Occup Environ Med 2191 1995;52:661-66. 65 Contains Nonbinding Recommendations 2192 Cristaudo A, Picardo M, Petrucci F, Forte G, Violante N, Senofonte O et al. Clinical and 2193 allergological biomonitoring of occupational hypersensitivity to platinum group elements. Anal 2194 Lett 2007;40:3343-59. 2195 EU SCOEL. Recommendation from the scientific committee on occupational exposure limits for 2196 platinum and platinum compounds. European Union Scientific Committee on Occupational 2197 Exposure Limits. 2011;SCOEL/SUM/150. 2198 IPCS. Platinum. Environmental Health Criteria 125. International Programme on Chemical 2199 Safety. World Health Organization, Geneva. 1991. 2200 Merget R; Kulzer R; Dierkes-Globisch A, Breitstadt R, Gebler A, Kniffka A, Artelt S, Koenig HP, 2201 Alt F, Vormberg R, Baur X, Schultze-Werninghaus G. Exposure-effect relationship of platinum 2202 salt allergy in a catalyst production plant: conclusions from a 5-year prospective cohort study. J 2203 Allergy Clin Immunol 2000;105:364-370. 2204 Merget R, Caspari C, Kulzer SA, Dierkes-Globisch R, Kniffka A, Degens P et al. Effectiveness 2205 of a medical surveillance program for the prevention of occupational asthma caused by platinum 2206 salts: a nested case control study. J Allergy Clin Immunol 2001;107:707-12. 2207 Pepys J, Pickering CAC, Hughes EG. Asthma due to inhaled chemical agents--complex salts of 2208 platinum. Clin Exp Allergy 1972;2:391-96. 2209 Pickering CAC. Inhalation tests with chemical allergens: complex salts of platinum. Proc R Soc 2210 Med 1972;65:2-4. 2211 Reichlmayr-Lais AM, Kirchgessner M, Bader R. Dose-response relationships of alimentary PtCl2 2212 and PtCl4 in growing rats. J Trace Elem Electrolytes Health Dis 1992;6(3):183-7. 2213 US DoL (OHSA). 29 CRF 1910.1000 Table Z-1. Limits for air contaminants. U.S. Department of 2214 Labor. 2013. 2215 US EPA. Platinum-group metals. Environmental Health Effects Research Series 1977;EPA- 2216 600/1-77- 040. 2217 US EPA. Toxicological review of halogenated platinum salts and platinum compounds. In 2218 support of summary information on the Integrated Risk Information System (IRIS). 2009. 2219 EPA/635/R-08/018 66 Contains Nonbinding Recommendations 2220 Platinum-Group Elements 2221 2222 Summary of PDE for Platinum-Group Elements Iridium (Ir), Osmium (Os), Rhodium (Rh), Ruthenium (Ru) Oral Parenteral Inhalation PDE (µg/day) 100 10 1.0 2223 2224 Introduction 2225 There is limited toxicological data for the Platinum-Group Elements (PGE) other than platinum, 2226 and, to a lesser extent, palladium. Occupational exposure to the PGE may cause hypersensitivity 2227 with respiratory symptoms and contact dermatitis (Goossens et al, 2011). Acute LD50s are 2228 available for some of the platinum-group elements but this information was not sufficient for 2229 setting a PDE; longer term toxicology studies are not available. RuO4 appears to be a stronger 2230 oxidizing agent than OsO4, at least when used in fixing tissues (Gaylarde and Sarkany, 1968; 2231 Swartzendruber et al, 1995). It appears that the soluble salts of the PGE are more toxic than the 2232 metal (Wiseman and Zereini, 2009). 2233 Based on the lack of information on toxicity of the PGE, the PDEs for all routes of 2234 administration are based on the palladium PDEs rather than platinum as the more conservative 2235 approach. The limited safety information for the PGE is described below. 2236 Safety Evaluation 2237 There are very few published data on the safety of Iridium, Osmium, Rhodium and Ruthenium. 2238 • Iridium 2239 o Iridium induced DNA single strand breaks in rat fibroblasts as measured in a 2240 Comet assay when fibroblasts were incubated with Ir(3+) chloride hydrate for 2241 24 hours No strand breaks were seen after a 2 hour incubation (Iavicoli et al, 2242 2012). 2243 o Groups of Wistar rats were administered Ir(3+) chloride hydrate in drinking 2244 water (0, 0.019, 0.19, 1.9, 9.5 and 19 µg Ir/d) for 90 days to assess 2245 nephrotoxicity Iavicoli et al, 2011). While there may have been some indication 2246 of renal toxicity from 0.19 µg/d, this study was not adequate to set an oral 2247 PDE. 2248 • Osmium 2249 o Osmium tetroxide is not very soluble in water (Luttrell and Giles, 2007). 2250 Metallic osmium is not toxic (McLaughlin et al, 1946). 2251 o Osmium tetroxide has been used as a treatment for arthritis. As a vapor, OsO4 2252 can cause severe eye damage and irritation to the eye, nose, throat and 2253 bronchial tubes, lung, skin, liver, and kidney damage (USDoL, 1978; Luttrell 2254 and Giles, 2007). 2255 o The Permitted Exposure Limit (PEL) TWA for osmium tetroxide (as osmium) 2256 is 0.002 mg/m3 (UsD0L, 2013). 2257 • Rhodium 67 Contains Nonbinding Recommendations 2258 o Rh salts (K2RhCl5, (NH4)3RhCl6) were genotoxic in Salmonella typhimurium 2259 (Bünger et al, 1996). In this assay, rhodium was similar to palladium in terms 2260 of cytotoxicity and genotoxicity and much less toxic than platinum. Rhodium 2261 induced DNA single strand breaks in rat fibroblasts as measured in a Comet 2262 assay when fibroblasts were incubated with Rh(3+) chloride hydrate for 2 or 24 2263 hours (Iavicoli et al, 2012). RhCl3 was genotoxic in the human lymphocyte 2264 micronucleus assay and increased DNA migration (Comet assay) in white 2265 blood cells (Migliore et al, 2002). 2266 o In a lifetime carcinogenicity bioassay in mice administered rhodium chloride, a 2267 higher incidence of tumors in treated animals compared to controls was noted 2268 at a dose of 5 ppm in drinking water. The data on tumors were too limited to 2269 allow a conclusion of carcinogenicity, a, similar to palladium (Schroeder and 2270 Mitchener, 1971). 2271 o The PEL TWA for rhodium (as Rh) metal fume and insoluble compounds is 0.1 2272 mg/m3. The PEL TWA for soluble compounds of Rh is 0.001 mg/m3 (UsD0L, 2273 2013). 2274 • Ruthenium 2275 o Several Ru complexes cause genotoxic responses in vitro in Salmonella 2276 typhimurium strains TA98 and TA100 (Monti-Bragadin et al, 1975; Yasbin et 2277 al, 1980; Benkli et al, 2009). 2278 o Oral absorption of Ru is low (about 4%); the half-life of a parenteral dose is 2279 about 200 days. Ingested ruthenium compounds are retained in bones (Furchner 2280 et al, 1971). 2281 2282 REFERENCES 2283 Benkli K, Tunali Y, Cantürk S, Artagan O, Alanyali F. Cytotoxic and genotoxic effects of 2284 [Ru(phi)3]2+ evaluated by Ames/Salmonella and MTT methods. Europ J Medic Chem 2285 2009;44:2601-5. 2286 Bünger J, Stork J, Stalder K. Cyto- and genotoxic effects of coordination complexes of platinum, 2287 palladium and rhodium in vitro. Int Arch Occup Environ Health 1996;69(1):33-8. 2288 Furchner JE, Richmond CR, Drake GA. Comparative Metabolism of Radionuclides in Mammals 2289 - VII. Retention of 106Ru in the Mouse, Rat, Monkey and Dog. Health Phuysics 1971;21(3):355- 2290 65. 2291 Gaylarde P, Sarkany I. Ruthenium tetroxide for fixing and staining cytoplasmic membranes. 2292 Science 1968;161(3846):1157-8. 2293 Goossens A, Cattaert N, Nemery B, Boey L, De Graef E. Occupational allergic contact dermatitis 2294 caused by rhodium solutions. Contact dermatitis 2011;64:158-61. 2295 Iavicoli I, Fontana L, Marinaccio A, Calabrese EJ, Alimonti M, Pino A et al. The effects of 2296 iridium on the renal function of female Wistar rats. Ecotoxicol Environ Safety 2011;74:1795-9. 68 Contains Nonbinding Recommendations 2297 Iavicoli I, Cufino V, Corbi M, Goracci M, Caredda E, Cittadini A et al. Rhodium and iridium salts 2298 inhibit proliferation and induce DNA damage in rat fibroblasts in vitro. Toxicol in vitro 2299 2012;26(6):963-9. 2300 Luttrell WE, Giles CB. Toxic tips: Osmium tetroxide. J Chemical Health Safety 2301 2007;Sept/Oct:40-1. 2302 McLaughlin AIG, Milton R, Perry KMA. Toxic manifestations of osmium tetroxide. Brit J Ind 2303 Med 1946;3:183-6. 2304 Migliore L, Frenzilli G, Nesti C, Fortaner S, Sabbioni E. Cytogenic and oxidative damage 2305 induced in human lymphocytes by platinum, rhodium and palladium compounds. Mutagenesis 2306 2002;17:411-7. 2307 Monti-Bragadin C, Tamaro M, Banfi E. Mtuagenic activity of platinum and tuthenium 2308 complexes. Chem Biol Interact 1975;11:469-72. 2309 Schroeder HA, Mitchener M. Scandium, chromium (VI), gallium, yttrium, rhodium, palladium, 2310 indium in mice: Effects on growth and life span. J Nutr 1971;101:1431-8. 2311 Swartzendruber DC, Burnett IH, Wertz PW, Madison KC, Squier CA. Osmium tetroxide and 2312 ruthenium tetroxide are complementary reagents for the preparation of epidermal samples for 2313 transmission electron microscopy. J Invest Dermatol 1995;104(3):417-20. 2314 USDoL (OHSA). Occupational health guideline for osmium tetroxide. U.S. Department of 2315 Labor. 1978. 2316 USDoL (OHSA). 29 CRF 1910.1000 Table Z-1. Limits for air contaminants. U.S. Department of 2317 Labor. 2013 2318 Wiseman CLS, Sereini F. Airborne particulate matter, platinum group elements and human 2319 health: A review of recent evidence. Sci Total Environ 20009;407:2493-500. 2320 Yasbin RE, Matthews CR, Clarke MJ. Mutagenic and toxic effects of ruthenium. Chem Biol 2321 Interact 1980:31:355-65. 69 Contains Nonbinding Recommendations 2322 SELENIUM 2323 2324 Summary of PDE for Selenium Selenium (Se) Oral Parenteral Inhalation PDE (µg/day) 170 85 135 2325 2326 Introduction 2327 Selenium (Se) is present in the earth's crust, often in association with sulfur-containing minerals. 2328 It can assume four oxidation states (-2, 0, +4, +6) and occurs in many forms, including elemental 2329 selenium, selenites and selenates. Selenium is an essential trace element for many species, 2330 including humans. Selenium is incorporated into proteins via a specific selenocysteine tRNA. 2331 Selenium is being used as a catalyst in the manufacture of rubber. Ru-Se catalysts are used in 2332 oxygen reduction. Aryl- and alkyl- Selenium reagents have various applications in organic 2333 synthesis. 2334 2335 Safety Limiting Toxicity 2336 Selenium was listed as a Group 3 compound (not classifiable for carcinogenesis) by IARC 2337 (1987). The only selenium compound that has been shown to be carcinogenic in animals is 2338 selenium sulfide (NTP, 1980). According to the US EPA, selenium sulfide is in Group B2 2339 (probable human carcinogen) (US EPA, 2002). Other selenium compounds are classified as D; 2340 not classifiable as to carcinogenicity in humans. 2341 The most significant toxicity observed with excessive exposure in humans to Se is selenosis, 2342 characterized primarily by dermal and neurological effects, including unsteady gait and paralysis 2343 (ATSDR, 2003). There is some concern over exposure to excessive levels of selenium in the diet; 2344 to limit the total exposure to Se, various organizations have set an upper tolerable limit at 400 2345 µg/day (WHO, 2011). Occupational studies describe respiratory effects such as irritation of the 2346 nose, respiratory tract, and lungs, bronchial spasms, and coughing following chronic exposure to 2347 selenium dioxide or elemental selenium as dust. Respiratory symptoms similar to those reported 2348 for occupationally-exposed humans have been seen in animals inhaling high doses of elemental 2349 selenium fumes or dust, and studies of animals with acute inhalation exposure to hydrogen 2350 selenide or elemental selenium fumes or dust have reported hepatocellular degeneration and 2351 atrophy of the liver. Absorption after inhalation exposure is uncertain (ATSDR, 2003). 2352 2353 PDE – Oral Exposure 2354 In a rat carcinogenicity study of selenium sulfide, the NOAEL for hepatocellular carcinoma was 3 2355 mg/kg/day (1.7 mg Se/kg/day) (NTP, 1980). Although, there is insufficient data to assess 2356 carcinogenicity of other forms of selenium, and the human relevance of the rodent liver tumors has 2357 been questioned (IARC, 1999), this is the best available study. Some human data are available but 2358 only in a limited number of subjects (ATSDR, 2003). The calculated PDE is in line with the MRL 2359 of 5 µg/kg/day for Se (ATSDR, 2003). Taking into account the modifying factors (F1-F5 as 2360 discussed in Appendix 1), the oral PDE is calculated as below. 2361 2362 PDE = 1.7 mg/kg/d x 50 kg / (5 x 10 x 1 x 10 x 1) = 170 µg/day 2363 70 Contains Nonbinding Recommendations 2364 A factor of ten was chosen for F4 because of the risk of selenosis. 2365 2366 PDE – Parenteral Exposure 2367 Studies in humans and experimental animals indicate that, when ingested, several selenium 2368 compounds including selenite, selenate, and selenomethionine are readily absorbed, often to 2369 greater than 80% of the administered dose (ATSDR, 2003). On the basis of oral bioavailability of 2370 ~80%, the parenteral PDE was calculated by dividing the oral PDE by a modifying factor of 2 2371 (as described in section 3.1). 2372 2373 PDE = 170 µg/d / 2 = 85 µg/day 2374 2375 PDE – Inhalation Exposure 2376 Respiratory endpoints are the most sensitive markers for inhalation exposure in occupational 2377 studies. Occupational limits have established time weighted averages for selenium exposures of 2378 0.2 mg/m3 (US DoL, 2013) and 0.07 by the European Union Scientific Expert Group (EU SEG, 2379 1992). However, the EU SEG Occupation Exposure Limits (OEL) was based on hydrogen 2380 selenide, a form not likely to be present in inhalation products. Thus, using the OEL derived by 2381 US DoL, and taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the 2382 inhalation PDE is calculated as below. 2383 2384 For continuous dosing = 0.2 mg/m3 8 hr/d x 5 d/wk = 0.048 mg/m3 = 0.000048 mg/L 2385 24 hr/d x 7 d/wk 1000 L/m3 2386 2387 Daily dose = 0.000048 mg/L x 28800 L = 0.027 mg/kg 2388 50 kg 2389 2390 PDE = 0.027 mg/kg x 50 kg / (1 x 10 x 1 x 1 x 1) = 0.135 mg/day =135 µg/day 2391 2392 REFERENCES 2393 ATSDR. Toxicological profile for selenium. Agency for Toxic Substances and Disease Registry, 2394 Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 2003. 2395 EU SEG. Recommendation from the Scientific Expert Group on Occupation Exposure Limits for 2396 Hydrogen selenide. European Union Scientific Expert Group. 1992;SEG/SUM/22C 2397 IARC. Overall evaluations of carcinogenicity: An update of IARC monographs volumes 1 to 42. 2398 Monographs on the Evaluation of the Carcinogenic Risks to Humans. International Agency for 2399 Research on Cancer, World Health Organization, Lyon. 1987;Suppl 7. 2400 IARC. Some aziridines, N-, S- and O-mustards and selenium. Summary of data reported and 2401 evaluation. Monographs on the Evaluation of Carcinogenic Risks to Humans. International 2402 Agency for Research on Cancer, World Health Organization, Lyon. 1999. 2403 NTP. Bioassay of selenium sulfide (gavage) for possible carcinogenicity. National Toxicology 2404 Program, US Department of Health and Human Services. 1980;Technical Report Series No 194. 2405 US DoL (OHSA). 29 CRF 1910.1000 Table Z-1. Limits for air contaminants. U.S. Department of 2406 Labor. 2013. 71 Contains Nonbinding Recommendations 2407 US EPA. Selenium and compounds (CAS No. 7782-49-2). Integrated Risk Information System 2408 (IRIS). 2002. 2409 WHO. Selenium in Drinking-water; Background document for development of WHO Guidelines 2410 for Drinking-water Quality. World Health Organization, Geneva. 2011. 2411 WHO/HSE/WSH/10.01/14 72 Contains Nonbinding Recommendations 2412 SILVER 2413 2414 Summary of PDE for Silver Silver (Ag) Oral Parenteral Inhalation PDE (µg/day) 167 16.7 7.0 2415 2416 Introduction 2417 Silver (Ag) is present in silver compounds primarily in the +1 oxidation state and less frequently 2418 in the +2 oxidation state. Silver occurs naturally mainly in the form of very insoluble and 2419 immobile oxides, sulfides, and some salts. The most important silver compounds in drinking- 2420 water are silver nitrate and silver chloride. Most foods contain traces of silver in the 10–100 2421 µg/kg range. Silver is nutritionally not essential, and no metabolic function is known. Silver is 2422 being used as a catalyst in the oxidation of ethylene to ethylene oxide. Silver-Cadmium alloy is 2423 used in selective hydrogenation of unsaturated carbonyl compounds. Silver oxide is used as a 2424 mild oxidizing agent in organic synthesis. 2425 2426 Safety Limiting Toxicity 2427 Silver is not mutagenic. Animal toxicity studies and human occupational studies have not 2428 provided sufficient evidence of carcinogenicity. Based on these data silver is not expected to be 2429 carcinogenic in humans (ATSDR, 1990). 2430 Argyria appears to be the most sensitive clinical effect in response to human Ag intake. Silver 2431 acetate lozenges are used in smoking cessation (Hymowitz and Eckholdt, 1996). Argyria, a 2432 permanent bluish- gray discoloration of the skin, results from the deposition of Ag in the dermis 2433 combined with a silver- induced production of melanin. Inhalation of high levels of silver can 2434 result in lung and throat irritation and stomach pains (ATSDR, 1990). 2435 2436 PDE – Oral Exposure 2437 Silver nitrate was added at 0.015% to the drinking water of female mice (0.9 g/mouse; 32.14 2438 mg/kg silver nitrate; 64% silver) for 125 days to examine neurobehavioral activity of the animals 2439 based on potential neurotoxicity of silver (Rungby and Danscher, 1984). Treated animals were 2440 hypoactive relative to controls; other clinical signs were not noted. In a separate study, silver was 2441 shown to be present in the brain after mice were injected with 1 mg/kg intra peritoneal silver 2442 lactate (Rungby and Danscher, 1983). The oral PDE is consistent with the reference dose of 5 2443 µg/kg/day (US EPA, 2003). Taking into account the modifying factors (F1-F5 as discussed in 2444 Appendix 1), the oral PDE is calculated as below. 2445 2446 PDE = 20 mg/kg x 50 kg / (12 x 10 x 5 x 1 x 10) = 167 µg/day 2447 2448 A factor ten was chosen for F5 because the LOAEL was used to set the PDE as few toxicological 2449 endpoints were examined. 2450 2451 PDE – Parenteral Exposure 2452 The safety review for silver identified one study in humans by the intravenous route published by 2453 Gaul and Staud in 1935. In this study silver arsphenamine was administered intravenously to 12 2454 patients in 31-100 injections over 2 to 9.75 years. Based on cases presented in the study, the 73 Contains Nonbinding Recommendations 2455 lowest cumulative dose of silver resulting in argyria was 1 g metallic silver. Argyria was reported 2456 in other patients at higher cumulative doses of silver. Using this study, the US EPA (2003) 2457 identified this dose as a LOAEL. This study was considered inadequate to set a parenteral PDE 2458 as it involved few patients and the dosing was not adequately described. However, the study was 2459 useful in that it identified argyria as a result of cumulative dosing. 2460 2461 Silver is known to be absorbed across mucosal surfaces. Absorption of silver acetate occurred 2462 after ingestion of a dose of radiolabelled silver with approximately 21% of the dose being 2463 retained at 1 week (ATSDR, 1990). In a review of the oral toxicity of silver, Hadrup and Lam 2464 (2014) report that absorption of a radionuclide of silver (as silver nitrate) was between 0.4 to 2465 18%, depending upon the species, with humans at 18%. On the basis of an oral bioavailability 2466 between 1% and 50% for silver, the parenteral PDE was calculated by dividing the oral PDE by a 2467 modifying factor of 10 (as described in section 3.1). The recommended PDE for silver for 2468 parenteral exposure is: 2469 2470 PDE = 167 µg/d / 10 = 16.7 µg/day 2471 2472 PDE – Inhalation Exposure 2473 Lung and throat irritation and stomach pains were the principal effects in humans after inhalation 2474 of high Ag levels. Using the Threshold Limit Value (TLV) of 0.01 mg/m3 for silver metal and 2475 soluble compounds (US DoL, 2013), and taking into account the modifying factors (F1-F5 as 2476 discussed in Appendix 1), the inhalation PDE is calculated as: 2477 2478 For continuous dosing = 0.2 mg/m3 8 hr/d x 5 d/wk = 0.048 mg/m3 = 0.000048 mg/L 2479 24 hr/d x 7 d/wk 1000 L/m3 2480 2481 Daily dose = 0.000048 mg/L x 28800 L = 0.027 mg/kg 2482 50 kg 2483 2484 PDE = 0.027 mg/kg x 50 kg / (1 x 10 x 1 x 1 x 1) = 0.135 mg/day =135 µg/day 2485 2486 REFERENCES 2487 ATSDR. Toxicological Profile for Silver. Agency for Toxic Substances and Disease Registry, 2488 Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 1990. 2489 Gaul LE, Staud AH. Clinical spectroscopy. Seventy cases of generalized argyrosis following 2490 organic and colloidal Ag medication. JAMA. 1935, 104:1387–1390. 2491 Hadrup N, Lam HR. Oral toxicity of silver ions, silver nanoparticles and colloidal silver - A 2492 review. Regul Toxicol Pharmacol. 2014 68(1):1-7. 2493 Hymowitz N, Eckholt H. Effects of a 2.5-mg silver acetate lozenge on initial and long-term 2494 smoking cessation. Prev Med 1996;25:537-46. 2495 Rungby J, Danscher G. Hypoactivity in silver exposed mice. Acta Pharmacol Toxicol 2496 1984;55:398-401. 2497 Rungby J, Danscher G. Localization of exogenous silver in brain and spinal cord of silver 2498 exposed rats. Acta Neuropathol 1983;60(1-2):92-8. 74 Contains Nonbinding Recommendations 2499 US DoL (OHSA). 29 CRF 1910.1000 Table Z-1. Limits for air contaminants. U.S. Department of 2500 Labor. 2013. 2501 US EPA. Silver (CASRN 7440-22-4). Integrated Risk Information System (IRIS). 2003. 75 Contains Nonbinding Recommendations 2502 THALLIUM 2503 2504 Summary of PDE for Thallium Thallium (Tl) Oral Parenteral Inhalation PDE (µg/day) 8.0 8.0 8.0 2505 2506 Introduction 2507 Pure thallium (Tl) is a bluish-white metal. It exists primarily in two oxidation states: +1 and +3. 2508 Monovalent thallium is similar to potassium (K+) in ionic radius and electrical charge, which 2509 contributes to its toxic nature. Many of the thallium salts are soluble in water with the exception 2510 of the insoluble Tl(3+) oxide. Thallium sulfate has been used in medicine, primarily as a 2511 depilatory agent, but also to treat infections, such as venereal diseases, ringworm of the scalp, 2512 typhus, tuberculosis, and malaria. Tl(3+) salts are being used in organic synthesis. Thallium is 2513 nutritionally not essential and no metabolic function is known (ATSDR, 1992). 2514 2515 Safety Limiting Toxicity 2516 In humans and animals, the skin, especially the hair follicles, appears to be the most sensitive 2517 target of toxicity from repeated oral exposure to thallium (US EPA, 1992; US EPA, 2009). Water 2518 soluble salts (sulphate, acetate, or carbonate) have higher toxicity than other forms (Moore et al, 2519 1993). 2520 2521 PDE – Oral Exposure 2522 The primary target organ for oral exposure to thallium in humans and animals appears to be the 2523 skin, especially the hair follicles, as shown in a 90-day toxicity rat study with thallium sulfate. 2524 The NOAEL was defined at 0.04 mg Tl/kg on the basis of an increased incidence of alopecia at 2525 the higher doses (OEHHA, 1999; US EPA, 2009). Thus, the oral PDE was determined on the 2526 basis of the NOAEL of 0.04 mg Tl/kg in rat. 2527 Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral PDE is 2528 calculated as below. 2529 2530 PDE = 0.04 mg/kg/d x 50 kg / (5 x 10 x 5 x 1 x 1) = 0.008 mg/day = 8.0 µg/day 2531 2532 PDE – Parenteral Exposure 2533 No relevant data on parenteral exposure to thallium compounds were found. The bioavailability 2534 of soluble thallium salts is high (> 80%) (US EPA, 2009). Therefore, the parenteral PDE is the 2535 same as the oral PDE. 2536 2537 PDE = 8.0 µg/day 2538 2539 PDE – Inhalation Exposure 2540 No relevant data on inhalation exposure to thallium compounds were found. The US EPA 2541 concluded that information on the inhalation toxicity of thallium is insufficient to derive an 2542 inhalation reference concentration. Occupational epidemiology studies involving possible 2543 inhalation exposures to thallium were limited and inconclusive (US EPA, 2009). The major 76 Contains Nonbinding Recommendations 2544 toxicity identified in humans and animals is alopecia, and absorption and toxicity is considered 2545 high by the inhalation route (IPCS, 1996). Similar findings may be expected by Tl exposure via 2546 oral and respiratory routes. For this reason, the inhalation PDE is set at the parenteral PDE. 2547 2548 PDE = 8.0 µg/day 2549 2550 REFERENCES 2551 ATSDR. Toxicological profile for thallium. Agency for Toxic Substances and Disease Registry, 2552 Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 1992. 2553 IPCS. Thallium and thallium salts: health and safety guide. International Programme on 2554 Chemical Safety, World Health Organization, Geneva, 1996. Health and Safety Guide No. 102. 2555 Moore D, House I, Dixon A. Thallium poisoning. Br Med J 1993;306:1527-9. 2556 OEHHA. Public health goal for thallium in drinking water. Office of Environmental Health 2557 Hazard Assessment, Berkeley and Sacramento, CA. 1999. 2558 US EPA. Drinking water criteria document for thallium. Health and Ecological Criteria Division; 2559 Office of Science and Technology; Office of Water; U.S. Environmental Protection Agency, 2560 Washington DC, 1992. 2561 US EPA. Toxicological review of thallium and compounds (CAS No. 7440-28-0). Integrated 2562 Risk Information System (IRIS). 2009. EPA/635/R-08/001F 77 Contains Nonbinding Recommendations 2563 TIN 2564 2565 Summary of PDE for Tin Tin (Sn) Oral Parenteral Inhalation PDE (µg/day) 6400 640 64 2566 2567 Introduction 2568 Tin (Sn) is a silvery-white metal that exists in +2 and +4 oxidation states. The most important 2569 inorganic compounds of tin are its oxides, chlorides, fluorides, and halogenated sodium stannates 2570 and stannites. Tin is present in some multi-vitamin and mineral food supplements (at levels up to 2571 10 µg Sn/tablet). Tin is possibly nutritionally essential for some animals, but it has not been 2572 shown to be essential for humans. Tin(2+) chloride is being used as a reducing agent, and as a 2573 stabilizer of polyvinylchloride (PVC). This safety assessment focuses on inorganic tin 2574 considering that the more frequent occurrence of inorganic tin is more relevant with respect to 2575 metal impurities in drug products than organic tin compounds. 2576 2577 Safety Limiting Toxicity 2578 There is no indication of in vivo genotoxicity or carcinogenicity for tin and tin salts. In several 2579 studies in rats, a decrease in hemoglobin as an early sign for anemia was the most sensitive 2580 endpoint. In general, in in vitro assays tin and tin salts were negative for mutagenicity but some 2581 forms were positive for chromosomal damage (CICAD, 2005). Stannous chloride was not 2582 carcinogenic in the two-year assay in mice or rats (NTP, 1982). 2583 2584 PDE – Oral Exposure 2585 Anemia was the most sensitive endpoint in rats after repeated oral administration. Thus, the PDE 2586 for oral exposure was determined on the basis of the lowest NOAEL, i.e., 150 ppm (equivalent to 2587 32 mg Sn/kg/day; ATSDR, 2005). This value was obtained from a 90-day study in rats based on 2588 signs of anemia starting at 500 ppm in rats exposed to stannous chloride via diet (de Groot et al, 2589 1973). This study was considered more relevant than the NTP study (NTP, 1982) in determining 2590 the oral PDE because in the 13-week NTP dose range finding study, the toxicological evaluation 2591 was more limited (e.g., no clinical chemistry, including effects on hemoglobin) than in the study 2592 by de Groot et al. Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), 2593 the oral PDE is calculated as below. 2594 2595 PDE = 32 mg/kg/d x 50 kg / (5 x 10 x 5 x 1 x 1) = 6.4 mg/d = 6400 µg/day 2596 2597 PDE – Parenteral Exposure 2598 The safety review for tin was unable to identify any significant assessments upon which to 2599 calculate a PDE for parenteral routes of exposure. On the basis of an oral bioavailability of about 2600 5% for tin and inorganic tin compounds (ATSDR, 2005), the parenteral PDE was calculated by 2601 dividing the oral PDE by a modifying factor of 10 (as described in section 3.1). 2602 2603 PDE = 6400 µg/d / 10 = 640 µg/day 2604 78 Contains Nonbinding Recommendations 2605 PDE – Inhalation Exposure 2606 The safety review for tin was unable to identify any significant assessments on inorganic tin upon 2607 which to calculate a PDE for inhalation routes of exposure. Although a TLV is available for tin 2608 (2 mg/m3; US DoL, 2013), there is insufficient data to set a MRL (ATSDR 2005; EU SCOEL 2609 2003). Therefore, the PDE for tin is calculated by using a factor of 100 to convert the oral PDE 2610 to the inhalation PDE (as described in section 3.1). 2611 2612 PDE = 6400 µg/d / 100 = 64 µg/day 2613 2614 REFERENCES 2615 ATSDR. Toxicological profile for tin and tin compounds. Agency for Toxic Substances and 2616 Disease Registry, Public Health Service, U.S. Department of Health and Human Services, 2617 Atlanta, GA. 2005. 2618 CICAD. Tin and inorganic compounds. Concise International Chemical Assessment Document. 2619 World Health Organization, Geneva, 2005. Document 65. 2620 De Groot AP, Feron V, Til H. Short-term toxicity studies on some salts and oxides of tin in rats. 2621 Food Cos Toxicol 1973;11:19-30. 2622 EU SCOEL. Recommendation from the scientific committee on occupational exposure limits for 2623 tin and inorganic tin compounds. European Union Scientific Committee on Occupational 2624 Exposure Limits. 2003;SCOEL/SUM/97. 2625 NTP. Technical report on the carcinogenesis bioassay of stannous chloride (CAS NO. 7772-99-8) 2626 in F344/N and B6C3F1/N mice (feed study). National Toxicology Program. U.S. Department of 2627 Health and Human Services. 1982; Technical Report Series No. 231. 2628 US DoL (OHSA). 29 CRF 1910.1000 Table Z-1. Limits for air contaminants. U.S. Department of 2629 Labor. 2013. 79 Contains Nonbinding Recommendations 2630 VANADIUM 2631 2632 Summary of PDE for Vanadium Vanadium (V) Oral Parenteral Inhalation PDE (µg/day) 120 12 1.2 2633 2634 Introduction 2635 Vanadium (V) is present as a trace element in the earth's crust and can exist in a variety of 2636 oxidation states (-1, 0, +2, +3, +4 and +5). V is also present in trace quantities in most biological 2637 organisms with the principal ions being 3 vanadate, VO - and 2 vanadyl, VO +. Absorption of 2638 vanadium from the gastrointestinal tract is poor. Estimates of total dietary intake of vanadium in 2639 humans range from 10 to 60 µg/day. Intake from drinking water depends on the water source and 2640 estimates are up to 140 µg/day. Human populations have variable serum concentrations of 2641 vanadium, with 2 µg/L being the high end of the normal range. Despite its being ubiquitous in the 2642 body, an essential biological role for vanadium in humans has not been established. 2643 2644 Safety Limiting Toxicity 2645 Vanadium is genotoxic, but not mutagenic (ATSDR, 2012). Vanadium pentoxide is classified as 2646 a possible human carcinogen (Group 2B; IARC, 2012). 2647 2648 PDE – Oral Exposure 2649 Following oral administration to animals and humans the gastrointestinal tract, cardiovascular, 2650 and hematological system are the primary targets of toxicity. The most appropriate study to assess 2651 vanadium toxicity through oral administration was conducted in humans exposed to vanadium 2652 for 12 weeks. In this study, no significant alterations in hematological parameters, liver function 2653 (as measured by serum enzymes), cholesterol and triglyceride levels, kidney function (as 2654 measured by blood urea nitrogen), body weight, or blood pressure were observed in subjects 2655 administered via capsule 0.12 or 0.19 mg vanadium as ammonium vanadyl tartrate or vanadyl 2656 sulfate for 6–12 weeks (ATSDR, 2012). The oral NOAEL of 0.12 mg vanadium/kg/day for 2657 hematological and blood pressure effects was used to calculate the oral PDE. Taking into account 2658 the modifying factors (F1-F5 as discussed in Appendix 1), the oral PDE is calculated as below. 2659 2660 PDE = 0.12 mg/kg/d x 50 kg / (1 x 10 x 5 x 1 x 1) = 0.12 mg/d = 120 µg/day 2661 2662 PDE – Parenteral Exposure 2663 The safety review for vanadium was unable to identify any significant assessments upon which 2664 to calculate a PDE for parenteral routes of exposure. On the basis of an approximate oral 2665 bioavailability of <1–10% for vanadium and inorganic vanadium compounds (ATSDR, 2012), 2666 the parenteral PDE was calculated by dividing the oral PDE by a modifying factor of 10 (as 2667 described in section 3.1). 2668 2669 PDE = 120 µg/day / 10 = 12 µg/day 2670 80 Contains Nonbinding Recommendations 2671 PDE – Inhalation Exposure 2672 A two-year chronic inhalation exposure study in rats was considered for use for the inhalation 2673 PDE for vanadium. In this study, carcinogenic effects were observed to the lowest dose tested, 2674 0.5 mg/m3 vanadium pentoxide (Ress et al. 2003). Vanadium pentoxide is a caustic agent and is 2675 not considered to be present in drug products. Therefore, the inhalation PDE for vanadium was 2676 calculated by dividing the oral PDE by a modifying factor of 100 (as described in section 3.1). 2677 2678 PDE = 120 µg/d / 100 = 1.2 µg/day 2679 2680 REFERENCES 2681 ATSDR. Toxicological profile for vanadium. Agency for Toxic Substances and Disease Registry, 2682 Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 2012. 2683 IARC. Arsenic, metals, fibers, and dusts: a review of human carcinogens. Monographs on the 2684 Evaluation of Carcinogenic Risks to Humans. International Agency for Research on Cancer, 2685 World Health Organization, Lyon. 2012;100C. 2686 Ress NB, Chou BJ, Renne RA, Dill JA, Miller RA, Roycroft JH et al. Carcinogenicity of inhaled 2687 vanadium pentoxide in F344/N rats and B6C3F1 mice. Toxicol Sci 2003;74(2):287-96. 81 Contains Nonbinding Recommendations 2688 Appendix 4: Illustrative Examples 2689 2690 Examples for Converting PDEs into Permitted Elemental Impurity Concentrations 2691 2692 Option 1: Permitted common concentration limits of elemental impurities across drug product 2693 component materials for products with daily intakes of not more than ten grams. 2694 For this example, consider a solid oral drug product with a maximum daily intake of 2.5 grams, 2695 containing nine components (1 drug substance and eight excipients, see Table A.4.1). Because this 2696 drug product does not exceed a maximum daily intake of ten grams, the concentrations in Table 2697 A.2.2 may be used. As Option 1 has a common permitted concentration, the nine components can 2698 be used in any proportion in the formulation. The drug substance synthesis uses Pd and Ni 2699 catalysts, and Pb, As, Cd, Hg, and V are also of concern on the basis of the risk assessment. The 2700 maximum daily intake of each elemental impurity in the drug product is given in Table A.4.2 2701 assuming that each elemental impurity is present at the concentration given in Table A.2.2. The 2702 maximum potential daily intake of an elemental impurity is determined using the actual drug 2703 product daily intake and the concentration limit for the elemental impurity in Table A.2.2 2704 (concentration multiplied by the actual daily intake of the drug product of 2.5 grams). The 2705 maximum daily intake given for each elemental impurity is not a summation of values found in 2706 the individual columns of Table A.4.2. 2707 This calculation demonstrates that no elemental impurities exceed their PDEs. Thus, if these 2708 concentrations in each component are not exceeded, the drug product is assured to not exceed the 2709 PDEs for each identified elemental impurity. 2710 2711 Table A.4.1: Maximum Daily Intake of Components of the Drug Product Component Daily Intake, g Drug Substance 0.200 Microcrystalline Cellulose (MCC) 1.100 Lactose 0.450 Ca Phosphate 0.350 Crospovidone 0.265 Mg Stearate 0.035 Hydroxypropylmethyl Cellulose (HPMC) 0.060 Titanium Dioxide 0.025 Iron Oxide 0.015 Drug Product 2.500 2712 2713 Table A.4.2: Permitted Concentrations from Table A.2.2 (assuming uniform 2714 concentrations and 10 grams daily intake) Maximum Permitted Concentration (µg/g) Component Pb As Cd Hg Pd V Ni Drug Substance 0.5 1.5 0.5 3 10 10 20 MCC 0.5 1.5 0.5 3 10 10 20 Lactose 0.5 1.5 0.5 3 10 10 20 Ca Phosphate 0.5 1.5 0.5 3 10 10 20 Crospovidone 0.5 1.5 0.5 3 10 10 20 82 Contains Nonbinding Recommendations Mg Stearate 0.5 1.5 0.5 3 10 10 20 HPMC 0.5 1.5 0.5 3 10 10 20 Titanium 0.5 1.5 0.5 3 10 10 20 Dioxide Iron Oxide 0.5 1.5 0.5 3 10 10 20 Maximum Daily intake (µg) 1.25 3.75 1.25 7.5 25 25 50 PDE (µg) 5 15 5 30 100 100 200 2715 2716 Option 2a: Permitted common concentration limits across drug product component materials for 2717 a product with a specified daily intake: 2718 For this example, consider the same solid oral drug product with a maximum daily intake of 2.5 2719 grams, containing nine components (1 drug substance and eight excipients, see Table A.4.1) used 2720 in Option 1. As Option 2a has a common permitted concentration, the nine components can be 2721 used in any proportion in the formulation. The drug substance synthesis uses Pd and Ni catalysts, 2722 Pb, As, Cd, Hg, and V are also of concern on the basis of the risk assessment. The maximum 2723 concentration of each elemental impurity identified in the risk assessment can be calculated 2724 using the PDEs in Table A.2.1 and Equation 1. 2725 The maximum potential daily intake of an elemental impurity is determined using the actual drug 2726 product daily intake and the concentration limit for the elemental impurity in Table A.4.3 2727 (concentration multiplied by the actual daily intake of the drug product of 2.5 grams). The 2728 maximum daily intake given for each elemental impurity is not a summation of values found in the 2729 individual columns of Table A.4.3. 2730 This calculation also demonstrates that no elemental impurities exceed their PDEs. Thus, if these 2731 concentrations in each component are not exceeded, the drug product is assured to not exceed the 2732 PDEs for each identified elemental impurity. 2733 The factor of four increase in Option 2a for permitted concentration seen when comparing 2734 Option 1 and Option 2a concentration limits is due to the use of ten grams and 2.5 grams, 2735 respectively, as daily intake of the drug product. 2736 2737 Table A.4.3: Calculation of Maximum Permitted Concentrations Assuming Uniform 2738 Concentrations in a Product with a Specified Daily Intake: 2739 Maximum Permitted Concentration (µg/g) Component Pb As C Hg Pd V Ni d Drug Substance 2 6 2 12 40 40 80 MCC 2 6 2 12 40 40 80 Lactose 2 6 2 12 40 40 80 Ca Phosphate 2 6 2 12 40 40 80 Crospovidone 2 6 2 12 40 40 80 Mg Stearate 2 6 2 12 40 40 80 HPMC 2 6 2 12 40 40 80 83 Contains Nonbinding Recommendations Titanium Dioxide 2 6 2 12 40 40 80 Iron Oxide 2 6 2 12 40 40 80 Maximum Daily intake (µg) 5 15 5 30 100 100 200 PDE (µg) 5 15 5 30 100 100 200 2740 2741 2742 Option 2b: Permitted concentration limits of elemental impurities across drug product 2743 component materials for a product with a specified daily intake: 2744 For this example, consider the same solid oral drug product with a maximum daily intake of 2.5 2745 grams, containing nine components (1 drug substance and eight excipients, see Table A.4.1) used 2746 in Option 1 and 2a. The drug substance synthesis uses Pd and Ni catalysts, and Pb, As, Cd, Hg, 2747 and V are also of concern on the basis of the risk assessment. To use Option 2b, the composition 2748 of the drug product and additional knowledge regarding the content of each elemental impurity in 2749 the components of the drug product are considered. The following table shows example data on 2750 elemental impurities that may be derived from the sources described in section 5.5: 2751 2752 Table A.4.4: Concentrations of Elemental Impurities (µg/g) in the Components Concentration (µg/g) Component Pb As Cd Hg Pd V Ni Drug Substance <LoQ 0.5 <LoQ <LoQ 20 <LoQ 50 MCC 0.1 0.1 0.1 0.1 * <LoQ <LoQ Lactose 0.1 0.1 0.1 0.1 * <LoQ <LoQ Ca Phosphate 1 1 1 1 * 10 5 Crospovidone 0.1 0.1 0.1 0.1 * <LoQ <LoQ Mg Stearate 0.5 0.5 0.5 0.5 * <LoQ 0.5 HPMC 0.1 0.1 0.1 0.1 * <LoQ <LoQ Titanium Dioxide 20 1 1 1 * 1 <LoQ Iron Oxide 10 10 10 10 * 2000 50 2753 * = The risk assessment determined that Pd was not a potential elemental impurity; a quantitative 2754 result was not obtained. 2755 Using the information presented in Table A.4.4, one can evaluate different sets of potential 2756 concentrations for each elemental impurity in each component. In table A.4.5, an example of one 2757 set of these concentrations is displayed. In this case, a high concentration of lead has been 2758 allocated to titanium dioxide and the PDE would not be exceeded due to the low proportion of 2759 this component in the drug product, and the low concentrations of lead in the other components. 2760 Using these concentrations and the component percent composition (Table A.4.1), levels of 2761 elemental impurities in the drug product can be determined using Equation 2 and compared to the 2762 established PDE. The concentrations given in Table A.4.5 are only suitable for the component 2763 proportions given in Table A.4.1. 2764 84 Contains Nonbinding Recommendations 2765 Table A.4.5: Example of Potential Concentrations of Elemental Impurities in the Components Potential Concentration (µg/g) Component Pb As Cd Hg Pd V Ni Drug Substance <LoQ 5 <LoQ <LoQ 500 <LoQ 750 MCC 0.5 5 1 5 * <LoQ <LoQ Lactose 0.5 5 1 5 * <LoQ <LoQ Ca Phosphate 5 5 5 35 * 70 80 Crospovidone 0.5 5 1 5 * <LoQ <LoQ Mg Stearate 5 10 5 125 * <LoQ 100 HPMC 2.5 5 1 5 * <LoQ <LoQ Titanium Dioxide 50 40 10 35 * 20 <LoQ Iron Oxide 50 100 50 200 * 5000 1200 2766 * The risk assessment determined that Pd was not a potential elemental impurity; a quantitative 2767 result was not obtained. 2768 2769 Option 3: Finished Product Analysis 2770 For this example, consider the same solid oral drug product with a maximum daily intake of 2.5 2771 grams, containing nine components (1 drug substance and eight excipients) used in Option 1, 2a 2772 and 2b. The drug substance synthesis uses Pd and Ni catalysts, and Pb, As, Cd, Hg, and V are also 2773 of concern on the basis of the risk assessment. The maximum concentration of each elemental 2774 impurity in the drug product may be calculated using the daily intake of drug product and the 2775 PDE of the elemental impurity using Equation 1. The total mass of each elemental impurity 2776 should be not more than the PDE. 2777 2778 Table A.4.6: Calculation of Concentrations for the Finished Product Maximum Permitted Concentration (µg/g) Daily Intake (g) Pb As Cd Hg Pd V Ni Drug Product 2.5 2 6 2 12 40 40 80 Maximum Daily Intake (µg) 5 15 5 30 100 100 200 2779 2780 Illustrative Example – Elemental Impurities Assessment 2781 The following example is intended as illustration of an elemental impurities risk assessment. 2782 This example is intended for illustrative purposes and not as the only way to document the 2783 assessment. There are many different ways to approach the risk assessment process and its 2784 documentation. 2785 2786 This example relies on the oral drug product described in Appendix 4. Consider a solid oral drug 2787 product with a maximum daily intake of 2.5 grams, containing nine components (1 drug substance 2788 and eight excipients). The drug substance synthesis uses Pd and Ni catalysts. 2789 The applicant conducts the risk assessment starting with the identification of potential elemental 2790 impurities following the process described in Section 5. Because the applicant had limited 2791 historical data for the excipients used in the drug product, the applicant determined that the Class 85 Contains Nonbinding Recommendations 2792 1 elements (As, Cd, Hg, Pb) would be taken through the evaluation phase. The table below 2793 shows a summary of the findings of the identification stage of the assessment. 2794 2795 Table A.4.7: Identification of Potential Elemental Impurities Potential Elemental Impurities Component Intentionally Potential Potential Potential added elemental elemental elemental impurities with a impurities from impurities from relatively high manufacturing container abundance equipment closure systems and/or are impurities in excipients Drug Substance Pd, Ni As Ni None MCC None As, Cd, Hg, Pb None None Lactose None As, Cd, Hg, Pb None None Ca Phosphate None As, Cd, Hg, Pb V, Ni None Crospovidone None As, Cd, Hg, Pb None None Mg stearate None As, Cd, Hg, Pb Ni None HPMC None As, Cd, Hg, Pb None None Titanium Dioxide None As, Cd, Hg, Pb V None Iron Oxide None As, Cd, Hg, Pb V, Ni None 2796 2797 The assessment identified seven potential elemental impurities requiring additional evaluation. 2798 Three of the identified elements were found in multiple components. The applicant continued the 2799 risk assessment by collecting information from vendors, published literature and data. The 2800 individual component data in the risk assessment process is shown below in Table A.4.8. Total 2801 daily masses of elemental impurities are calculated as the daily intake of the component times the 2802 concentration. 2803 2804 86 Contains Nonbinding Recommendations 2805 Table A.4.8: Elemental Impurity Assessment – Evaluation of Daily Contribution to the Total Mass of Elemental Impurities 2806 in the Drug Product 2807 Daily Measured Concentration (µg/g) Total Daily Mass of Elemental Impurity, µg Component intake, Pb As Cd Hg Pd V Ni Pb As Cd Hg Pd V Ni g Drug 0.2 <LoQ 0.5 <LoQ <LoQ 20 <LoQ 50 0 0.1 0 0 4 0 10 Substance MCC 1.1 0.1 0.1 0.1 0.1 * <LoQ <LoQ 0.11 0.11 0.11 0.11 0 0 0 Lactose 0.45 0.1 0.1 0.1 0.1 * <LoQ <LoQ 0.045 0.045 0.045 0.045 0 0 0 Ca Phosphate 0.35 1 1 1 1 * 10 5 0.35 0.35 0.35 0.35 0 3.5 1.75 Crospovidone 0.265 0.1 0.1 0.1 0.1 * <LoQ <LoQ 0.0265 0.0265 0.0265 0.0265 0 0 0 Mg stearate 0.035 0.5 0.5 0.5 0.5 * <LoQ 0.5 0.0175 0.0175 0.0175 0.0175 0 0 0.0175 HPMC 0.06 0.1 0.1 0.1 0.1 * <LoQ <LoQ 0.006 0.006 0.006 0.006 0 0 0 Titanium 0.025 20 1 1 1 * 1 <LoQ 0.5 0.025 0.025 0.025 0 0.025 0 Dioxide Iron Oxide 0.015 10 10 10 10 * 400 50 0.15 0.15 0.15 0.15 0 6 0.75 TOTAL 2.5 g - - - - - - - 1.2 µg 0.8 µg 0.7 µg 0.7 µg 4 µg 9.5 µg 12.5 µg 2808 * The risk assessment determined that Pd was not a potential elemental impurity; a quantitative result was not obtained. 2809 2810 The next step in the risk assessment is to compare the measured or predicted levels in the drug product to the control threshold, using the 2811 information in Table A.4.8, and determine appropriate actions. 2812 2813 Table A.4.9: Assessment Example – Data Entry Descriptions 2814 Column 1: Review the components of drug product for any elements intentionally added in the production (the primary source is 2815 the drug substance). For those used, record the elements for further consideration in the assessment. 2816 Column 2: Identify any potential elements or impurities that are associated with excipients used in the preparation of the drug 2817 product. Record the source(s) for further consideration in the assessment. 2818 Column 3: Identify any elemental impurities known or expected to be leached from the manufacturing equipment. Record the 2819 specific elemental impurities for further consideration in the assessment. 87 Contains Nonbinding Recommendations 2820 Column 4: Identify any elemental impurities known or expected to be leached from the container closure system. Record the 2821 specific elemental impurities for further consideration in the assessment. 2822 Column 5: Calculate the total contribution of the potential elemental impurity by summing the contributions across the 2823 components of the drug product. 2824 Column 6: Assess the variability of the elemental impurity level(s) in the components 2825 Column 7: Enter the control threshold of each potential elemental impurity identified. If the variability is known and it is within 2826 acceptable limits, the control threshold (30% of the PDE) for each elemental impurity can be applied. 2827 Column 8: Describe action taken – none if the value in column 5 is less than or equal to the control threshold (Column 7). Define 2828 control element if material variability is high or control threshold is exceeded. 2829 1 2 3 4 5 6 7 8 Leached from Acceptable Intention- Elemental impurities Total elemental Manufacturing container variability of Control ally added with a relatively high impurity Element equipment closure systems contribution elemental threshold Action (if used in abundance and/or impurity the process) are impurities in µg/ Contribution excipients As No Observed impurity in No No 0.8 Yes 4.5 no further controls all excipients and drug required substance Cd No Observed impurity No No 0.7 Yes 1.5 no further controls in all excipients required Hg No Observed impurity No No 0.7 Yes 9 no further controls in all excipients required Pb No Observed impurity No No 1.2 Yes 1.5 no further controls in all excipients required Pd API No No No 4.0 Yes 30 no further controls cata- required lyst Ni API Observed in 3 No No 12.5 Yes 60 no further controls cata- excipients required lyst 88 Contains Nonbinding Recommendations V No Observed in 3 No No 9.5 Yes 30 no further controls excipients required 2830 2831 89 Contains Nonbinding Recommendations 2832 Appendix 5: Limits for Elemental Impurities by the Cutaneous and Transcutaneous 2833 Route 2834 2835 TABLE OF CONTENTS 2836 2837 I. BACKGROUND (1) ...................................................................................................... 91 2838 II. SCOPE (2) ...................................................................................................................... 92 2839 III. PRINCIPLES OF SAFETY ASSESSMENT FOR CUTEANEOUS PRODUCTS (3) 2840 ......................................................................................................................................... 92 2841 A. TRANSCUTANEOUS ABSORPTION OF ELEMENTAL IMPURITIES (E1) (3.1) 2842 ......................................................................................................................................... 92 2843 B. PDE FOR DRUG PRODUCTS DIRECTLY APPLIED TO THE DERMIS (3.2) . 93 2844 IV. ESTABLISHING THE CUTANEOUS PERMITTED DAILY EXPOSURE (PDE) 2845 (4)..................................................................................................................................... 93 2846 A. ESTABLISHING THE CUTANEOUS MODIFYING FACTOR (CMF) (4.1) ....... 93 2847 B. CUTANEOUS PDE (4.2) .............................................................................................. 94 2848 V. CUTANEOUS CONCENTRATION LIMITS FOR NI AND CO (5) ...................... 95 2849 VI. PRODUCT RISK ASSESSMENT (6) ......................................................................... 95 2850 VII. CUTANEOUS PDE VALUES (7) ................................................................................ 96 2851 VIII. REFERENCES (8)......................................................................................................... 98 2852 2853 2854 90 Contains Nonbinding Recommendations 2855 I. BACKGROUND (1) 2856 2857 In December 2014, ICH approved the ICH Q3D Guidance for Elemental Impurities developed 2858 by the Expert Working Group. The Guidance provided Permitted Daily Exposures (PDEs) for 2859 24 elemental impurities (EI) for the oral, parenteral, and inhalation routes of administration. In 2860 section III.B (3.2) of the guidance, principles for establishing PDEs for other routes of 2861 administration are described. During the course of the development of Q3D, interest was 2862 expressed in developing PDEs for the cutaneous and transcutaneous route, as these products 2863 remain the most significant area where PDEs for EI have not been formally established. 2864 Appendix 5 is intended to expand upon the information given in the main text of the Q3D 2865 Guidance and to provide more specific information regarding the cutaneous and 2866 transcutaneous route of administration. 2867 In establishing cutaneous and transcutaneous limits, the role of skin is paramount. The skin is 2868 an environmental barrier and a complex organ that has many functions, including limiting the 2869 penetration of exogenous materials, metabolism, prevention of water loss, temperature 2870 regulation, and as an immune organ (Monteiro-Riviere and Filon, 2017). The skin is composed 2871 of both an outer epidermis and an inner dermis, each composed of multiple cellular layers. 2872 Dermal (or transcutaneous) absorption, i.e., the transport of a chemical from the outer surface 2873 of the skin into systemic circulation, is dependent upon the properties of the skin, the 2874 anatomical site, the nature of the chemical applied and the characteristics of the application. 2875 The primary barrier to absorption is the outermost layer of the epidermis (i.e., the stratum 2876 corneum) which typically consists of 15-20 layers of non-viable cells. The stratum corneum 2877 (horny layer) serves as a highly effective barrier, especially to charged species, such as metal 2878 ions. For this reason, transcutaneous delivery into the systemic circulation of materials 2879 including any active pharmaceutical ingredient (API) typically requires physical and chemical 2880 agents (e.g., penetration enhancers) to assist in the transcutaneous absorption of the API. 2881 In respect to these "penetration enhancers," it is noteworthy that agents that enhance 2882 penetration of an API are usually not applicable for EI because of fundamental differences in 2883 physico-chemical properties. Limited research has been conducted to evaluate the systemic 2884 absorption of EIs applied to the skin. The skin may respond to exposure in various ways. For 2885 example, approximately half of mercury vapor taken up by the skin (1 - 4% of the dose) was 2886 shed by desquamation of epidermal cells for several weeks after exposure, while the remainder 2887 in the skin was slowly released into general circulation (Hursh et al., 1989). Hostýnek et al. 2888 (1993) describes that silver (Ag) is preferentially accumulated in the skin and is not liberated. 2889 Available data indicate that gold (Au) is not readily absorbed through skin because of inertness 2890 and lack of ionization by bodily fluids (Lansdown, 2012). Gold, in salt form, has been shown 2891 to bind readily to sulfhydryl groups of epidermal keratin and remain in the skin (Lansdown, 2892 2012). Metal binding proteins are present in some fetal and adult skin (e.g., basal keratinocytes 2893 of epidermis and outer hair root sheath) but not in other cell types (e.g., exocrine portion of the 2894 eccrine glands), indicating the skin has the potential for binding and metabolism of metals (van 2895 den Oord and De Ley, 1994). 2896 Together these properties of the skin layers represent a significant barrier to systemic exposure 2897 as illustrated by quantitative absorption data reviewed by Hostýnek et al. (1993). This systemic 2898 exposure is reported to be < 1% absorption for most of the evaluated EI in scope of this 2899 guidance. Transcutaneous absorption of EI is discussed in more detail in section III (3). 2900 Elements evaluated in this guidance were assessed by reviewing publicly available data 2901 contained in scientific journals, government research reports and studies, and regulatory 2902 authority research and assessment reports. In general, studies in the scientific literature simply 91 Contains Nonbinding Recommendations 2903 report disappearance of EI from the cutaneous layer rather than transcutaneous absorption. 2904 Quantitative data are generally lacking for most EI and the associated counterion (Hostynek, 2905 2003). Furthermore, there are no suitable standards for occupational exposure for the dermal 2906 route for risk assessment. Consequently, a generic approach was adopted to establish limits as 2907 opposed to an element-by-element basis. 2908 2909 II. SCOPE (2) 8 2910 This Appendix to the Q3D Guidance applies to cutaneous and transcutaneous drug products 2911 (referred to as "cutaneous products" throughout this Appendix) whether intended for local or 2912 systemic effect. This Appendix does not apply to drug products intended for mucosal 2913 administration (oral, nasal, vaginal), topical ophthalmic, rectal, or subcutaneous and subdermal 2914 routes of administration. Products not covered by this Appendix should be evaluated in 2915 accordance with the approach discussed in section III.B (3.2) of the main text of the Q3D 2916 Guidance. 2917 2918 III. PRINCIPLES OF SAFETY ASSESSMENT FOR CUTANEOUS PRODUCTS (3) 2919 2920 The literature review focuses on the forms likely to be present in pharmaceutical products (see 2921 main guidance) and therefore the assessment relied on evaluating the available data for 2922 inorganic forms of the EI and ranking the relevance of the data in the following order: human in 2923 vivo data; animal in vivo data; in vitro data. 2924 2925 Local and systemic toxicities were considered. In general, there is no indication for local 2926 toxicity on the skin, with the exception of sensitization. Review of systemic toxicity by the 2927 dermal route, shows significant systemic toxicity for thallium. Since there is limited 2928 information available on transcutaneous absorption of the elements addressed in this Addendum 2929 it is not possible to address this percent absorption on an element-by-element basis and to allow 2930 conversion of an existing PDE to the dermal route to support an element- by-element approach. 2931 Therefore, a generic approach has been developed based on a systematic adjustment of the 2932 parenteral PDE, which assumed 100% bioavailability, to derive a cutaneous PDE by using a 2933 Cutaneous Modifying Factor (CMF) (see section IV (4)). The cutaneous PDE has been derived 2934 for daily, chronic application to the skin. 2935 2936 A. Transcutaneous Absorption of Elemental Impurities (EI) (3.1) 2937 The extent of absorption into the systemic circulation (systemic absorption) is considered an 2938 important component to the safety assessment of the elements. Review of studies of skin 2939 penetration, absorption, systemic bioavailability and toxicity of the elements shows a lack of 2940 data for many elements. For those elements that have been studied for transcutaneous 2941 absorption and/or toxicity, the available data are rarely suitable for proper quantitative analysis 2942 and the diverse experimental designs preclude inter-study or inter-element comparability 2943 (Hostynek, 2003). The available data indicate that EIs are generally poorly absorbed through 2944 intact skin even in the presence of enhancers. For example, absorption of Pb from lead oxide 2945 under occlusion in rats was less than 0.005%, as measured by urinary Pb for 12 days following 2946 exposure. Penetration of lead oxide was not detectable in an in vitro system with human skin 2947 (ATSDR, 2019). 8 The Q3D guidance is not intended to provide recommendations for labelling of allergens. Applicants should refer to regional guidance/recommendations or best practice for managing and labeling of allergens. 92 Contains Nonbinding Recommendations 2948 There are numerous factors that may influence transcutaneous absorption and systemic 2949 bioavailability after cutaneous administration of a substance. These factors may be categorized 2950 as: 2951 • compound-related factors (e.g., physical state, ionization, solubility, binding 2952 properties, reactivity, and the counterion of the EI), and/or 2953 • application-related factors (e.g., concentration and total dose applied, duration of 2954 application/exposure, cleaning between applications, surface area, co-applied 2955 materials/excipients and occlusion status), 2956 • subject-related factors (e.g., comparative species differences, location on the body, 2957 hydration of the skin/age, temperature). 2958 Transcutaneous penetration through the skin is element and chemical species-specific and each 2959 element would need to be experimentally assessed under different conditions to develop an 2960 effective model. Because of this complexity, it is not feasible to address every possible 2961 scenario for each EI in each drug product. 2962 Given the limited amount of data on transcutaneous absorption and toxicity by the cutaneous 2963 route of administration that has been generated in well-designed studies, the available data were 2964 used to develop a generic, conservative approach. The cutaneous PDE is derived from the 2965 previously established element-specific parenteral PDEs for which adequate toxicity data are 2966 available. To address the presumed low but unquantified transcutaneous absorption, and in 2967 consideration of all the potential factors that can influence this absorption, a 10-fold factor will 2968 be applied to the parenteral PDE for most EIs. The derivation and application of the factor of 2969 10 is described in more detail in section IV (4) below. 2970 2971 B. PDE for Drug Products Directly Applied to the Dermis (3.2) 2972 A compromised basal cell layer could facilitate direct entry of EIs into the dermis and its 2973 associated blood vessels (potentially increasing systemic absorption). Therefore, the generic 2974 PDE for the cutaneous route described in this Addendum should not be applied to drug products 2975 intended to treat skin with substantial disruption of the basal cell layer of the epidermis. For 2976 indications in which drug product is intentionally brought into contact with the dermis (e.g., 2977 skin ulcers, second- and third-degree burns, pemphigus, epidermolysis bullosa) it is 2978 recommended to develop a case-specific justification based on principles outlined in ICH Q3D 2979 section III.C (3.3). The parenteral PDE is generally an appropriate starting point for these 2980 drug products. 2981 Small cuts, needle pricks, skin abrasions and other quick healing daily skin injuries are not 2982 associated with substantial basal cell layer disruption of the epidermis as defined above. The 2983 total amount of drug product which can potentially come into contact with the dermis is 2984 therefore considered negligible. Therefore, cutaneous PDEs will apply to drug products 2985 intended to treat these skin abrasions or other quick healing acute injuries. 2986 2987 IV. ESTABLISHING THE CUTANEOUS PERMITTED DAILY EXPOSURE (PDE) 2988 (4) 2989 2990 The cutaneous PDE for all relevant EIs is calculated by applying a cutaneous modifying factor 2991 (CMF) to the parenteral PDE for each EI. 2992 2993 A. Establishing the Cutaneous Modifying Factor (CMF) (4.1) 2994 The limited available data suggest that transcutaneous absorption of most EI, when studied in 2995 intact skin, is less than 1% as described previously (Section I (1) and III (3)). As described in 93 Contains Nonbinding Recommendations 2996 section III.A (3.1), there are multiple factors that can influence this absorption. In lieu of 2997 accounting for such factors individually, and in consideration of the relative lack of reliable 2998 quantitative transcutaneous absorption data, an approach has been adopted for the derivation 2999 of cutaneous PDEs, which is considered protective against potential systemic toxicities. To 3000 account for these uncertainties, a CMF is generated using the approach outlined below. 3001 3002 1. For EIs other than arsenic (As) and thallium (Tl), a maximum Cutaneous 3003 Bioavailability (CBA) of 1% is used. 3004 3005 2. To account for the various factors that can enhance CBA, a factor of 10 is applied to 3006 increase the CBA (adjusted CBA). 3007 3008 3. To calculate the CMF, the parenteral BA (100%) is divided by the adjusted CBA. 3009 3010 B. Cutaneous PDE (4.2) 3011 The Cutaneous PDE is calculated as 3012 Cutaneous PDE = Parenteral PDE x CMF 3013 Parenteral PDE calculations already include safety factors F1-F5 or are derived from Oral PDE, 3014 which also include safety factors (see Appendix 1of ICH Q3D) to account for variability and 3015 extrapolation. Therefore, no further adjustments are necessary for the cutaneous PDE. 3016 3017 The derived cutaneous PDEs are listed in Table A.5.1. 3018 3019 4.2.1 Derivation of PDE for EI, other than Arsenic (As) and Thallium (Tl) 3020 For EI with low CBA (< 1%), a CMF of 10 is applied. 3021 3022 For EI with < 1% CBA, the adjusted CBA is 1% x 10 = 10% 3023 Divide the parenteral BA by the adjusted CBA to derive the CMF 3024 100%/10% = 10 3025 3026 The cutaneous PDE is derived as: 3027 Cutaneous PDE = Parenteral PDE x CMF 3028 Cutaneous PDE = Parenteral PDE x 10 3029 3030 See Table A.5.1 for cutaneous PDEs for individual EI. 3031 3032 4.2.2 Derivation of PDE for Arsenic 3033 For inorganic arsenic, the available data indicate that the transcutaneous absorption is greater 3034 than that observed for most other EI (approximately 5%) (ATSDR, 2016). Based on this, the 3035 CMF for arsenic is 2, as shown in the calculation below 3036 3037 Derive the adjusted CBA: 5% x 10 = 50% 3038 Divide parenteral BA by the adjusted CBA to derive the CMF 3039 100%/50% = 2 3040 3041 The cutaneous PDE is derived as: 3042 Cutaneous PDE = Parenteral PDE x CMF 3043 Cutaneous PDE = 15 μg/day x 2 = 30 μg/day 94 Contains Nonbinding Recommendations 3044 3045 4.2.3 Derivation of PDE for Thallium 3046 Thallium is highly absorbed through the skin. Since quantitative data are not available, it is 3047 assumed to be effectively equivalent to parenteral levels. The adjusted PDE equals the 3048 parenteral PDE, a CMF of 1 is used. 3049 3050 The cutaneous PDE is derived as: 3051 Parenteral PDE = 8 μg/day 3052 Cutaneous PDE = 8 μg/day x 1 = 8 μg/day 3053 3054 3055 V. CUTANEOUS CONCENTRATION LIMITS FOR NI AND CO (5) 3056 3057 The concentrations of EI generally present in cutaneous products as impurities are not 3058 considered sufficient to induce sensitization. However, a concentration limit in addition to the 3059 PDE is warranted for Nickel (Ni) and Cobalt (Co) to reduce the likelihood of eliciting skin 3060 reactions in already sensitized individuals. This concentration limit is referred to as the 3061 cutaneous and transcutaneous concentration limit (CTCL). For other EI such as Chromium 3062 (Cr), the threshold to elicit a sensitizing response is either approximately equal to the cutaneous 3063 PDE (Cr) or much greater than the cutaneous PDE and therefore additional controls are not 3064 necessary (Nethercott et al., 1994). 3065 3066 The dermal concentration limit of 0.5 μg/cm2/week for Ni was originally established by Menné 3067 et al., (1987) as a detection limit in the dimethylglyoxime (DMG) test. The use of Ni in 3068 consumer products (e.g., jewelry) intended for direct and prolonged skin contact was regulated 3069 by this limit under the EU countries Ni regulations and under the EU Nickel Directive 3070 (currently, REACH, Entry 27, Annex XVII). After implementation of the directive, the 3071 prevalence of Ni allergy decreased significantly (Thyssen et al., 2011; Ahlström et al., 2019). 3072 This limit is applied to set a cutaneous concentration of Ni in drug products. The minimum unit 3073 applied to the diseased area is referred to as 1 fingertip unit (FTU), which is approximately 3074 equivalent to 0.5 g (equivalent to the amount of ointment applied to distal skin-crease to the tip 3075 of the index finger). Usually, cutaneous products are designed to apply 1 FTU in approximately 3076 250 cm2 (Long and Finlay, 1991). Since the volume of cutaneous products per skin area usually 3077 does not vary with the region of the skin, the CTCL value does not depend on the applied dose 3078 and region. Based on the application of a 0.5 g dose of drug product per day to a skin surface 3079 area of 250 cm2, a CTCL of 35 µg/g drug product is derived, as below. As a recently derived 3080 limit to minimize elicitation of allergies to Co shows a similar limit of 31-259 ppm as Ni 3081 (Fischer et al., 2015), the same CTCL is applied to Co. 3082 3083 0.5 μg/cm2/week = 0.07 μg/cm2/day 3084 0.07 μg/cm2/day x 250 cm2 = 17.5 μg/day 3085 17.5μg/day / 0.5 g/day = 35 µg/g 3086 3087 3088 VI. PRODUCT RISK ASSESSMENT (6) 3089 3090 Product assessments for cutaneous drug products should be prepared following the guidance 3091 provided in ICH Q3D Section V (5). The considerations of potential sources of EI, 3092 calculation options and considerations for additional controls are the same for products for 95 Contains Nonbinding Recommendations 3093 the cutaneous route of administration as for products for the oral, parenteral and inhalation 3094 routes of administration. 3095 For Ni and Co, in addition to considering the EI levels in the drug product relative to the PDE, 3096 the concentration of this EI (µg/g) in the drug product should be assessed relative to the CTCL 3097 identified in Table A.5.1. The product risk assessment should therefore confirm that the total 3098 Ni and Co level (μg/day) is at or below the PDE and that their respective concentrations in the 3099 drug product do not exceed the CTCL shown in Table A.5.1. 3100 As described in ICH Q3D Section V.B (5.2), the drug product risk assessment is summarized 3101 by reviewing relevant product or component specific data combined with information and 3102 knowledge gained across products or processes to identify the significant probable EI that may 3103 be observed in the drug product. 3104 The summary should consider the significance of the observed or predicted level of the EI 3105 relative to the corresponding PDE and in the case of Ni and Co, the Ni- and Co-CTCL. As a 3106 measure of the significance of the observed EI level, a control threshold is defined as a level 3107 that is 30% of the established PDE and CTCL (for Ni and Co) in the drug product. The control 3108 threshold may be used to determine if additional controls may be required. If the total observed 3109 or predicted EI level (µg/day) or cutaneous concentration (µg/g) in the drug product is 3110 consistently less than 30% of the established PDE or CTCL, then additional controls are not 3111 required, provided the applicant has appropriately assessed the data and demonstrated adequate 3112 controls on elemental impurities. 3113 3114 Since the maximum total daily dose for cutaneous products is not always clearly stated, a 3115 prerequisite for the product risk assessment is a justified estimation of a worst-case exposure 3116 to the EI that can form the basis for the assessment (SCCP, 2006; Long, 1991, Api et al., 2008). 3117 In addition, the number of applications per day may not be clear. Since the CTCL is calculated 3118 based on a once-daily application, the acceptable concentration may need to be modified 3119 according to the maximum number of applications per day and following an assessment of 3120 various factors such as retention time of the drug product. Although the risk of sensitization 3121 does not depend on the dose per application, it may increase with multiple daily applications 3122 to the same area. 3123 Dermal products differ from oral, parenteral or inhalation products in that they may be removed 3124 or rinsed from the area of application. In evaluating the potential EI to which the patient may 3125 be exposed, it may be important to evaluate the retention time of the drug product during typical 3126 conditions of use. For example, certain products such as shampoos have a short application 3127 duration time. Thus, the risk assessment may propose an adjustment by use of a retention factor 3128 (see Module 1 of the ICH Q3D training package for more information on retention time; 3129 https://www.ich.org/products/guidelines/quality/article/quality-guidelines.html). If the PDE is 3130 adjusted in this manner, the new level proposed should be referred to as an Acceptable Level 3131 and is subject to consideration by the relevant authorities on a case-by-case basis. 3132 3133 VII. CUTANEOUS PDE VALUES (7) 3134 The calculated PDE for the cutaneous and transcutaneous route are listed in Table A.5.1. To 3135 be compliant with Q3D, for sensitizing EI (Ni, Co), a second limit- the CTCL (µg/g)- will also 3136 need to be met. 3137 There are insufficient data to set PDEs by any route of administration for iridium, osmium, 3138 rhodium, and ruthenium. For these elements, the palladium PDE for the relevant route will 3139 apply. 96 Contains Nonbinding Recommendations 3140 Table A.5.2 provides example concentrations for a drug product with a daily dose of 10 g. 3141 Table A.5.1: Cutaneous products – PDE, CTCL and elements to be included in risk 3142 assessment 3143 Element Class From ICH Q3D for comparison Cutaneous products PDE PDE CTCL Include in Risk (μg/day) (μg/day) (µg/g) Assessment if for not sensitizers intentionally Oral Parenteral Inhalation added1,2,3 Cd 1 5 2 3 20 - yes Pb 1 5 5 5 50 - yes As 1 15 15 2 30 - yes Hg 1 30 3 1 30 - yes Co 2A 50 5 3 50 35 4 yes V 2A 100 10 1 100 - yes Ni 2A 200 20 6 200 35 4 yes Tl 2B 8 8 8 8 - no Au 2B 300 300 3 3000 - no Pd5 2B 100 10 1 100 - no Se 2B 150 80 130 800 - no Ag 2B 150 15 7 150 - no Pt 2B 100 10 1 100 - no Li 3 550 250 25 2500 - no Sb 3 1200 90 20 900 - no Ba 3 1400 700 300 7000 - no Mo 3 3000 1500 10 15000 - no Cu 3 3000 300 30 3000 - no Sn 3 6000 600 60 6000 - no Cr 3 11000 1100 3 11000 - no 3144 1 Intentionally added elements should always be included in the Risk Assessment. 3145 2 Class 2B elements were excluded from the assessment of oral, parenteral and inhalation products because of the 3146 low likelihood that they would be present if not intentionally added (see section 4 of ICH 3147 Q3D). 3148 3 Class 3 elements with a cutaneous PDE above 500 μg/day do not have to be included in the risk assessment 3149 unless intentionally added (see section 4 of ICH Q3D). 3150 4 For elements with a cutaneous PDE and a CTCL, both limits need to be met. In case the results are conflicting, 3151 the lowest limit is applied. Using Co as an example, based on the PDE and a 1 g maximum daily dose of drug 3152 product, the calculated cutaneous concentration is 50 µg/g which exceeds the CTCL of 35 µg/g. In this situation, 3153 the CTCL limit should be used. 3154 5 Pd PDE will apply to iridium, osmium, rhodium, and ruthenium. 97 Contains Nonbinding Recommendations 3155 Table A.5.2: Cutaneous PDE and Concentration Limits for a 10 g Dose Cutaneous conc1 CTCL Cutaneous for a 10 g daily Element Class (µg/g) PDE (μg/day) dose (μg/g) for sensitizers Cd 1 20 2 - Pb 1 50 5 - As 1 30 3 - Hg 1 30 3 - Co 2A 50 52 35 V 2A 100 10 - Ni 2A 200 20 2 35 Tl 2B 8 0.8 - Au 2B 3000 300 - Pd3 2B 100 10 - Se 2B 800 80 - Ag 2B 150 15 - Pt 2B 100 10 - Li 3 2500 250 - Sb 3 900 90 - Ba 3 7000 700 - Mo 3 15000 1500 - Cu 3 3000 300 - Sn 3 6000 600 - Cr 3 11000 1100 - 3156 1 PDE expressed in concentration terms, calculated using a 10 g daily dose. 3157 2 For elements with a cutaneous PDE and a CTCL, both limits need to be met. In case the results are conflicting, 3158 the lowest limit is applied. Using Co as an example, based on a 10 g maximum daily dose of drug product, the 3159 calculated cutaneous concentration is 5 µg/g; based on a 1 g maximum daily dose of drug product, the calculated 3160 cutaneous concentration is 50 µg/g which exceeds the CTCL of 35 µg/g. In this situation, the CTCL limit should 3161 be used. 3162 3 Pd PDE will apply to iridium, osmium, rhodium, and ruthenium. 3163 3164 3165 VIII. REFERENCES (8) 3166 3167 Ahlström MG, Thyssen JP, Wennervaldt M, Menné T, Johansen JD. Nickel allergy and allergic 3168 contact dermatitis: A clinical review of immunology, epidemiology, exposure and treatment. 3169 Contact Dermatitis 2019; 1-15. 3170 3171 Api AA, Basketter DA, Cadby PA, Cano MF, Ellis G, Gerberick ZF, Griem P, McNamee PM, 3172 Ryan CA, Safford R. Dermal sensitization quantitative risk assessment (QRA) for fragrance 3173 ingredients. Reg Toxicol Pharmacol 52 (1) 2008, 3-23. 3174 3175 ATSDR. Toxicological profile for lead. 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