Ich Q3D (R2)

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
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U.S. Department of Health and Human Services

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.
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
916 Appendix 3: Individual Safety Assessments

917
918 ANTIMONY
919
920 Summary of PDE for Antimony
Antimony (Sb)
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
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
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
1020 ARSENIC
1021
1022 Summary of PDE for Arsenic
Arsenic (As)
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
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
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
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
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
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
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
1137 BARIUM
1138
1139 Summary of PDE for Barium
Barium (Ba)
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
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
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
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
1178
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
1210 CADMIUM
1211
1212 Summary of PDE for Cadmium
Cadmium (Cd)
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
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
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
1251
1253
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
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
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
1295 REFERENCES
1296 ATSDR. Toxicological profile of cadmium. Agency for Toxic Substances and Disease Registry,
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
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
1317 CHROMIUM
1318
1319 Summary of PDE for Chromium
Chromium (Cr)
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
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
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

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
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
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,
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
1399 Toxicology Program, Public Health Service, U.S. Department of Health and Human Services.
1400 2010;NTP TR 556.
1402 Labor. 2013.
1403 US EPA. Chromium (III), insoluble salts. Integrated Risk Information System (IRIS). 1998.
41
1404 COBALT
1405
1406 Summary of PDE for Cobalt
Cobalt (Co)
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
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
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.
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
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
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
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
1465
1466 REFERENCES
1467 ATSDR. Toxicological profile for cobalt. Agency for Toxic Substances and Disease Registry,
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
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
1489 COPPER
1490 Summary of PDE for Copper
Copper (Cu)
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
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
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
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
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
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
1547 GOLD
1548
1549 Summary of PDE for Gold
Gold (Au)
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
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
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
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
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
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
1626 LEAD
1627
1628 Summary of PDE for Lead
Lead (Pb)
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).
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
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
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
1662 The oral effects of Pb are based on blood levels. Therefore, the inhalation PDE is equal to the oral
1663 PDE.
1664
49
1665 PDE = 5.0 µg/day

1666
1667 REFERENCES
1668 ATSDR. Toxicological profile for lead. Agency for Toxic Substances and Disease Registry,
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
1677 LITHIUM
1678
1679 Summary of PDE for Lithium
Lithium (Li)
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
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
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
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
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
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
1741 MERCURY
1742
1743 Summary of PDE for Mercury
Mercury (Hg)
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
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
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
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

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
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
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,
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
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
1833 MOLYBDENUM
1834
1835 Summary of PDE for Molybdenum
Molybdenum (Mo)
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
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
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

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
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
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
1923 NICKEL
1924
1925 Summary of PDE for Nickel
Nickel (Ni)
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
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
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
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
1971 A factor of 10 was chosen for F5 because a LOAEL was used to set the PDE.

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
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,
2007 Benson J, Chang I-Y, Cheny YS, Hahn FF, Kennedy CH et al. Fundam Appl Toxicol
2008 1995;28:232-244.
60
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
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
2042 PALLADIUM
2043
2044 Summary of PDE for Palladium
Palladium (Pd)
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
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
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
2077
2078 A factor of five was chosen for F5 because a LOEL was used in deriving the PDE.
2079
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
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
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
2107 PLATINUM
2108
2109 Summary of PDE for Platinum
Platinum (Pt)
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
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
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
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
2154
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
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
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.
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
2220 Platinum-Group Elements

2221
2222 Summary of PDE for Platinum-Group Elements
Iridium (Ir), Osmium (Os), Rhodium (Rh), Ruthenium (Ru)
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
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
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
2322 SELENIUM
2323
2324 Summary of PDE for Selenium
Selenium (Se)
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
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
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
2363
70
2364 A factor of ten was chosen for F4 because of the risk of selenosis.
2365
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
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,
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.
2406 Labor. 2013.
71
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
2412 SILVER
2413
2414 Summary of PDE for Silver
Silver (Ag)
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
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
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
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
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
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,
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
2500 Labor. 2013.
2501 US EPA. Silver (CASRN 7440-22-4). Integrated Risk Information System (IRIS). 2003.
75
2502 THALLIUM
2503
2504 Summary of PDE for Thallium
Thallium (Tl)
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
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
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.
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
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
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
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,
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
2563 TIN
2564
2565 Summary of PDE for Tin
Tin (Sn)
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
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
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
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

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.
2629 Labor. 2013.
79
2630 VANADIUM
2631
2632 Summary of PDE for Vanadium
Vanadium (V)
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
2645 Vanadium is genotoxic, but not mutagenic (ATSDR, 2012). Vanadium pentoxide is classified as
2646 a possible human carcinogen (Group 2B; IARC, 2012).
2647
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
2661
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

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,
2683 IARC. Arsenic, metals, fibers, and dusts: a review of human carcinogens. Monographs on the
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
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
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
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
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:
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
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
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
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
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
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
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
Pb No Observed impurity No No 1.2 Yes 1.5 no further controls
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
V No Observed in 3 No No 9.5 Yes 30 no further controls

excipients required
2830
2831
89
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
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
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
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
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:
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
3043 Cutaneous PDE = 15 μg/day x 2 = 30 μg/day
94
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
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
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
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
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. Agency for Toxic Substances and Disease Registry,
3176 Public Health Service, U.S. Department of Health and Human Services, Atlanta GA. 2019.
3177 ATSDR. Addendum to the toxicological profile for arsenic Agency for Toxic Substances and
3178 Disease Registry, Public Health Service, U.S. Department of Health and Human Services,
3179 Atlanta GA. 2016.
98
3180 Fischer LA, Johansen JD, Voelund A, Lidén C, et al. Elicitation threshold of cobalt chloride:
3181 analysis of patch test dose-response studies. Contact Dermatitis 2015; 74: 105-109.
3182
3183 Hostýnek JJ, Hinz RS, Lorence CR, Price M, Guy RH. Metals and the skin. Critical Reviews
3184 in Toxicology 1993; 23(2): 171-235.
3185
3186 Hostynek JJ. Factors determining percutaneous metal absorption. Food Chem Toxicol 2003;
3187 41 (3): 327–345.
3188
3189 Hursh JB, Clarkson TW, Miles EF, Goldsmith LA. Percutaneous absorption of mercury vapor
3190 by man. Arch Environ Health 1989; 44(2): 120-127.
3191
3192 Lansdown ABG. Silver and Gold. In Patty’s Toxicology 6th Edition. Ed Bingham E, Cohrssen
3193 B; John Wiley & Sons 2012; pp 75-112
3194
3195 Long CC, Finlay AY. The Finger-Tip Unit-a New Practical Measure. Clinical and experimental
3196 dermatology 1991; 16.6: 444–447.
3197
3198 Menné T, Brandup F, Thestrup-Pedersen K et al. Patch test reactivity to nickel alloys. Contact
3199 Dermatitis 1987; 16: 255-259.
3200
3201 Monteiro-Riviere NA, Filon, FL. Skin. In B Badeel, A Pietroiusti Anna A. Shvedova Adverse
3202 Effects of Engineered Nanomaterials. Exposure, Toxicology and Impact on human Health 2nd
3203 Edition 2017: 357-380 Elsevier
3204
3205 Nethercott J, Paustenbach D, Adams R, Fowler J, et al. A study of chromium induced allergic
3206 contact with 54 volunteers: implications for environmental risk assessment. Occup Environ
3207 Med 1994; 51: 371-380.
3208
3209 SCCP’s (European Commission Scientific Committee on Consumer Products) Notes of
3210 Guidance for the Testing of Cosmetic Ingredients and Their Safety Evaluation, sixth revision,
3211 2006. http://ec.europa.eu/health/ph_risk/committees/04_sccp/docs/sccp_o_03j.pdf .
3212
3213 Thyssen JP, Uter W, McFadden J, Menné T, Spiewalk R, Vigan M, Gimenez-Arnau A, Lidén
3214 C. The EU Nickel Directive revisited—future steps towards better protection against nickel
3215 allergy. Contact Dermatitis 2011; 64(3): 121-125.
3216
3217 Van den Oord JJ and De Ley M. Distribution of metallothionein in normal and pathological
3218 human skin. Arch Dermatol Res 1994; 286: 62-8.

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Q3D(R2) ELEMENTAL

U.S. Department of Health and Human Services

U.S. Department of Health and Human Services

I. INTRODUCTION (1) ....................................................................................................... 1

III. PRINCIPLES OF SAFETY ASSESSMENT FOR CUTANEOUS PRODUCTS (3)

1 Q3D(R2) ELEMENTAL IMPURITIES

Water ** Container Excipients

397 • Published literature

723 PEL: Permitted Exposure Limit.

794 Appendix 1: Method for Establishing Exposure Limits

875 F4 = 1 because no severe toxicity was encountered

878 Table A.1.1: Values Used in the Calculations in this Document

896 Appendix 2: Established PDEs for Elemental Impurities

907 Table A.2.2: Permitted Concentrations of Elemental Impurities for Option 1

916 Appendix 3: Individual Safety Assessments

1358 PDE – Parenteral Exposure

1588 PDE = 32.2 mg/kg x 50 kg / (5 x 10 x 10 x 1 x 10) = 322 µg/day

1665 PDE = 5.0 µg/day

1783 PDE – Parenteral Exposure

1874 PDE – Parenteral Exposure

1915 RIVM. RIVM Report 711701025: Re-evaluation of human-toxicological maximum permissible

1972 PDE – Parenteral Exposure

2220 Platinum-Group Elements

2258 o Rh salts (K2RhCl5, (NH4)3RhCl6) were genotoxic in Salmonella typhimurium

2605 PDE – Inhalation Exposure

2671 PDE – Inhalation Exposure

2688 Appendix 4: Illustrative Examples

Mg Stearate 0.5 1.5 0.5 3 10 10 20

Leached from Acceptable

V No Observed in 3 No No 9.5 Yes 30 no further controls

2855 I. BACKGROUND (1)

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